Molecular analysis and favorable clinical outcomes in real-world patients with metastatic renal cell carcinoma.

BACKGROUND: Prior biomarker studies have mainly been restricted to advanced RCC patients treated in clinical trials or have had limited integration of immunotherapy features such as programmed death ligand (PD-L)-1 with gene expression signatures intended to capture other canonical pathways to confirm their prognostic value. MATERIAL AND METHODS: PD-L1 and PD-L2 by immunohistochemistry (IHC), PD-L2 messenger RNA (mRNA), and 10 gene expression profile (GEP) signatures targeting immune, angiogenesis and canonical pathways were analyzed in nephrectomy specimens from 227 advanced clear cell RCC (ccRCC) and 42 non-clear cell RCC (nccRCC) patients treated with targeted therapies including VEGF and mTOR inhibitors. Biomarker association with best overall response (BOR), progression-free survival (PFS), and overall survival (OS) were evaluated using multivariable modeling. Except for PD-L1 IHC and angiogenesis, tested with a nominal p-value of .05, multiplicity control was applied with a 0.1 significance level given limited experience in this setting. RESULTS: The strongest biomarker correlations were observed for hypoxia inducible factor (HIF)-2a and angiogenesis signatures (rho = 0.860 [ccRCC], 0.819 [nccRCC]); hypoxia and glycolysis signatures (rho = 0.943 [ccRCC], 0.973 [nccRCC]); PD-L2 mRNA and T-cell-inflamed GEP signatures (rho = 0.764 [ccRCC], 0.897 [nccRCC]); and PD-L2 mRNA and monocytic myeloid-derived suppressor cell signature (rho = 0.787 [ccRCC], 0.815 [nccRCC]). For ccRCC, higher angiogenesis expression was associated with improved BOR (OR:2.85 [95%CI:1.37, 5.93]), longer PFS (HR:0.61 [95%CI:0.45, 0.82]) and OS (HR:0.74 [95%CI:0.54, 1.00]); higher PD-L1 expression with shorter OS (HR:1.44 [95%CI:1.01, 2.07]). For nccRCC, there was more than a two-fold increased risk with longer OS associated with lower angiogenesis (HR:2.43 [95%CI:1.04, 5.68]), glycolysis (HR:7.03 [95%CI:1.51, 32.76]) and hypoxia (HR:8.83 [95%CI:1.69, 46.05]) gene signature expression. CONCLUSION: Data pointed at PD-L1 IHC and angiogenesis expression in ccRCC and hypoxia, glycolysis, and angiogenesis expression in nccRCC as potential prognostic factors. These findings may have implications for the design and interpretation of advanced RCC trials and to identify potential targets for combination therapy strategies.

Temporal Trends in Clinical Evidence of 5-Year Survival Within Electronic Health Records Among Patients With Early-Stage Colon Cancer Managed With Laparoscopy-Assisted Colectomy vs Open Colectomy.

Importance: Temporal shifts in clinical knowledge and practice need to be adjusted for in treatment outcome assessment in clinical evidence. Objective: To use electronic health record (EHR) data to (1) assess the temporal trends in treatment decisions and patient outcomes and (2) emulate a randomized clinical trial (RCT) using EHR data with proper adjustment for temporal trends. Design, Setting, and Participants: The Clinical Outcomes of Surgical Therapy (COST) Study Group Trial assessing overall survival of patients with stages I to III early-stage colon cancer was chosen as the target trial. The RCT was emulated using EHR data of patients from a single health care system cohort who underwent colectomy for early-stage colon cancer from January 1, 2006, to December 31, 2017, and were followed up to January 1, 2020, from Mass General Brigham. Analyses were conducted from December 2, 2019, to January 24, 2022. Exposures: Laparoscopy-assisted colectomy (LAC) vs open colectomy (OC). Main Outcomes and Measures: The primary outcome was 5-year overall survival. To address confounding in the emulation, pretreatment variables were selected and adjusted. The temporal trends were adjusted by stratification of the calendar year when the colectomies were performed with cotraining across strata. Results: A total of 943 patients met key RCT eligibility criteria in the EHR emulation cohort, including 518 undergoing LAC (median age, 63 [range, 20-95] years; 268 [52%] women; 121 [23%] with stage I, 165 [32%] with stage II, and 232 [45%] with stage III cancer; 32 [6%] with colon adhesion; 278 [54%] with right-sided colon cancer; 18 [3%] with left-sided colon cancer; and 222 [43%] with sigmoid colon cancer) and 425 undergoing OC (median age, 65 [range, 28-99] years; 223 [52%] women; 61 [14%] with stage I, 153 [36%] with stage II, and 211 [50%] with stage III cancer; 39 [9%] with colon adhesion; 202 [47%] with right-sided colon cancer; 39 [9%] with left-sided colon cancer; and 201 [47%] with sigmoid colon cancer). Tests for temporal trends in treatment assignment (χ2 = 60.3; P < .001) and overall survival (χ2 = 137.2; P < .001) were significant. The adjusted EHR emulation reached the same conclusion as the RCT: LAC is not inferior to OC in overall survival rate with risk difference at 5 years of -0.007 (95% CI, -0.070 to 0.057). The results were consistent for stratified analysis within each temporal period. Conclusions and Relevance: These findings suggest that confounding bias from temporal trends should be considered when conducting clinical evidence studies with long time spans. Stratification of calendar time and cotraining of models is one solution. With proper adjustment, clinical evidence may supplement RCTs in the assessment of treatment outcome over time.

A Thematic Analysis of Students' Perceptions and Experiences of Bullying in UK Higher Education.

Bullying in higher education (HE) has been relatively under-researched; despite its likely prevalence and impact on student wellbeing there is scant understanding of students' lived experiences of bullying. We conducted online and physical focus groups with UK HE students (40 undergraduates from 17 UK universities, mean age: 22), exploring their perceptions and experiences of bullying at university. Thematic analysis was used to identify key issues, specifically 1) the importance of a power imbalance and perpetuation of existing systemic inequality in a HE context; 2) bullying in HE is motivated by attainment of social and personal gains; 3) the tactics used to bully in HE resemble those seen in other contexts, but may be more nuanced; 4) bullying can be minimised and justified within HE, leading to its continued prevalence. We conclude that HE bullying shares features in common with school and workplace bullying, and with sexual harassment. However, further research is needed to accurately define and conceptualise bullying in this unique context. HE providers should consider attending to issues of power and inequality within their bullying and harassment policies. They should also ensure there is clear information and guidance to prevent and reduce bullying in universities.

Primary-secondary school transition under Covid-19: Exploring the perceptions and experiences of children, parents/guardians, and teachers.

The transition from primary to secondary school is a major life event for eleven-year-old children in the United Kingdom, where they face simultaneous changes. Following the outbreak of Covid-19, transfer children face additional uncertainty on top of this. Negotiation of the multiple challenges, combined with the reduced support associated with Covid-19, could have a negative impact on children's school adjustment and mental health. Given the rapidity of changes associated with Covid-19, there are key empirical and practical gaps on how best to support children as they negotiate these two key events. To date, there is no published research which has explored the experiences of transfer children, and that of their parents and teachers during this time. The present research aimed to narrow this research gap by answering the research question: What are parents', children's, and teachers' experiences of primary-secondary school transition during Covid-19? This research used a series of UK wide surveys to gather data from 101 Year 7 children, 88 Year 7 parents, 26 primary school teachers, and 40 secondary school teachers using a mixture of open and closed questions. The data were analysed using Thematic Framework Analysis, taking an inductive-open coding approach. All three stakeholders reported negative impacts of Covid-19 on the transition, for example, in terms of missed opportunities. There were also many comments about the emotional impact of Covid-19 on children, parents, and teachers. Numerous strategies were reported that were used to meet children's needs pre and post-transition, highlighting areas of good practice, along with practical suggestions for how to approach transition in the future. The study has identified ways that transition can be managed more effectively, thus, having short term implications in providing an evidence base to support transfer children this year, and long-term implications for future transition years.

The Early Humor Survey (EHS): A reliable parent-report measure of humor development for 1- to 47-month-olds.

We created a 20-item parent-report measure of humor development from 1 to 47 months: the Early Humor Survey (EHS). We developed the EHS with Study 1 (N = 219) using exploratory factor analysis, demonstrating the EHS works with 1- to 47-month-olds with excellent reliability and a strong correlation with age, showing its developmental trajectory. We replicated the EHS with Study 2 (N = 587), revealing a one-factor structure, showing excellent reliability, and replicating a strong correlation with age. Study 3 (N = 84) found the EHS correlated with a humor experiment, however it no longer correlated once age was accounted for, suggesting low convergent validity. Subsamples of parents from Studies 2 and 3 showed excellent inter-observer reliability between both parents, and good longitudinal stability after 6 months. Combining participants from all studies, we found the EHS is reliable across countries (Australia, United Kingdom, United States), parent education levels, and children's age groups. We charted expected humor development by age (in months), and the expected proportion of children who would appreciate each humor type by age (in months). Finally, we found no demographic differences (e.g., country: Australia, Canada, United Kingdom, United States; parents' education) in humor when pooling all data. The EHS is a valuable tool that will allow researchers to understand how humor: (1) emerges; and (2) affects other aspects of life, e.g., making friends, coping with stress, and creativity. The EHS is helpful for parents, early years educators, and children's media, as it systematically charts early humor development.

Replication of Oncology Randomized Trial Results using Swedish Registry Real World-Data: A Feasibility Study.

Nationwide healthcare registries are potential important real-world data (RWD) sources for assessing drug effectiveness in oncology. However, it is unclear whether registry-derived RWD are suitable for clinical development. In this study, we replicate results from the comparator arm of two previously published oncology randomized controlled trials (RCTs) using RWD from Swedish nationwide healthcare registries. For replication 1, the RCT included 553 patients and the RWD included 283 patients treated with sorafenib for advanced hepatocellular cancer. The median overall survival (OS) was 11.2 (95% confidence interval (CI): 10.1-13.2) months in the RCT and 8.2 (95% CI: 7.0-9.9) months in the RWD, unadjusted hazard ratio (HR) 0.75 (95% CI: 0.63-0.88). For time-to-treatment discontinuation (TTD), the HR was 1.00 (95% CI: 0.87-1.16). For replication 2, the RCT included 154 patients and the RWD included 704 patients treated with melphalan, prednisone, and thalidomide for untreated multiple myeloma. The median OS was 52.6 (95% CI: 40-not applicable) months in the RCT and 36.9 (95% CI: 33.8-40.5) months in the RWD, unadjusted HR 0.67 (95% CI: 0.51-0.87). For TTD, the HR was 0.89 (95% CI: 0.74-1.06). The results were similar when applying various propensity-based confounding adjustments. In conclusion, OS was shorter in the RWD, whereas TTD was similar. Importantly, the data necessary (ex: eligibility criteria and baseline confounders) for replicating RCTs was mostly not available and these results further underscore the importance of developing frameworks for capturing relevant patient-level RWD for clinical and regulatory decision making in oncology.

'You're in this world now': Students', teachers', and parents' experiences of school transition and how they feel it can be improved.

BACKGROUND: Primary-secondary school transition is a major life event for 11-year-old children in the United Kingdom and can also be a stressful period for parents and teachers. However, most research focuses on the impact of transition on children's academic performance and social well-being and we have a limited understanding of their emotional experiences in the lead up to and during the transition, from the perspective of key stakeholders: students, parents, and teachers. AIMS: To explore transfer students', parents', and teachers' experiences in the lead up to and over the transition period, and how they feel it could be improved. SAMPLE: The sample consisted of 45 year seven students, 8 year seven parents, 8 year seven teachers, and 8 year six teachers, recruited from five primary and five secondary schools. METHOD: Students participated in face-to-face semi-structured focus groups and adults in asynchronous online focus groups. Transcribed audio-recordings were analysed using inductive thematic analysis. RESULTS: Students, parents, and teachers were shown to navigate a similar process over primary-secondary school transition. All talked about managing their own and others' emotions, relationships, and expectations. These were shaped by shared communication across primary and secondary schools and between the stakeholders, and impacted by how good transition provision was seen to be. CONCLUSIONS: There is a need to understand the transition period from the perspective of students, teachers, and parents, to improve school transition. This information will allow us to design emotional centred support interventions that reflect these lived experiences.

Longitudinal associations between younger children's humour styles and psychosocial adjustment.

Whilst a multitude of studies have examined links between different styles of humour and aspects of adjustment, longitudinal research is noticeably lacking. Following a study which identified bidirectional associations between humour styles and psychosocial adjustment in older children, the current research aimed to investigate these associations in younger children. In total, 413 children aged 8-11 years completed the humour styles questionnaire for younger children (HSQ-Y) alongside measures of psychosocial adjustment in both the autumn and the summer over the course of a school year. Findings across the school year suggested that children's adjustment may impact significantly on their use of different styles of humour. Further longitudinal research over a longer time period would now be beneficial to further increase our understanding of the associations between humour styles and adjustment throughout development. Statement of contribution What is already known on this subject? Research has identified associations between children's humour styles and psychosocial adjustment. Research with older children has also identified longitudinal associations. What does this study add? This is the first study to identify longitudinal associations between humour styles and adjustment in younger children. This allows for stronger statements to be made about causal relationships.

"As a Parent You Become a Tiger": Parents Talking about Bullying at School.

Bullying at school can be a distressing experience for children. It is also likely to be distressing for their parents. In spite of this, research in the field of school bullying and peer victimisation has tended to overlook the experience of parents when their child is bullied. This study explored school bullying from the parent's perspective. Twenty-one parents took part in semi-structured focus groups and interviews to share their experiences. Thematic analysis of the interview transcripts identified two main themes: 'perceived institutional factors' and 'being a good parent'. It was found that parents viewed their principal role as protecting their child; they referred to this as an instinct and fundamental to them being a good parent. However, during their attempts to help their child, many parents talked about difficulties working with schools and this triggered frustration and distrust towards teachers. The findings highlight the importance of communication between parents and teachers and ensuring that parents are kept informed of progress when teachers are trying to address the problem. Additionally, the findings indicate that parents may hold different views to teachers about their role in school bullying situations. This would suggest that parents looking at the situation from the teacher's perspective, and vice versa, could help to build better parent-teacher relationships when tackling school bullying.

Longitudinal Associations Between Humor Styles and Psychosocial Adjustment in Adolescence.

This study assessed the concurrent and prospective associations between psychosocial adjustment and four humor styles, two of which are adaptive (affiliative, self-enhancing) and two maladaptive (aggressive, self-defeating). Participants were 1,234 adolescents (52% female) aged 11-13 years, drawn from six secondary schools in England. Self-reports of psychosocial adjustment (loneliness, depressive symptomatology, and self-esteem) and humor styles were collected at two time points (fall and summer). In cross-lagged panel analyses, self-defeating humor was associated with an increase in both depressive symptoms and loneliness, and with a decrease in self-esteem. In addition, depressive symptoms predicted an increase in the use of self-defeating humor over time, indicating that these may represent a problematic spiral of thoughts and behaviors. Self-esteem was associated with an increase in the use of affiliative humor over the school year but not vice-versa. These results inform our understanding of the ways in which humor is associated with psychosocial adjustment in adolescence.

Children's Understanding of Self-Focused Humor Styles.

It has been proposed that four main styles of humor exist, two which are thought to be adaptive (affiliative, self-enhancing) and two which are thought to be maladaptive (aggressive, self-defeating). Whilst the existence of these four humor styles has been supported in older children, it is suggested that for younger children, self-enhancing and self-defeating humor may develop at a later point. To investigate this further, the current research involved five semi-structured paired interviews with children aged eight to eleven years to explore the use and understanding of self-enhancing and self-defeating humor in this age group. Findings indicated that use of both self-enhancing and self-defeating humor were apparent in some children, but not all. It therefore seems appropriate that attempts to investigate humor in this age group should aim to include all four styles of humor. The current research also demonstrated the value of paired interviews when carrying out this sort of research with children.

Humor style similarity and difference in friendship dyads.

This study assessed the concurrent and prospective (fall to spring) associations between four different humor styles to assess the degree to which stable friendships are characterized by similarity, and to assess whether best friends' humor styles influence each other's later use of humor. Participants were aged 11-13 years, with 87 stable, reciprocal best friend dyads. Self-report assessments of humor styles were completed on both occasions. Results indicated that there was no initial similarity in dyads' levels of humor. However, dyads' use of humor that enhances interpersonal relationships (Affiliative humor) became positively correlated by spring. Additionally, young people's use of this humor style was positively associated with their best friend's later use of the same. No such effects were present for humor which was aggressive, denigrating toward the self, or used to enhance the self. These results have clear implications for theories of humor style development, highlighting an important role for Affiliative humor within stable friendship dyads.

Development of the Attitudes to Domestic Violence Questionnaire for Children and Adolescents.

To provide a more robust assessment of the effectiveness of a domestic abuse prevention education program, a questionnaire was developed to measure children's attitudes to domestic violence. The aim was to develop a short questionnaire that would be easy to use for practitioners but, at the same time, sensitive enough to pick up on subtle changes in young people's attitudes. We therefore chose to ask children about different situations in which they might be willing to condone domestic violence. In Study 1, we tested a set of 20 items, which we reduced by half to a set of 10 items. The factor structure of the scale was explored and its internal consistency was calculated. In Study 2, we tested the factor structure of the 10-item Attitudes to Domestic Violence (ADV) Scale in a separate calibration sample. Finally, in Study 3, we then assessed the test-retest reliability of the 10-item scale. The ADV Questionnaire is a promising tool to evaluate the effectiveness of domestic abuse education prevention programs. However, further development work is necessary.

Does the gender of the bully/victim dyad and the type of bullying influence children's responses to a bullying incident?

Children's responses to bullying are context related; they will vary depending on the specific bullying episode. The aim of the present study was to explore whether children's responses to bullying vary depending on the gender of the bully and victim and the type of bullying portrayed. In total, 437 children aged 9-11 years from four primary schools in the UK took part in the study. Each child read a story about one child bullying another. There were 12 different versions of the story, varying the type of bullying (verbal, physical, or relational/indirect) and the gender of the bully and victim (i.e., male bully-female victim, female bully-male victim, male bully-male victim, female bully-female victim). Each child was randomly allocated to one of the 12 stories. After reading the story the children then responded to a series of questions to assess their perceptions of the victim and bully and situation. Overall females liked the bully more than males; females also reported liking the female victim more than the male victim and females were more likely than males to intervene with a female victim. The bullying was viewed as more serious, more sympathy was shown to the victim, and there was a greater likelihood of intervention when the incident involved a female bully. There was less liking for the bully if the situation involved a female victim of physical bullying. The findings are explained in terms of social identity theory and social norms about typical male and female behavior.

Gender differences in the relationships between bullying at school and unhealthy eating and shape-related attitudes and behaviours.

BACKGROUND. Previous research has found links between being a victim of bullying and reporting more unhealthy eating behaviours and cognitions, particularly in girls. However, little is known about the factors that might mediate these relationships. AIM. The present study compared the relationships between bullying, emotional adjustment, restrained eating, and body dissatisfaction in adolescent boys and girls. SAMPLE/METHOD. Self-report data were collected from a sample of 11- to 14-year-olds (N= 376) on experiences of bullying, emotional symptoms, and unhealthy eating and shape-related attitudes and behaviours. RESULTS. Bullying, emotional symptoms, restrained eating, and body dissatisfaction were all correlated. Emotional symptoms were found to significantly mediate the relationships between verbal bullying with body dissatisfaction in girls but not in boys. CONCLUSIONS. Findings suggest that the experience of being verbally bullied places adolescent girls at risk of developing emotional problems which can then lead to body dissatisfaction. Longitudinal research is necessary to disentangle these pathways in more detail to facilitate the development of informed interventions to support children who are being bullied.

The relation between trust beliefs and loneliness during early childhood, middle childhood, and adulthood.

Four studies examined the relation between trust and loneliness. Studies 1, 2, and 3 showed that trust beliefs negatively predicted changes in loneliness during early childhood (5-7 years), middle childhood (9-11 years), and young adulthood (18-21 years). Structural equation modeling yielded support for the hypothesis that the relation between trust beliefs and loneliness was mediated, in part, by social disengagement, which varied by age and gender. Study 4 showed that when young adults were primed for distrust rather than for trust cognitions, they showed greater withdrawal (loneliness) affect, lower willingness to disclose, and less perceived success in achieving rapport. The findings yielded support for the hypotheses that (a) low trust beliefs promote loneliness from childhood to adulthood and (b) social disengagement and cognitive schema mechanisms account for the relation.

The association between adolescents' beliefs in a just world and their attitudes to victims of bullying.

BACKGROUND: Research which has investigated children's attitudes to bullying has found that the majority of children display anti-bullying attitudes. However, a small minority of children do appear to admire the bully and lack sympathy for victims of bullying. The just world belief theory has received a great deal of attention in recent years with evidence emerging in support of a two-dimensional model distinguishing between beliefs in a just world (BJW) for self and BJW for others. BJW-self (and not BJW-others) has been found to uniquely predict psychological well-being, whereas BJW-others (and not BJW-self) uniquely predicts harsh social attitudes and derogation of victims. AIM: The aim of the present study was to measure BJW-self and others in a sample of UK secondary schoolchildren and to see whether BJW-others can account for adolescents' negative attitudes towards victims of bullying. SAMPLE: In total, 346 pupils aged 11-16 years of age (270 males, 76 females) from two schools took part in the study. METHODS: The participants completed measures of BJW-self and others, attitudes to victims of bullying, empathy, and self-esteem on a whole class basis. RESULTS: It was found that BJW-others uniquely predicted adolescents' attitudes to victims but in the opposite direction to that which was predicted - high BJW were associated with stronger anti-bullying attitudes. As predicted, BJW-self (but not BJW-others) was positively and uniquely correlated with self-esteem. CONCLUSION: The findings are discussed in the context of research which has found that the direction of the relationship between BJW-others and derogation of victims appears to depend on the nature of the injustice, with people with strong BJW less tolerant of severe injustices.

Global and physical self-esteem and body dissatisfaction as mediators of the relationship between weight status and being a victim of bullying.

Research has found evidence of a link between being overweight or obese and bullying/peer victimisation, and also between obesity and adjustment problems such as low self-esteem and body dissatisfaction. Studies have also found that adjustment problems can put children at an increased risk of being bullied over time. However, to date the factors that place overweight or obese children at risk of being bullied have been poorly elucidated. Self-report data were collected from a sample of 11-14 year olds (N=376) about their weight status, about their experiences of three different types of bullying (Verbal, Physical and Social), their global self-worth, self-esteem for physical appearance, and body dissatisfaction. Overweight or obese children reported experiencing significantly more verbal and physical (but not social) bullying than their non-overweight peers. Global self-worth, self-esteem for physical appearance and body dissatisfaction each fully mediated the paths between weight status and being a victim of bullying.

Longitudinal associations between submissive/nonassertive social behavior and different types of peer victimization.

Previous research, primarily in North America, has found that submissive and nonassertive behaviors are associated with peer victimization during childhood. A limitation of this work has been the failure to examine the relationships between such behaviors and different types of peer victimization. To overcome this weakness, we developed an inventory to assess the bidirectional longitudinal associations between three different types of victimization and submissive/nonassertive social behavior. The inventory was completed by 449 children aged 9 to 11 years at two time points over the course of an academic year. The inventory generated self-report scores and peer nominations. A robust finding was that submissive/nonassertive social behavior predicted an increase in social exclusion only. In examining the other direction of the relationship, we found that only social exclusion predicted changes in submissive/nonassertive social behavior over time. The findings advance our understanding of the social skills deficits that put children at risk for peer victimization, and of the implications of victimization for the development of submissive/nonassertive social skills problems.

Cross-sectional and longitudinal relations among children's trust beliefs, psychological maladjustment and social relationships: are very high as well as very low trusting children at risk?

Four hundred and thirty-four children enrolled in school years 5 and 6 in the United Kingdom were administered measures of trust beliefs in peers/best friends and psychosocial functioning (internalized maladjustment, self-perceived social acceptance, social preference, and social exclusion) across an 8-month period (mean age = 9 years-9 months at Time 1). The relation between children's trust beliefs in peers or trust beliefs within best friend dyads and measures of psychosocial functioning conformed to a quadratic pattern. Compared to children in the middle range of trust beliefs, children with very low trust beliefs and those with very high trust beliefs in peers and/or within best friend dyads displayed higher internalized maladjustment, lower self-perceived social acceptance, higher social exclusion, and lower social preference. The relation between the trust beliefs and internalized maladjustment was asymmetrical, with children who held very low trust beliefs being comparatively more disadvantaged.