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Purpose Mokken scale analysis (MSA) is an attractive scaling procedure for ordinal data. MSA is frequently used in health-related quality of life research. Two of MSA's prime features are the scalability coefficients and the automated item selection procedure (AISP). The AISP partitions a (large) set of items into scales based on the observed item scores; the resulting scales can be used as measurement instruments. There exist two issues in MSA: First, point estimates, standard errors, and test statistics for scalability coefficients are inappropriate for clustered item scores, which are omnipresent in quality of life research data. Second, the AISP insufficiently takes sampling fluctuation of Mokken’s scalability coefficients into account. Methods We solved both issues by providing point estimates and standard errors for the scalability coefficients for clustered data and by implementing a Wald-based significance test in the AISP algorithm, resulting in a test-guided AISP (T-AISP), that is available for both nonclustered and clustered test scores. Results We integrated the T-AISP into a two-step, test-guided MSA for scale construction, to guide the analysis for nonclustered and clustered data. The first step is performing a T-AISP and select the final scale( s ). For clustered data, within-group dependency is investigated on the final scale(s). In the second step, the strength of the scale(s) is determined and further analyses are performed. The procedure was demonstrated on clustered item scores obtained from administering a questionnaire on quality of life in schools to 639 students nested in 30 classrooms. Conclusions We developed a two-step, test-guided MSA for scale construction that takes into account sample fluctuation of all scalability coefficients and that can be applied to item scores obtained by a nonclustered or clustered sampling design.

For the construction of tests and questionnaires that require multiple raters (e.g., a child behaviour checklist completed by both parents) a novel ordinal scaling technique is currently being further developed, called two-level Mokken scale analysis. The technique uses within-rater and between-rater coefficients to assess the scalability of the test. These coefficients are generalizations of Mokken's scalability coefficients. In this paper we derived standard errors for the two-level coefficients and for their ratios. The coefficients, the estimates, the estimated standard errors and the software implementation are discussed and illustrated using a real-data example, and a small-scale simulation study demonstrates the accuracy of the estimates.

Organizations are confronted with a constant need for efficiency, which affects the working atmosphere, often typified by velocity, time pressure, competition, job insecurity, and information overload, which may lead to stress, burnout, work-life disbalance, and lowered work functioning. This study evaluated an 8-week, 1.5 h-per-week group-based standardized mindfulness program (“Finding peace in a frantic world”), applied on-site in a large multinational company. In a naturalistic longitudinal design self-selected employees (n = 150) completed measurements at wait-list, pre-test, post-test, and 2 and 6 months follow-up. Nearly all participants followed at least five out of eight sessions, were highly satisfied with the training (8.3 out 10), and almost 90% intended to continue with mindfulness practices. Primary outcomes were stress and risk for dropout from work. Using multilevel analyses, mean pre-test scores were compared to the other measurement occasions, and the rate of change in the training period (M = 67 days; SD = 12) was compared to the rate of change in the wait-list period (M = 29 days; SD = 8). Direct and long-term positive effects on risk for dropout from work (p p p

Background With few RCTs having compared active treatments for paediatric PTSD, little is known about whether or which baseline (i.e. pre-randomization) variables predict or moderate outcomes in the evaluated treatments. Objective To identify predictors and moderators of paediatric PTSD outcomes for Eye Movement Desensitization and Reprocessing Therapy (EMDR) and Cognitive Behavioural Writing Therapy (CBWT). Method Data were obtained as part of a multi-centre, randomized controlled trial of up to six sessions (up to 45 minutes each) of either EMDR therapy, CBWT, or wait-list, involving 101 youth (aged 8–18 years) with a PTSD diagnosis (full/subthreshold) tied to a single event. The predictive and moderating effects of the child’s baseline sociodemographic and clinical characteristics, and parent’s psychopathology were evaluated using linear mixed models (LMM) from pre- to post-treatment and from pre- to 3- and 12-month follow-ups. Results At post-treatment and 3-month follow-up, youth with an index trauma of sexual abuse, severe symptoms of PTSD, anxiety, depression, more comorbid disorders, negative posttraumatic beliefs, and with a parent with more severe psychopathology fared worse in both treatments. For children with more severe self-reported PTSD symptoms at baseline, the (exploratory) moderator analysis showed that the EMDR group improved more than the CBWT group, with the opposite being true for children and parents with a less severe clinical profile. Conclusions The most consistent finding from the predictor analyses was that parental symptomatology predicted poorer outcomes, suggesting that parents should be assessed, supported and referred for their own treatment where indicated. The effect of the significant moderator variables was time-limited, and given the large response rate (>90%) and brevity (, HIGHLIGHTS Given the time-limited significance of differential treatment effects on outcome, brevity and large effect size for EMDR and cognitive-behavioural writing therapy for paediatric PTSD, future focus should be on enhancing delivery of these treatments, rather than tailoring them.

Background Both the presence of psychological problems and the absence of an employment contract are related to long-term sickness absence, prolonged work disability and unemployment. Studies researching the effectiveness of return-to-work interventions on these non-permanent workers, including unemployed and temporary agency workers and workers with an expired fixed-term contract, are lagging behind. Therefore, a return-to-work intervention called “Brainwork” was developed. The aim of this study was to assess the effectiveness of the ‘Brainwork Intervention’ in reducing the duration of sick leave compared to usual care over a 12-month follow-up. Methods In a multicenter controlled clinical trial, using a quasi-randomization procedure, we compared the Brainwork Intervention (n = 164) to usual care (n = 156). The primary outcome was the duration of sick leave. Secondary outcomes were the duration of sick leave starting from Social Security Agency transfer; the proportion of workers returned to work; the number of hours of paid employment during the follow-up period; the degree of worker participation; the level of psychological complaints; and the self-efficacy for return to work. Protocol adherence (Brainwork Intervention) was considered sufficient when at least three of the five protocol steps were followed. Cox regressions, linear and ordinal regression, and Mixed Model analyses were performed. Results All 320 participants were analyzed. The Brainwork Intervention resulted in a non-significant reduction of the duration of sick leave compared to usual care (269 days versus 296 days; HR = 1.29; 95% CI 0.94–1.76; p = 0.11). For those working (46%) during the 12-month follow-up, the mean number of hours of paid employment was non-significantly higher in the usual care group (682 h versus 493 h; p = 0.053). No significant differences were found for other secondary outcomes. Protocol adherence was 10%. Conclusions The Brainwork Intervention as performed with a low protocol adherence did not result in a significant reduction of the duration of sick leave compared to usual care. It remains unclear what the results would have been if the Brainwork Intervention had been executed according to protocol. Trial registration The Netherlands Trial Register (NTR); NTR3976 (old registration number NTR4190). Registered September 27th 2013.

In the wake of the COVID-19 pandemic, physical distancing behavior turned out to be key to mitigating the virus spread. Therefore, it is crucial that we understand how we can successfully alter our behavior and promote physical distancing. We present a framework to systematically assess the effectiveness of behavioral interventions to stimulate physical distancing. In addition, we demonstrate the feasibility of this framework in a large-scale natural experiment (N = 639) conducted during an art fair. In an experimental design, we varied interventions to evaluate the effect of face masks, walking directions, and immediate feedback on visitors’ contacts. We represent visitors as nodes, and their contacts as links in a contact network. Subsequently, we used network modelling to test for differences in these contact networks. We find no evidence that face masks influence physical distancing, while unidirectional walking directions and buzzer feedback do positively impact physical distancing. This study offers a feasible way to optimize physical distancing interventions through scientific research. As such, the presented framework provides society with the means to directly evaluate interventions, so that policy can be based on evidence rather than conjecture.

Lessons Learned Background Endoglin is an angiogenic receptor expressed on proliferating tumor vessels and renal cell carcinoma (RCC) stem cells that is implicated as a mechanism of resistance to vascular endothelial growth factor receptor (VEGFR) inhibitors. This study evaluated an antiendoglin monoclonal antibody (carotuximab, TRC105) combined with axitinib in patients with advanced or metastatic clear cell renal cell carcinoma (mccRCC) who had progressed following one or more prior VEGF inhibitors. Methods TRAXAR was a multicenter, international randomized 1:1 (stratified by ECOG, 0 vs. 1), phase II study of carotuximab combined with axitinib versus axitinib alone in mccRCC patients who had progressed following one or more prior VEGF inhibitors. The primary endpoint was progression-free survival (PFS) assessed by independent central review (ICR) per RECIST 1.1 Results A total of 150 patients were randomized. The combination therapy resulted in shorter median PFS by RECIST 1.1 than axitinib monotherapy (6.7 vs. 11.4 months). The combination was tolerated similarly to axitinib monotherapy, and there were no treatment related deaths. Exploratory evaluation of pretreatment circulating biomarkers suggested the combination might benefit patients who have low baseline VEGF levels. Conclusion The combination of carotuximab with axitinib did not demonstrate additional efficacy over single agent axitinib in patients with mccRCC who progressed following one or more prior VEGF inhibitor treatment.

We investigated whether early algebra lessons that explicitly aimed to elicit mathematical discussions (shift-problem lessons) invoke more and qualitatively better mathematical discussions and raise students’ mathematical levels more than conventional lessons in a small group setting. A quasi-experimental study (pre- and post-test, control group) was conducted in 6 seventh-grade classes (N = 160). An analysis of the interaction processes of five student groups showed that more mathematical discussions occurred in the shift-problem condition. The quality of the mathematical discussions in the shift-problem condition was better compared to that in the conventional textbook condition, but there is still more room for improvement. A qualitative illustration of two typical mathematical discussions in the shift-problem condition are provided. Although students’ mathematical levels were raised a fair amount in both conditions, no differences between conditions were found. We concluded that shift-problem lessons are powerful for eliciting mathematical discussions in seventh-grade shift-problem early algebra lessons.

Two-level Mokken scale analysis is a generalization of Mokken scale analysis for multi-rater data. The bias of estimated scalability coefficients for two-level Mokken scale analysis, the bias of their estimated standard errors, and the coverage of the confidence intervals has been investigated, under various testing conditions. It was found that the estimated scalability coefficients were unbiased in all tested conditions. For estimating standard errors, the delta method and the cluster bootstrap were compared. The cluster bootstrap structurally underestimated the standard errors of the scalability coefficients, with low coverage values. Except for unequal numbers of raters across subjects and small sets of items, the delta method standard error estimates had negligible bias and good coverage. Post hoc simulations showed that the cluster bootstrap does not correctly reproduce the sampling distribution of the scalability coefficients, and an adapted procedure was suggested. In addition, the delta method standard errors can be slightly improved if the harmonic mean is used for unequal numbers of raters per subject rather than the arithmetic mean.

This study provides an overview of components of teacher identity that are found in quantitative measurement instruments; and reports on the psychometric quality of these measurement instruments. Our search included studies that assessed components of teacher identity published in English-written, peer-reviewed articles between 2000 and 2018. We analyzed a total of 59 components in 20 studies. After we categorized the components on the basis of a substantive analysis, six main domains of teacher identity became apparent: Self-image, Motivation, Commitment, Self-efficacy, Task perception, and Job satisfaction. Whereas the overall psychometric properties of the measurement instruments used in the different studies were acceptable to good, our systematic overview revealed several conceptual and methodological issues that need to be resolved. The results may contribute to the further operationalization of the complex construct of teacher identity.

Additional file 2. Figure Brainwork Intervention.

Additional file 1. Table Brainwork category classification.

This study aimed to design and validate the Teacher Identity Measurement Scale (TIMS) for assessing primary student teachers’ professional identity. Based on identity theory and a systematic review into quantitative instruments of teacher identity, teacher identity was decomposed in four first-order constructs: motivation, self-image, self-efficacy, and task perception. This resulted in a measurement scale consisting of 46 items. The factorial design was examined by administering the TIMS to first- and second-year primary student teachers. In phase 1, involving 17 students, qualitative scale development methods were used to assess the construct validity. In phase 2, its second-order factor structure was tested and confirmed among a sample of 211 students. In phase 3, this structure was cross-validated among a new sample of 419 students. The instrument may contribute to understanding primary student teacher’s professional development and can be used as a tool to support the process of developing a professional teacher identity.

Background TRC105 is an IgG1 endoglin monoclonal antibody that potentiates VEGF inhibitors in preclinical models. We assessed safety, pharmacokinetics, and antitumor activity of TRC105 in combination with axitinib in patients with metastatic renal cell carcinoma (mRCC). Subjects, Materials, and Methods Heavily pretreated mRCC patients were treated with TRC105 weekly (8 mg/kg and then 10 mg/kg) in combination with axitinib (initially at 5 mg b.i.d. and then escalated per patient tolerance to a maximum of 10 mg b.i.d.) until disease progression or unacceptable toxicity using a standard 3 + 3 phase I design. Results Eighteen patients (median number of prior therapies = 3) were treated. TRC105 dose escalation proceeded to 10 mg/kg weekly without dose-limiting toxicity. Adverse event characteristics of each drug were not increased in frequency or severity when the two drugs were administered concurrently. TRC105 and axitinib demonstrated preliminary evidence of activity, including partial responses (PR) by RECIST in 29% of patients, and median progression-free survival (11.3 months). None of the patients with PR had PR to prior first-line treatment. Lower baseline levels of osteopontin and higher baseline levels of TGF-β receptor 3 correlated with overall response rate. Conclusion TRC105 at 8 and 10 mg/kg weekly was well tolerated in combination with axitinib, with encouraging evidence of activity in patients with mRCC. A multicenter, randomized phase II trial of TRC105 and axitinib has recently completed enrollment (NCT01806064). Implications for Practice TRC105 is a monoclonal antibody to endoglin (CD105), a receptor densely expressed on proliferating endothelial cells and also on renal cancer stem cells that is implicated as a mediator of resistance to inhibitors of the VEGF pathway. In this Phase I trial, TRC105 combined safely with axitinib at the recommended single agent doses of each drug in patients with renal cell carcinoma. The combination demonstrated durable activity in a VEGF inhibitor-refractory population and modulated several angiogenic biomarkers. A randomized Phase II trial testing TRC105 in combination with axitinib in clear cell renal cell carcinoma has completed accrual.

Background: Metastatic undifferentiated pleomorphic sarcoma (UPS) and the genetically related myxofibrosarcoma (MFS) are soft tissue sarcoma (STS) subtypes with poor prognoses. While responses to front line chemotherapy can approach 20%, in the 2nd line setting and beyond, efficacy remains limited. Pazopanib, the only approved treatment in the refractory setting has demonstrated an objective response rate (ORR) of 4%. Envafolimab is a single domain PD-L1 antibody administered rapidly by subcutaneous (SQ) injection that is being studied in two additional pivotal trials: MSI-H cancer and biliary tract cancer. The activity of envafolimab is similar to other PD-1 antibodies administered intra-venously. Envafolimab demonstrated a 32% ORR in MSI-H colorectal cancer that failed three approved chemotherapeutics, similar to the ORR of 28% and 33%, with nivolumab and pembrolizumab, respectively. The rationale for the ENVASARC trial is based on the previously reported efficacy of checkpoint inhibition in UPS/MFS. Single agent pembrolizumab demonstrated a 23% ORR, while the combination of nivolumab and ipilimumab demonstrated a 29% ORR in refractory UPS/MFS. Methods: ENVASARC (NCT 04480502) is a pivotal multicenter (at ~25 U.S. centers) open-label, randomized, non-comparative, parallel cohort study of treatment with envafolimab 300 mg every 3 weeks by SQ injection (cohort A; n=80) or envafolimab 300 mg every 3 weeks by SQ injection combined with ipilimumab 1 mg/kg every 3 weeks intra-venously for four doses (cohort B; n=80) in patients with locally advanced, unresectable or metastatic UPS/MFS who have progressed on one or two lines of prior therapy. The primary objective of each of parallel cohort is to demonstrate an ORR with a lower limit of the 95% confidence interval that excludes 5.0% in each cohort. If ≥ 9 responders are observed of the 80 patients enrolled in each cohort, then the lower bound of the 95% confidence interval will exclude 5.0%. Secondary endpoints include duration of response (DOR), PFS and OS. Key inclusion criteria: ≤ 2 prior lines of therapy (neoadjuvant and adjuvant therapy excluded), ECOG ≤ 1. Citation Format: Sandra D'Angelo, Steven Robinson, Joelle Lam, Bonne Adams, James Freddo, Charles P. Theuer, Robert Maki. ENVASARC: A Pivotal Trial of Envafolimab, and Envafolimab in Combination with Ipilimumab, in Patients with Advanced or Metastatic Undifferentiated Pleomorphic Sarcoma or Myxofibrosarcoma who have Progressed on Prior Chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT239.

In common models for dyadic network regression, the density and reciprocity parameters are dependent on each other. Here, the j1 and j2 models are introduced with a density parameter that represents the log odds of a single tie. Consequently, the density and reciprocity parameters are independent and the interpretation of both parameters more straightforward. Estimation procedures and simulation results for these new models are discussed as well as an illustrative example.

This study investigated the long-term effects of a professional development intervention for beginning urban teachers and explored which characteristics and activities in school organisations contributed to the sustainability of these effects. A quasi-experimental study (n = 72) investigated whether the positive effects of the programme were observed one year after the programme ended. Interviews with teachers and principals (n = 19) were used to explore which characteristics and activities in schools contributed to those positive effects. A significant long-term effect of the programme was found on teachers’ competences and professional orientation. An open culture in the schools was experienced as an important factor for the sustainability of the programme’s effects.

This mixed-method study examined the relationship between teachers' inquiry-based work and students' inquiry habit of mind. The study consisted of a survey, followed by a case study. Questionnaire data were collected from 1,104 students and 249 teachers at 31 primary schools. The case study was conducted in two primary schools. The survey data revealed a relationship between teachers' inquiry-based work and students' curiosity. However, no relationship was found between teachers' inquiry-based approach and students' critical thinking habits. The case study results illustrate how teachers' inquiry-based working can be related to students’ curiosity and critical thinking habits.

This research aims to develop and validate an instrument for measuring primary student teachers’ professional identity tensions. Based on dissonance theory, we transformed existing vignettes ( Pillen, Den Brok, & Beijaard, 2013 ) into to a quantitative Professional Identity Tensions Scale (PITS) and added tensions regarding teaching in urban contexts. We examined the psychometric quality of the PITS by administering this scale to primary student teachers from teacher education institutions in urban areas across the Netherlands. Two studies were conducted in the process of validating the PITS. First, items were tested among a sample of 211 students to explore whether they measure underlying constructs of professional identity tensions. Second, retained items were administered to a new sample of 271 students. Confirmatory factor analysis demonstrated a similar factor structure. The final instrument includes 34 items rated on a 5-point Likert scale measuring nine different professional identity tensions. Implications for future research and practice are discussed.

2511 Background: CD73 is implicated in tumor resistance to checkpoint immunotherapy (CPI) and plays a critical role in adenosine-mediated immune suppression. Uliledlimab, a differentiated CD73 antibody, inhibits the adenosine pathway in a non-competitive and unique intra-dimer binding mode. Uliledlimab suppresses tumor growth when combined with a PD-(L)1 inhibitor in multiple pre-clinical models. Methods: This 3+3 dose-escalation phase 1 study (NCT03835949) evaluated safety, tolerability, PK, PD and preliminary efficacy in cancer patients. Uliledlimab was administered intravenously at doses of 5, 10 or 15 mg/kg weekly (QW) or 15 or 20 mg/kg every 3 weeks (Q3W) alone in the first cycle and in combination with atezolizumab (1,200 mg Q3W) starting on week 4. Soluble CD73 in serum and CD73 receptor occupancy (RO) in circulating CD19+ B cells were measured. Expression of PD-L1, CD73 and A2A receptor was analyzed in baseline tumor specimens (n = 14). Tumor responses were assessed by RECIST/iRECIST. Results: As of 17 January 2021, 20 patients with advanced solid tumors were enrolled (M:F 8:12; mean age = 64; median prior regimens = 3 (range 1-9)). Uliledlimab was well-tolerated with no dose limiting toxicity. The most common treatment-related adverse events were first dose infusion related reactions (65%, n = 13) most commonly comprising chills/rigors, nausea, and vomiting (Grade 1 or 2) that resolved in subsequent infusions. PK appears linear at doses ≥ 10 mg/kg and modelling indicated a mean derived effective half-life of ̃19 days. Soluble CD73 was undetectable and complete RO was achieved in all patients after the first dose at ≥ 10 mg/kg. Anti-drug antibody was detected in 3/20 patients (15%). Among 13 efficacy-evaluable patients dosed at ≥ 10 mg/kg, complete response (CR = 1) and partial response (PR = 2) were observed in 3 patients (ORR = 23%) together with 3 stable disease (SD) patients (DCR = 46%). One PD-(L)1 inhibitor naïve patient with clear cell ovarian cancer achieved CR at 10 mg/kg QW and remains on study after 12 months. Two patients with NSCLC dosed at 15 mg/kg QW and 20 mg/kg Q3W, respectively, achieved PR. One patient failed nivolumab and the other received no prior PD-(L)1 inhibitor treatment. CD73 was expressed on 78% (mean) of malignant cells from archival tumor specimens in responders compared to 23% in non-responders. Conclusions: Uliledlimab is safe and well tolerated up to 20 mg/kg Q3W and 15 mg/kg QW. Full saturation of circulating and cell-bound CD73 was achieved at doses ≥ 10 mg/kg. Uliledlimab exhibited evidence of clinical activity in both PD-(L)1 treatment naïve and refractory cancer patients with high archival tumor expression of CD73. The results of this phase 1 study encourage further clinical investigation to evaluate the efficacy of uliledlimab in the treatment of solid tumors. Clinical trial information: NCT03835949.

TPS11581 Background: Metastatic undifferentiated Pleomorphic Sarcoma (UPS) and the genetically related myxofibrosarcoma (MFS) are soft tissue sarcoma (STS) subtypes with poor prognoses. While responses to front line chemotherapy can approach 20%, efficacy remains limited in the 2nd line setting and beyond. Pazopanib, the only approved treatment in the refractory setting, has demonstrated an objective response rate (ORR) of 4%. Envafolimab is a single domain PD-L1 antibody administered rapidly by subcutaneous (SQ) injection that is being studied in two additional pivotal trials: microsatellite instability-high (MSI-H) cancer and biliary tract cancer. The activity of envafolimab appears to be similar to other PD-1 antibodies administered i.v. Envafolimab demonstrated a 32% objective response rate (ORR) in MSI-H colorectal cancer patients who failed three approved chemotherapeutics, similar to the ORR of 28% and 33% with nivolumab and pembrolizumab in these patient populations, respectively. The rationale for the ENVASARC trial is based on the previously reported activity of checkpoint inhibition in UPS/MFS. Single agent pembrolizumab demonstrated a 23% ORR, while the combination of nivolumab and ipilimumab demonstrated a 29% ORR in refractory UPS/MFS. Methods: ENVASARC (NCT 04480502) is a pivotal multicenter (at ̃25 U.S. centers) open-label, randomized, non-comparative, parallel cohort study of treatment with envafolimab 300 mg every 3 weeks by SQ injection (cohort A; n = 80) or envafolimab 300 mg every 3 weeks by SQ injection combined with ipilimumab 1 mg/kg every 3 weeks i.v. for four doses (cohort B; n = 80) in patients with locally advanced, unresectable or metastatic UPS/MFS who have progressed on one or two lines of prior therapy. The primary objective of each of parallel cohort is to demonstrate an ORR with a lower limit of the 95% confidence interval that excludes 5.0% in each cohort. If ≥ 9 responders are observed of the 80 patients enrolled in each cohort, then the lower bound of the 95% confidence interval will exclude 5.0%. Secondary endpoints include duration of response (DOR), PFS and OS. Key inclusion criteria: ≤ 2 prior lines of therapy (neoadjuvant and adjuvant therapy excluded), ECOG ≤ 1. Clinical trial information: NCT 04480502.

A conceptual framework is presented to understand and study the role of students’ agency in their school (dis-)engagement from a Funds of Identity (FoI) perspective. The framework includes the notion of agency combined with Funds of Learner Identity (FoLI): learning preferences that can be considered part of people’s Funds of Identity. The framework holds that students manifest agency to negotiate engaging learning experiences when the school’s affordances and constraints are considerably relatable to their FoLI and allow them to define themselves in desired ways. However, adolescents who feel that possibilities to engage their FoLI are rather limited in school are expected to turn to other contexts to learn, such as home, peer groups and workplaces. An exemplary case study is presented to illustrate the framework and implications are discussed.

This randomized controlled trial investigated the efficacy of a stand-alone virtual reality exposure intervention comprising verbal interaction with virtual humans to target heterogeneous social fears in participants with social anxiety disorder. Sixty participants (Mage = 36.9 years; 63.3% women) diagnosed with social anxiety disorder were randomly assigned to individual virtual reality exposure therapy (VRET), individual in vivo exposure therapy (iVET), or waiting-list. Multilevel regression analyses revealed that both treatment groups improved from pre-to postassessment on social anxiety symptoms, speech duration, perceived stress, and avoidant personality disorder related beliefs when compared to the waiting-list. Participants receiving iVET, but not VRET, improved on fear of negative evaluation, speech performance, general anxiety, depression, and quality of life relative to those on waiting-list. The iVET condition was further superior to the VRET condition regarding decreases in social anxiety symptoms at post- and follow-up assessments, and avoidant personality disorder related beliefs at follow-up. At follow-up, all improvements were significant for iVET. For VRET, only the effect for perceived stress was significant. VRET containing extensive verbal interaction without any cognitive components can effectively reduce complaints of generalized social anxiety disorder. Future technological and psychological improvements of virtual social interactions might further enhance the efficacy of VRET for social anxiety disorder.

Background Endoglin is an essential angiogenic receptor expressed on proliferating tumor vessels and RCC stem cells that is implicated as a mechanism of VEGF resistance. TRC105 is an endoglin monoclonal antibody that potentiates the anti-tumor activity of VEGF inhibitors in preclinical models and demonstrated a 29% RECIST response rate when combined with AX in patients with mRCC in a Phase 1b trial. Methods TRAXAR was a multicenter, randomized 1:1 (stratified by ECOG, 0 vs. 1), Phase 2 study of TRAX vs AX in patients with mRCC who had progressed following one prior VEGF inhibitor at 33 centers in the US and EU. The primary endpoint was progression-free survival (PFS) assessed by RECIST by independent review committee (IRC). Secondary endpoints included overall response rate (ORR), and safety. PFS and ORR were also assessed by Investigator review (INV) and according to Choi criteria (CC). Results Of 150 pts (TRAX, 75; AX, 75), 106 (71%) were male, 142 (95%) were white; median age was 64 years (range, 38-82). Treatment with TRAX did not prolong PFS compared to AX. ORR was not different based on IRC, INV or CC (Table). Most all-grade common adverse events (AEs) in TRAX vs AX: headache (65.8% vs. 16.2%), epistaxis (63.0% vs. 8.1%), and diarrhea (60.3% vs. 59.5%); most common serious AEs included: anemia (6.9% vs. 1.4%) and dehydration (4.1% vs. 0%). Table . 912PD IRC INV CC TRAX AX TRAX AX TRAX AX Median PFS, mo (95% CI) 6.7 (5.6-13.1) 11.4 (5.8-NE) 7.2 (5.5-9.1) 7.4 (5.5-12.8) 7.2 (5.6-9.4) 7.5 (5.6-20.3) HR (95% CI) p-value 1.42 (0.88-2.30) 0.15 1.41 (0.95-2.10) 0.09 1.30 (0.83-2.03) 0.26 ORR, % 33.8 32.9 34.8 30.6 66.2 67.1 Odds ratio (95% CI) p-value 1.04 (0.50-2.15) 0.92 1.19 (0.58-2.44) 0.63 0.96 (0.47-1.96) 0.91 NE: not estimable; CI: confidence interval; mo: months Conclusions TRC105 did not demonstrate activity when combined with AX in patients with mRCC who had received prior VEGF inhibitor treatment, whether assessed using RECIST or Choi criteria. TRAX was generally well tolerated in pts with advanced or metastatic RCC. Clinical trial identification NCT01806064. Legal entity responsible for the study TRACON Pharmaceuticals. Funding TRACON Pharmaceuticals. Disclosure T.K. Choueiri: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: TRACON; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): BMS; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Cerulean; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Foundation Medicine; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Ipsen; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Genentech; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Roche Products Limited; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): GSM; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Peloton; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Prometheus; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Corvus; Honoraria (institution): Calithera. R.K. Pachynski: Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Advisory / Consultancy: Jounce Therapeutics; Speaker Bureau / Expert testimony: Dendreon; Speaker Bureau / Expert testimony: Merck; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Genentech/Roche; Speaker Bureau / Expert testimony: Genomic Health; Advisory / Consultancy: Bayer. Y. Zakharia: Advisory / Consultancy: Amgen; Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Jansen; Advisory / Consultancy: Eisai; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Castle Bioscience; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Array. T.H. Ho: Advisory / Consultancy: Roche; Advisory / Consultancy: Pfizer; Advisory / Consultancy: ipensenlivemeetings; Advisory / Consultancy: cardinal health; Advisory / Consultancy: Exelixis. B.E. Simpson: Shareholder / Stockholder / Stock options, Full / Part-time employment: TRACON Pharmaceuticals. B. Adams: Shareholder / Stockholder / Stock options, Full / Part-time employment: TRACON. L. Robertson: Shareholder / Stockholder / Stock options, Full / Part-time employment: TRACON. M. Darif: Advisory / Consultancy: TRACON. C. Theuer: Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: TRACON. N. Agarwal: Advisory / Consultancy: Astellas; Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: Argos; Advisory / Consultancy: Bayer; Advisory / Consultancy: Clovis; Advisory / Consultancy, Research grant / Funding (self): Eisai; Advisory / Consultancy, Research grant / Funding (self): Exelixis; Advisory / Consultancy: EMD Serono; Advisory / Consultancy, Research grant / Funding (self): Ely Lilly; Advisory / Consultancy: Foundation One; Advisory / Consultancy: Genentech; Advisory / Consultancy, Research grant / Funding (self): Janssen; Advisory / Consultancy, Research grant / Funding (self): Merck; Advisory / Consultancy: Medivation; Advisory / Consultancy, Research grant / Funding (self): Novartis; Advisory / Consultancy: Nektar; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Advisory / Consultancy: Pharmacyclics; Research grant / Funding (institution): Bavarian Nordic; Research grant / Funding (self): TRACON. All other authors have declared no conflicts of interest.

This study examined the effects of a professional development programme aimed at equipping teachers for the challenges of teaching in urban schools. The contribution of the programme to teacher quality and teacher retention was evaluated using a mixed research design in which both quantitative (N = 133) and qualitative (N = 42) approaches were used. The results showed a significant effect of the programme on teacher knowledge and self-efficacy. Furthermore, teachers greatly appreciated the programme and they perceived a positive impact on their competences, self-efficacy and professional orientation. The opportunity to share experiences within a network of teachers was considered the most valuable element of the programme.

Introduction In pediatric epilepsy, comorbidities are reported to be frequent. The present study focusedon the cognitive patterns of children with isolated epilepsy, children with isolated neurodevelopmental disorders (reading disorders, math disorders, autism spectrum disorders), and children with epilepsy and these neurodevelopmental disorders as comorbidities. Methods Based on two samples of referred children, one with epilepsy, reading disorders, math disorders, or ASDs occurring in “ isolation ” ( n = 117) and one with reading disorders, math disorders, and ASDs occurring comorbid with epilepsy ( n = 171), cognitive patterns were compared. The patterns displayed by verbal and nonverbal abilities from the WISC series were studied with repeated measures ANOVA. Thereafter, an exploratory 2 ∗ 3 ∗ 2 factorial analysis was done to study the independent contribution of the type of comorbidity and of the presence or absence of epilepsy to the VIQ–PIQ pattern. Results In isolated epilepsy, a VIQ > PIQ pattern was found, which was not seen in the other disorders. When epilepsy and another disorder co-occurred, patterns were altered. They resembled partly the pattern seen in isolated epilepsy and partly the pattern seen in the isolated neurodevelopmental disorder. In comorbid reading disorders, the VIQ > PIQ pattern was mitigated; in comorbid math disorders, it was exacerbated. In comorbid ASDs, no clear pattern emerged. In the presence of epilepsy, patterns characteristic of isolated disorders appeared systematically shifted toward relatively lowered performance abilities or relatively spared verbal abilities. The similar “impact” exerted by epilepsy on the patterns of the various conditions suggested shared mechanisms.

Background: Practice guidelines for childhood posttraumatic stress disorder (PTSD) recommend trauma-focused psychotherapies, mainly cognitive behavioral therapy (CBT). Eye movement desensitization and reprocessing (EMDR) therapy is a brief trauma-focused, evidence-based treatment for PTSD in adults, but with few well-designed trials involving children and adolescents. Methods: We conducted a single-blind, randomized trial with three arms (n = 103): EMDR (n = 43), Cognitive Behavior Writing Therapy (CBWT; n = 42), and wait-list (WL; n = 18). WL participants were randomly reallocated to CBWT or EMDR after 6 weeks; follow-ups were conducted at 3 and 12 months posttreatment. Participants were treatment-seeking youth (aged 8–18 years) with a DSM-IV diagnosis of PTSD (or subthreshold PTSD) tied to a single trauma, who received up to six sessions of EMDR or CBWT lasting maximally 45 min each. Results: Both treatments were well-tolerated and relative to WL yielded large, intent-to-treat effect sizes for the primary outcomes at posttreatment: PTSD symptoms (EMDR: d = 1.27; CBWT: d = 1.24). At posttreatment 92.5% of EMDR, and 90.2% of CBWT no longer met the diagnostic criteria for PTSD. All gains were maintained at follow-up. Compared to WL, small to large (range d = 0.39–1.03) intent-to-treat effect sizes were obtained at posttreatment for negative trauma-related appraisals, anxiety, depression, and behavior problems with these gains being maintained at follow-up. Gains were attained with significantly less therapist contact time for EMDR than CBWT (mean = 4.1 sessions/140 min vs. 5.4 sessions/227 min). Conclusions: EMDR and CBWT are brief, trauma-focused treatments that yielded equally large remission rates for PTSD and reductions in the severity of PTSD and comorbid difficulties in children and adolescents seeking treatment for PTSD tied to a single event. Further trials of both treatments with PTSD tied to multiple traumas are warranted.

TRC105 is an anti-endoglin antibody currently being tested in combination with VEGF inhibitors. In the phase Ib trial, 38 patients were treated with both TRC105 and bevacizumab (BEV), and improved clinical outcomes were observed, despite the fact that 30 patients (79%) were refractory to prior anti-VEGF therapy. Plasma samples were tested for angiogenic and inflammatory biomarkers at baseline and on-treatment. To provide broader context of this combination biomarker study, direct cross-study comparisons were made to biomarker studies previously conducted in patients treated with either BEV or TRC105 monotherapy. Upon treatment with BEV and TRC105, pharmacodynamic changes in response to both BEV (PlGF increase) and TRC105 (soluble endoglin increase) were noted. In addition, distinct patterns of change were identified (similar, opposing, neutralizing). Similar patterns were observed when the combination elicited similar effects to those observed with monotherapy treatment (i.e., decreases of Ang-2, increases of IL6 and VCAM-1). Opposing patterns were observed when the combination led to opposing effects compared with monotherapy treatment (i.e., TGFβ1, PDGF-AA and PDGF-BB, PAI-1). Lastly, neutralizing patterns were observed when one drug led to increase, whereas the other drug led to decrease, and the combination elicited no overall effect on the marker (i.e., VEGF-A, VEGF-D, and IGFBP-3). Patients achieving partial responses or stable disease from the combination exhibited significantly lower expression of E-Cadherin, HGF, ICAM-1, and TSP-2 at baseline. Taken together, the novel biomarker modulations identified may deepen our understanding of the underlying biology in patients treated with BEV and TRC105 compared with either drug alone. Mol Cancer Ther; 17(10); 2248–56. ©2018 AACR.

The Chronic Sleep Reduction Questionnaire is a validated questionnaire that measures symptoms of prolonged insufficient and/or poor sleep and therefore accounts for individuals' sleep need and sleep debt. This study extends its psychometric properties by providing cut-off scores, using a matched sample of 298 healthy adolescents (15.38 +/- 1.63years, 37.9% male, mean Chronic Sleep Reduction Questionnaire score: 32.98 +/- 6.51) and 298 adolescents with insomnia/delayed sleep-wake phase disorder (15.48 +/- 1.62years;37.9% male, mean Chronic Sleep Reduction Questionnaire score: 42.59 +/- 7.06). We found an area under the curve of 0.84 (95% confidence interval: 0.81-0.87). Cut-off scores for optimal sensitivity, optimal specificity and based on Youden's criterion are provided. These cut-off scores are highly relevant for use of the Chronic Sleep Reduction Questionnaire in future studies and clinical practice.

Stress in children and adolescents is common and related to many developmental problems. However, most studies have made no distinction between temporary or chronic stress due to the lack of a suitable questionnaire. This study tested the factor structure, reliability and validity of the 17-item self-report Chronic Stress Questionnaire for Children and Adolescents (CSQ-CA) in three samples, that is, 717 adolescents from the general population, 161 adolescents of parents with a severe chronic medical condition (CMC) like multiple sclerosis, and 113 adolescents with healthy parents. Results showed that a one-factor solution provided a reasonable fit overall. Reliability was good (α = .80 to .88). Convergent validity was supported by positive relations between total stress scores and internalizing and externalizing problem behaviors, experience of daily hassles, and maladaptive emotion regulation strategies and negative relations with quality of life, happiness, mindfulness, self-esteem, and coping skills. Adolescents from all samples, who themselves had a light CMC like asthma, showed higher chronic stress levels than those without a CMC. In line, adolescents of parents with a severe CMC reported more chronic stress than those of healthy parents, and adolescents with a chronic illness themselves and a parent with a chronic illness, showed the highest scores across the two family types. Overall, this study presents good psychometric properties of the first available measure of chronic stress in children and adolescents.

Inquiry-based working by teachers includes working with an inquiry habit of mind, being data literate, contributing to a culture of inquiry at the school level, and creating a culture of inquiry at the classroom level. Inquiry-based working has been found to contribute to educational improvements and the professionalisation of teachers. This study investigates the relationship between psychological factors – attitude, experienced social pressure, self-efficacy and collective efficacy – and inquiry-based working by teachers. Questionnaire data were collected from a representative sample of 249 Dutch teachers. The results show a significant relationship between self-efficacy and all aspects of inquiry-based working. In addition, collective efficacy, attitude and experienced social pressure are all related to aspects of inquiry-based working. School leaders and teacher educators who aim to stimulate inquiry-based working should not only focus on increasing teachers’ inquiry skills, but also on psychological factors related to inquiry-based working.

PurposeThe purpose of this paper is to improve the understanding of psychological factors that influence inquiry-based leadership. This study investigates how affective attitude, experienced social pressure, and self-efficacy relate to aspects of inquiry-based school leadership. A school leader’s inquiry habit of mind, data literacy, and the extent to which he or she creates a culture of inquiry in the school are each identified as aspects of inquiry-based leadership.Design/methodology/approachData were collected from questionnaires completed by a sample of 79 school leaders.FindingsA significant relationship was found between self-efficacy regarding inquiry-based leadership and all aspects of inquiry-based leadership. Affective attitude toward inquiry-based leadership was significantly related to creating a culture of inquiry. There was no unique relationship between experienced social pressure and inquiry-based leadership.Practical implicationsAdministrators and educators of school leaders who aim to stimulate inquiry-based school leadership should not only focus on increasing the capacity of school leaders to lead their school in an inquiry-based way, but they should also focus on leaders’ self-efficacy and on fostering leaders’ positive attitude toward inquiry-based school leadership. Administrators and educators can, for example, give positive feedback, emphasize the added value of inquiry-based leadership, encourage working with critical friends, and stimulate collaboration with other leaders.Originality/valueThis study addresses two gaps in the existing research, by focusing on inquiry-based leadership instead of data use and on psychological factors instead of knowledge and skills that are related to this type of leadership.

TRC105 is an endoglin-targeting drug that possesses anti-angiogenic and antitumor potential. Analysis of the initial phase I trial of TRC105 demonstrated good tolerability and efficacy in cancer patients. In this report, we analyzed multiple circulating biomarkers at baseline, cycle 2 day 1 (C2D1), and end of study (EOS) for each patient. The baseline level and the fold change from baseline to both C2D1 and EOS for each marker were statistically analyzed. At C2D1, seven markers were significantly downregulated (angiopoietin-2 [Ang-2], insulin-like growth factor-binding protein-3 [IGFBP-3], plasminogen activator inhibitor-1 [PAI-1] total, platelet-derived growth factor [PDGF]-AA, PDGF-BB, thrombospondin-1 [TSP-1], and vascular endothelial growth factor [VEGF]-D). Meanwhile, seven markers were upregulated by C2D1 (E-Cadherin, soluble Endoglin [sEnd], E-Selectin, interleukin-6 [IL-6], osteopontin [OPN], TSP-2, and von Willebrand factor [vWF]). At EOS, seven markers were upregulated including Ang-2, C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), IGFBP-1, IL-6, TSP-2, and vascular cell adhesion molecule-1 (VCAM-1). A statistical trend was also seen for increases of VEGF-A and placenta growth factor (PlGF) at EOS. Throughout treatment, sEnd levels significantly increased, an observation that was recapitulated in cultured endothelial cells. This is the first report of plasma-based biomarkers in patients receiving TRC105. TRC105 treatment by C2D1 was associated with decreases in several angiogenic factors, including Ang-2, PDGF isoforms, and VEGF isoforms, offering insight into the mechanisms underlying TRC105's anti-angiogenic, antitumor function. Increases in sEnd were the most significant of all observed biomarker changes and may reflect direct drug effects. Additionally, biomarker changes in response to TRC105 are distinct from those seen in patients treated with VEGF-targeting drugs, suggesting the possible utility of combining these two classes of angiogenesis inhibitors in patients.

Objective: To study the pattern of cognitive development in relation to duration of epilepsy. Methods: Participants were 113 children with epilepsy referred because of concerns about their cognitive development and tested at least twice at tertiary epilepsy settings. Verbal, Performance, and Full Scale IQ were measured with Wechsler Intelligence Scales. Various epilepsy and demographic variables were included. Change over time was modeled with multilevel analysis for longitudinal data with variable measurement occasion.Results: The Verbal and Full Scales could be fitted best as a downward progressing function. Earlier in time, decline was likely to be largest; later in time, decline followed a continuous, dwindling course. A similar trend was seen for the Performance Scale. Initially, Verbal IQ was higher than Performance IQ but this discrepancy decreased over time. Later onset of epilepsy was associated with an attenuated decline of the Verbal Scale. None of the other epilepsy variables were related to the course of cognitive development. Higher parental education was associated with higher IQ, but was not protective against decline.Conclusions: Verbal IQ, though initially spared, drops. The Performance IQ, which may have shown its vulnerability earlier in the course of the epilepsy, shows overall smaller changes. It is suggested that seizures impact synergistically on an affected brain, which leads to progressive cognitive decline. Earlier onset of epilepsy is associated with relatively higher VIQ, larger VIQ > PIQ discrepancies and more decline.

Background The intervention Home-Start is a wide spread program in a number of countries, among which the Netherlands. In Home-Start, trained volunteers visit families with young children in need of support once or twice a week to help them to deal with problems in family life and parenting. Little is known, however, about the effects of Home-Start. This study describes short-term and long term changes in families that participated in Home-Start. Methods Three groups of families with young children (at the start mean age 1 1/2 years) were followed over a period of four years. One of the groups of families participated in the Home-Start family support program in the first 6.6 months of this period. The two other groups were (1) a randomly selected community sample and (2) a group of families with elevated parenting stress and a need for support. Data were collected at the beginning of the study, (after median 1.4 months), directly after the intervention (median 6.6 months) and at two follow-up occasions (respectively, median 12.5 and 49.2 months after the first measurement). At the last measurement, data were available for 33, 45 and 34 families respectively. Results Multilevel analysis showed more positive changes in parental wellbeing, competence and behavior (more consistent behavior and less rejection) during the intervention period in the Home-Start group than in the two other groups. At the three year follow up, the Home-Start group showed, compared to the other groups, more improvements in parenting (more responsiveness), but also diminished child externalizing and internalizing behavior problems (less oppositional defiant behavior, affective problems and anxiety problems). Conclusions Home-Start seems a promising family support intervention that deserves to be studied more extensively.

With the development of an MCMC algorithm, Bayesian model selection for the p2 model for directed graphs has become possible. This paper presents an empirical exploration in using approximate Bayes factors for model selection. For a social network of Dutch secondary school pupils from different ethnic backgrounds it is investigated whether pupils report that they receive more emotional support from within their own ethnic group. Approximated Bayes factors seem to work, but considerable margins of error have to be reckoned with. © VVS, 2005.

Background and ObjectivesDuring the past decades, blood transfusions have become an ever safer clinical procedure in developed countries. Extensive donor screening together with improved infectious disease testing has led to a minimization of risks for transfusion recipients. Still, the general public perceives the process of blood transfusion as risky.Materials and MethodsThis study tested variation in perceived transfusion safety across countries and explained it with individual and country factors. We examined whether individual demographic and macro-level factors (i.e. Human Development Index and Power Distance Index) explain variation within and across European countries. We applied multilevel models to 2009 Eurobarometer data collected in 26 countries (N = 20 874).ResultsResults were largely in line with expectations derived from risk perception and power and status difference theories. Generally, women, older adults, the lower educated and those earning lower incomes perceived heightened risk. Most of the variation across Europe was explained by the Human Development Index. Risk perception regarding blood transfusions was lower in countries with higher Human Development Indices, that is countries with higher average education, life expectancy and Gross Domestic Product.ConclusionThis study provides new insights of how risk perception regarding blood transfusions is shaped within and across Europe. Both individual demographic factors and country characteristics play a role.

Purpose: TRC105 is a chimeric IgG1 monoclonal antibody that binds CD105 (endoglin). This first-in-human, phase I, open-label study assessed safety, pharmacokinetics, and antitumor activity of TRC105 in patients with advanced refractory solid tumors. Patients and Methods: Patients received escalating doses of intravenous TRC105 until disease progression or unacceptable toxicity using a standard 3 + 3 phase I design. Results: Fifty patients were treated with escalating doses of TRC105. The maximum tolerated dose (MTD) was exceeded at 15 mg/kg every week because of dose-limiting hypoproliferative anemia. TRC105 exposure increased with increasing dose, and continuous serum concentrations that saturate CD105 receptors were maintained at 10 mg/kg weekly (the MTD) and 15 mg/kg every 2 weeks. Common adverse events including anemia, telangiectasias, and infusion reactions reflected the mechanism of action of the drug. Antibodies to TRC105 were not detected in patients treated with TRC105 from Chinese hamster ovary cells being used in ongoing phase Ib and phase II studies. Stable disease or better was achieved in 21 of 45 evaluable patients (47%), including two ongoing responses at 48 and 18 months. Conclusion: TRC105 was tolerated at 10 mg/kg every week and 15 mg/kg every 2 weeks, with a safety profile that was distinct from that of VEGF inhibitors. Evidence of clinical activity was seen in a refractory patient population. Ongoing clinical trials are testing TRC105 in combination with chemotherapy and VEGF inhibitors and as a single agent in prostate, ovarian, bladder, breast, and hepatocellular cancer. Clin Cancer Res; 18(17); 4820–9. ©2012 AACR.

Background: Genomic fusions between ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) and more than 20 genes drive many types of cancer. Only a handful of ROS1-positive (ROS1+) cancer models exist to use in research and developing new treatments. Few research facilities encounter ROS1+ patients–the incidence of ROS1+ cancer is only 1% to 2% in non-small cell lung cancer (NSCLC) and ROS1 testing is rarely done in other cancers. To address this, a group of ROS1+ patients and caregivers (“the ROS1ders") collaborated with advocacy organizations, researchers and industry to form the Global ROS1 Initiative. Methods: The ROS1ders and partners informed patients, caregivers, and clinicians of the initiative through social media, patient blogs, websites, distribution of fliers in several languages at cancer conferences, and contacts with their clinicians. The ROS1der online community shared ROS1+ information about treatment options and side effects, expert clinicians, clinical trials, research and general support. An epidemiologic survey captured data about ROS1 patient histories and treatments. When a member in the ROS1der community shared news of an upcoming surgery, biopsy or thoracentesis, a ROS1der leader told them of an opportunity to donate excess fresh specimens to create cancer models. Tumor samples and resulting cell lines underwent drug testing and sequencing for mechanisms of resistance. Results: The ROS1ders members include 166 patients (more than twice the largest ROS1 clinical trial cohort to date) from 16 countries representing 6 types of ROS1+ cancer. Four attempted fresh specimen donations resulted in 2 new ROS1+ cells lines, CUTO27 (CD74-ROS1) and CUTO28 (TPM3-ROS1). These cell lines have already been distributed to academic and industry partners to increase the value of these rare resources. The ROS1ders shared study results within their online group. The Initiative is now working to continue the longitudinal epidemiologic survey and create clinical studies that will generate ROS1+ cell lines and/or patient-derived xenograft (PDX) mouse models. We will conduct genomic analysis of the models to determine the presence of resistance mutations as well as ROS1 pairing partner genes. The resultant renewable tissue resources of PDX models and cell lines, when linked to the clinically annotated genomic database, will be broadly shared to help clinical and translational research understand mechanisms of response and resistance to therapies, and assist in drug development. Conclusions: This project demonstrates that partnerships between patient-caregiver groups, advocacy groups, researchers and industry, combined with social media outreach, can increase the available oncogene-driven patient data, specimens, and cancer models in small, geographically distributed patient populations. Citation Format: Janet Freeman-Daily, Lisa Goldman, Tori Tomalia, The ROS1ders, Christine M. Lovly, Manali I. Patel, Alice T. Shaw, Bonne J. Addario, Guneet Walia, Steven W. Young, Robert C. Doebele. The Global ROS1 Initiative: A patient-researcher partnership generating open-source, oncogene-driven cancer models and data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4766.

TPS403 Background: Resistance to AR-targeted therapy is a challenge in the treatment of mCRPC. Single amino acid mutations of the AR ligand binding domain may mediate resistance to second generation AR inhibitors, including enzalutamide (Rathkopf, Annals of Oncology 2017). Development of potent antagonists of wild-type (WT) AR as well as mutated AR is a priority. TRC253 is an orally available, high-affinity, small molecule antagonist of AR with inhibitory activity against WT AR as well as mutated variants. TRC253 blocks AR nuclear translocation and AR binding to DNA and antagonizes transcription. TRC253 does not have agonist activity toward WT or mutated ARs. Methods: This phase 1/2a study of TRC253 in patients with mCRPC will be conducted in two parts: dose-escalation (part 1) and dose-expansion (part 2). Objectives include assessment of safety, selection of a phase 2 dose, and to evaluate PSA response at week 12. Secondary objectives include the evaluation of the extent of receptor occupancy (FDHT PET) and anti-tumor effects of TRC253. Toxicity and efficacy assessments will be determined using NCI-CTCAE and PCWG3 criteria. Dose escalation will begin with single-patient cohorts. Cohorts will be expanded to 3 patients when pre-defined grades of drug-related toxicity occur. TRC253 doses in part 1 are 40 mg, 80 mg, 160 mg, 240 mg, 320 mg, and 400 mg. The DLT evaluation period will be the first 28 days of continuous daily dosing. Six patients have been enrolled to Part 1 to date. Part 2 will consist of two cohorts of up to 30 patients each. Cohort 1 (AR F876L mutation positive) and cohort 2 (AR F876L mutation negative) will receive TRC253 at the RP2D. Circulating tumor DNA will be analyzed in plasma samples to test for AR mutations. In Part 1 patients must have received ≥ 2 prior therapies. Part 2 patients must have demonstrated acquired resistance to enzalutamide or apalutamide. Descriptive statistics will be used to summarize patient characteristics, safety, efficacy, PK, and immunologic biomarkers. Clinical trial information: NCT02987829.

301 Background: Endoglin plays a critical role in angiogenesis and is implicated in resistance to VEGF inhibition. TRC105, an endoglin antibody potentiates anti-tumor activity of sorafenib (S) in preclinical HCC models. The combination of TRC105 and S demonstrated encouraging evidence of activity, including a 33% partial response rate (5/15 pts) by RECIST, at RP2D doses of TRC105 in HCC ( Clin Can Res 2017). Adverse events characteristic of each drug were not increased in frequency or severity when the two drugs were administered concurrently, and most commonly included epistaxis, fatigue, headache and anemia. Methods: Following dose escalation, 21 pts will be enrolled at the RP2D. Four objective responses are required to reject the null hypothesis that the true response rate probability is < 5% with an alpha level of 0.1 and 80% power. Secondary endpoints: DR, PFS, frequency and severity of AEs, PK, immunogenicity, angiogenic biomarkers. Key inclusion criteria: disease not amendable to surgical or local therapies, ECOG ≤ 1; Child-Pugh A or B (7 points) classification. Results: Four pts have been enrolled in phase 1b at TRC105 10 mg/kg (n=4) weekly for four doses and 15 mg/kg every other week thereafter + S 800 mg daily without DLT. One of 3 evaluable pts achieved PR (41% reduction), ongoing at month 4. Serum levels of TRC105 exceeded the target concentration following 4 weekly doses of TRC105 at 10 mg/kg (mean = 59 µg/ml, range 43-80). Mean trough concentration decreased following every other week dosing (mean = 21 µg/ml, range 17-31). Common TRC105 related AEs included ≤ G2 epistaxis and G1 headache. Common S related AEs included G3 hand foot syndrome, ≤G3 periodontal disease, G2 hypertension, ≤G2 increased lipase, ≤G2 fatigue and G1 epistaxis. Conclusions: TRC105 dosed by a hybrid schedule of 10 mg/kg weekly for four doses followed by every other week dosing at 15 mg/kg was tolerable and did not potentiate the toxicity of S. The combination of TRC105 + S demonstrated additional signs of activity, including a PR in 1/3 evaluable pts. 21 pts will be enrolled at the RP2D to assess the primary endpoint of ORR by RECIST. Clinical trial information: NCT01806064.

The p(2) model is a statistical model for the analysis of binary relational data with covariates, as occur in social network studies. It can be characterized as a multinomial regression model with crossed random effects that reflect actor heterogeneity and dependence between the ties from and to the same actor in the network. Three Markov chain Monte Carlo (MCMC) estimation methods for the p2 model are presented to improve iterative generalized least squares (IGLS) estimation developed earlier, two of which use random walk proposals. The third method, an independence chain sampler, and one of the random walk algorithms use normal approximations of the binary network data to generate proposals in the MCMC algorithms. A large-scale simulation study compares MCMC estimates with IGLS estimates for networks with 20 and 40 actors. It was found that the IGLS estimates have a smaller variance but are severely biased, while the MCMC estimates have a larger variance with a small bias. For networks with 20 actors, mean squared errors are generally comparable or smaller for the IGLS estimates. For networks with 40 actors, mean squared errors are the smallest for the MCMC estimates. Coverage rates of confidence intervals are good for the MCMC estimates but not for the IGLS estimates.

Purpose Sunitinib is an oral, multitargeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor, stem cell factor receptor (KIT), and colony-stimulating factor-1 receptor. This phase II, open-label, multicenter study evaluated sunitinib monotherapy in patients with metastatic breast cancer (MBC). Patients and Methods Sixty-four patients previously treated with an anthracycline and a taxane received sunitinib 50 mg/d in 6-week cycles (4 weeks on, then 2 weeks off treatment). The primary end point was objective response rate. Plasma samples were obtained for pharmacokinetic and biomarker analysis. Results Seven patients achieved a partial response (median duration, 19 weeks), giving an overall response rate of 11%. Three additional patients (5%) maintained stable disease for ≥ 6 months. Median time to progression and overall survival were 10 and 38 weeks, respectively. Notably, responses occurred in triple negative tumors and HER2-positive, trastuzumab-treated patients. Thirty-three patients (52%) required dose interruption during ≥ 1 cycle, and 25 patients required dose reduction (39%). Thirty-six patients (56%) had dose modifications due to adverse events (AEs). Treatment was associated with increases in plasma VEGF and decreases in soluble VEGFRs and KIT. The most common AEs were fatigue, nausea, diarrhea, mucosal inflammation, and anorexia. Most AEs were mild to moderate (grade 1 to 2) in severity and were effectively managed with dose delays or reductions. Conclusion Sunitinib is active in patients with heavily pretreated MBC. Most AEs were of mild-to-moderate severity and manageable with supportive treatment and/or dose modification. Further studies in breast cancer are warranted.

Ethnic boundaries were tested in students' networks in 34 Flemish and 19 Dutch high schools. Each network consisted of a school cohort in an intermediate level of education (track). While students from the native majority predominantly had friendships within their own ethnic category, minority students often had more inter-ethnic than intra-ethnic friendships. However, a multilevel p2 model for analysing the networks showed that this was due mainly to the quantitative dominance of native students in the networks. Native students were more inclined than minority students to engage in inter-ethnic friendships. The study found ethnic boundaries to be stronger in the Dutch networks than in the Flemish networks. It is unclear whether this is due to methodological reasons or to more substantial differences between the Netherlands and Flanders.

For this study, information on Who Bullies Who was collected from 54 school classes with 918 children (M age = 11) and 13,606 dyadic relations. Bullying and victimization were viewed separately from the point of view of the bully and the victim. The two perspectives were highly complementary. The probability of a bully-victim relationship was higher if the bully was more dominant than the victim, and if the victim was more vulnerable than the bully and more rejected by the class. In a bully-victim dyad, boys were more often the bullies. There was no finding of sex effect for victimization. Liking reduced and disliking increased the probability of a bully-victim relationship.

In the Netherlands, the Dutch government instituted policies that enable persons with profound intellectual and multiple disabilities (PIMD) to attend day services. Over the past 15 years, surveys have indicated a progressive increase in the number of hours that such adults spend at day activities centers. However, information about how these hours are spent is lacking. This study was designed to sample 7 residential centers to determine the amount of time spent in day activities centers, the number of hours that were spent on fixed programming or individually orientated activities, and what types of activities were prominent. Results showed that persons with PIMD spent, on average, 14.2 h per week at day activities centers. Of that time, 28.9% was spent on group activities and 13.0% on individual activities. Whether these activities could be considered purposeful or productive for an individual participant is unknown. The authors question whether the policies of the Dutch government aimed at enabling persons with PIMD to enjoy purposeful, rather than just longer, activities during the day, have been productively implemented.

International audience; The isotopic composition of near surface (or planetary boundary layer) water vapor on the south coast of Iceland (63.83°N, 21.47°W) has been monitored in situ between November 2011 and April 2013. The calibrated data set documents seasonal variations in the relationship between δ 18 O and local humidity (ppmv) and between deuterium excess and δ 18 O. These seasonal variations are attributed to seasonal changes in atmospheric transport. A strong linear relationship is observed between deuterium excess and atmospheric relative humidity calculated at regional sea surface temperature. Surprisingly, we find a similar relationship between deuterium excess and relative humidity as observed in the Bermuda Islands. During days with low amount of isotopic depletion (more enriched values), our data significantly deviate from the global meteoric water line. This feature can be explained by a supply of an evaporative flux into the planetary boundary layer above the ocean, which we show using a 1-d box model. Based on the close relationship identified between moisture origin and deuterium excess, we combine deuterium excess measurements performed in Iceland and south Greenland with moisture source diagnostics based on back trajectory calculations to establish the distribution of d-excess moisture uptake values across the North Atlantic. We map high deuterium excess in the Arctic and low deuterium excess for vapor in the subtropics and midlatitudes. This confirms the role of North Atlantic water vapor isotopes as moisture origin tracers.

The p 2 model is a random effects model with covariates for the analysis of binary directed social network data coming from a single observation of a social network. Here, a multilevel variant of the p 2 model is proposed for the case of multiple observations of social networks, for example, in a sample of schools. The multilevel p 2 model defines an identical p 2 model for each independent observation of the social network, where parameters are allowed to vary across the multiple networks. The multilevel p 2 model is estimated with a Bayesian Markov Chain Monte Carlo (MCMC) algorithm that was implemented in free software for the statistical analysis of complete social network data, called StOCNET. The new model is illustrated with a study on the received practical support by Dutch high school pupils of different ethnic backgrounds.