Multiple ETS Factors Participate in the Transcriptional Control of TERT Mutant Promoter in Thyroid Cancers

Hotspot mutations in the TERT (telomerase reverse transcriptase) gene are key determinants of thyroid cancer progression. TERT promoter mutations (TPM) create de novo consensus binding sites for the ETS (“E26 transformation specific”) family of transcription factors. In this study, we systematically knocked down each of the 20 ETS factors expressed in thyroid tumors and screened their effects on TERT expression in seven thyroid cancer cell lines with defined TPM status. We observed that, unlike in other TPM-carrying cancers such as glioblastomas, ETS factor GABPA does not unambiguously regulate transcription from the TERT mutant promoter in thyroid specimens. In fact, multiple members of the ETS family impact TERT expression, and they typically do so in a mutation-independent manner. In addition, we observe that partial inhibition of MAPK, a central pathway in thyroid cancer transformation, is more effective at suppressing TERT transcription in the absence of TPMs. Taken together, our results show a more complex scenario of TERT regulation in thyroid cancers compared with other lineages and suggest that compensatory mechanisms by ETS and other regulators likely exist and advocate for the need for a more comprehensive understanding of the mechanisms of TERT deregulation in thyroid tumors before eventually exploring TPM-specific therapeutic strategies.

Association between oral health status and family quality of life among schoolchildren – A cross-sectional study

Objectives: The objective of this study was to assess the association between oral health and family quality of life (QoL) among 6-12 years schoolchildren. Materials and Methods: A cross-sectional study was conducted among 300 schoolchildren of age group 6–12 years in Bengaluru, India. A 14-item pre-validated family impact scale (FIS) instrument was used to assess parental family QoL. The World Health Organization oral health pro forma (2013) was used to assess oral health status of children. Pearson’s correlation, Spearman’s correlation, and logistic regression analysis were performed. P <0.05 was considered as statistically significant. Results: Mean age of the study participants was 9.33 ± 1.85 years. Mean FIS score was 8.1 ± 5.5. The proportion of participants with caries experience, gingival bleeding, dental trauma, and dentinal erosion was 66%, 41%, 16%, and 17%, respectively. Children with caries experience were more likely to have family impact than those without caries (decay, missing, filled teeth) [P < 0.05]). Conclusion: There was an association between oral health status and family QoL among 6–12 years schoolchildren. Dental caries had an impact on family QoL among the schoolchildren in Bengaluru city.

Multiple ETS Factors Participate in the Transcriptional Control of TERT Mutant Promoter in Thyroid Cancers

Hotspot mutations in the TERT (telomerase reverse transcriptase) gene are key determinants of thyroid cancer progression. TERT promoter mutations (TPM) create de novo consensus binding sites for the ETS (“E26 transforming sequence”) family of transcription factors. In this study, we systematically knocked down each of the 20 ETS factors expressed in thyroid tumors and screened their effects on TERT expression in seven thyroid cancer cell lines with defined TPM status. We observed that, unlike in other TPM-carrying cancers such as glioblastomas, ETS factor GABPA does not unambiguously regulate transcription from the TERT mutant promoter in thyroid specimens. In fact, multiple members of the ETS family impact TERT expression, and they typically do so in a mutation-independent manner. In addition, we observe that partial inhibition of MAPK, a central pathway in thyroid cancer transformation, is more effective at suppressing TERT transcription in the absence of TPMs. Taken together, our results show a more complex scenario of TERT regulation in thyroid cancers compared to other lineages, suggest that compensatory mechanisms by ETS and other regulators likely exist and advocate for the need of a more comprehensive understanding of the mechanisms of TERT deregulation in thyroid tumors before eventually exploring TPM-specific therapeutic strategies.Graphical Abstract

Adaptation and validation of two autism-related measures of skills and quality of life in Ethiopia

Although most children with autism and other neurodevelopmental disorders live in low- and middle-income countries, assessment tools are lacking in these settings. This study aims to culturally adapt and validate two questionnaires for use in Ethiopia: the Autism Treatment Evaluation Checklist and the Pediatric Quality of Life Inventory™ Family Impact Module. Both questionnaires were adapted to be suitable for administration in low-literate caregivers and translated using the backward translation procedure. The factor structure, reliability and validity were investigated using caregiver-reports on 300 children with neurodevelopmental disorders or physical health conditions. Confirmatory factor analysis of the Pediatric Quality of Life Inventory™ Family Impact Module data indicated an acceptable fit of the hypothesised eight-factor structure. Internal consistency was high for both measures. Test–retest reliability was excellent for the Autism Treatment Evaluation Checklist and moderate to excellent for the Pediatric Quality of Life Inventory™ Family Impact Module. Both questionnaires demonstrated adequate known-group validity, with moderate to very large effect size group differences between case and control groups. The questionnaires correlated moderately with each other. In conclusion, the Ethiopian adaptations of the Autism Treatment Evaluation Checklist and the Pediatric Quality of Life Inventory™ Family Impact Module are valid and reliable tools for use in parents of children with neurodevelopmental disorders including autism. These adapted measures may also be valuable for use in other low-income settings. Lay abstract Although most children with autism and other neurodevelopmental disorders live in low- and middle-income countries, reliable tools to assess these conditions are often not available in these settings. In this study, we adapted two questionnaires developed in Western high-income contexts for use in Ethiopia – the Autism Treatment Evaluation Checklist and the Pediatric Quality of Life Inventory™ Family Impact Module. Both measures are completed by a child’s caregiver and both are relatively short and easy to complete. The Autism Treatment Evaluation Checklist is used to monitor the developmental issues of the child, while the Pediatric Quality of Life Inventory™ Family Impact Module measures the impact of the child’s condition on the caregiver. We translated both tools into the Ethiopian language Amharic, and adapted them to the local cultural context. Three hundred caregivers, half of whom were parents of children with neurodevelopmental disorders, and half were parents of children with physical health problems, completed the questionnaires through a face-to face interview, so that non-literate caregivers could also take part. Both tools performed adequately, measured what we aimed to measure and were reliable. Both the Autism Treatment Evaluation Checklist and Pediatric Quality of Life Inventory™ are suitable tools to assess children with developmental and other health problems in Ethiopia and their caregivers. We believe that more similar tools should be developed or adapted for use in low-income countries like Ethiopia, to gain a better understanding of developmental problems in those settings, and allowing clinicians and service providers to use these tools in their practice. Moreover, these tools can be used in future studies to evaluate interventions to improve support for families.

Exploring the psychological impact of COVID-19 on adolescents with borderline personality disorder and their mothers: A focus group study

The aim of this study was to explore the impact of the coronavirus pandemic on adolescents diagnosed with Borderline Personality Disorder (BPD) and their mothers. This exploratory study used a qualitative focus group approach. This study’s sample group consisted in nine participants: five adolescents diagnosed with BPD and their four mothers. Patients were recruited from a specialized BPD outpatient unit of a university hospital psychiatry department. The results are divided into two main areas, the first regarding the lockdown period and the second examining the period of gradual relaxation of lockdown restrictions. The results show that the adolescents had difficulties in the management of their interpersonal relationships, especially in striking a balance between individual and family space, as well as in communication, cohesion, and family dynamics. During the COVID lockdown, adolescents experienced a stabilization of psychopathological symptoms, but these symptoms worsened when the lockdown restrictions were lifted. Nevertheless, they reported having learned and implemented self-care strategies. The findings are discussed in terms of both individual and family impact, shedding light on some of the challenges precipitated by the COVID-19 pandemic.

Defining the Critical Components of Informed Consent for Genetic Testing

Purpose: Informed consent for genetic testing has historically been acquired during pretest genetic counseling, without specific guidance defining which core concepts are required. Methods: The Clinical Genome Resource (ClinGen) Consent and Disclosure Recommendations Workgroup (CADRe) used an expert consensus process to identify the core concepts essential to consent for clinical genetic testing. A literature review identified 77 concepts that are included in informed consent for genetic tests. Twenty-five experts (9 medical geneticists, 8 genetic counselors, and 9 bioethicists) completed two rounds of surveys ranking concepts’ importance to informed consent. Results: The most highly ranked concepts included: (1) genetic testing is voluntary; (2) why is the test recommended and what does it test for?; (3) what results will be returned and to whom?; (4) are there other types of potential results, and what choices exist?; (5) how will the prognosis and management be impacted by results?; (6) what is the potential family impact?; (7) what are the test limitations and next steps?; and (8) potential risk of genetic discrimination and legal protections. Conclusion: Defining the core concepts necessary for informed consent for genetic testing provides a foundation for quality patient care across a variety of healthcare providers and clinical indications.

20 Adolescent and caregiver perspectives on living with a limb fracture: A qualitative study

Primary Subject area Emergency Medicine - Paediatric Background Fractures occur in up to half of children by age 16 years. After initial emergency care for a fracture, function is universally impaired in children, and impacts extend to the immediate family. Knowledge of expected functional limitations is key to providing proper discharge instructions and anticipatory guidance to families. Objectives Our study objectives were to understand: 1) how adolescents (12-17 years) describe the functional impact of fractures on their lives; 2) how adolescents’ reports of their experiences compare to those of their caregivers; and 3) the impact of the fracture on the family unit. Design/Methods We conducted individual, semi-structured interviews from June 2019 to November 2020 with adolescents and their caregivers, 7-14 days following their initial visit to a pediatric emergency department. We utilized qualitative content analysis methodology. Recruitment proceeded until thematic saturation was achieved. Coding and analysis were concurrent with recruitment and interviews. A secondary coder reviewed 40% of the transcripts, and the coding team met regularly to discuss the coding framework and key themes. The interview script was modified in an iterative process, to reflect emerging themes. Results We completed a total of 29 interviews. The most commonly affected functions were: a) showering and hygiene (which required the most caregiver support); b) sleep variability (due to pain and cast-related discomfort); and c) exclusion from sports/activities. Many adolescents experienced disruptions to social activities and gatherings. Adolescents valued independence and often chose to take more time to complete a task to preserve this, regardless of inconvenience. Both adolescents and caregivers reported feelings of frustration as a result of day-to-day impacts imposed by the injury. Generally, caregivers’ perspectives were in keeping with the experiences that adolescents described for themselves. Notable family impacts included what we described as ‘sibling burden’ or conflicts that arose when a sibling had to take on extra chores/tasks. Conclusion These themes highlight an opportunity to better tailor discharge instructions for adolescents with fractures. Key messages include: 1) expect pain and impaired sleep, especially in the first few days; 2) allow extra time to complete tasks independently, especially for grooming and hygiene; 3) consider family impact, especially sibling burden; 4) prepare for changes in activities and social dynamics; and 5) frustration is normal, for both adolescents and caregivers. Future work can focus on developing a novel, family-informed tool to assess functional outcomes following injury.

Efficacy of Bifidobacterium animalis subsp. lactis, BB-12® on infant colic – a randomised, double-blinded, placebo-controlled study

To evaluate the administration of Bifidobacterium animalis subsp. lactis, BB-12® (BB-12) on infant colic in breastfed infants, a double-blind, placebo-controlled randomised study was conducted in Chengdu, China from April 2016 to October 2017 with 192 full-term infants less than 3 months of age and meeting the ROME III criteria for infant colic. After a 1-week run-in the infants were randomly assigned to receive daily BB-12 (1×109 cfu/day) or placebo for 3 weeks. Crying/fussing time were recorded using a 24 h structured diary. The primary endpoint was the proportion of infants achieving a reduction in crying and fussing time of ≥50% from baseline. Parent’s/caregiver’s health related quality of life was measured using a modified PedsQL™ 2.0 Family Impact Module and immunological biomarkers were evaluated from faecal samples at baseline and after the 21-day intervention. The percentage of infants achieving a reduction in the daily crying/fussing time ≥50% after the 21-day intervention was significantly higher in the infants supplemented with BB-12 (P<0.001). The mean number of crying episodes was significantly reduced in the BB-12 group compared to the placebo group (10.0±3.0 to 5.0±1.87 vs 10.5±2.6 to 7.5±2.8, respectively) (P<0.001) and the mean daily sleep duration was markedly increased from baseline to end of intervention in the BB-12 group compared to the infants in the placebo group (60.7±104.0 vs 31.9±102.7 min/day, respectively) (P<0.001). The faecal levels of human beta defensin 2, cathelicidin, slgA, calprotectin and butyrate were statistically higher in the BB-12 group compared to the placebo group after the 21-day intervention. At the end of the intervention the parent’s/caregiver’s physical, emotional and social functioning scores were significantly higher for the BB-12 group compared to the placebo group (all P<0.05). Supplementation of BB-12 is effective in reducing crying and fussing in infants diagnosed with infant colic.