Systematic Critical Review of Genetic Factors Associated with Cisplatin-induced Ototoxicity: Canadian Pharmacogenomics Network for Drug Safety 2022 Update.

BACKGROUND: Cisplatin is commonly used to treat solid tumors; however, its use can be complicated by drug-induced hearing loss (ie, ototoxicity). The presence of certain genetic variants has been associated with the development/occurrence of cisplatin-induced ototoxicity, suggesting that genetic factors may be able to predict patients who are more likely to develop ototoxicity. The authors aimed to review genetic associations with cisplatin-induced ototoxicity and discuss their clinical relevance. METHODS: An updated systematic review was conducted on behalf of the Canadian Pharmacogenomics Network for Drug Safety, based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 statement. Pharmacogenomic studies that reported associations between genetic variation and cisplatin-induced ototoxicity were included. The evidence on genetic associations was summarized and evaluated, and knowledge gaps that can be used to inform future pharmacogenomic studies identified. RESULTS: Overall, 40 evaluated reports, considering 47 independent patient populations, captured associations involving 24 genes. Considering GRADE criteria, genetic variants in 2 genes were strongly (ie, odds ratios ≥3) and consistently (ie, replication in ≥3 independent populations) predictive of cisplatin-induced ototoxicity. Specifically, an ACYP2 variant has been associated with ototoxicity in both children and adults, whereas TPMT variants are relevant in children. Encouraging evidence for associations involving several other genes also exists; however, further research is necessary to determine potential clinical relevance. CONCLUSIONS: Genetic variation in ACYP2 and TPMT may be helpful in predicting patients at the highest risk of developing cisplatin-induced ototoxicity. Further research (including replication studies considering diverse pediatric and adult patient populations) is required to determine whether genetic variation in additional genes may help further identify patients most at risk.

Role of Cisplatin Dose Intensity and TPMT Variation in the Development of Hearing Loss in Children.

BACKGROUND: Cisplatin, widely used in the treatment of solid tumors, causes permanent hearing loss in more than 60% of treated children. Previous studies have implicated several clinical factors in the development of ototoxicity, including cumulative cisplatin dose. However, the role of cisplatin dose intensity in the development of hearing loss in children remains unclear. Pharmacogenetic studies have also identified genetic variants in TPMT that increase the risk of cisplatin-induced hearing loss. This study aims to determine whether cisplatin dose intensity contributes to the risk of hearing loss in children and whether genetic variations in TPMT further modifies the risk of cisplatin-induced hearing loss. METHODS: The authors genotyped 371 cisplatin-treated children for the presence of any 3 TPMT -risk variants. Patients were categorized into high-, moderate-, and low-intensity cisplatin dosing groups according to the cisplatin dose administered per unit time. Kaplan-Meier curves were plotted to compare the cumulative incidence of hearing loss between the genotype and dose intensity groups. RESULTS: Patients receiving cisplatin at high dose intensity experienced significantly higher incidences of ototoxicity than those receiving cisplatin at low dose intensity ( P = 9 × 10 -7 ). Further stratification by TPMT genotype revealed that carriers of ≥1 TPMT variants receiving high-intensity cisplatin developed ototoxicity sooner and more often than their wild-type counterparts (93.8% vs. 56.6% at 12 months; P = 5 × 10 -5 ) and noncarriers receiving low-intensity cisplatin (21.2% at 12 months). CONCLUSIONS: Cisplatin dose intensity is strongly associated with ototoxicity development in children, and this risk is further increased by the presence of TPMT -risk alleles.

Appraising the need for audiological assessment before autism spectrum disorder referral.

Objectives: Mandatory audiological testing before autism spectrum disorder (ASD) assessment is common practice. Hearing impairment (HI) in the general paediatric population is estimated at 3%; however, hearing impairment prevalence among children with ASD is poorly established. Our objective was to determine which children referred for ASD assessment require preliminary audiological assessment. Methods: Retrospective chart review of children (n=4,173; 0 to 19 years) referred to British Columbia's Autism Assessment Network (2010 to 2014). We analyzed HI rate, risk factors, and timing of HI diagnosis relative to ASD referral. Results: ASD was diagnosed in 53.4%. HI rates among ASD referrals was 3.3% and not significantly higher in children with ASD (ASD+; 3.5%) versus No-ASD (3.0%). No significant differences in HI severity or type were found, but more ASD+ females (5.5%) than ASD+ males (3.1%) had HI (P<0.05). Six HI risk factors were significant (problems with intellect, language, vision/eye, ear, genetic abnormalities, and prematurity) and HI was associated with more risk factors (P<0.01). Only 12 children (8.9%) were diagnosed with HI after ASD referral; all males 6 years or younger and only one had no risk factors. ASD+ children with HI were older at ASD referral than No-ASD (P<0.05). Conclusions: Children with ASD have similar hearing impairment rates to those without ASD. HI may delay referral for ASD assessment. As most children were diagnosed with HI before ASD referral or had at least one risk factor, we suggest that routine testing for HI among ASD referrals should only be required for children with risk factors.

The cumulative incidence of cisplatin-induced hearing loss in young children is higher and develops at an early stage during therapy compared with older children based on 2052 audiological assessments.

BACKGROUND: Ototoxicity is a common adverse event of cisplatin treatment. The authors investigated the development of cisplatin-induced hearing loss (CIHL) over time in children with cancer by age and examined the influence of other clinical characteristics on the course of CIHL. METHODS: Data from Canadian patients with childhood cancer were retrospectively reviewed. Hearing loss was graded according to International Society of Pediatric Oncology criteria. The Kaplan-Meier method was applied to estimate the cumulative incidence of CIHL for the total cohort and according to age. Cox regression models were used to explore the effects of independent variables on CIHL development up to 3 years after the start of therapy. RESULTS: In total, 368 patients with 2052 audiological assessments were included. Three years after initiating therapy, the cumulative incidence of CIHL was highest in patients aged ≤5 years (75%; 95% confidence interval [CI], 66%-84%), with a rapid increase observed to 27% (95% CI, 21%-35%) at 3 months and to 61% (95% CI, 53%-69%) at 1 year, compared with patients aged >5 years (48%; 95% CI, 37%-62%; P < .001). The total cumulative dose of cisplatin at 3 months (per 100 mg/m2 increase: hazard ratio [HR], 1.20; 95% CI, 1.01-1.41) vincristine (HR, 2.87; 95% CI, 1.89-4.36) and the total duration of concomitantly administered antibiotics (>30 days: HR, 1.85; 95% CI, 1.17-2.95) further influenced CIHL development over time. CONCLUSIONS: In young children, the cumulative incidence of CIHL is higher compared with that in older children and develops early during therapy. The course of CIHL is further influenced by the total cumulative dose of cisplatin and other ototoxic (co-)medication. These results highlight the need for audiological monitoring at each cisplatin cycle.

Recommendations for Age-Appropriate Testing, Timing, and Frequency of Audiologic Monitoring During Childhood Cancer Treatment: An International Society of Paediatric Oncology Supportive Care Consensus Report.

IMPORTANCE: Ototoxicity is an irreversible direct and late effect of certain childhood cancer treatments. Audiologic surveillance during therapy as part of the supportive care pathway enables early detection of hearing loss, decision-making about ongoing cancer treatment, and, when applicable, the timely use of audiologic interventions. Pediatric oncologic clinical practice and treatment trials have tended to be driven by tumor type and tumor-specific working groups. Internationally accepted standardized recommendations for monitoring hearing during treatment have not previously been agreed on. OBJECTIVE: To provide standard recommendations on hearing loss monitoring during childhood cancer therapy for clinical practice. METHODS: An Ototoxicity Task Force was formed under the umbrella of the International Society of Paediatric Oncology, consisting of international audiologists, otolaryngologists, and leaders in the field of relevant pediatric oncology tumor groups. Consensus meetings conducted by experts were organized, aimed at providing standardized recommendations on age-directed testing, timing, and frequency of monitoring during cancer treatment based on literature and consensus. Consensus statements were prepared by the core group, adapted following several videoconferences, and finally agreed on by the expert panel. FINDINGS: The consensus reached was that children who receive ototoxic cancer treatment (platinum agents, cranial irradiation, and/or brain surgery) require a baseline case history, monitoring of their middle ear and inner ear function, and assessment of tinnitus at each audiologic follow-up. As a minimum, age-appropriate testing should be performed before and at the end of treatment. Ideally, audiometry with counseling before each cisplatin cycle should be considered in the context of the individual patient, specific disease, feasibility, and available resources. CONCLUSIONS AND RELEVANCE: This is an international multidisciplinary consensus report providing standardized supportive care recommendations on hearing monitoring in children undergoing potentially ototoxic cancer treatment. The recommendations are intended to improve the care of children with cancer and facilitate comparative research on the timing and development of hearing loss caused by different cancer treatment regimens.

Prevalence and risk factors for cisplatin-induced hearing loss in children, adolescents, and young adults: a multi-institutional North American cohort study.

BACKGROUND: Cisplatin is used to treat a wide range of childhood cancers and cisplatin-induced hearing loss (CIHL) is a common and debilitating toxicity. We aimed to address persistent knowledge gaps in CIHL by establishing benchmarks for the prevalence of and risk factors for CIHL. METHODS: In this multi-institutional cohort study, children (age 0-14 years), adolescents, and young adults (age 15-39 years) diagnosed with a cisplatin-treated tumour from paediatric cancer centres, who had available cisplatin dosing information, and primary audiology data for central review from consortia located in Canada and the USA were eligible for inclusion. Audiology was centrally reviewed and CIHL graded using the consensus International Society of Pediatric Oncology (SIOP) Boston Ototoxicity Scale. We assessed the prevalence of moderate or severe CIHL (SIOP grade ≥2) at latest follow-up and end of therapy, in each demographic, diagnosis, and treatment group and their relative contributions to risk for CIHL. Secondary endpoints explored associations of cisplatin dose reductions and CIHL with survival. We also examined whether cisplatin dose reductions and CIHL were associated with survival outcomes. FINDINGS: We included 1481 patients who received cisplatin. Of the 1414 (95·5%) participants who had audiometry at latest follow-up (mean 3·9 years [SD 4·2] since diagnosis), 620 (43·8%) patients developed moderate or severe CIHL. The highest prevalence of CIHL was seen in the youngest patients (aged <5 years; 360 [59·4%] of 606 patients) and those with a CNS tumour (221 [50·9%] of 434 patients), hepatoblastoma (110 [65·9%] of 167 patients), or neuroblastoma (154 [62·1%] of 248 patients). After accounting for cumulative cisplatin dose, higher fractionated doses were associated with risk for CIHL (for each 10mg/m2 increase per day, adjusted odds ratio [aOR] 1·15 [95% CI 1·07-1·25]; for each 50 mg/m2 increase per cycle aOR 2·16 [1·37-3·51]). Vincristine exposure was newly identified as a risk factor for CIHL (aOR 3·55 [2·19-5·84]). Dose reductions and moderate or severe CIHL were not significantly associated with survival differences. INTERPRETATION: Using this large, multicentre cohort, benchmarks were established for the prevalence of CIHL in patients treated with cisplatin. Variations in cisplatin dosing confer additive risk for developing CIHL and warrant investigation as a potential approach to decrease the burden of therapy. FUNDING: US National Institutes of Health and National Institute on Deafness and Other Communication Disorders, US National Institutes of Health and National Cancer institute, St Baldrick's Foundation, Genome Canada, Genome British Columbia, Canadian Institutes of Health Research, the Canada Foundation for Innovation, University of British Columbia, British Columbia Children's Hospital Research Institute, British Columbia Provincial Health Services Authority, Health Canada, and C17 Research Network.

Pharmacogenomics of Cisplatin-Induced Ototoxicity: Successes, Shortcomings, and Future Avenues of Research.

Cisplatin is a highly effective chemotherapeutic. Unfortunately, its use is limited by cisplatin-induced ototoxicity (CIO). Substantial research has been performed to uncover the genetic variants associated with CIO; however, there has been a lack of consistency in the results that have been reported. This paper aims to provide an overview of the current state of CIO genomics research, delving into the shortcomings of past research, and providing recommendations for future avenues of study.

Recommendations for ototoxicity surveillance for childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCare Consortium.

Childhood, adolescent, and young adult (CAYA) cancer survivors treated with platinum-based drugs, head or brain radiotherapy, or both have an increased risk of ototoxicity (hearing loss, tinnitus, or both). To ensure optimal care and reduce consequent problems-such as speech and language, social-emotional development, and learning difficulties-for these CAYA cancer survivors, clinical practice guidelines for monitoring ototoxicity are essential. The implementation of surveillance across clinical settings is hindered by differences in definitions of hearing loss, recommendations for surveillance modalities, and remediation. To address these deficiencies, the International Guideline Harmonization Group organised an international multidisciplinary panel, including 32 experts from ten countries, to evaluate the quality of evidence for ototoxicity following platinum-based chemotherapy and head or brain radiotherapy, and formulate and harmonise ototoxicity surveillance recommendations for CAYA cancer survivors.

Suggestions to nurse authors from one manuscript reviewer.

Many others have written about how to prepare a manuscript for publication. Therefore the purpose of this article is to share the experiences of one reviewer and suggest the need for using a theory or conceptual framework to guide research, practice, and publications. Many times while reading a manuscript I feel I am on a journey of discovery without a road map. My sense is authors may be confused about when to include the conceptual framework or the "theory part" in a manuscript if the work being described was not a research study per se. The author shares recommendations from a recent publication on how to use theory or a conceptual framework in manuscript preparation.

Further Investigation of the Role of ACYP2 and WFS1 Pharmacogenomic Variants in the Development of Cisplatin-Induced Ototoxicity in Testicular Cancer Patients.

Purpose: Adverse drug reactions such as ototoxicity, which occurs in approximately one-fifth of adult patients who receive cisplatin treatment, can incur large socioeconomic burdens on patients with testicular cancer who develop this cancer during early adulthood. Recent genome-wide association studies have identified genetic variants in ACYP2 and WFS1 that are associated with cisplatin-induced ototoxicity. We sought to explore the role of these genetic susceptibility factors to cisplatin-induced ototoxicity in patients with testicular cancer.Experimental Design: Extensive clinical and demographic data were collected for 229 patients with testicular cancer treated with cisplatin. Patients were genotyped for two variants, ACYP2 rs1872328 and WFS1 rs62283056, that have previously been associated with hearing loss in cisplatin-treated patients. Analyses were performed to investigate the association of these variants with ototoxicity in this cohort of adult patients with testicular cancer.Results: Pharmacogenomic analyses revealed that ACYP2 rs1872328 was significantly associated with cisplatin-induced ototoxicity [P = 2.83 × 10-3, OR (95% CI):14.7 (2.6-84.2)]. WFS1 rs62283056 was not significantly associated with ototoxicity caused by cisplatin (P = 0.39); however, this variant was associated with hearing loss attributable to any cause [P = 5.67 × 10-3, OR (95% CI): 3.2 (1.4-7.7)].Conclusions: This study has provided the first evidence for the role of ACYP2 rs1872328 in cisplatin-induced ototoxicity in patients with testicular cancer. These results support the use of this information to guide the development of strategies to prevent cisplatin-induced ototoxicity across cancers. Further, this study has highlighted the importance of phenotypic differences in replication studies and has provided further evidence for the role of WFS1 rs62283056 in susceptibility to hearing loss, which may be worsened by cisplatin treatment. Clin Cancer Res; 24(8); 1866-71. ©2018 AACR.

Ototoxicity monitoring in children treated with platinum chemotherapy.

OBJECTIVE: To review the prevalence, mechanisms, clinical presentation, risk factors and implications of platinum-induced ototoxicity in paediatric cancer patients based on published evidence, discuss options for monitoring hearing in young children during treatment and review long-term follow-up guidelines. DESIGN: Narrative literature review. RESULTS: Children treated with cisplatin are at high risk of hearing loss and early, accurate identification of ototoxicity is important for medical decision making and hearing rehabilitation. Challenges of monitoring hearing in young children during cancer treatment and options for monitoring hearing are discussed. CONCLUSION: Hearing loss has important consequences for the survivors of childhood cancer including communication, learning, cognition and quality of life. Due to the presentation and configuration of ototoxic hearing loss, the test frequencies that are prioritised and the sequence of testing may differ from standard paediatric hearing evaluations. Hearing should be monitored during treatment and after completion of therapy.

Association Between SLC16A5 Genetic Variation and Cisplatin-Induced Ototoxic Effects in Adult Patients With Testicular Cancer.

IMPORTANCE: Cisplatin-induced ototoxic effects are an important complication that affects testicular cancer survivors as a consequence of treatment. The identification of genetic variants associated with this adverse drug reaction will further our mechanistic understanding of its development and potentially lead to strategies to prevent ototoxic effects. OBJECTIVE: To identify the genetic variants associated with cisplatin-induced ototoxic effects in adult testicular cancer patients. DESIGN, SETTING, AND PARTICIPANTS: This retrospective study was performed by the Canadian Pharmacogenomics Network for Drug Safety using patients recruited from 5 adult oncology treatment centers across Canada. Male patients who were 17 years or older, diagnosed with germ cell testicular cancer, and previously treated with cisplatin-based chemotherapy were recruited from July 2009 to April 2013 using active surveillance methodology. Cisplatin-induced ototoxic effects were independently diagnosed by 2 audiologists. Patients were genotyped for 7907 variants using a custom pharmacogenomic array. Logistic regression was used to identify genetic variants that were significantly associated with ototoxic effects. The validity of these findings was confirmed through independent replication and cell-based functional assays. EXPOSURES: Cisplatin-based chemotherapy. MAIN OUTCOMES AND MEASURES: Cisplatin-induced ototoxic effects. RESULTS: After exclusions, 188 patients (median [interquartile range] age, 31 [24-39] years) were enrolled in this study to form the discovery and replication cohorts. Association and fine-mapping analyses identified a protein-coding variant, rs4788863 in SLC16A5, that was associated with protection against cisplatin-induced ototoxic effects in 2 independent cohorts (combined cohort: odds ratio, 0.06; 95% CI, 0.02-0.22; P = 2.17 × 10-7). Functional validation of this transporter gene revealed that in vitro SLC16A5-silencing altered cellular responses to cisplatin treatment, supporting a role for SLC16A5 in the development of cisplatin-induced ototoxic effects. These results were further supported by the literature, which provided confirmatory evidence for the role that SLC16A5 plays in hearing. CONCLUSIONS AND RELEVANCE: This study has identified a novel association between protein-coding variation in SLC16A5 and cisplatin-induced ototoxic effects. These findings have provided insight into the molecular mechanisms of this adverse drug reaction in adult patients with germ cell testicular cancer. Given that previous studies have shown that cimetidine, an SLC16A5-inhibitor, prevents murine cisplatin-induced ototoxic effects, the findings from this study have important implications for otoprotectant strategies in humans.

Clinical Skills Assessment: The Effects of Moving Certification Requirements Into Neurology, Child Neurology, and Psychiatry Residency Training.

BACKGROUND: A few years ago, when the American Board of Psychiatry and Neurology decided to phase out the patient-based oral examinations in its 3 primary specialties, requirements for assessing clinical skills during residency training were instituted. OBJECTIVE: The purpose of this report is to describe the experiences of training program directors and graduates with these new credentialing requirements (labeled CSEs) as well as other effects on the specialties. METHODS: Surveys were administered electronically in 2012 to all current neurology, child neurology, and psychiatry program directors, and to a convenience sample of graduates who applied for the 2012 certification examinations. RESULTS: Response rates for graduates were similar across the 3 specialties but low (28%-33%). Response rates were higher for program directors (53%-62%) and were similar across the 3 specialties. The results indicated that the CSEs were usually administered early in training, were completed toward the end, were often passed on first attempt, generally took place during routine clinical assignments, were used to assess additional competencies, almost always included feedback to the residents, and did not often lead to remediation. Furthermore, the CSEs were perceived to be useful components in the assessment of clinical skills. CONCLUSIONS: The results obtained from the early implementation of the CSEs suggest that they provide an opportunity to assess clinical skills with the additional benefit of feedback to trainees. Other effects included eventual incorporation into training program requirements, milestones, and related faculty development and research efforts.

Aligning Provider Team Members With Polyvalent Community Health Workers.

In light of the fragmentation of health care services and the need for health promotion and disease prevention, it is time to consider the important role community health workers (CHWs) could play as part of the health care team. Globally, CHWs tend to focus on a single patient condition, resulting in fragmented, uncoordinated health care services. Polyvalent (or multimodal) CHWs can provide a comprehensive, patient-centric range of care coordination services with other members of the health care team, ultimately improving patient outcomes and decreasing the cost of care. The potential benefits of the polyvalent CHW to the health care team are not widely understood in the United States. To fill this knowledge gap, a toolkit for nurse leaders in mainstream health care settings was created. The toolkit outlines the key elements essential to a successful CHW program and offers strategies for navigating the various challenges involved when integrating this new role into existing models of care.

A New Model of Governance: One University's Journey.

In the nearly 50 years, since the Medicare Program established funding for nursing education in the United States, there has been a steady migration away from hospital-controlled programs toward those which function as wholly owned subsidiaries within larger health care systems. Private sector health care organizations in particular are under increasing pressure to adapt at the risk of losing all of their funding. However, accomplishing this presents multiple challenges for today's nursing education programs in terms of their regulatory compliance, accreditation, autonomy, and, above all, governance model. The authors outline the journey toward, and specific challenges involved in creating, implementing and administering a new governance model, which sustains the overall mission and vision of the education institution while functioning seamlessly within a modern corporate health care system.

An emerging role: the nurse content curator.

A new phenomenon, the inverted or "flipped" classroom, assumes that students are no longer acquiring knowledge exclusively through textbooks or lectures. Instead, they are seeking out the vast amount of free information available to them online (the very essence of open source) to supplement learning gleaned in textbooks and lectures. With so much open-source content available to nursing faculty, it benefits the faculty to use readily available, technologically advanced content. The nurse content curator supports nursing faculty in its use of such content. Even more importantly, the highly paid, time-strapped faculty is not spending an inordinate amount of effort surfing for and evaluating content. The nurse content curator does that work, while the faculty uses its time more effectively to help students vet the truth, make meaning of the content, and learn to problem-solve. Brooks.

Nursing leadership education: an innovative executive solution.

As nursing leaders retire from the nursing workforce, too few nurses are preparing to replace them. The barriers to obtaining the educational credentials necessary to take this important step in a leadership career can appear insurmountable because of cost and time restraints. The authors present an executive format master of science program whose delivery method and content align with the professional and personal needs of emerging nurse leaders.

Psychometric properties of the Chinese-version Quality of Nursing Work Life Scale.

In this study, we developed and tested the psychometric properties of the Chinese-version Quality of Nursing Work Life Scale along seven subscales: supportive milieu with security and professional recognition, work arrangement and workload, work/home life balance, head nurse's/supervisor's management style, teamwork and communication, nursing staffing and patient care, and milieu of respect and autonomy. An instrument-development procedure with three phases was conducted in seven hospitals in 2010-2011. Phase I comprised translation and the cultural-adaptation process, phase II comprised a pilot study, and phase III comprised a field-testing process. Purposive sampling was used in the pilot study (n = 150) and the large field study (n = 1254). Five new items were added, and 85.7% of the original items were retained in the 41 item Chinese version. Principal component analysis revealed that a model accounted for 56.6% of the variance with acceptable internal consistency, concurrent validity, and discriminant validity. This study gave evidence of reliability and validity of the 41 item Chinese-version Quality of Nursing Work Life Scale.

Relationship between performance on child and adolescent psychiatry in-training and certification examinations.

BACKGROUND: Studies across a range of specialties have consistently yielded positive associations between performance on in-training examinations and board certification examinations, supporting the use of the in-training examination as a valuable formative feedback tool for residents and residency programs. That association to date, however, has not been tested in child and adolescent psychiatry residents. OBJECTIVE: This is the first study to explore the relationship between performance on the American College of Psychiatrists' Child Psychiatry Resident In-Training Examination (CHILD PRITE) and subsequent performance on the American Board of Psychiatry and Neurology's (ABPN) subspecialty multiple-choice examination (Part I) in child and adolescent psychiatry (CAP). METHODS: Pearson correlation coefficients were used to examine the relationship between performance on the CHILD PRITE and the CAP Part I examination for 342 fellows. RESULTS: Second-year CAP fellows performed significantly better on the CHILD PRITE than did the first-year fellows. The correlation between the CHILD PRITE total score and the CAP Part I examination total score was .41 (P  =  .01) for first-year CAP fellows; it was .52 (P  =  .01) for second-year CAP fellows. CONCLUSIONS: The significant correlations between scores on the 2 tests show they assess the same achievement domain. This supports the use of the CHILD PRITE as a valid measure of medical knowledge and formative feedback tool in child and adolescent psychiatry.