Core features of callous-unemotional traits: a cross-cultural comparison of youth in four countries.

With considerable debate concerning the impact of culture on the expression of callous-unemotional (CU) traits, it is unclear whether the core features of CU traits generalize to youth across cultures. This study aimed to examine whether cultural differences are reflected in the core features of CU traits and the associations among these features. Network analysis was employed to identify the core features and to examine the network structure of CU traits operationalized by the Inventory of Callous Unemotional traits (ICU) in four community youth samples from different nations (Australia, N = 190; the UK, N = 437; the USA, N = 330; China, N = 503). The item "Apologizes to people" was identified as a cross-cultural core feature in the ICU network with a greater centrality of this item compared to others in all four samples. In addition, some items were identified as culture-specific core features in the network, differing in their centrality across samples. The network structures of the youth self-report ICU items were moderately similar across samples, while the structures of parent-report items showed substantial differences. These findings have important implications for cross-cultural research on CU traits as well as practical implications for screening and treatment. The core features of ICU appear to be generalizable in youth across cultures, although cultural-specific manifestations should be noted.

Callous-unemotional Traits and Child Response to Teacher Rewards, Discipline, and Instructional Methods in Chinese Preschools: A Classroom Observation Study.

Atypical responses to teacher rewards, discipline and different forms of instructional methods have been identified as potential contributors to disruptive behavior, low school engagement, and academic underachievement in children with elevated callous-unemotional (CU) traits. To date, research on CU traits in schools has relied on interview or questionnaire methods and has predominantly been conducted in Western countries. Thus, the present study aims to investigate the relationships between CU traits and children's responses to teacher rewards, discipline and instructional methods in the Chinese preschool context using classroom observation. Eight teachers (7 females, 1 male; M = 37.66 years) and 116 children (56% girls; M = 5.16 years) from two mainstream Chinese preschools participated in the study. Of the 116 eligible children, the behavior of 108 children from four classes were observed during classroom activities. Findings indicated that CU traits were not related to children's responses to discipline, nor did CU traits moderate the relationship between instructional methods and children's academic engagement. Higher CU traits predicted a greater frequency of one-to-one teacher-child interaction. Our findings offer initial insights into the potential of early school-based interventions in fostering engagement and prosocial behavior among children with CU traits. However, they also highlight the need for additional support for preschool teachers, who face the challenge of managing these high-risk children who appear to require more individual time and attention.

A Developmental Psychopathology Perspective on Adverse Childhood Experiences (ACEs): Introduction to the Special Issue.

Adverse childhood experiences (ACEs), including child maltreatment and other adversities in the home context and beyond (e.g., witnessing domestic violence; parental mental illness; parental separation; living in a disadvantaged neighborhood) are prevalent in the population and often covary together. Research based on the construct of ACEs has transformed the field of adult mental health, yet child and adolescent mental health has often been overlooked in this work. This special issue of Research on Child and Adolescent Psychopathology focuses on the developmental science of ACEs and child psychopathology. The research presented here draws on the extensive evidence base that now exists regarding the co-occurrence of common childhood adversities, while informing the integration of theory and research on ACEs with that of developmental psychopathology at large. This Introduction provides an overview of ACEs and child mental health from a developmental psychopathology perspective, with an emphasis on key concepts and recent progress spanning the prenatal period through to adolescence and intergenerational pathways. Models of ACEs that emphasize the multi-dimensional nature of adversity and the importance of developmental timing to risk and protective pathways, have played a driving role in this progress. Methodological innovations in this work are highlighted, along with implications for prevention and intervention.

The association between callous-unemotional traits and substance use in childhood and adolescence: A systematic review and meta-analysis.

Callous-unemotional (CU) traits are characterized by a lack of guilt and empathy, restricted affect, and low concern about performance, and are increasingly recognized as co-occurring with substance use in youth. However, there is mixed evidence concerning whether they make a unique contribution to substance use. This systematic review and meta-analysis sought to quantify the association between CU traits and substance use in childhood, accounting for potential moderators including sample characteristics (age, gender, community versus clinical/forensic samples), CU traits measure and informant, and study design (cross-sectional or longitudinal). Separate meta-analyses were conducted for alcohol, cannabis, and a substance use composite. Small, significant associations were found between CU traits and alcohol (θ = 0.17), cannabis (θ = 0.17) and the substance use composite (θ = 0.15), which were present in both community and clinical/forensic samples. Findings suggest that CU traits co-occur with a range of substance use problems, and that CU traits should be considered in assessments of youth presenting with substance use problems regardless of the nature of the setting.

The influence of individual, peer, and family factors on the educational aspirations of adolescents in rural China.

Educational aspirations are an important predictor of academic outcomes. While there has been considerable research on educational aspirations in the West, there has been little research in East Asia, and the investigation of factors influencing adolescent aspirations has been neglected, particularly in rural areas. Drawing on ecological systems theory and social cognitive career theory, this study investigated the associations between educational aspirations and factors at the individual, peer, and family levels among rural Chinese adolescents. A total of 606 students (M age = 14.85 years; 50% boys) from a rural town in Central China completed questionnaires assessing their educational aspirations, individual factors (academic performance, academic self-perception, academic self-regulation, attitudes toward teachers, and goal valuation), and contextual factors (family socioeconomic status, parent and peer relationship quality, and parental and close friends' aspirations). Individual factors and aspirations of others had significant direct effects on adolescents' educational aspirations, while parent and peer attachments were significantly related to educational aspirations via individual factors. Family socioeconomic status was not significantly related to adolescents' educational aspirations. The findings highlight the importance of individual factors as mechanisms explaining the link between contextual factors and rural Chinese adolescents' educational aspirations. Our results suggest that interventions can be designed to increase and maintain the aspirations of rural Chinese youth by targeting multiple domains of influence.

Do interventions principally targeting excessive alcohol use in young people improve depression symptoms?: a systematic review and meta-analysis.

BACKGROUND: Excessive alcohol use is common in young people and is associated with a range of adverse consequences including an increased risk of depression. Alcohol interventions are known to be effective in young people, however it is not known if these interventions can also improve depression. OBJECTIVE: To investigate whether psychosocial interventions principally targeting excessive alcohol use in young people reduce depression symptoms compared to controls. DESIGN: We conducted a systematic review and meta-analysis of controlled intervention trials, that measured depression symptoms at follow-up. We used a generic inverse variance random effect meta-analysis to pool the standardised mean difference in change in depression symptoms from baseline to follow-up between intervention and control arms. We used I2 to measure heterogeneity, the Cochrane tool for randomised trials to assess risk of bias, and Egger's tests to assess small study bias. DATA SOURCES: APA PsycNET, PubMed, Cochrane Central Register of Controlled Trials, Web of Science, Embase (including MEDLINE), and clinicaltrials.gov were searched for relevant studies published from inception to December 2020. Reference lists of studies were also searched, and authors contacted where articles presented insufficient data. STUDY ELIGIBILITY CRITERIA: Intervention studies that primarily targeted existing excessive alcohol use in young people (aged 10 to 24) and assessed depression outcomes at baseline with a minimum of four-week follow-up. RESULTS: Five studies were included in the meta-analysis. Interventions targeting excessive alcohol use were associated with a reduction in depression symptoms from baseline to follow-up when compared to control, standardised mean difference = - 0.26, and 95% confidence interval [- 0.41, - 0.12], p < .001. CONCLUSIONS: This study found evidence that interventions primarily targeting excessive alcohol use can reduce depression symptoms in young people. However, this finding should be taken with caution given concerns about risk of bias in all studies. More research is needed to examine whether these findings generalise beyond populations of undergraduate students primarily living in high income countries. TRIAL REGISTRATION: PROSPERO registration number: CRD42020177260 .

Longitudinal Associations between Callous-unemotional (CU) Traits and School-based Affiliative Relationships among South Korean Children.

OBJECTIVE: Callous-unemotional traits (CU) traits are characterized by low empathy, guilt, and reduced sensitivity to others' feelings, along with a reduced drive for social affiliation. However, little is known about the relationships between CU traits and social affiliation in the school context, or the influence of gender on these associations. This study tested reciprocal associations between CU traits and school-based affiliative relationships and explored gender as a potential moderator. METHOD: The sample included South Korean children aged 10 to 12 years (N = 218, M = 11.03, SD = .65, 52% boys). Children reported on CU traits, antisocial behavior, teacher-student relationship quality, and peer affiliation. Three-wave longitudinal cross-lagged models tested reciprocal associations between CU traits and affiliation with both teachers and peers, with multi-group modeling employed to test the moderating effect of gender. RESULTS: Higher CU traits at time 1 predicted decreases in teacher affiliation at time 2 controlling for CU traits, teacher-child affiliation, and antisocial behavior at time 1, while lower teacher-child affiliation at time 2 predicted increases in CU traits at time 3 accounting for CU traits, teacher-child affiliation, and antisocial behavior at time 2. However, there were no reciprocal associations between CU traits and teacher affiliation nor significant associations between CU traits and peer affiliation. Gender did not moderate any pathways between CU traits and teacher or peer affiliation. CONCLUSIONS: Findings indicate CU traits may reduce teacher-child affiliation, potentially escalating risk for further increases in CU traits. Thus, teacher-child affiliation may represent an important target for school-based intervention for children with elevated CU traits regardless of gender.

The Influence of Antisocial Behavior and Callous-Unemotional Traits on Trajectories of School Engagement and Achievement in South-Korean Children.

Poor educational outcomes are common among children with antisocial behavior problems, including among a subgroup of antisocial children with callous-unemotional traits, who show deficits in empathy, guilt, and prosociality. However, few studies have explored the unique contributions of antisocial behavior and callous-unemotional traits to school outcomes and most prior studies have been conducted in Western countries. The current study thus tested associations between callous-unemotional traits, antisocial behavior, and trajectories of school outcomes among South Korean children. Participants aged 10-12 years (N = 218; 52% boys) completed questionnaires assessing antisocial behavior, callous-unemotional traits, verbal ability, and school engagement, and teachers provided children's Math and Korean grades at three time points during a single academic year. Prospective associations were explored in conditional latent growth curve models. Both antisocial behavior and callous-unemotional traits were related to lower school engagement at the start of the academic year, but the magnitude of the associations was greater for callous-unemotional traits, suggesting a greater adverse effect of callous-unemotional traits on engagement than antisocial behavior. Moreover, children with high levels of callous-unemotional traits showed stable and low levels of school engagement. There were no significant predictive associations between antisocial behavior or callous-unemotional traits and trajectories of academic grades. The findings suggest that interventions aimed at improving educational outcomes among antisocial children should be tailored according to the presence of callous-unemotional traits to target the specific needs of individual students, particularly at the start of the school year.

Assessing the Measurement Invariance of the Inventory of Callous-Unemotional Traits in School Students in China and the United Kingdom.

The current study investigated the measurement invariance of the Inventory of Callous-Unemotional Traits in school-attending youth in the UK (N = 437) and China (N = 364). The original 24-item ICU and five shortened versions proposed in previous studies were tested and compared using confirmatory factor analysis in the UK sample. Results indicated that the original ICU was a poor fit in the UK sample. A shortened, 11-item version (ICU-11) featuring two factors (Callousness and Uncaring) provided the best fit and was invariant across gender in both the UK and Chinese samples. Comparisons of the ICU-11 in UK and Chinese school children revealed a similar item-factor combination and factor loadings, but different item thresholds. Findings indicate that the ICU-11 may be a preferable alternative to the original version, but that average ICU-11 scores may have a different meaning in the UK and China.

To what extent does punishment insensitivity explain the relationship between callous-unemotional traits and academic performance in secondary school students?

BACKGROUND: Callous-unemotional (CU) traits are related to low achievement but not to deficits in verbal ability, commonly regarded as a major risk factor for poor academic outcomes in antisocial youth. This suggests that CU traits may have utility in explaining heterogeneous risk pathways for poor school performance in antisocial children. Reduced sensitivity to teacher discipline has been suggested as a potential explanation for the association between CU traits and low achievement, given its importance in facilitating engagement in learning. This study is the first to examine punishment insensitivity as a potential mechanism explaining the relationship between CU traits and poor achievement. AIM: The current study investigated the indirect pathway from CU traits via the predictor of punishment insensitivity to English, Maths, and Science grades. SAMPLE: A total of 437 English secondary school students aged 11 to 14 years (49% girls). METHODS: We conducted a mediation analysis within a structural equation modelling framework. CU traits and punishment insensitivity were assessed using child report questionnaires and academic grades were obtained from school records. RESULTS: CU traits were indirectly associated with low academic grades in Maths and Science, but not English, via punishment insensitivity, controlling for child age, gender, single parent household status, free school meals eligibility, externalizing problems, and classroom effects. CONCLUSIONS: Findings indicated that reduced sensitivity to discipline forms a pathway linking CU traits to poor performance in Maths and Science. Teachers may therefore need additional support to implement discipline effectively with children high in CU traits in order to prevent poor academic outcomes.

PROgesterone Therapy for Endometrial Cancer Prevention in Obese Women (PROTEC) Trial: A Feasibility Study.

Obesity is the major etiologic driver for endometrial cancer. The levonorgestrel intrauterine system (LNG-IUS) reduces the risk of endometrial cancer and its precursor, atypical hyperplasia. We assessed feasibility and uptake of the LNG-IUS for primary prevention of endometrial cancer in high-risk women and its impact on endometrial tissue biomarkers. Women with class-III obesity [body mass index (BMI) > 40 kg/m2] and histologically normal endometrium were invited to participate in a clinical trial of the LNG-IUS for endometrial protection. Recruitment, successful LNG-IUS insertion, and adherence to trial procedures were recorded. We measured impact of the LNG-IUS on circulating biomarkers of endometrial cancer risk, endometrial proliferation (Ki-67, pAKT, PTEN), endometrial hormone receptor status [estrogen receptor and progesterone receptor (PR)], mental wellbeing, and menstrual function. At 6 months, women chose to keep their LNG-IUS or have it removed. In total, 103 women were approached, 54 were offered a participant information sheet, 35 agreed to participate, and 25 received a LNG-IUS. Their median age and BMI were 54 years [interquartile range (IQR) 52-57] and 47 kg/m2 (IQR 44-51), respectively. Three women (3/35, 9%) were ineligible due to atypical hyperplasia/endometrial cancer on their baseline biopsy. The LNG-IUS was well tolerated and had a positive overall effect on bleeding patterns and mental wellbeing. The LNG-IUS was associated with endometrial morphologic change, reduced Ki-67, and PR expression, but circulating biomarkers of endometrial cancer risk were unchanged. All but one woman (96%) kept her LNG-IUS. The LNG-IUS appears to be acceptable to some women with class-III obesity for primary prevention of endometrial cancer, which could provide a strategy for a prevention trial.Prevention Relevance: Novel strategies are urgently needed to prevent the rise in endometrial cancer diagnoses predicted by escalating obesity rates. Here, we show that women with class III obesity are willing to engage in risk reduction with a levonorgestrel intrauterine system, which could provide a strategy for an endometrial cancer prevention trial.

Callous-Unemotional Traits and Antisocial Behavior in South Korean Children: Links with Academic Motivation, School Engagement, and Teachers' Use of Reward and Discipline.

Callous-unemotional (CU) traits have been associated with atypical responses to reward and punishment cues, with evidence suggesting that such traits may shape caregiver use of reward and punishment practices over time. To date, research has predominantly focused on parental rewards and discipline, with far less attention paid to teacher behavior management strategies. The first aim of the current study was to investigate the potential moderating effect of CU traits on the relationship between teacher classroom management strategies (rewards and discipline) and two important school-related outcomes: student engagement and academic motivation. The second aim was to examine whether CU traits were related to teachers' use of discipline and reward strategies over time. Children attending South Korean primary schools (N = 218; aged 10-12 years; 52% boys) reported on CU traits, antisocial behavior, teacher classroom management strategies, school engagement and academic motivation at two time points (the beginning and end of a single academic year). First, harsh teacher discipline predicted lower school engagement, but only for children low in CU traits. Second, cross-lagged longitudinal models showed that CU traits predicted decreased use of teacher rewards, over and above associations with antisocial behavior. CU traits were not related to harsh discipline cross-sectionally or longitudinally in models that accounted for antisocial behavior. Findings show that CU traits are related to reduced sensitivity to teacher discipline, suggesting that teachers may need additional support to implement both discipline and reward-based strategies with children high in these traits.

Callous-Unemotional Traits and Academic Performance in Secondary School Students: Examining the Moderating Effect of Gender.

Callous-unemotional (CU) traits and male gender are both known risk factors for poor academic outcomes in children and adolescents. However, despite gender differences in CU trait severity, comorbid difficulties and correlates of CU traits, research has yet to examine whether the CU traits and male gender may work together to increase risk for poor academic performance. That is, whether boys high in CU traits perform more poorly across academic disciplines than girls high in these traits. This study therefore aimed to investigate i) the relationships between CU traits, student gender and English, Science and Math grades, and ii) whether gender moderates the association between CU traits and academic outcomes. Participants were 437 children aged 11 to 14 years (mean age 12.50 years; 49% girls; 85% White) attending a state secondary school in England. Students reported on CU traits and externalizing problems and their English, Math and Science grades were gathered from school records. Using hierarchical linear modelling, CU traits were found to be significantly related to lower English, Math and Science grades when controlling for age, gender, sociodemographic disadvantage and externalizing problems. CU traits were significantly related to lower Science grades for boys but not girls. However, gender did not moderate the association between CU traits for English or Math grades. Findings enhance our understanding of how child characteristics may interact to increase the likelihood of poor school outcomes, and therefore help us to identify youth at-risk for poor academic performance.

A Systematic Review of Risk and Protective Factors for Externalizing Problems in Children Exposed to Intimate Partner Violence.

Intimate partner violence (IPV) is a serious public health issue with innumerable costs to the victims, children, and families affected as well as society at large. The evidence is conclusive regarding a strong association between exposure to IPV and children's externalizing problems. Moving forward, the next step is to enhance our understanding of risk and protective factors associated with these outcomes in order to tailor treatments to meet the needs of both parents and children. The databases Medline, PubMed, and PsyINFO were searched combining variations of the key words such as parent*, child*, mother, partner abuse, domestic abuse, spousal abuse, interpersonal violence, domestic violence, or intimate partner violence. This search were combined with child externalizing behaviors specifically conduct*, oppositional defiant disorder, externaliz*, aggress*, hyperactivity, and ADHD. A total of 31 studies from all three databases were reviewed following application of inclusion and exclusion criteria. The main findings were that child age and gender, callous-unemotional traits, cognitive appraisals, maternal mental health, and quality of parenting emerged as key mediating and moderating factors of the relationship between IPV exposure and child externalizing problems. These findings suggest that interventions provided to families exposed to IPV need to target both maternal and child risk factors in order to successfully reduce child externalizing problems.

PRE-surgical Metformin In Uterine Malignancy (PREMIUM): a Multi-Center, Randomized Double-Blind, Placebo-Controlled Phase III Trial.

PURPOSE: Endometrioid endometrial cancer is strongly associated with obesity and insulin resistance. Metformin, an insulin sensitizer, reduces endometrial tumor growth in vitro. Presurgical window studies allow rapid in vivo assessment of antitumor activity. Previous window studies found metformin reduced endometrial cancer proliferation but these lacked methodological rigor. PREMIUM measured the anti-proliferative effect of metformin in vivo using a robust window study design.Patients and Methods: A multicenter, double-blind, placebo-controlled trial randomized women with atypical hyperplasia or endometrioid endometrial cancer to receive metformin (850 mg daily for 3 days, and twice daily thereafter) or placebo for 1 to 5 weeks until surgery. The primary outcome was posttreatment IHC expression of Ki-67. Secondary outcomes investigated the effect of metformin on markers of the PI3K-Akt-mTOR and insulin signaling pathways and obesity. RESULTS: Eighty-eight women received metformin (n = 45) or placebo (n = 43) and completed treatment. There was no overall difference in posttreatment Ki-67 between the metformin and placebo arms, in an ANCOVA analysis adjusting for baseline Ki-67 expression (mean difference -0.57%; 95% CI, -7.57%-6.42%; P = 0.87). Metformin did not affect expression of markers of the PI3K-Akt-mTOR or insulin signaling pathways, and did not result in weight loss. CONCLUSIONS: Short-term treatment with standard diabetic doses of metformin does not reduce tumor proliferation in women with endometrioid endometrial cancer awaiting hysterectomy. This study does not support a biological effect of metformin in endometrial cancer and casts doubt on its potential application in the primary and adjuvant treatment settings.

Vesicle trafficking pathways that direct cell migration in 3D matrices and in vivo.

Cell migration is a vital process in development and disease, and while the mechanisms that control motility are relatively well understood on two-dimensional surfaces, the control of cell migration in three dimensions (3D) and in vivo has only recently begun to be understood. Vesicle trafficking pathways have emerged as a key regulatory element in migration and invasion, with the endocytosis and recycling of cell surface cargos, including growth factor and chemokine receptors, adhesion receptors and membrane-associated proteases, being of major importance. We highlight recent advances in our understanding of how endocytic trafficking controls the availability and local activity of these cargoes to influence the movement of cells in 3D matrix and in developing organisms. In particular, we discuss how endocytic trafficking of different receptor classes spatially restricts signals and activity, usually to the leading edge of invasive cells.

Parent-dependent stressors and the onset of anxiety disorders in children: links with parental psychopathology.

Exposure to stressors is associated with an increased risk for child anxiety. Investigating the family origins of stressors may provide promising avenues for identifying and intervening with children at risk for the onset of anxiety disorders and their families. The aim of this study was to compare the frequency of parent-dependent negative life events and chronic adversities experienced by children with an anxiety disorder (n = 34) in the 12 months prior to the onset of the child's most recent episode, compared to healthy controls (n = 34). Life events and chronic adversities were assessed using maternal report during an investigator-based interview, which provided independent panel ratings of the extent that reported experiences were related to parent behaviour. There were no group differences in the number of parent-dependent negative life events for anxious children compared to controls. However, significantly more parent-dependent chronic adversities were present for anxious children compared to controls. Findings suggest that parents contribute to an increased frequency of chronic adversities but not negative life events prior to their child's most recent onset of anxiety. Furthermore, increased child exposure to parent-dependent chronic adversities was related to parental history of mental disorder.

α5ß1 integrin recycling promotes Arp2/3-independent cancer cell invasion via the formin FHOD3.

Invasive migration in 3D extracellular matrix (ECM) is crucial to cancer metastasis, yet little is known of the molecular mechanisms that drive reorganization of the cytoskeleton as cancer cells disseminate in vivo. 2D Rac-driven lamellipodial migration is well understood, but how these features apply to 3D migration is not clear. We find that lamellipodia-like protrusions and retrograde actin flow are indeed observed in cells moving in 3D ECM. However, Rab-coupling protein (RCP)-driven endocytic recycling of α5ß1 integrin enhances invasive migration of cancer cells into fibronectin-rich 3D ECM, driven by RhoA and filopodial spike-based protrusions, not lamellipodia. Furthermore, we show that actin spike protrusions are Arp2/3-independent. Dynamic actin spike assembly in cells invading in vitro and in vivo is regulated by Formin homology-2 domain containing 3 (FHOD3), which is activated by RhoA/ROCK, establishing a novel mechanism through which the RCP-α5ß1 pathway reprograms the actin cytoskeleton to promote invasive migration and local invasion in vivo.

The coculture organotypic assay of angiogenesis.

Angiogenesis is a complex process involving the interactions of endothelial cells not only with pro-angiogenic factors but also with stromal cells and stromal matrix components. Modeling this process in vitro is challenging, and many different assays have been described, each with their own particular strengths and weaknesses. The coculture assay is a long-term assay of angiogenesis that uses fibroblasts to secrete and condition a stromal matrix that more closely mimics tissue than a simple collagen gel. The assay is particularly suited to screening for angiogenic regulators and also for high-resolution imaging of endothelial cells undergoing angiogenic morphogenesis.

Reciprocal influences between negative life events and callous-unemotional traits.

Children with conduct problems and co-occurring callous-unemotional (CU) traits show more severe, stable, and aggressive antisocial behaviors than those without CU traits. Exposure to negative life events has been identified as an important contributing factor to the expression of CU traits across time, although the directionality of this effect has remained unknown due to a lack of longitudinal study. The present longitudinal study examined potential bidirectional effects of CU traits leading to experiencing more negative life events and negative life events leading to increases in CU traits across 3 years among a sample of community-based school-aged (M = 10.9, SD = 1.71 years) boys and girls (N = 98). Repeated rating measures of CU traits, negative life events and conduct problems completed by children and parents during annual assessments were moderately to highly stable across time. Cross-lagged models supported a reciprocal relationship of moderate magnitude between child-reported CU traits and "controllable" negative life events. Parent-reported CU traits predicted "uncontrollable" life events at the earlier time point and controllable life events at the later time point, but no reciprocal effect was evident. These findings have important implications for understanding developmental processes that contribute to the stability of CU traits in youth.