Ribosome subunit attrition and activation of the p53-MDM4 axis dominate the response of MLL-rearranged cancer cells to WDR5 WIN site inhibition.

The chromatin-associated protein WD Repeat Domain 5 (WDR5) is a promising target for cancer drug discovery, with most efforts blocking an arginine-binding cavity on the protein called the 'WIN' site that tethers WDR5 to chromatin. WIN site inhibitors (WINi) are active against multiple cancer cell types in vitro, the most notable of which are those derived from MLL-rearranged (MLLr) leukemias. Peptidomimetic WINi were originally proposed to inhibit MLLr cells via dysregulation of genes connected to hematopoietic stem cell expansion. Our discovery and interrogation of small-molecule WINi, however, revealed that they act in MLLr cell lines to suppress ribosome protein gene (RPG) transcription, induce nucleolar stress, and activate p53. Because there is no precedent for an anticancer strategy that specifically targets RPG expression, we took an integrated multi-omics approach to further interrogate the mechanism of action of WINi in human MLLr cancer cells. We show that WINi induce depletion of the stock of ribosomes, accompanied by a broad yet modest translational choke and changes in alternative mRNA splicing that inactivate the p53 antagonist MDM4. We also show that WINi are synergistic with agents including venetoclax and BET-bromodomain inhibitors. Together, these studies reinforce the concept that WINi are a novel type of ribosome-directed anticancer therapy and provide a resource to support their clinical implementation in MLLr leukemias and other malignancies.

Percutaneous tibial nerve stimulation versus sacral nerve stimulation for the treatment of faecal incontinence.

Introduction: Faecal incontinence (FI) is a common condition with a significant impact on quality of life (QoL). Neuromodulation treatments delivered by members of the multidisciplinary team including sacral nerve stimulation (SNS) and percutaneous tibial nerve stimulation (PTNS) are options for FI refractory to conservative management. The aim of this study was to assess whether a successful treatment with one neuromodulation modality corresponds with success in the other. Methods: A retrospective review of a prospectively managed neuromodulation database identified 15 patients who had undergone both PTNS and SNS. The definition of success of each treatment was a >50% improvement in any of The St. Mark's Incontinence Score, Manchester Health Questionnaire, or weekly faecal urgency or FI episodes. Results: Complete data from 12 patients was available for assessment and PTNS was delivered as the first treatment in nine patients. Overall, seven patients (58%) had successful PTNS treatment, with 10 (83%) having a successful SNS trials. Of the seven patients who had successful PTNS treatment, six patients (85.4%) went on to have success with SNS. Of the five patients who failed PTNS, four (80%) went on to have SNS success. Five (71%) of those who had positive PTNS outcomes had permanent SNS implantation as their final treatment decision. Conclusion: This study suggests that there is no clear relationship between successful PTNS treatment and an SNS trial period which may be explained by differing mechanisms of action or the potential placebo effect of PTNS. Further work is required to investigate any association in larger studies to inform clinical practice.

Ribosome subunit attrition and activation of the p53-MDM4 axis dominate the response of MLL-rearranged cancer cells to WDR5 WIN site inhibition.

The chromatin-associated protein WD Repeat Domain 5 (WDR5) is a promising target for cancer drug discovery, with most efforts blocking an arginine-binding cavity on the protein called the "WIN" site that tethers WDR5 to chromatin. WIN site inhibitors (WINi) are active against multiple cancer cell types in vitro, the most notable of which are those derived from MLL-rearranged (MLLr) leukemias. Peptidomimetic WINi were originally proposed to inhibit MLLr cells via dysregulation of genes connected to hematopoietic stem cell expansion. Our discovery and interrogation of small molecule WIN site inhibitors, however, revealed that they act in MLLr cell lines to suppress ribosome protein gene (RPG) transcription, induce nucleolar stress, and activate p53. Because there is no precedent for an anti-cancer strategy that specifically targets RPG expression, we took an integrated multi-omics approach to further interrogate the mechanism of action of WINi in MLLr cancer cells. We show that WINi induce depletion of the stock of ribosomes, accompanied by a broad yet modest translational choke and changes in alternative mRNA splicing that inactivate the p53 antagonist MDM4. We also show that WINi are synergistic with agents including venetoclax and BET-bromodomain inhibitors. Together, these studies reinforce the concept that WINi are a novel type of ribosome-directed anti-cancer therapy and provide a resource to support their clinical implementation in MLLr leukemias and other malignancies.

Subtypes of Depressed Youth Admitted for Inpatient Psychiatric Care: A Latent Profile Analysis.

Depressed youth frequently present with comorbid symptoms. Comorbidity is related to a poorer prognosis, including treatment resistance, academic problems, risk of suicide, and overall impairment. Studies examining the latent structure of depression support the notion of multiple presentations of depressed youth; however, it is unclear how these presentations are represented among acutely impaired youth. Participants (n = 457) in this naturalistic study were admitted to a psychiatric inpatient unit (Mean age = 14.33 years, SD = 1.94;76% female;46.6% Black/African-American). Selected subscales from the parent-report Behavior Assessment System for Children, Second Edition, were utilized as indicators in a latent profile analysis. Subgroups were validated based on their relationships with meaningful clinical correlates (e.g., family factors, discharge diagnosis) and further described by their associations with demographic variables. A five-class model provided the best balance of fit and parsimony. Subtypes of depressed youth included Predominantly Depressed (39.1%), Oppositional (28.2%), Severely Disruptive (12.3%), Anxious-Oppositional (11.6%), and Anxious-Withdrawn (8.8%). Comorbid symptoms were present in four of the five classes (60.9% of sample). High levels of externalizing symptoms were a prominent clinical feature associated with three classes (52.1% of the sample). Construct validity of the respective classes was demonstrated by differential association with clinical correlates, family characteristics, and demographics. Findings suggest that depressed youth presenting for acute inpatient psychiatric care displayed varied clinical presentations. The identified latent groups aligned with existing research reflecting comorbidity with anxiety, inattention, and externalizing disorders. Findings underscore the need for an increased clinical appreciation of comorbidity and encourage more targeted and effective prevention and treatment strategies.

Understanding the impact of pediatric single large-scale mtDNA deletion syndromes on caregivers: Burdens and challenges.

Single large-scale mitochondrial deletion syndromes (SLSMDS) are ultra-rare, progressive multi-system diseases that make children largely dependent on their caregivers for both medical and non-medical needs. Yet, few studies have examined the burden felt among caregivers. As part of a larger research study, 42 caregivers of children with SLSMDS completed two surveys to assess caregiver burden. The Mitochondrial Care Network Patient Needs Survey (MCN-PNS) is a novel assessment that examines the logistical, time, and financial costs experienced by caregivers of children with SLSMDS. The Zarit Burden Interview (ZBI-22) is a validated assessment that examines caregivers' psychological health. Results demonstrate the unique burden experienced by caregivers of children with SLSMDS. One notable finding was the high psychological burden. Nearly 90% of caregivers experience psychological burden, with 20% of caregivers at risk for anxiety and depression. Caregivers were primarily concerned about what the future held for their child. Additional burdens included the time required to coordinate the child's healthcare visits and financial strains. Caregivers reported minimal delays in establishing care with a mitochondrial care specialist and felt confident in their understanding of their child's disease and treatment(s). Overall, there is a need for expanded logistical, financial, and psychological support from mitochondrial disease centers and advocacy groups for caregivers of children with SLSMDS.

Genetic inhibitors of APOBEC3B-induced mutagenesis.

The cytidine deaminases APOBEC3A (A3A) and APOBEC3B (A3B) are prominent mutators of human cancer genomes. However, tumor-specific genetic modulators of APOBEC-induced mutagenesis are poorly defined. Here, we used a screen to identify 61 gene deletions that increase A3B-induced mutations in yeast. We also determined whether each deletion was epistatic with Ung1 loss, which indicated whether the encoded factors participate in the homologous recombination (HR)-dependent bypass of A3B/Ung1-dependent abasic sites or suppress A3B-catalyzed deamination by protecting against aberrant formation of single-stranded DNA (ssDNA). We found that the mutation spectra of A3B-induced mutations revealed genotype-specific patterns of strand-specific ssDNA formation and nucleotide incorporation across APOBEC-induced lesions. Combining these three metrics, we were able to establish a multifactorial signature of APOBEC-induced mutations specific to (1) failure to remove H3K56 acetylation, (2) defective CTF18-RFC complex function, and (3) defective HR-mediated bypass of APOBEC-induced lesions. We extended these results by analyzing mutation data for human tumors and found BRCA1/2-deficient breast cancers display three- to fourfold more APOBEC-induced mutations. Mirroring our results in yeast, Rev1-mediated C-to-G substitutions are mainly responsible for increased APOBEC-signature mutations in BRCA1/2-deficient tumors, and these mutations associate with lagging strand synthesis during replication. These results identify important factors that influence DNA replication dynamics and likely the abundance of APOBEC-induced mutation during tumor progression. They also highlight a novel role for BRCA1/2 during HR-dependent lesion bypass of APOBEC-induced lesions during cancer cell replication.

Caregiver-reported psychological and behavioural functioning of children with suicidal thoughts and behaviour: A case-control design.

OBJECTIVE: This exploratory project aims to provide an empirical understanding of the caregiver-reported emotional and behavioural functioning of children 12 and under who present to an inpatient psychiatric unit with suicidal ideation and/or attempts. METHOD: A retrospective chart review was conducted, including all patients (n = 573) aged 12 and under admitted to a psychiatric inpatient unit between September 2011-December 2015 for suicidal ideation without proximal attempt (n = 155) or a suicide attempt (n = 37). Inpatients without suicidal thoughts and behaviour in the same age range (n = 381) served as a control group. The three groups were compared on a range of variables, including patient history/demographics, caregiver-reported emotional/behavioural functioning, and discharge diagnoses. RESULTS: Children who were admitted to a psychiatric inpatient unit following suicide attempts and/or ideation demonstrated clinically significant levels of externalizing and internalizing symptoms. Children with suicidal thoughts and behaviour (STB) were more likely to be female and older than their peers without STB, more likely to report a history of sexual abuse and non-suicidal self-injury, and to be diagnosed with a depressive disorder. CONCLUSIONS: Children with STB differ demographically, symptomatically, and diagnostically from their peers without STB with comparable levels of psychiatric impairment (i.e., necessitating inpatient admission). Results provide provisional information on this concerning group of children, which can be used to aid identification of risk factors, inform treatment, and stimulate future work.

The Coronavirus Impact Scale: Construction, Validation, and Comparisons in Diverse Clinical Samples.

Objective: This report is of the construction and initial psychometric properties of the Coronavirus Impact Scale in multiple large and diverse samples of families with children and adolescents. The scale was established to capture the impact of the coronavirus pandemic during its first wave. Differences in impact between samples and internal structure within samples were assessed. Method: A total of 572 caregivers of children and adolescents or expecting mothers in diverse clinical and research settings completed the Coronavirus Impact Scale. Samples differed in regard to developmental stage, background, inpatient/outpatient status, and primary research or clinical setting. Model free methods were used to measure the scale's internal structure and to determine a scoring method. Differences between samples in specific item responses were measured by multivariate ordinal regression. Results: The Coronavirus Impact Scale demonstrated good internal consistency in a variety of clinical and research populations. Across the groups studied, single, immigrant, predominantly Latinx mothers of young children reported the greatest impact of the pandemic, with noteworthy effects on food access and finances reported. Individuals receiving outpatient or inpatient care reported greater impacts on health care access. Elevated scores on the Coronavirus Impact Scale were positively associated with measures of caregiver anxiety and both caregiver- and child-reported stress at a moderate effect size. Conclusion: The Coronavirus Impact Scale is a publicly available scale with adequate psychometric properties for use in measuring the impact of the coronavirus pandemic in diverse populations.

Newborn Screening Conditions: Early Intervention and Probability of Developmental Delay.

OBJECTIVES: The purpose of this study is to explore which newborn screening (NBS) conditions are automatically eligible for early intervention (EI) across states and to determine the extent to which each disorder should automatically qualify for EI because of a high probability of developmental delay. METHODS: We examined each state's EI eligibility policy and reviewed the literature documenting developmental outcomes for each NBS condition. Using a novel matrix, we assessed the risk of developmental delay, medical complexity, and risk of episodic decompensation, revising the matrix iteratively until reaching consensus. Three NBS conditions (biotinidase deficiency, severe combined immunodeficiency, and propionic acidemia) are presented in detail as examples. RESULTS: Most states (88%) had Established Conditions lists to autoqualify children to EI. The average number of NBS conditions listed was 7.8 (range 0-34). Each condition appeared on average in 11.7 Established Conditions lists (range 2-29). After the literature review and consensus process, 29 conditions were likely to meet national criteria for an Established Condition. CONCLUSION: Despite benefiting from NBS and timely treatment, many children diagnosed with NBS conditions are at risk for developmental delays and significant medical complexity. The results demonstrate a need for more clarity and guidance regarding which children should qualify for EI. We suggest that most NBS conditions should automatically qualify based on the probability of resulting in a developmental delay. These findings suggest a future opportunity for collaboration between NBS and EI programs to create a consistent set of Established Conditions, potentially expediate referrals of eligible children, and streamline children's access to EI services.

Genetic modifiers of APOBEC-induced mutagenesis.

The cytidine deaminases APOBEC3A and APOBEC3B (A3B) are prominent mutators of human cancer genomes. However, tumor-specific genetic modulators of APOBEC-induced mutagenesis are poorly defined. Here, we utilized a screen to identify 61 gene deletions that increase A3B-induced mutations in yeast. Also, we determined whether each deletion was epistatic with UNG1 loss, which indicated whether the encoded factors participate in the error-free bypass of A3B/Ung1-dependent abasic sites or suppress A3B-catalyzed deamination by protecting against aberrant formation of single stranded DNA (ssDNA). Additionally, we determined that the mutation spectra of A3B-induced mutations revealed genotype-specific patterns of strand-specific ssDNA formation and nucleotide incorporation across APOBEC-induced lesions. Combining these three metrics we were able to establish a multifactorial signature of APOBEC-induced mutations specific to (1) failure to remove H3K56 acetylation, which results in extremely high A3B-induced mutagenesis, (2) defective CTF18-RFC complex function, which results in high levels of A3B induced mutations specifically on the leading strand template that synergistically increase with loss of UNG1, and (3) defective HR-mediated bypass of APOBEC-induced lesions, which were epistatic with Ung1 loss and result from increased Rev1-mediated C-to-G substitutions. We extended these results by analyzing mutation data for human tumors and found BRCA1/2-deficient breast cancer tumors display 3- to 4-fold more APOBEC-induced mutations. Mirroring our results in yeast, for BRCA1/2 deficient tumors Rev1-mediated C-to-G substitutions are solely responsible for increased APOBEC-signature mutations and these mutations occur on the lagging strand during DNA replication. Together these results identify important factors that influence the dynamics of DNA replication and likely the abundance of APOBEC-induced mutation during tumor progression as well as a novel mechanistic role for BRCA1/2 during HR-dependent lesion bypass of APOBEC-induced lesions during cancer cell replication.

Enhancing Quality of Care Through Evidence-Based Practice: Training and Supervision Experiences.

OBJECTIVE: Evidence-based practice (EBP) is the preferred approach to treatment in mental health settings because it involves the integration of the best available research, clinical expertise, and patient values to optimize patient outcomes. Training on empirically supported treatments (ESTs) in mental health settings is an important component of EBP, and supervision of therapists' implementation of ESTs is critical for therapists to develop and maintain a strong EBP skill set. This study aimed to evaluate training and supervision histories of therapists in outpatient and inpatient psychiatric care settings as an essential first step in improving patient outcomes. METHODS: Electronic surveys were completed by 69 therapists, most of whom had a master's degree, within a psychiatry and behavioral sciences department at an academic institution. Participating therapists were recruited from several outpatient and inpatient mental health settings serving children, adolescents, and adults. RESULTS: Although most therapists reported completing some form of EST-related coursework, a majority did not receive any supervision related to implementation of ESTs (51% for cognitive-behavioral therapy cases, 76% for dialectical behavior therapy cases, and 52% for other EST cases) during graduate and postgraduate training. CONCLUSIONS: Although research from the past decade has supported the need for improvements in training on ESTs, and especially in supervision, problems related to limited exposure to training and supervision among therapists still exist. These findings have implications for how mental health centers can evaluate staff members' EST training and supervision experiences, training needs, and associated training targets to improve the quality of routine care.

Long gaps between turns are awkward for strangers but not for friends.

When people feel connected they tend to respond quickly in conversation, creating short gaps between turns. But are long gaps always a sign that things have gone awry? We analysed the frequency and impact of long gaps (greater than 2 s) in conversations between strangers and between friends. As predicted, long gaps signalled disconnection between strangers. However, long gaps between friends marked moments of increased connection and friends tended to have more of them. These differences in connection were also perceived by independent raters: only the long gaps between strangers were rated as awkward, and increasingly so the longer they lasted. Finally, we show that, compared to strangers, long gaps between friends include more genuine laughter and are less likely to precede a topic change. This suggests that the gaps of friends may not function as 'gaps' at all, but instead allow space for enjoyment and mutual reflection. Together, these findings suggest that the turn-taking dynamics of friends are meaningfully different from those of strangers and may be less bound by social conventions. More broadly, this work illustrates that samples of convenience-pairs of strangers being the modal paradigm for interaction research-may not capture the social dynamics of more familiar relationships. This article is part of a discussion meeting issue 'Face2face: advancing the science of social interaction'.

A Hepatogastrophrenic Trunk, Celiacomesenteric Trunk, and a Middle Mesenteric Artery in a 68-Year-Old White Male Donor.

A detailed understanding of the enteric vascular supply is of great importance for pre-operative planning. In the case of this 68-year-old white male donor, the following variations were observed: a hepatogastrophrenic trunk, a celiacomesenteric trunk, and a middle mesenteric artery. Literature review was conducted to understand the frequency and clinical significance of these variations.

Fast response times signal social connection in conversation.

Clicking is one of the most robust metaphors for social connection. But how do we know when two people "click"? We asked pairs of friends and strangers to talk with each other and rate their felt connection. For both friends and strangers, speed in response was a robust predictor of feeling connected. Conversations with faster response times felt more connected than conversations with slower response times, and within conversations, connected moments had faster response times than less-connected moments. This effect was determined primarily by partner responsivity: People felt more connected to the degree that their partner responded quickly to them rather than by how quickly they responded to their partner. The temporal scale of these effects (<250 ms) precludes conscious control, thus providing an honest signal of connection. Using a round-robin design in each of six closed networks, we show that faster responders evoked greater feelings of connection across partners. Finally, we demonstrate that this signal is used by third-party listeners as a heuristic of how well people are connected: Conversations with faster response times were perceived as more connected than the same conversations with slower response times. Together, these findings suggest that response times comprise a robust and sufficient signal of whether two minds "click."

Factors Associated With Pediatric Burn Clinic Follow-up After Emergency Department Discharge.

Attrition between emergency department discharge and outpatient follow-up is well documented across a variety of pediatric ailments. Given the importance of outpatient medical care and the lack of related research in pediatric burn populations, we examined sociodemographic factors and burn characteristics associated with outpatient follow-up adherence among pediatric burn patients. A retrospective review of medical records was conducted on patient data extracted from a burn registry database at an urban academic children's hospital over a 2-year period (January 2018-December 2019). All patients were treated in the emergency department and discharged with instructions to follow-up in an outpatient burn clinic within 1 week. A total of 196 patients (Mage = 5.5 years; 54% male) were included in analyses. Average % TBSA was 1.9 (SD = 1.5%). One third of pediatric burn patients (33%) did not attend outpatient follow-up as instructed. Older patients (odds ratio [OR] = 1.00; 95% confidence interval [CI]: [0.99-1.00], P = .045), patients with superficial burns (OR = 9.37; 95% CI: [2.50-35.16], P = .001), patients with smaller % TBSA (OR = 1.37; 95% CI: [1.07-1.76], P = .014), and patients with Medicaid insurance (OR = 0.22; 95% CI: [0.09-0.57], P = .002) or uninsured/unknown insurance (OR = 0.07; 95% CI: [0.02-0.26], P = .000) were less likely to follow up, respectively. Patient gender, race, ethnicity, and distance to clinic were not associated with follow-up. Follow-up attrition in our sample suggests a need for additional research identifying factors associated with adherence to follow-up care. Identifying factors associated with follow-up adherence is an essential step in developing targeted interventions to improve health outcomes in this at-risk population.

The Role of Social Adjustment in a Collegiate Behavioral Activation Program.

The transition to college is associated with significant changes in social support networks and concomitant increases in depressive symptoms. First-year students who are more socially engaged within their new academic settings may experience greater overall wellbeing. Behavioral activation (BA) is an evidence-based intervention which promotes individuals' engagement with valued activities and has been examined as a possible primary prevention for depressive symptoms among first-year students. Yet, the important role of social adjustment, and its impact on students' activity level, has not yet been considered. The current study is a secondary data analysis of research evaluating a BA-based intervention embedded into a first-year orientation course. The aim of the project was to evaluate the efficacy of BA on improving social adjustment and the effect of social adjustment on subsequent depressive symptoms. A diverse sample of college students (n = 71) attending a state university in the mid-Atlantic region reported on their levels of depression, behavioral activation, and social adjustment. Students then received either BA or standard programming. Results suggest that improved engagement in valued activities at mid-intervention was associated with increases in students' perceptions of their own social adjustment. This, in turn, predicted steeper decreases in rates of depressive symptoms post-intervention. Findings also indicate that greater social adjustment improved the efficacy of a BA-based intervention in reducing depressive symptoms, but had no impact on depressive symptoms for students receiving the standard orientation programming.

Factors associated with a change in disposition for mental health patients boarding in an urban Paediatric emergency department.

AIM: Paediatric emergency departments (ED) nationwide experience a shared burden of boarding mental health patients. Whilst boarding, some patients have a change in disposition from hospitalization to discharge home. This phenomenon raises concern because EDs often have scarce resources for mental health patients. We sought to understand which patient and clinical factors are associated with a change in disposition outcome. METHODS: A nested age-sex-race frequency-matched case-control study was conducted including paediatric patients who presented to an urban PED for mental healthcare over a 36-month period. Control patients included patients admitted to an inpatient psychiatric facility, whilst case patients were those discharged home. Descriptive statistics and multivariable logistic regression analyses were performed to compare groups. RESULTS: Case patients were more likely to receive intramuscular Haloperidol (OR 2.2 [CI 1.1-4.4]) for agitation and a psychiatric consult (OR 2.3 [1.4-3.9]) whilst boarding. Case patients were also more likely to present with behavioural concerns (OR 1.8 [CI 1.1-3.1]) and have additional complexities such as medical comorbidities (OR 1.8 [CI 1.1-2.9]) or suicidal ideation/attempt (OR 2.6 [CI 1.1-6.1]). Amongst the most common themes for disposition change was improved patient status (58.8%). CONCLUSION: These findings suggest that boarding mental health patients have different disposition outcomes and thus may benefit from patient-specific treatment interventions. Given that patients' statuses may change during the boarding period prompting discharge to home, more focus should be directed to developing brief evidence-based practises that may be implemented in the ED and effectively bridge the gap to outpatient mental health services.