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Abstract To enable interrogation of tumor HLA LOH as a clinical diagnostic for precision oncology, we developed and validated an assay that detects HLA LOH within the context of an FDA-approved clinical diagnostic test, Tempus xT CDx. Validation was conducted via: (1) analytical evaluation of 17 archival patient samples and 42 cell line admixtures and (2) independent clinical evaluation of LOH prevalence in the HLA-A gene (HLA-A LOH) across 10,982 patients. To evaluate the prognostic relevance of HLA-A LOH we assessed 256 immunotherapy-treated non-small cell lung cancer (NSCLC) patients. To determine the feasibility of prospectively identifying and enrolling HLA-A LOH patients into a clinical trial, we established BASECAMP-1 (NCT04981119). We observed a positive predictive agreement of 97% and a negative predictive agreement of 100% in samples with ≥ 40% tumor purity. We observed HLA-A LOH in 16.1% of patients (1771/10,982), comparable to previous reports. HLA-A LOH was associated with longer survival among NSCLC adenocarcinoma patients (HR = 0.60, 95% CI [0.37, 0.96], p = 0.032) with a trend towards shorter survival among squamous cell patients (HR = 1.64, 95% CI [0.80, 3.41], p = 0.183). In 20 months, we prospectively screened 1720 subjects using the Tempus AWARE program, identifying 26 HLA-A*02 LOH patients at 8 sites, with 14 (54%) enrolled into BASECAMP-1. In conclusion, we developed and validated an investigational assay that detects tumor HLA LOH within an FDA-approved clinical diagnostic test, enabling HLA LOH utilization in diagnostic, prognostic, and therapeutic applications.

Abstract Introduction A dynamic molecular biomarker that can identify early efficacy of immune checkpoint inhibitor (ICI) therapy remains an unmet clinical need. Here we evaluate if a novel circulating tumor DNA (ctDNA) assay, xM, used for treatment response monitoring (TRM), that quantifies changes in ctDNA tumor fraction (TF), can predict outcome benefits in patients treated with ICI alone or in combination with chemotherapy in a real-world (RW) cohort. Methods This retrospective study consisted of patients with advanced cancer from the Tempus de-identified clinical genomic database who received longitudinal liquid-based next-generation sequencing. Eligible patients had a blood sample ≤ 40 days prior to the start of ICI initiation and an on-treatment blood sample 15–180 days post ICI initiation. TF was calculated via an ensemble algorithm that utilizes TF estimates derived from variants and copy number information. Patients with molecular response (MR) were defined as patients with a ≥ 50% decrease in TF between tests. In the subset of patients with rw-imaging data between 2 and 18 weeks of ICI initiation, the predictive value of MR in addition to rw-imaging was compared to a model of rw-imaging alone. Results The evaluable cohort (N = 86) was composed of 14 solid cancer types. Patients received either ICI monotherapy (38.4%, N = 33) or ICI in combination with chemotherapy (61.6%, N = 53). Patients with MR had significantly longer rw-overall survival (rwOS) (hazard ratio (HR) 0.4, P = 0.004) and rw-progression free survival (rwPFS) (HR 0.4, P = 0.005) than patients with molecular non-response (nMR). Similar results were seen in the ICI monotherapy subcohort; HR 0.2, P = 0.02 for rwOS and HR 0.2, P = 0.01 for rwPFS. In the subset of patients with matched rw-imaging data (N = 51), a model incorporating both MR and rw-imaging was superior in predicting rwOS than rw-imaging alone (P = 0.02). Conclusions xM used for TRM is a novel serial quantitative TF algorithm that can be used clinically to evaluate ICI therapy efficacy.

Some cancer patients with impaired HLA-I still respond to immunotherapy. Here the authors combine a cytotoxic gene signature from CD4+ and CD8+ T cells with tumor mutational burden to predict immunotherapy response in NSCLC patients, including those with HLA-LOH.

Susceptibility to asthma and severity of symptoms are regulated by a number of different genomic regions. Here the authors characterise a 5kb regulatory region and demonstrate genetic and topological regulation of IL33 and association with disease in different human cohorts.

Abstract Sex-specific differences in prevalence are well documented for many common, complex diseases, especially for immune-mediated diseases, yet the precise mechanisms through which factors associated with biological sex exert their effects throughout life are not well understood. We interrogated sex-specific transcriptional responses of peripheral blood leukocytes (PBLs) to innate immune stimulation by lipopolysaccharide (LPS) in 46 male and 66 female members of the Hutterite community, who practice a communal lifestyle. We identified 1217 autosomal and 54 X-linked genes with sex-specific responses to LPS, as well as 71 autosomal and one X-linked sex-specific expression quantitative trait loci (eQTLs). Despite a similar proportion of the 15 HLA genes responding to LPS compared to all expressed autosomal genes, there was a significant over-representation of genes with sex by treatment interactions among HLA genes. We also observed an enrichment of sex-specific differentially expressed genes in response to LPS for X-linked genes compared to autosomal genes, suggesting that HLA and X-linked genes may disproportionately contribute to sex disparities in risk for immune-mediated diseases.

Summary: Patient-derived tumor organoids (TOs) are emerging as high-fidelity models to study cancer biology and develop novel precision medicine therapeutics. However, utilizing TOs for systems-biology-based approaches has been limited by a lack of scalable and reproducible methods to develop and profile these models. We describe a robust pan-cancer TO platform with chemically defined media optimized on cultures acquired from over 1,000 patients. Crucially, we demonstrate tumor genetic and transcriptomic concordance utilizing this approach and further optimize defined minimal media for organoid initiation and propagation. Additionally, we demonstrate a neural-network-based high-throughput approach for label-free, light-microscopy-based drug assays capable of predicting patient-specific heterogeneity in drug responses with applicability across solid cancers. The pan-cancer platform, molecular data, and neural-network-based drug assay serve as resources to accelerate the broad implementation of organoid models in precision medicine research and personalized therapeutic profiling programs.

The retina of the mosquito Aedes aegypti can be divided into four regions based on the non-overlapping expression of a UV sensitive Aaop8 rhodopsin and a long wavelength sensitive Aaop2 type rhodopsin in the R7 photoreceptors. We show here that another rhodopsin, Aaop9, is expressed in all R7 photoreceptors and a subset of R8 photoreceptors. In the dorsal region, Aaop9 is expressed in both the cell body and rhabdomere of R7 and R8 cells. In other retinal regions Aaop9 is expressed only in R7 cells, being localized to the R7 rhabdomere in the central and ventral regions and in both the cell body and rhabdomere within the ventral stripe. Within the dorsal-central transition area ommatidia do not show a strict pairing of R7-R8 cell types. Thus, Aaop9 is coexpressed in the two classes of R7 photoreceptors previously distinguished by the non-overlapping expression of Aaop8 and Aaop2 rhodopsins. Electroretinogram analysis of transgenic Drosophila shows that Aaop9 is a short wavelength rhodopsin with an optimal response to 400-450 nm light. The coexpressed Aaop2 rhodopsin has dual wavelength sensitivity of 500-550 nm and near 350 nm in the UV region. As predicted by the spectral properties of each rhodopsin, Drosophila photoreceptors expressing both Aaop9 and Aaop2 rhodopsins exhibit a uniform sensitivity across the broad 350-550 nm light range. We propose that rhodopsin coexpression is an adaptation within the R7 cells to improve visual function in the low-light environments in which Ae. aegypti is active.

Genomic imprinting is the phenomena that leads to silencing of one copy of a gene inherited from a specific parent. Mutations in imprinted regions have been involved in diseases showing parent of origin effects. Identifying genes with evidence of parent of origin expression patterns in family studies allows the detection of more subtle imprinting. Here, we use allele specific expression in lymphoblastoid cell lines from 306 Hutterites related in a single pedigree to provide formal evidence for parent of origin effects. We take advantage of phased genotype data to assign parent of origin to RNA-seq reads in individuals with gene expression data. Our approach identified known imprinted genes, two putative novel imprinted genes, PXDC1 and PWAR6, and 14 genes with asymmetrical parent of origin gene expression. We used gene expression in peripheral blood leukocytes (PBL) to validate our findings, and then confirmed imprinting control regions (ICRs) using DNA methylation levels in the PBLs.

Introduction: Early childhood is recognised as a critical window of opportunity for physical literacy development, however early childhood educators typically lack the training required to effectively provide appropriate physical literacy opportunities for children. We examined the effects of an online physical literacy professional development program-relative to continuing with 'standard' practice-on early childhood educators' physical literacy knowledge and application., Methods: We conducted a parallel two-arm randomised controlled trial, in which 88 early childhood educators were randomly assigned to an online professional development program designed to support educators' physical literacy instructional skills (intervention arm; n = 37), or a 'standard practice' control condition (n = 51). Data were collected prior to and after the four-week intervention period. We measured educators' physical literacy knowledge and application (our primary outcome) through independent coding of open-ended survey responses, and educators' self-reported perceptions of values, confidence, behaviours, and barriers (secondary outcomes). Between-group differences were assessed through analysis of covariance., Results: One intervention arm participant withdrew from the study, resulting in 87 participants included in analysis. Educators in the intervention arm scored significantly higher on post-intervention physical literacy knowledge (d = 0.62) and application (d = 0.33) than those in the control arm. Educators in the intervention arm also scored significantly higher than controls on confidence in teaching physical activity (d = 0.42) and significantly lower than controls on perceived personal barriers to physical activity (d = 0.53). Thirteen participants in the intervention arm (36%) did not begin the online professional development program., Conclusion: Improvements in physical literacy instructional outcomes indicate the potential for further investigation into broader implementation of online professional development programs of this nature in the future., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: No funding to declare. MR and AD are involved in the ongoing design and development of the KIDDO program, and MR, AD, ALT, & BJ are involved in a research group conducting other research on KIDDO’s services and impact. Due to strict blinding protocol throughout data collection and analysis, it is unlikely that this conflict of interest had an impact on study outcomes., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Numerous factors have, to date, been identified as playing a role in the regulation of Agr activity in Staphylococcus aureus , including transcription factors, antisense RNAs, and host elements. Herein we investigated the product of SAUSA300_1984 (termed MroQ), a transmembrane Abi-domain/M79 protease-family protein, as a novel effector of this system. Using a USA300 mroQ mutant, we observed a drastic reduction in proteolysis, hemolysis, and pigmentation that was fully complementable. This appears to result from diminished agr activity, as transcriptional analysis revealed significant decreases in expression of both RNAII and RNAIII in the mroQ mutant. Such effects appear to be direct, rather than indirect, as known agr effectors demonstrated limited alterations in their activity upon mroQ disruption. A comparison of RNA sequencing data sets for both mroQ and agr mutants revealed a profound overlap in their regulomes, with the majority of factors affected being known virulence determinants. Importantly, the preponderance of alterations in expression were more striking in the agr mutant, indicating that MroQ is necessary, but not sufficient, for Agr function. Mechanism profiling revealed that putative residues for metalloprotease activity within MroQ are required for its Agr-controlling effect; however, this was not wielded at the level of AgrD processing. Virulence assessment demonstrated that both mroQ and agr mutants exhibited increased formation of renal abscesses but decreased skin abscess formation alongside diminished dermonecrosis. Collectively, we present the characterization of a novel agr effector in S. aureus which would appear to be a direct regulator, potentially functioning via interaction with the AgrC histidine kinase., (Copyright © 2019 American Society for Microbiology.)

The social cognition and object relations scale-global rating method is a clinical rating system assessing 8 domains of self and interpersonal functioning. It can be applied to score numerous forms of narrative data. In this study, we investigate the SCORS-G relationship to measures of alliance and readiness for psychotherapy with an adolescent inpatient sample. Seventy-two psychiatrically hospitalized adolescents were consented and subsequently rated by their individual and group therapist using the SCORS-G. The unit psychiatrist also completed an assessment of patients' readiness for inpatient psychotherapy. The patients completed a self-report of their alliance with the inpatient treatment team as a whole. SCORS-G ratings were positively correlated with assessments of readiness for inpatient psychotherapy and patient-reported alliance. This study further demonstrates the clinical utility of the SCORS-G with adolescents., (Copyright © 2018 John Wiley & Sons, Ltd.)

The Social Cognition and Object Relations Scales-Global Rating Method (SCORS-G) contains 8 scales for coding narrative content. This study explores the factor structure of this measure using college (n = 171), outpatient (n = 239), and inpatient (n = 78) samples. Participants told stories to the Thematic Apperception Test (TAT; Murray, 1943) cards. Stories were transcribed and coded by blind raters using the SCORS-G. Cases were randomly assigned to an exploratory or validation group. Exploratory factor analysis with the exploratory group suggested 2- and 3-factor models. The Emotional Investment in Relationships (EIR) scale did not obtain a primary loading on any factor and was not included in subsequentmodels. After modifications, confirmatory factor analysis indicated good-to-adequate fit for 2- and 3-factor models. Both models showed good fit in the validation group and met criteria for invariance across models. Findings indicated that some SCORS-G scales tap cognitive-structural elements, whereas others assess affective-relational components of narratives. We found mild support separating the affective-relational scales in terms of internal representations for the self and others and relationships. The results reported here indicate that clinicians and researchers can calculate a separate cognitive-structural composite score and an affective-relational composite score when using the SCORS-G to rate TAT stories.

The current study developed a new index of violence risk from scales within the Personality Assessment Inventory (PAI). Clinical patients from inpatient and outpatient settings completed the PAI along with reports of violence history and arrest record. A forward-selection hierarchical logistic regression was employed (N = 388) to identify the PAI scales (AGG-P, AGG-A, NON, PAR-H, and ANT-A) that could effectively distinguish patients with and without a history of violence. These indicators were then aggregated into a single index, labeled the Violence and Aggression Risk Index (VARI). The VARI modestly incremented other PAI subscales and indices in an independent clinical sample (N = 387). The authors discuss how the VARI can be incorporated with the other PAI scales to assess violence risk.

The current study sought to develop and validate a new measure of chronic suicide risk (the S_Chron) from the Personality Assessment Inventory in a mixed sample of psychiatric inpatients and outpatients. In an initial development sample (N=397), hierarchical logistic regression identified six PAI variables uniquely associated with multiple versus single/no prior suicide attempts after controlling for sample demographics: Negative Impression Management, Situational Stress, Mania - Grandiosity, Borderline - Negative Relationships, Borderline - Self-Harm, and Antisocial Behaviors. These indicators were then aggregated into a single index (S_Chron) and evaluated in terms of validity in an independent clinical sample (N=398). Results indicated the S_Chron effectively differentiated between groups with multiple versus single/no prior suicide attempts, even after controlling for the effects of the PAI Suicidal Ideation (SUI) and Suicide Potential (SPI) indices, with moderate to large effect sizes observed (range of Cohen's d's=0.30-0.91). Further, the S_Chron incremented all other PAI indices and SUI in predicting multiple suicide attempts. The potential clinical application and ways in which the S_Chron may augment other existing measures of suicide risk are discussed., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

This study seeks to evaluate the construct validity of the Symptom Assessment-45 by investigating the instrument's correlation with selected scales from the Personality Assessment Inventory and life-event data in a sample of 93 psychiatric patients. The life-event data used in the study included: education and employment, as well as history of suicide attempts, psychiatric hospitalizations, medical problems, hallucinations, and paranoid ideation. Bivariate correlations were computed to explore the associations among the SA-45 scales and the validity criteria. The results indicated that the SA-45 scales demonstrated adequate convergent and divergent validity with target scales from the PAI. They were also found to be meaningfully associated with a variety of life event variables. These findings add to the emerging body of evidence corroborating the convergent and discriminant validity of the SA-45., (Copyright © 2015 Elsevier Inc. All rights reserved.)

This brief report explores the external correlates of 2 higher order structures of the Personality Assessment Inventory (PAI; Morey, 1991, 2007); Hoelzle and Meyer's (2009a, 2009b) PAI Components and Hopwood and Moser's (2011) Internalizing and Externalizing Dimensions. Scores from these higher order structures were correlated with life-event data including education, marital status, employment, suicide attempts, psychiatric hospitalizations, trauma, medical problems, hallucinations, paranoid ideation, drug abuse, alcohol abuse, and arrest. Although some differences were noted, the results showed that both Hoelzle and Meyer's Components and Hopwood and Moser's Dimensions were meaningfully correlated with a wide range of life outcomes in a conceptually consistent manner. Overall, these findings provide support for the utility of these higher order variables.

This study contributes to the ongoing construct validation of the personality assessment inventory (PAI; Morey, 1991 , 2007 ) by identifying nontest life-event correlates of the PAI full scales and subscales in a sample of psychiatric patients. The life-event data used in this study included education, marital status, and employment, as well as a history of suicide attempts, psychiatric hospitalizations, trauma, medical problems, hallucinations, paranoid ideation, drug abuse, alcohol abuse, and arrest. Correlations were calculated to explore the convergent and discriminant validity of the PAI scales relative to the life-event data. The results showed that the majority of the PAI scales (11 of 13) had meaningful correlations with at least 1 life-event variable. The PAI BOR scale had the greatest number of correlations and was associated with 8 life-event variables. In contrast, the PAI ANX and MAN scales had no correlations above a predetermined threshold (r ≥ .21). These findings add to the growing body of empirical correlates of the PAI and generally provide support for the construct validity of the PAI scales.

The goal of this investigation was the development of an inconsistency scale (ICN-SF) for the personality assessment inventory-short form (PAI-SF). In Study 1, 503 inpatient profiles were randomly assigned to a derivation or cross-validation sample. Ten correlated item pairs were identified using the derivation sample and placed on the ICN-SF. Psychometric properties of the ICN-SF total scores were comparable in the derivation and cross-validation samples. Total ICN-SF scores in both samples were significantly lower than scores obtained from computer-generated random samples. Diagnostic efficiency statistics are reported using multiple cut-off scores at various base rate estimates. ICN-SF scores greater than 8 reasonably balanced sensitivity and specificity rates. This cutoff correctly classified 92% of the random protocols and inaccurately classified 9% of the patient protocols in study 1. In study 2, PAI-SF scores from 627 forensic and civil inpatients produced similar results, effectively identifying cases with elevated scores on the full-form inconsistency scale. Overall the results of both studies suggest that the ICN-SF can aid examiners in assessing for inconsistent responding.

Objectives: To further our understanding of social functioning in children with chronic pain, and particularly how social functioning relates to school impairment in this population., Methods: This study involved 126 adolescents (12 to 17 y) evaluated at a multidisciplinary pain clinic. Adolescents completed measures assessing social functioning, pain, physical limitations, somatic symptoms, and school impairment., Results: Lower social functioning scores were significantly associated with pain, physical limitations, somatic symptoms, and school impairment. Social functioning mediated the relations between adolescents' pain experience (ie, pain, physical symptoms, physical limitations) and school impairment., Discussions: These findings highlight the importance of assessing and addressing social functioning in youth with chronic pain. Future research targeting school impairment should include evaluating the potential role that peer difficulties may play.