Structural basis for the action of the drug trametinib at KSR-bound MEK.

The MAPK/ERK kinase MEK is a shared effector of the frequent cancer drivers KRAS and BRAF that has long been pursued as a drug target in oncology1, and more recently in immunotherapy2,3 and ageing4. However, many MEK inhibitors are limited owing to on-target toxicities5-7 and drug resistance8-10. Accordingly, a molecular understanding of the structure and function of MEK within physiological complexes could provide a template for the design of safer and more effective therapies. Here we report X-ray crystal structures of MEK bound to the scaffold KSR (kinase suppressor of RAS) with various MEK inhibitors, including the clinical drug trametinib. The structures reveal an unexpected mode of binding in which trametinib directly engages KSR at the MEK interface. In the bound complex, KSR remodels the prototypical allosteric pocket of the MEK inhibitor, thereby affecting binding and kinetics, including the drug-residence time. Moreover, trametinib binds KSR-MEK but disrupts the related RAF-MEK complex through a mechanism that exploits evolutionarily conserved interface residues that distinguish these sub-complexes. On the basis of these insights, we created trametiglue, which limits adaptive resistance to MEK inhibition by enhancing interfacial binding. Our results reveal the plasticity of an interface pocket within MEK sub-complexes and have implications for the design of next-generation drugs that target the RAS pathway.

On prediction, refutation, and explanatory reach: A consideration of the Interpersonal Theory of Suicidal Behavior.

Theory proposition, empirical evaluation, and resulting support or refutation are core pieces of the scientific process. These steps of theory-testing, however, can be complicated by relative rigidity and dogmatism, in combination with the logistical challenges inherent in conducting comprehensive, real-world tests of theories explicating complex scientific phenomena, especially rare ones. It may be argued that suicide is one such phenomenon, and one for which the field of psychology has struggled to develop satisfactory understanding. One leading theory of suicide, the Interpersonal Theory of Suicide, has garnered attention and, to a considerable degree, has weathered substantial scrutiny. Still, it is arguable that the theory has yet to be tested in full-that is, in accordance with all propositions originally put forth. In this effort, we sought to evaluate the current state of knowledge regarding the Interpersonal Theory of Suicide, as well as to suggest potential directions via which future work may proceed. We draw from the fields of philosophy, psychology, physics, and engineering in the hopes of engendering curiosity and critical thought about the assumptions researchers (ourselves included) bring to their work. We direct particular attention to the role of refutation in theory-testing; the supposed dichotomy of explanatory vs. algorithmic approaches; and the categorization of research programs as progressive vs. degenerative. In doing so, we hope not only to promote these ideas in the study of suicidal behavior but also to empiricists of all creeds and foci. We also include implications for suicide prevention efforts.

Presence and severity of suicidal thoughts and behaviors across the eating disorder diagnostic spectrum: A pilot study.

OBJECTIVES: There is a dearth of research on suicidal thoughts and behaviors among eating disorder patients diagnosed with binge eating disorder (BED) or other specified feeding or eating disorder (OSFED). This pilot study evaluated presence and severity of suicidal thoughts and behaviors by eating disorder diagnosis in a transdiagnostic clinical eating disorder sample. METHODS: Participants were individuals (N = 257; 91.1% female; 94.6% Caucasian) currently receiving eating disorder treatment for anorexia nervosa (AN), bulimia nervosa (BN), BED, or OSFED. Participants completed online measures of variables. RESULTS: Lifetime and current presence and severity of suicidal ideation and suicide attempts were statistically similar among diagnostic groups. CONCLUSION: Though largely overlooked, treatment-utilizing individuals with BED and OSFED may experience elevated rates and severity of suicidal thoughts and behaviors, like those with AN and BN. Attention to suicide-related risk assessment and management is needed when treating individuals with eating disorders, regardless of diagnosis.

Body Trust, agitation, and suicidal ideation in a clinical eating disorder sample.

OBJECTIVE: Research has established pairwise relationships between suicidal ideation (SI), low Body Trust, elevated agitation, and eating disorders, but knowledge of how these aspects relate in a single model is lacking. This study tested an indirect pathway with low Body Trust relating to severity of SI via agitation in a clinical eating disorder sample. METHOD: Participants (N = 319; 92.8% female; 93.4% Caucasian; mean age 21.8 years) were adults currently receiving specialized eating disorder treatment (44.3% intensive outpatient or higher level-of-care) who completed online self-report measures of study variables. The PROCESS macro was utilized to test proposed pathways. RESULTS: Low Body Trust was significantly directly associated with increased severity of current SI, both before (B = -.89, p < .001) and after (B = -.51, p = .001) accounting for the indirect effect through agitation, also significant (B = -.37, SE = .06, CI -.52 to -.26). DISCUSSION: Perception of the body as unsafe may be related to agitation, and this intolerable sensation of trapped arousal could contribute to a desire to die. Future work should investigate these relationships prospectively to determine the relevance of Body Trust for assessment and treatment of suicide-related factors among individuals with eating disorders.

eXpression2Kinases (X2K) Web: linking expression signatures to upstream cell signaling networks.

While gene expression data at the mRNA level can be globally and accurately measured, profiling the activity of cell signaling pathways is currently much more difficult. eXpression2Kinases (X2K) computationally predicts involvement of upstream cell signaling pathways, given a signature of differentially expressed genes. X2K first computes enrichment for transcription factors likely to regulate the expression of the differentially expressed genes. The next step of X2K connects these enriched transcription factors through known protein-protein interactions (PPIs) to construct a subnetwork. The final step performs kinase enrichment analysis on the members of the subnetwork. X2K Web is a new implementation of the original eXpression2Kinases algorithm with important enhancements. X2K Web includes many new transcription factor and kinase libraries, and PPI networks. For demonstration, thousands of gene expression signatures induced by kinase inhibitors, applied to six breast cancer cell lines, are provided for fetching directly into X2K Web. The results are displayed as interactive downloadable vector graphic network images and bar graphs. Benchmarking various settings via random permutations enabled the identification of an optimal set of parameters to be used as the default settings in X2K Web. X2K Web is freely available from http://X2K.cloud.

Examining the association between body trust and body mass index with quantile regression.

PURPOSE: Schachter's externality theory posits a connection between the inability to eat according to internal cues and higher body mass index (BMI); however, related work has not investigated associations between body trust and the wide range of BMIs found in general samples. This study examined the association between body trust and BMI across levels of BMI to determine whether this relationship differed as a function of BMI level. METHODS: Participants were 534 adults (55.4% female), mean age 36 years, BMIs 15.13-67.90 (M = 27.89, SD = 7.25), recruited via MTurk. They completed self-report assessments of body trust, height, and weight. Quantile regression was utilized to estimate effects of body trust on BMI at five equidistant quantiles of BMI. RESULTS: Overall linear regression analyses indicated that body trust was significantly negatively associated with BMI. Quantile regression revealed a significant negative relationship at each quantile of BMI, and Wald tests indicated the association was significantly stronger at the 0.7 and 0.9 quantiles than at the 0.1, 0.3, and 0.5 quantiles, which did not differ. CONCLUSIONS: Quantile regression identified a stronger relationship between body trust and BMI at 0.7 and 0.9 quantiles than at 0.1, 0.3, and 0.5 quantiles of BMI. Results align with the externality hypothesis, which suggests those at higher weights experience difficulty using internal cues to guide eating. A weaker-than-expected association between body trust and low BMI may be due to restricted range (few low-BMI participants). Replication in eating disorder samples is merited. LEVEL OF EVIDENCE: Level V, cross-sectional descriptive study.

Examining the link between prior suicidality and subsequent suicidal ideation among high-risk US military service members.

BACKGROUND: Research is needed to identify the factors that explain the link between prior and future suicidality. This study evaluated possible mediators of the relationship between: (1) the severity of prior suicidality and (2) suicidal ideation severity at 3-month follow-up among a sample of high-risk military personnel. METHODS: US military service members referred to or seeking care for suicide risk (N = 624) completed self-report psychiatric domain measures and a clinician interview assessing prior suicidality severity at baseline. Three months later, participants completed a self-report measure of suicidal ideation severity. Three separate percentile bootstrap mediation models were used to examine psychiatric factors (i.e. alcohol abuse, anxiety sensitivity, hopelessness, insomnia, posttraumatic stress symptoms, suicidal ideation, and thwarted belongingness) as parallel mediators of the relationship between prior suicidality severity (specifically, suicidal ideation, suicide attempt, and overall suicidality - i.e. ideation/attempt severity combined) at baseline and suicidal ideation severity at follow-up. RESULTS: Hopelessness, specifically, and the total effect of all mediators, each significantly accounted for the relationship between prior suicidality severity and subsequent ideation severity across models. In the models with attempt severity and overall suicidality severity as predictors, thwarted belongingness was also a significant mediator. CONCLUSIONS: Hopelessness, thwarted belongingness, and overall severity of psychiatric indices may explain the relationship between prior suicidality severity and future suicidal ideation severity among service members at elevated suicide risk. Research is needed to replicate these findings and examine other possible mediators.

Psychotic symptoms and suicidal ideation in child and adolescent bipolar I disorder.

OBJECTIVES: The purpose of this study was to explore associations between specific types of hallucinations and delusions and suicidal ideation in a sample of children and adolescents with bipolar I disorder. METHODS: Participants (N = 379) were children and adolescents aged 6-15 years (M = 10.2, SD = 2.7) with DSM-IV diagnoses of bipolar I disorder, mixed or manic phase. The study sample was 53.8% female and primarily White (73.6% White, 17.9% Black, and 8.5% Other). Presence and nature of psychotic symptoms, suicidal ideation, and functioning level were assessed through clinician-administered measures. A series of logistic regressions was performed to assess the contribution of each subtype of psychotic symptom to the presence of suicidal ideation above and beyond age, sex, socio-economic status, age at bipolar disorder onset, and global level of functioning. RESULTS: Hallucinations overall, delusions of guilt, and number of different psychotic symptom types were uniquely associated with increased odds of suicidal ideation after accounting for covariates. Other forms of delusions (eg, grandiose) and specific types of hallucinations (eg, auditory) were not significantly uniquely associated with the presence of suicidal ideation. CONCLUSIONS: Findings of this study suggest the presence of hallucinations as a whole, delusions of guilt specifically, and having multiple concurrent types of psychotic symptoms are associated with the presence of suicidal ideation in children and adolescents with bipolar I disorder. Psychotic symptom subtypes, as opposed to psychosis as a whole, are an under-examined, potentially important, area for consideration regarding suicidal ideation in pediatric bipolar I disorder.

An investigation of indirect effects of personality features on anorexia nervosa severity through interoceptive dysfunction in individuals with lifetime anorexia nervosa diagnoses.

OBJECTIVE: This study examined a hypothesized pathway by which interoceptive dysfunction accounted for associations between personality features (harm avoidance, self-directedness, and perfectionism) and anorexia nervosa (AN) severity (indicated by drive for thinness, eating disorder-related preoccupations and rituals, and body mass index). METHOD: The study sample (n = 270, mean age = 28.47, 95.2% female, 98% White/Caucasian) consisted of probands and biological relatives who met DSM-IV criteria for lifetime diagnoses of AN (omitting criterion D, amenorrhea) drawn from the Price Foundation Anorexia Nervosa Affected Relative Pairs Study (AN-ARP). Participants completed measures assessing personality, interoceptive dysfunction, and eating pathology. RESULTS: Associations between personality features of low self-directedness and high perfectionism and indicators of AN severity (drive for thinness and eating disorder-related preoccupations and rituals) were significant, as were the hypothesized indirect pathways through interoceptive dysfunction. Neither harm avoidance nor body mass index was significantly related to other study variables, and the proposed indirect pathways involving these variables were not significant. DISCUSSION: Findings suggest that certain personality features may relate to AN severity, in part, through their associations with interoceptive dysfunction. Future research should examine prospective associations and the value of interventions targeting interoceptive dysfunction for interrupting the link between personality and AN severity.

Investigating the reliability of suicide attempt history reporting across five measures: A study of US military service members at risk of suicide.

OBJECTIVE: Utilizing a sample of military service members at risk of suicide, this study aimed to: (a) identify patterns of suicide attempt (SA) history reporting across five measures and (b) evaluate whether consistent SA reporters (i.e., individuals who consistently report an SA history across measures) differ from inconsistent SA reporters on other clinical severity indices. METHOD: Participants (N = 984) completed five validated SA history measures and self-report psychiatric symptom measures. RESULTS: Of the sample, 35.4% inconsistently responded to SA history measures. Inconsistent reporters disclosed more severe suicide threat histories than consistent reporters. On all other clinical severity indices, inconsistent reporters evinced either less severe or comparable symptom levels. CONCLUSIONS: A nontrivial portion of service members may respond inconsistently to different assessments of SA history. Research is needed to identify factors that account for inconsistent SA history reporting and to improve the accuracy of SA history assessments among military personnel.

Exercise dependence: Associations with capability for suicide and past suicidal behavior.

OBJECTIVE: Exercise dependence has been linked to capability for suicide and suicidal behavior; however, less understood are which facets of exercise dependence confer risk for suicidal behavior and the potential mechanisms of this association. This study examined relationships between exercise dependence, capability for suicide, and past suicidal behavior. METHODS: A sample of 540 individuals recruited via MTurk completed online measures of their exercise dependence, capability for suicide, and history of suicidal behavior. RESULTS: Suicide attempters reported higher levels of continuance in exercise despite physical or psychological consequences, lack of control over exercise, and reductions in other activities due to exercise than nonattempters. Capability for suicide accounted for the relationship between continuance in exercise despite adverse consequences and lifetime number of suicide attempts. CONCLUSIONS: When exercise becomes pathological in the form of exercise dependence, steps should be taken to reduce such engagement due to its observed association with suicidal behavior.

Body trust as a moderator of the association between exercise dependence and suicidality.

OBJECTIVES: Exercise dependence and interoceptive deficits, particularly low body trust, have been associated with suicidality. This study tested whether low body trust predicted current suicidal ideation and past suicide attempts in individuals exhibiting symptoms of exercise dependence. METHODS: 540 individuals (55.6% female, mean age 36) recruited via MTurk completed online measures of exercise dependence, interoception, and history of suicidal ideation and attempts. RESULTS: Exercise dependence symptoms and low body trust were associated with suicidal ideation. Body trust moderated the relationship between exercise dependence symptoms and suicidal ideation. Continuance in exercise despite adverse consequences and low body trust were associated with past suicide attempts. CONCLUSIONS: Body trust was associated with suicidal ideation and suicide attempts in individuals with exercise dependence symptoms, and the associations strengthened as body trust decreased. The experience of not trusting one's own body may exacerbate suicide risk in at-risk individuals.

Development and Psychometric Evaluation of the Professional Practice Work Environment Inventory.

OBJECTIVE: The purpose is to examine the psychometric properties of the professional practice work environment inventory (PPWEI). BACKGROUND: Derived from the Professional Practice Environment (PPE) and the Revised PPE scales, the PPWEI was designed to measure 8 components of the PPE that can be used to assist nurse administrators in decision-making. METHODS: A psychometric evaluation was undertaken with 874 nurses who were providing direct care to patients at the Massachusetts General Hospital and who provided no missing data on the newly developed 72-item PPWEI. RESULTS: Cronbach's α internal consistency reliability of the total score was .93, with 61 items having factor loadings more than .50, the factor loading cutoff used to define the component subscales. Principal component analyses with varimax rotation and Kaiser normalization demonstrated 8 components, explaining 64.6% of variance. Cronbach's α reliability coefficients of the PPWEI subscales ranged from .82 to .93. CONCLUSION: The multidimensional PPWEI is a psychometrically sound measure of several components of the PPE in the acute care setting and sufficiently reliable and valid for use as independent subscales in healthcare research.

Initial Psychometric Evaluation of the Staff Perception of the Disruptive Patient Behavior Scale.

OBJECTIVE: The aim of this study is to develop and psychometrically test the Staff Perception of Disruptive Patient Behavior (SPDPB) Scale. BACKGROUND: Disruptive patient behaviors impact work safety for nurses in hospitals. There is no standardized approach to capturing staff perceptions of these behaviors. METHOD: A mixed-methods approach was used to develop and psychometrically evaluate the SPDPB Scale. Items were generated from a survey completed by 770 healthcare providers. A prototype 66-item instrument was developed and content validity was obtained. Evaluation of the psychometric properties of the SPDPB Scale was completed with 558 nurses. Evaluation included internal consistency reliability, principal components analysis, and internal consistency reliability derived subscales to refine the final scale. RESULTS: The SPDPB Scale is a multidimensional measure of perceptions of disruptive patient behaviors. The analysis identified 6 components explaining 54.1% of the variance. The final scale contained 65 items. CONCLUSION: This scale demonstrated psychometric adequacy and can be recommended to measure staff perceptions of disruptive patient behavior.

Non-specific terminology: Moderating shame and guilt in eating disorders.

To examine the effects of terminology on affect, 110 women with eating disorders were randomly assigned to read a manufactured discussion thread with uses of the term "acting out," a thread with clinical terms, or were assigned to a no-reading control. An interaction effect was found in which participants who were treated at a day or inpatient level and were in the "acting out" condition experienced reductions in shame and guilt, while those in the clinical term condition experienced increases in shame and guilt, relative to control participants. The ability of terminology to moderate shame and guilt in this population has implications for clinical practice.

Words on walls: Passive eating disorder education.

This study examined the effect of a short-term passive intervention on nursing students' beliefs about eating disorders (EDs). Before and after a weeklong ED education poster campaign, participants completed questionnaires assessing their attitudes about individuals with EDs. Results showed a reduction in the belief that people with EDs are almost always women, increased attribution to biological and genetic factors, and decreased attribution to society's thin ideal. Personal connection moderated response to the items: [people with EDs] "are putting their lives at risk" and "would not improve with treatment." This intervention shows promise for reducing ED-associated stereotype endorsement among medical professionals.

Development and psychometric evaluation of the patient care associates' work environment scale.

OBJECTIVE: The purpose of this study is to examine the psychometric properties of the Patient Care Associates' Work Environment Scale (PCA-WES). BACKGROUND: Few studies exist examining patient care associates (PCAs) working in acute care settings, and no instruments are available to examine the impact of the work environment on their practice. METHODS: A psychometric evaluation using a nonprobability purposive sample of 390 PCAs was undertaken. RESULTS: Cronbach's α internal consistency reliability of the total score was .95. Principal components analysis with varimax rotation and Kaiser normalization identified 5 components that accounted for 57.2% of variance and confirmed the original theoretical structure. The resulting 35-item scale had subscale Cronbach's α reliability estimates that ranged from .84 to .93. CONCLUSIONS: The multidimensional PCA-WES is a psychometrically sound measure of 5 components of the PCA practice environment in the acute care setting and is sufficiently reliable and valid for use as independent subscales in healthcare research.

Eyes Fixed on Heaven's Gate: An Empirical Examination of Blink Rate and Suicide.

Anecdotal and theoretical work suggests blink rate as an indicator of imminent suicide risk. We sought to empirically examine whether suicide decedents displayed a reduced blink rate in goodbye videos filmed before death, compared to several control groups. Independent raters coded blink rates from videos of 34 suicide decedents and four comparison groups: "mundane" product review, non-suicidal arousal, non-suicidal depression, and non-imminent risk of suicidal ideation. Mean blink rate was lower in the suicide decedent group relative to all comparison groups (ps < .001), except the depressed (p = .976) and suicidal ideation (p = .393) groups. Findings indicate blink rate may be reduced among individuals at imminent risk for suicide, exhibiting clinically-significant depressive symptoms, or experiencing suicidal ideation.

A comparative study of suicidal and nonsuicidal self-injury characteristics in heterosexual versus sexual minority females.

Sexual minorities are at heightened risk for nonsuicidal self-injury (NSSI), suicidal ideation and attempts. We tested whether sexual minority and heterosexual females differ on these characteristics. Sexual minority females (n = 45) had higher lifetime frequency of NSSI and higher thwarted belonginess compared to heterosexual females (n = 47). These specific factors may contribute to the higher rates of suicide attempts among sexual minorities than heterosexual individuals.

Has COVID-19 Complicated Eating Disorder Treatment? An Examination of Comorbidities and Treatment Response Before and During the COVID-19 Pandemic.

Objective: Recent evidence suggests psychosocial stressors stemming from coronavirus disease 2019 (COVID-19) exposure and public health recommendations and policies have exacerbated eating disorder symptoms. Consequentially, eating disorder acuity has increased during the COVID-19 pandemic. Currently, it is still unclear how the COVID-19 pandemic may be impacting individuals receiving treatment for eating disorders at higher levels of care. The purpose of this study was to examine the impact of COVID-19 on eating disorder symptoms and associated outcomes in a sample of individuals receiving eating disorder treatment compared to individuals receiving treatment in 2019.Methods: Blinded outcomes data from 272 adults who completed treatment at an eating disorder treatment center between April and October of 2019 (pre-COVID-19 group) and 2020 (COVID-19 group) were examined. Repeated measures analyses of variance with Bonferroni correction were used to examine differences in outcome variables and treatment response.Results: Fewer participants reported trauma in 2020, but symptoms were more severe when present. A significant interaction effect for treatment (eg, admission, discharge) and year (eg, pre-COVID-19, COVID-19) was found for eating disorder and trauma symptoms. Moreover, trauma symptom scores were higher in 2020 than in 2019. The interaction among year, trauma, and treatment was significant (F3,268 = 2.11, P = .027, η2 = 0.034), indicating that individuals with severe trauma in 2020 reported less eating disorder symptom score reduction.Conclusions: Results extend understanding of effects during the COVID-19 pandemic on treatment-seeking individuals with eating disorders. Clinical implications suggest that greater attention to trauma when screening eating disorder patients and selecting treatment approaches are needed, particularly during the COVID-19 pandemic.