A Panel-Based Mutational Signature of Mismatch Repair Deficiency is Associated With Durable Response to Pembrolizumab in Metastatic Castration-Resistant Prostate Cancer.

INTRODUCTION/BACKGROUND: Immune checkpoint inhibitors (ICIs) have limited efficacy in prostate cancer (PCa). Better biomarkers are needed to predict responses to ICIs. We sought to demonstrate that a panel-based mutational signature identifies mismatch repair (MMR) deficient (MMRd) PCa and is a biomarker of response to pembrolizumab. PATIENTS AND METHODS: Clinico-genomic data was obtained for 2664 patients with PCa sequenced at Dana-Farber Cancer Institute (DFCI) and Memorial Sloan Kettering (MSK). Clinical outcomes were collected for patients with metastatic castration-resistant PCa (mCRPC) treated with pembrolizumab at DFCI. SigMA was used to characterize tumors as MMRd or MMR proficient (MMRp). The concordance between MMRd with microsatellite instability (MSI-H) was assessed. Radiographic progression-free survival (rPFS) and overall survival (OS) were collected for patients treated with pembrolizumab. Event-time distributions were estimated using Kaplan-Meier methodology. RESULTS: Across both cohorts, 100% (DFCI: 12/12; MSK: 43/43) of MSI-H tumors were MMRd. However, 14% (2/14) and 9.1% (6/66) of MMRd tumors in the DFCI and MSK cohorts respectively were microsatellite stable (MSS), and 26% (17/66) were MSI-indeterminate in the MSK cohort. Among patients treated with pembrolizumab, those with MMRd (n = 5) versus MMRp (n = 14) mCRPC experienced markedly improved rPFS (HR = 0.088, 95% CI: 0.011-0.70; P = .0064) and OS (HR = 0.11, 95% CI: 0.014-0.80; P = .010) from start of treatment. Four patients with MMRd experienced remissions of >= 2.5 years. CONCLUSION: SigMA detects additional cases of MMRd as compared to MSI testing in PCa and identifies patients likely to experience durable response to pembrolizumab.

Child-focused infant and early childhood mental health consultation: Shifting adult attributions to reduce the risk for preschool expulsion.

Infant and early childhood mental health consultation (IECMHC) in early care and education (ECE) settings is a promising approach to support young children. Although research on the effects of IECMHC is encouraging, it is limited by the complexities of the systems in which IECMHC is implemented and the variability in IECMHC models. The current study aims to clearly articulate a statewide, child-focused, short-term IECMHC model, assess consultee satisfaction, examine the effects of consultation on children's functioning in the school and home settings, and evaluate changes in teacher perceptions associated with expulsion risk following consultation. In total, 268 children ages 1-5 (69% White, 75% male) and their family and school caregivers participated in consultation in a New England state, and 95 children and caregivers were included in an evaluation subsample. Of this subsample, teachers and ECE administrators, but not families, indicated significant improvement in children's functioning from referral to end of consultation. There was also a significant decrease in children's risk of expulsion, as measured by teachers' perceptions associated with expulsion decisions. This study contributes to the IECMHC literature by providing results specific to a child-focused model of consultation and highlighting the possible role of adult attributions for children in ECE.

La consulta de salud mental infantil y la temprana niñez (IECMHC) en los entornos de cuidados y educación tempranos (ECE) es un acercamiento prometedor para apoyar a los niños pequeños. A pesar de que la investigación sobre los efectos de IECMHC es alentadora, está limitada por las complejidades de los sistemas dentro de los cuales se implementa IECMHC y la variabilidad en los modelos de IECMHC. El presente estudio se propone articular claramente un modelo de IECMHC para todo el estado, con enfoque en el niño y a corto plazo, evaluar la satisfacción que quienes participan de la consulta, examinar los efectos de la consulta sobre el funcionamiento de los niños en la escuela y en el entorno del hogar, así como evaluar los cambios en las percepciones de los maestros asociadas con los riesgos de expulsión después de la consulta. En total, 268 niños de edad 1­5 (69% blancos, 75% varones) y sus familias y quienes les cuidaba en la escuela participaron en la consulta en un estado de Nueva Inglaterra, y se incluyó a 95 niños y sus cuidadores en una evaluación de un subgrupo muestra. De este subgrupo muestra, los maestros y los administradores de ECE, pero no las familias, indicaron significativas mejorías en el funcionamiento de los niños desde la referencia hasta el final de la consulta. Se dio también una significativa disminución en el riesgo de expulsión de los niños, tal como se midió por medio de las percepciones de los maestros asociadas con las decisiones de expulsión. Este estudio contribuye a la literatura informativa sobre IECMHC por medio de ofrecer resultados específicos al modelo de consulta enfocado en el niño y subrayar el posible papel de las atribuciones del adulto para los niños en ECE.

La consultation de santé mentale du nourrisson et de la petite enfance (Infant and early childhood mental health consultation abrégé en anglais IECMHC) dans des contextes éducatifs et de crèches (abrégé ici CEC selon le français) est une approche prometteuse pour le soutien aux jeunes enfants. Bien que les recherches sur les effets de l'IECMHC sont encourageantes, elles sont limitées par les complexités des systèmes dans lesquels l'IECMHC est mise en oeuvre et la variabilité des modèles de l'IECMHC. Cette étude s'est donné pour but de clairement articuler un modèle IECMHC au niveau de l'état, focalisé sur l'enfant et à court terme, d'évaluer la satisfaction de la personne consultée, d'examiner les effets de la consultation sur le fonctionnement des enfants à l'école et à la maison, et d'évaluer les changements dans les perceptions de l'enseignant liée au risque d'expulsion après la consultation. En tout 268 enfants âgés de 1­5 ans (69% blancs, 75% garçons) et leur famille et les personnes prenant soin d'eux à l'école ont participé à une consultation dans un état de nous Nouvelle Angleterre (aux Etats­Unis), et 95 enfants et personnes prenant soin d'eux ont été inclus dans un sous­échantillon d'évaluation. Dans ce sous­échantillon les enseignants et administrateurs CEC, mais pas les familles, ont fait état d'une amélioration important dans le fonctionnement des enfants du moment de la référence à la fin de la consultation. Il n'a pas de baisse importante du risque d'expulsion des enfants, mesurée par les perceptions des enseignants liées aux décisions d'expulsion. Cette étude contribue aux recherches sur l'IECMHC en offrant des résultats spécifiques à un modèle de consultation focalisé sur l'enfant et en mettant en lumière le rôle possible des attributions adultes pour les enfants dans les CEC.

Pretest Video Education Versus Genetic Counseling for Patients With Prostate Cancer: ProGen, A Multisite Randomized Controlled Trial.

PURPOSE: Germline genetic testing (GT) is recommended for men with prostate cancer (PC), but testing through traditional models is limited. The ProGen study examined a novel model aimed at providing access to GT while promoting education and informed consent. METHODS: Men with potentially lethal PC (metastatic, localized with a Gleason score of ≥8, persistent prostate-specific antigen after local therapy), diagnosis age ≤55 years, previous malignancy, and family history suggestive of a pathogenic variant (PV) and/or at oncologist's discretion were randomly assigned 3:1 to video education (VE) or in-person genetic counseling (GC). Participants had 67 genes analyzed (Ambry), with results disclosed via telephone by a genetic counselor. Outcomes included GT consent, GT completion, PV prevalence, and survey measures of satisfaction, psychological impact, genetics knowledge, and family communication. Two-sided Fisher's exact tests were used for between-arm comparisons. RESULTS: Over a 2-year period, 662 participants at three sites were randomly assigned and pretest VE (n = 498) or GC (n = 164) was completed by 604 participants (VE, 93.1%; GC, 88.8%), of whom 596 participants (VE, 98.9%; GC, 97.9%) consented to GT and 591 participants completed GT (VE, 99.3%; GC, 98.6%). These differences were not statistically significant although subtle differences in satisfaction and psychological impact were. Notably, 84 PVs were identified in 78 participants (13.2%), with BRCA1/2 PV comprising 32% of participants with a positive result (BRCA2 n = 21, BRCA1 n = 4). CONCLUSION: Both VE and traditional GC yielded high GT uptake without significant differences in outcome measures of completion, GT uptake, genetics knowledge, and family communication. The increased demand for GT with limited genetics resources supports consideration of pretest VE for patients with PC.

Reflective supervision and consultation and its impact within early childhood-serving programs: A systematic review.

Reflective supervision and consultation (RS/C) is regarded as best practice within the infant/early childhood mental health field. Benefits of RS/C on the early childhood workforce and children and families have been demonstrated through case studies, conceptual pieces, and individual research studies. However, findings across studies have not been summarized using gold-standard methodology, thus the state of existing empirical support for RS/C is unclear. This systematic review examined the collective evidence for RS/C across diverse early childhood-serving programs. Electronic databases were searched to identify studies investigating associations between RS/C and professionals' reflective capacity and well-being, child/family outcomes, and implementation factors. Twenty-eight papers were identified. Studies showed positive associations between RS/C and early childhood-serving professionals' reflective capacity and well-being, with qualitative studies reporting more consistent results than studies using quantitative methods. Many methodological limitations were identified, including incomplete reporting of study designs and participant characteristics, variability in outcome measures, and lack of randomization and comparison groups. Furthermore, few studies examined child and family outcomes. Therefore, while RS/C shows great promise, it was difficult to ascertain its overall effectiveness from an empirical standpoint. Establishing RS/C as an empirically supported approach will be possible with more rigorous research.

A la consulta y supervisión con reflexión (RS/C) se le considera como práctica óptima dentro del campo de la salud mental infantil y la temprana niñez. Los beneficios de RS/C en la fuerza laboral de la temprana niñez, así como en niños y familias, han quedado demostrados a través de estudios de casos, componentes conceptuales y estudios individuales de investigación. Sin embargo, los resultados en la gama de estudios no han sido resumidos usando una metodología arquetípica; por tanto, el estado del apoyo empírico existente para RS/C no está claro. Esta sistemática revisión examinó la evidencia colectiva de RS/C a lo largo de los diversos programas que se dedican a la temprana niñez. Se investigaron bancos electrónicos de datos para identificar estudios que investigaron las asociaciones entre RS/C y la capacidad de reflexión y bienestar de profesionales, los resultados en niño y familia, así como los factores de implementación. Se identificaron veintiocho artículos. Los estudios mostraron asociaciones positivas entre RS/C y la capacidad de reflexión y bienestar de profesionales que prestan servicios en al campo de la temprana niñez, con estudios cualitativos que reportaron resultados más consistentes que los estudios que usaron métodos cuantitativos. Se identificaron muchas limitaciones metodológicas, incluyendo un incompleto reporte de los diseños del estudio y las características de los participantes, la variabilidad en las medidas para los resultados, así como una falta de aleatorización y grupos de comparación. Es más, pocos estudios examinaron los resultados en el niño y la familia. Por tanto, mientras que RS/C muestra gran promesa, fue difícil cerciorarse de su efectividad en términos generales desde un punto de vista empírico. Establecer RS/C como un acercamiento empíricamente apoyado será posible con una investigación más rigurosa.

La supervision et la conversation par réflexion (RS/C) est considérée comme étant la meilleure pratique dans le domaine de la santé mentale du nourrisson et de la petite enfance. Les bénéfices de la RS/C sur les effectifs de la petite enfance et les enfants et leurs familles ont été prouvés au travers d'études de cas, de travaux conceptuels et d'études individuelles de recherche. Cependant les résultats au travers des études n'ont pas été résumés au moyen d'une méthodologie de référence et par conséquent l'état du soutien empirique existent pour le RS/C n'est pas clair. Cette revue systématique a examiné les preuves collectives de la RS/C au travers de divers programmes servant la petite enfance. Les bases de données électroniques ont été utilisées afin d'identifier des études se penchant sur les liens entre la RS/C et la capacité de réflexion des professionnels ainsi que leur bien-être, les résultats pour l'enfant/la famille et les facteurs de mise en place. Vingt-huit études ont été identifiées. Les études ont démontré des liens positifs entre la RS/C et la capacité de réflexion et le bien-être de professionnels de la petite enfance, avec des études qualitatives faisant état de résultats plus constants que les études utilisant des méthodes quantitatives. Plusieurs limitations méthodologiques ont été identifiées, y compris le fait de rapporter de manière incomplète les méthodologies des études et les caractéristiques des participants, la variabilité des mesures des résultats, et le manque de de groupes de randomisation et de contrôle. De plus, peu d'études ont examiné les résultats de l'enfant et de la famille. En conclusion, bien que la RS/C soit promettante, il était difficile de vérifier son efficacité générale d'un point de vue empirique. L'établissement de la RS/C en tant qu'approche soutenue empiriquement sera possible avec des recherches plus rigoureuses.

Addition of Germline Testing to Tumor-Only Sequencing Improves Detection of Pathogenic Germline Variants in Men With Advanced Prostate Cancer.

PURPOSE: Guidelines recommend somatic and germline testing for men with advanced prostate cancer (PCa). Barriers to widespread implementation result in underutilization of germline testing. Somatic testing alone risks missing pathogenic germline variants (PGVs). We sought to determine whether the addition of germline testing to tumor-only sequencing improves detection of PGVs in men with advanced PCa. Secondarily, we sought to define the added value of combining somatic and germline testing to optimize detection of clinically actionable alterations. PATIENTS AND METHODS: We analyzed results of independent germline testing and tumor-only sequencing from 100 men with advanced PCa from a prospective clinical trial (ClinicalTrials.gov identifier: NCT03328091). The primary outcome was the proportion of PGVs not reported with tumor-only sequencing. The secondary outcome was the association of locus-specific loss of heterozygosity for PGVs in homologous recombination genes with clinical-genomic features. RESULTS: In the 100 men who underwent germline testing and tumor-only sequencing, 24 PGVs were identified, 17 of which were clinically actionable, in 23 patients. Tumor-only sequencing failed to report four (17%) of the PGVs. One additional PGV (4.2%) had variant allele frequency on tumor-sequencing below the threshold for follow-up germline testing. When integrating tumor-only sequencing with germling testing results, 33% of patients harbored clinically actionable alterations. Rates of locus-specific loss of heterozygosity were higher for BRCA2 PGVs in castration-resistant PCa than PGVs in other homologous recombination genes in hormone-sensitive PCa (P = .029). CONCLUSION: Tumor-only sequencing failed to report more than 20% of PGVs in men with advanced PCa. These findings strongly support guideline recommendations for universal germline and somatic testing in this population. Combining tumor and germline sequencing doubled the chance of detecting a clinically actionable alteration.

Modeling Androgen Deprivation Therapy-Induced Prostate Cancer Dormancy and Its Clinical Implications.

Treatment-induced tumor dormancy is a state in cancer progression where residual disease is present but remains asymptomatic. Dormant cancer cells are treatment-resistant and responsible for cancer recurrence and metastasis. Prostate cancer treated with androgen-deprivation therapy (ADT) often enters a dormant state. ADT-induced prostate cancer dormancy remains poorly understood due to the challenge in acquiring clinical dormant prostate cancer cells and the lack of representative models. In this study, we aimed to develop clinically relevant models for studying ADT-induced prostate cancer dormancy. Dormant prostate cancer models were established by castrating mice bearing patient-derived xenografts (PDX) of hormonal naïve or sensitive prostate cancer. Dormancy status and tumor relapse were monitored and evaluated. Paired pre- and postcastration (dormant) PDX tissues were subjected to morphologic and transcriptome profiling analyses. As a result, we established eleven ADT-induced dormant prostate cancer models that closely mimicked the clinical courses of ADT-treated prostate cancer. We identified two ADT-induced dormancy subtypes that differed in morphology, gene expression, and relapse rates. We discovered transcriptomic differences in precastration PDXs that predisposed the dormancy response to ADT. We further developed a dormancy subtype-based, predisposed gene signature that was significantly associated with ADT response in hormonal naïve prostate cancer and clinical outcome in castration-resistant prostate cancer treated with ADT or androgen-receptor pathway inhibitors. IMPLICATIONS: We have established highly clinically relevant PDXs of ADT-induced dormant prostate cancer and identified two dormancy subtypes, leading to the development of a novel predicative gene signature that allows robust risk stratification of patients with prostate cancer to ADT or androgen-receptor pathway inhibitors.

Prospective Evaluation of Clinical Outcomes Using a Multiplex Liquid Biopsy Targeting Diverse Resistance Mechanisms in Metastatic Prostate Cancer.

PURPOSE: Nearly all men with prostate cancer treated with androgen receptor (AR) signaling inhibitors (ARSIs) develop resistance via diverse mechanisms including constitutive activation of the AR pathway, driven by AR genomic structural alterations, expression of AR splice variants (AR-Vs), or loss of AR dependence and lineage plasticity termed neuroendocrine prostate cancer. Understanding these de novo acquired ARSI resistance mechanisms is critical for optimizing therapy. MATERIALS AND METHODS: A novel liquid biopsy technology was used to collect mRNA from circulating tumor cells (CTCs) to measure expression of AR-Vs, AR targets, and neuroendocrine prostate cancer markers. An institutional review board-approved prospective cohort (N = 99) was used to identify patterns of gene expression. Two prospective multicenter phase II clinical trials of ARSIs for men with castration-resistant prostate cancer (ClinicalTrials.gov: NCT01942837 [enzalutamide, N = 21] and NCT02025010 [abiraterone, N = 27]) were used to further validate these findings. RESULTS: Hierarchical clustering of CTC transcripts identified two distinct clusters. Cluster 2 (C2) exhibited increased expression of AR-regulated genes and was associated with worse overall survival (median 8.6 v 22.4 months; P < .01; hazard ratio [HR] = 3.45 [1.9 to 6.14]). In multivariable analysis, C2 was prognostic independent of other clinicopathologic variables. AR-V status was not significant when accounting for C2. Upon further validation in pooled multicenter phase II trials, C2 was associated with worse overall survival (15.2 months v not reached; P < .01; HR = 8.43 [2.74 to 25.92]), prostate-specific antigen progression-free survival (3.6 v 12 months; P < .01; HR = 4.64 [1.53 to 14.11]), and radiographic progression-free survival (2.7 v 40.6 months; P < .01; HR = 4.64 [1.82 to 17.41]). CONCLUSION: We demonstrate that a transcriptional profile detectable in CTCs obtained from liquid biopsies can serve as an independent prognostic marker beyond AR-V7 in patients with metastatic prostate cancer and can be used to identify the emergence of multiple ARSI resistance mechanisms. This is currently being investigated in additional prospective trials.

Impact of Pathogenic Germline DNA Damage Repair alterations on Response to Intense Neoadjuvant Androgen Deprivation Therapy in High-risk Localized Prostate Cancer.

BACKGROUND: Intense neoadjuvant androgen deprivation therapy (ADT) before radical prostatectomy (RP) is an investigational approach to reduce recurrence rates in men with high-risk localized prostate cancer (PCa). The impact of germline DNA damage repair (gDDR) gene alterations on response to intense neoadjuvant ADT is not known. OBJECTIVE: To evaluate the prevalence of gDDR alterations among men with localized PCa at high risk of recurrence and evaluate their impact on response to intense neoadjuvant ADT. DESIGN, SETTING, AND PARTICIPANTS: We performed germline panel sequencing for 201 men with intermediate- and high-risk localized PCa from five randomized multicenter clinical trials of intense neoadjuvant ADT before RP. INTERVENTION: Intense neoadjuvant ADT followed by RP. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The prevalence of pathogenic gDDR alterations and their association with exceptional pathologic response (complete response or minimal residual disease, defined as residual tumor with the largest cross-section dimension ≤5 mm) to intense neoadjuvant ADT and rates of post-RP biochemical recurrence. RESULTS AND LIMITATIONS: Pathogenic gDDR alterations were detected in 19 (9.5%) of the 201 PCa patients. The most frequently altered genes were BRCA2 (n = 6; 3.0%) and ATM (n = 4; 2.0%). Patients with gDDR alterations exhibited similar rates of exceptional pathologic response (26% vs 22%), pT3 disease (42% vs 53%), lymph node involvement (5.3% vs 10%), extraprostatic extension (35% vs 54%), and positive margins (5.3% vs 13%) to patients without gDDR alterations (all p > 0.05). The 3-yr biochemical recurrence-free survival was also similar at 45% (95% confidence interval 7.9-78%) for men with gDDR alterations and 55% (95% confidence interval 44-64%) for men without gDDR alterations. CONCLUSIONS: gDDR alterations are common among men with intermediate- and high-risk localized PCa. Men with gDDR alterations appear to have a comparable response to intense neoadjuvant ADT to that among men without gDDR alterations and should not be excluded from consideration for this treatment approach. PATIENT SUMMARY: Intense therapy to inhibit the production of androgen hormones (eg, testosterone) before surgery may minimize the risk of cancer recurrence for men with high-risk localized prostate cancer. Inherited mutations in certain DNA repair genes are associated with particularly high rates of recurrence. We found that men with these mutations respond equally well to this intense androgen inhibition before surgery as men without the mutations.

Transcriptional mediators of treatment resistance in lethal prostate cancer.

Metastatic castration-resistant prostate cancer is typically lethal, exhibiting intrinsic or acquired resistance to second-generation androgen-targeting therapies and minimal response to immune checkpoint inhibitors1. Cellular programs driving resistance in both cancer and immune cells remain poorly understood. We present single-cell transcriptomes from 14 patients with advanced prostate cancer, spanning all common metastatic sites. Irrespective of treatment exposure, adenocarcinoma cells pervasively coexpressed multiple androgen receptor isoforms, including truncated isoforms hypothesized to mediate resistance to androgen-targeting therapies2,3. Resistance to enzalutamide was associated with cancer cell-intrinsic epithelial-mesenchymal transition and transforming growth factor-ß signaling. Small cell carcinoma cells exhibited divergent expression programs driven by transcriptional regulators promoting lineage plasticity and HOXB5, HOXB6 and NR1D2 (refs. 4-6). Additionally, a subset of patients had high expression of dysfunction markers on cytotoxic CD8+ T cells undergoing clonal expansion following enzalutamide treatment. Collectively, the transcriptional characterization of cancer and immune cells from human metastatic castration-resistant prostate cancer provides a basis for the development of therapeutic approaches complementing androgen signaling inhibition.

Outcomes of Post-Neoadjuvant Intense Hormone Therapy and Surgery for High Risk Localized Prostate Cancer: Results of a Pooled Analysis of Contemporary Clinical Trials.

PURPOSE: We report on the post-radical prostatectomy outcomes of patients enrolled in 3 randomized, multicenter, clinical trials of intense neoadjuvant androgen deprivation therapy prior radical prostatectomy. MATERIALS AND METHODS: All patients included were enrolled in trials evaluating intense androgen deprivation therapy followed by radical prostatectomy. The primary end point was time to biochemical recurrence, defined as the time from radical prostatectomy to prostate specific antigen >0.1 ng/ml or start of first post-radical prostatectomy therapy, stratified by pathological response at radical prostatectomy (presence or absence of exceptional pathological response defined as residual tumor at radical prostatectomy measuring 0-5 mm). Secondary end points included metastasis-free survival, overall survival, and time to testosterone recovery. RESULTS: Overall, 117 patients were included in the analysis, of whom 78.6% (92) had high risk disease. Following neoadjuvant therapy, 21.4% (25) had 0-5 mm of residual tumor, including 9.4% (11) with a pathological complete response. Overall, 49 patients (41.9%) experienced biochemical recurrence and the 3-year biochemical recurrence-free rate was 59.1% (95% CI 49.0-67.9). Of the 25 patients with an exceptional pathological response, 2 patients (8.0%) developed biochemical recurrence while 51.1% of nonresponders (47/92) developed biochemical recurrence. Testosterone recovery was observed in 93.8% of patients (106/113). PTEN loss and intraductal carcinoma were associated with shorter time to biochemical recurrence. CONCLUSIONS: In this pooled analysis of prospective trials, we demonstrate that exceptional pathological response following neoadjuvant therapy is associated with a favorable impact on biochemical recurrence. PTEN loss and intraductal carcinoma were associated with biochemical recurrence. Additional followup is warranted to evaluate the impact on long-term outcomes.

Treatment of metastatic castration resistant prostate cancer with radium-223: a retrospective study at a US tertiary oncology center.

BACKGROUND: Guidelines for optimal sequencing of radium-223 and chemotherapy for metastatic castration resistant prostate cancer (mCRPC) do not exist. This study evaluated treatment patterns and overall survival (OS) among patients with mCRPC treated with radium-223 in an academic clinical setting. METHODS: A retrospective study was conducted of bone metastases-predominant mCRPC patients treated with radium-223. Treatment patterns from 2013 to 2018 were evaluated in patients treated with radium-223 pre- vs. post-chemotherapy. OS was examined using Kaplan-Meier medians and 95% confidence intervals. RESULTS: In total, 220 patients were treated with radium-223 (64 pre-chemotherapy, 83 post-chemotherapy, 73 no chemotherapy). Mean radium-223 injections per patient was 5.3 and 4.3 in the pre- vs. post-chemotherapy cohorts, respectively (p < 0.001). The number of chemotherapy cycles was similar for chemotherapy given pre- or post-radium-223. Mean line of mCRPC therapy of radium-223 was 3rd and 5th when given pre- and post-chemotherapy, respectively (p < 0.001). 41.8% patients were treated with radium-223 in combination with another mCRPC therapy, commonly abiraterone acetate (43.5%) or enzalutamide (52.2%). The majority received combination therapy for the duration of radium-223 treatment; 20.7% started another agent after radium-223 initiation; 20.7% initiated radium-223 while on established therapy. Median OS from first mCRPC treatment was 39.4 months (95% CI 33.0, 48.8) for patients with radium-223 pre-chemotherapy vs. 37.4 months (95% CI 32.0, 43.5) post-chemotherapy (and 35.2 months [95% CI 27.9, 43.3] vs. 32.0 months [95% CI 26.9, 36.0] for patients with radium-223 combination vs. monotherapy). CONCLUSIONS: This retrospective analysis of patients treated with radium-223 demonstrates that administration of radium-223 pre-chemotherapy increased likelihood of completion of radium-223 treatment. Radium-223 given pre- or post-chemotherapy and with or without combination therapy did not result in significant differences in OS. Additional studies are needed to determine the optimal sequencing strategy of mCRPC in the modern era.

Transposon Mutagenesis Screen of Klebsiella pneumoniae Identifies Multiple Genes Important for Resisting Antimicrobial Activities of Neutrophils in Mice.

Klebsiella pneumoniae is a Gram-negative bacterial pathogen that causes a range of infections, including pneumonias, urinary tract infections, and septicemia, in otherwise healthy and immunocompromised patients. K. pneumoniae has become an increasing concern due to the rise and spread of antibiotic-resistant and hypervirulent strains. However, its virulence determinants remain understudied. To identify novel K. pneumoniae virulence factors needed to cause pneumonia, a high-throughput screen was performed with an arrayed library of over 13,000 K. pneumoniae transposon insertion mutants in the lungs of wild-type (WT) and neutropenic mice using transposon sequencing (Tn-seq). Insertions in 166 genes resulted in K. pneumoniae mutants that were significantly less fit in the lungs of WT mice than in those of neutropenic mice. Of these, mutants with insertions in 51 genes still had significant defects in neutropenic mice, while mutants with insertions in 52 genes recovered significantly. In vitro screens using a minilibrary of K. pneumoniae transposon mutants identified putative functions for a subset of these genes, including in capsule content and resistance to reactive oxygen and nitrogen species. Lung infections in mice confirmed roles in K. pneumoniae virulence for the ΔdedA, ΔdsbC, ΔgntR, Δwzm-wzt, ΔyaaA, and ΔycgE mutants, all of which were defective in either capsule content or growth in reactive oxygen or nitrogen species. The fitness of the ΔdedA, ΔdsbC, ΔgntR, ΔyaaA, and ΔycgE mutants was higher in neutropenic mouse lungs, indicating that these genes encode proteins that protect K. pneumoniae against neutrophil-related effector functions.

Amino Acid Biosynthetic Pathways Are Required for Klebsiella pneumoniae Growth in Immunocompromised Lungs and Are Druggable Targets during Infection.

The emergence of multidrug-resistant Klebsiella pneumoniae has rendered a large array of infections difficult to treat. In a high-throughput genetic screen of factors required for K. pneumoniae survival in the lung, amino acid biosynthesis genes were critical for infection in both immunosuppressed and wild-type (WT) mice. The limited pool of amino acids in the lung did not change during infection and was insufficient for K. pneumoniae to overcome attenuating mutations in aroA, hisA, leuA, leuB, serA, serB, trpE, and tyrA in WT and immunosuppressed mice. Deletion of aroA, which encodes 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase class I, resulted in the most severe attenuation. Treatment with the EPSP synthase-specific competitive inhibitor glyphosate decreased K. pneumoniae growth in the lungs. K. pneumoniae expressing two previously identified glyphosate-resistant mutations in EPSP synthase had significant colonization defects in lung infection. Selection and characterization of six spontaneously glyphosate-resistant mutants in K. pneumoniae yielded no mutations in aroA Strikingly, glyphosate treatment of mice lowered the bacterial burden of two of three spontaneous glyphosate-resistant mutants and further lowered the burden of the less-attenuated EPSP synthase catalytic mutant. Of 39 clinical isolate strains, 9 were resistant to glyphosate at levels comparable to those of selected resistant strains, and none appeared to be more highly resistant. These findings demonstrate amino acid biosynthetic pathways essential for K. pneumoniae infection are promising novel therapeutic targets.

MEASURING REFLECTIVE SUPERVISION WITHIN HOME VISITING: CHANGES IN SUPERVISORS' SELF-PERCEPTION OVER TIME.

Despite widespread belief in the early childhood field of the benefits of reflective supervision, there has been limited empirical evidence to support the effectiveness of reflective supervision for home visitors and the children and families they serve. The present study examined the psychometric properties of four adapted self-report measures assessing supervisors' reflective supervision capacities; the study also investigated whether these measures captured change in reflective capacity over time as supervisors participated in professional development activities focused on reflective supervision. Results from 33 participants (home visiting supervisors and program managers) suggested that three of the four measures demonstrated acceptable internal consistency, and these three measures were correlated with each other. Two of these measures also captured significant change over time. Finally, there was some evidence that those with less education demonstrated more substantial improvement in their reflective supervision capacities than did those with an advanced degree. Findings provide initial evidence for reliable, efficient, and cost-effective supervisor self-report measures that could be used in research and program evaluation to assess change in supervisor reflective capacity over time.

Mental health screening and consultation in primary care: The role of child age and parental concerns [corrected].

OBJECTIVE: To determine (1) how child age relates to parent concerns about child behavior and (2) how child age and parent concerns correlate with provider referrals and family attendance at mental health consultant (MHC) appointments. METHODS: Data were obtained from Rhode Island's Project, Linking Actions for Unmet Needs in Children's Health, in which universal developmental and behavioral screening and MHCs were embedded within primary care sites serving low-income diverse families. Children 9 months to 8 years of age were eligible for the study if they had a scheduled screening well-child visit in 2010 (N = 1451). Families completing screening and/or those referred for a MHC appointment were included in analyses (n = 700). Outcome measures included parent-reported concerns about child behavior, referral status following screening, and family attendance at the MHC appointment. RESULTS: For every 1-month increase in child age, there was a 1.02 times increase in the likelihood of parent behavioral concern and a 1.04 times increase in the likelihood of mental health referral, even when controlling for child behavior. MHC-referred children older than 5 years were 2.61 times more likely to attend than children less than 5 years. When examining parent behavioral concerns and child age jointly, only concerns remained significant. CONCLUSIONS: Infants and toddlers, who have the highest rates of unmet mental health needs, may be least likely to benefit from universal screening and on-site MHC support. Efforts to incorporate behaviorally based screening tools and increase parent concerns where appropriate appear warranted, particularly for families with very young children.

Expressive writing in people with traumatic brain injury and learning disability.

BACKGROUND: There is a dearth of systematic studies of expressive writing disorder (EWD) in persons with Traumatic Brain Injury (TBI). It is unclear if TBI survivors' written expression differs significantly from that experienced by persons with learning disabilities. It is also unclear which cognitive or neuropsychological variables predict problems with expressive writing (EW) or the EWD. OBJECTIVE: This study investigated the EW skill, and the EWD in adults with mild traumatic brain injuries (TBI) relative to those with learning disabilities (LD). It also determined which of several cognitive variables predicted EW and EWD. METHODS: Principle Component Analysis (PCA) of writing samples from 28 LD participants and 28 TBI survivors revealed four components of expressive writing skills: Reading Ease, Sentence Fluency, Grammar and Spelling, and Paragraph Fluency. RESULTS: There were no significant differences between the LD and TBI groups on any of the expressive writing components. Several neuropsychological variables predicted skills of written expression. The best predictors included measures of spatial perception, verbal IQ, working memory, and visual memory. CONCLUSIONS: TBI survivors and persons with LD do not differ markedly in terms of expressive writing skill. Measures of spatial perception, visual memory, verbal intelligence, and working memory predict writing skill in both groups. Several therapeutic interventions are suggested that are specifically designed to improve deficits in expressive writing skills in individuals with TBI and LD.

Embedding the Family Check Up and Evidence-Based Parenting Programs in Head Start to Increase Parent Engagement and Reduce Conduct Problems in Young Children.

Parent engagement (i.e., enrollment, ongoing attendance, participation quality) remains a major obstacle to fully realizing the benefits of evidence-based preventive parent management training in community settings. We describe an approach to parent engagement that addresses the myriad motivational, cognitive, and pragmatic barriers parents face by embedding services in Head Start and applying a parent engagement model, the Family Check Up, as a pre-intervention to augment parent training. In this article, we present the rationale for applying FCU to advance parent readiness for engagement and we describe the process by which we partnered with the community to modify FCU to be most impactful for enhancing parent engagement in one specific program, the Incredible Years Parenting Series. We conclude with preliminary data from our ongoing pilot trial that supports our approach.

Measuring and manipulating subjective organization after traumatic brain injury.

This study presents a method for assessing subjective organization (SO) after brain injury and techniques for planning cognitive rehabilitation therapy based on the survivor's SO ability. Eighty-seven college students, 50 persons with traumatic brain injury (TBI), and 30 participants with specific learning disability (SLD) learned two overlapping lists of unrelated nouns in which half of the second list were words that the person had learned on the first list. The study assessed whether different patterns of recall for the overlapping words versus the new words on the second list would discriminate persons with brain injury relative to college students and persons with SLD. The results indicated that college students and the SLD participants showed significantly diminished recall of overlapping words on the second list. However, the TBI participants showed significantly improved recall of the overlapping words. The results indicated that this task provides a simple diagnostic assessment of a participant's SO ability. The results also suggested that a TBI survivor's level of SO may moderate the success of prevocational cognitive rehabilitation therapies.

The impact of parents, child care providers, teachers, and peers on early externalizing trajectories.

This study utilized growth mixture modeling to examine the impact of parents, child care providers, teachers, and peers on the prediction of distinct developmental patterns of classroom externalizing behavior in elementary school. Among 241 children, three groups were identified. 84.6% of children exhibited consistently low externalizing behavior. The externalizing behavior of the Chronic High group (5.8%) remained elevated throughout elementary school; it increased over time in the Low Increasing group (9.5%). Negative relationships with teachers and peers in the kindergarten classroom increased the odds of having chronically high externalizing behavior. Teacher-child conflict increased the likelihood of a developmental pattern of escalating externalizing behavior. Boys were overrepresented in the behaviorally risky groups, and no sex differences in trajectory types were found.

Validity and reliability of self-monitoring indices.

PRIMARY OBJECTIVE: This research concerns the measurement of self-monitoring in people who were diagnosed with traumatic brain injury (TBI), learning disability (LD) and emotional disorder (ED). Two measures of self-monitoring were evaluated: (1) the correlation between participants' self-predicted and observed standardized sub-test scores (R) on 17 WAIS-III 1 sub-tests and (2) the average difference between the participants' predicted and observed sub-tests scores (B). It was then determined if these measures could discriminate the three diagnostic groups. RESEARCH DESIGN: Canonical analysis assessed the relationship between the self-monitoring measures and four WAIS-III IQ measures. This study also evaluated if the R and B measures could discriminate the diagnostic groups. METHODS AND PROCEDURES: One hundred and twenty-four participants, 42 with TBI, 42 with LD and 40 with ED predicted their performance on 17 WAIS-III sub-tests. MAIN OUTCOMES AND RESULTS: Canonical analysis demonstrated a significant relationship between the R and B measures and four WAIS-III IQ measures. Results of a MANOVA showed that the R and B measures differed significantly among the diagnostic groups. CONCLUSIONS: The R and B measures are two valid and reliable indices of self-monitoring that can be conveniently estimated from the WAIS-III.