Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells.

Characterizing the multifaceted contribution of genetic and epigenetic factors to disease phenotypes is a major challenge in human genetics and medicine. We carried out high-resolution genetic, epigenetic, and transcriptomic profiling in three major human immune cell types (CD14+ monocytes, CD16+ neutrophils, and naive CD4+ T cells) from up to 197 individuals. We assess, quantitatively, the relative contribution of cis-genetic and epigenetic factors to transcription and evaluate their impact as potential sources of confounding in epigenome-wide association studies. Further, we characterize highly coordinated genetic effects on gene expression, methylation, and histone variation through quantitative trait locus (QTL) mapping and allele-specific (AS) analyses. Finally, we demonstrate colocalization of molecular trait QTLs at 345 unique immune disease loci. This expansive, high-resolution atlas of multi-omics changes yields insights into cell-type-specific correlation between diverse genomic inputs, more generalizable correlations between these inputs, and defines molecular events that may underpin complex disease risk.

Insurance denials and diagnostic rates in a pediatric genomic research cohort.

PURPOSE: This study aimed to assess the amount and types of clinical genetic testing denied by insurance and the rate of diagnostic and candidate genetic findings identified through research in patients who faced insurance denials. METHODS: Analysis consisted of review of insurance denials in 801 patients enrolled in a pediatric genomic research repository with either no previous genetic testing or previous negative genetic testing result identified through cross-referencing with insurance prior-authorizations in patient medical records. Patients and denials were also categorized by type of insurance coverage. Diagnostic findings and candidate genetic findings in these groups were determined through review of our internal variant database and patient charts. RESULTS: Of the 801 patients analyzed, 147 had insurance prior-authorization denials on record (18.3%). Exome sequencing and microarray were the most frequently denied genetic tests. Private insurance was significantly more likely to deny testing than public insurance (odds ratio = 2.03 [95% CI = 1.38-2.99] P = .0003). Of the 147 patients with insurance denials, 53.7% had at least 1 diagnostic or candidate finding and 10.9% specifically had a clinically diagnostic finding. Fifty percent of patients with clinically diagnostic results had immediate medical management changes (5.4% of all patients experiencing denials). CONCLUSION: Many patients face a major barrier to genetic testing in the form of lack of insurance coverage. A number of these patients have clinically diagnostic findings with medical management implications that would not have been identified without access to research testing. These findings support re-evaluation of insurance carriers' coverage policies.

How Emergency Medicine Residents Have Conversations About Life-Sustaining Treatments in Critical Illness: A Qualitative Study Using Inductive Thematic Analysis.

STUDY OBJECTIVE: The inherent pressures of high-acuity, critical illness in the emergency department create a unique environment whereby acute goals-of-care discussions must be had with patients or substitute decision makers to rapidly decide between divergent treatment paths. Among university-affiliated hospitals, resident physicians are often conducting these highly consequential discussions. This study aimed to use qualitative methods to explore how emergency medicine residents make recommendations regarding life-sustaining treatments during acute goals-of-care discussions in critical illness. METHODS: Using qualitative methods, semistructured interviews were conducted with a purposive sample of emergency medicine residents in Canada from August to December 2021. Inductive thematic analysis of the interview transcripts was conducted using line-by-line coding, and key themes were identified through comparative analysis. Data collection continued until thematic saturation was reached. RESULTS: Seventeen emergency medicine residents from 9 Canadian universities were interviewed. Two factors guided residents' treatment recommendations (a duty to provide a recommendation and the balance between disease prognosis and patient values). Three factors influenced residents' comfort when making recommendations (time constraints, uncertainty, and moral distress). CONCLUSION: While conducting acute goals-of-care discussions with critically ill patients or their substitute decision makers in the emergency department, residents felt a sense of duty to provide a recommendation informed by an intersection between the patient's disease prognosis and the patient's values. Their comfort in making these recommendations was limited by time constraints, uncertainty, and moral distress. These factors are important for informing future educational strategies.

Assessing the utility of a novel entrustment-supervision assessment tool.

BACKGROUND: Work-based assessments (WBAs) are increasingly used to inform decisions about trainee progression. Unfortunately, WBAs often fail to discriminate between trainees of differing abilities and have poor reliability. Entrustment-supervision scales may improve WBA performance, but there is a paucity of literature directly comparing them to traditional WBA tools. METHODS: The Ottawa Emergency Department Shift Observation Tool (O-EDShOT) is a previously published WBA tool employing an entrustment-supervision scale with strong validity evidence. This pre-/post-implementation study compares the performance of the O-EDShOT with that of a traditional WBA tool using norm-based anchors. All assessments completed in 12-month periods before and after implementing the O-EDShOT were collected, and generalisability analysis was conducted with year of training, trainees within year and forms within trainee as nested factors. Secondary analysis included assessor as a factor. RESULTS: A total of 3908 and 3679 assessments were completed by 99 and 116 assessors, for 152 and 138 trainees in the pre- and post-implementation phases respectively. The O-EDShOT generated a wider range of awarded scores than the traditional WBA, and mean scores increased more with increasing level of training (0.32 vs. 0.14 points per year, p = 0.01). A significantly greater proportion of overall score variability was attributable to trainees using the O-EDShOT (59%) compared with the traditional tool (21%, p < 0.001). Assessors contributed less to overall score variability for the O-EDShOT than for the traditional WBA (16% vs. 37%). Moreover, the O-EDShOT required fewer completed assessments than the traditional tool (27 vs. 51) for a reliability of 0.8. CONCLUSION: The O-EDShOT outperformed a traditional norm-referenced WBA in discriminating between trainees and required fewer assessments to generate a reliable estimate of trainee performance. More broadly, this study adds to the body of literature suggesting that entrustment-supervision scales generate more useful and reliable assessments in a variety of clinical settings.

Stress and conflict from tacit culture forges professional identity in newly graduated independent physicians.

To transition successfully into independent practice, newly graduated independent physicians (new "attendings") undergo a process of professional identity formation (PIF) as a clinician within a new community of practice (CoP). PIF is crafted by socialization within a CoP including transfer of tacit knowledge. While certain tacit knowledge is critical for professional identity, we understand little how it shapes PIF. We set out to describe the tacit knowledge acquired by new attendings within a CoP and how it contributes to PIF. Informed by constructivist grounded theory, we interviewed 23 new attendings about the tacit knowledge they acquired in early practice. Data collection and analysis occurred iteratively. We identified themes using constant comparative analysis and generated a theory that underwent member checking and feedback. Implicit standards from group culture imparted high expectations on new attendings and led to internal stress. New attendings also encountered a tacit code of conduct as behavioral elements of group culture. These elements created external conflict between new attendings and group members such as departmental colleagues, consulting physicians, and other health professionals. Depending on the support they received, new attendings responded to the stress and conflict in three ways: they doubted, adjusted, or avoided. These strategies molded their professional identity, and moved them towards or away from the CoP as they navigated their transition and PIF. We describe a novel theory of how tacit group culture shaped new attending physicians' professional identity in a new community of practice. Internal stress and external conflict occurred due to high expectations and tacit culture elements. New attendings' doubt, adjust, or avoid responses, shaped by support they received, in turn crafted their professional identity. Education leaders should prepare graduating trainees to navigate aspects of transition to independent practice successfully.

A systematic review of sufentanil for the management of adults with acute pain in the emergency department and pre-hospital setting.

BACKGROUND: Pain is commonly encountered in the Emergency Department (ED) and pre-hospital setting and often requires opioid analgesia. We sought to synthesize the available evidence on the effectiveness of sufentanil for acute pain relief for adult patients in the pre-hospital or ED setting. METHODS: This systematic review was conducted in accordance with PRISMA guidelines. Medline, Embase, Cochrane CENTRAL, and CINAHL were searched from inception to February 1, 2022. The grey literature was also searched. We included randomized controlled trials of adult patients with acute pain who were treated with sufentanil. Two reviewers independently completed screening, full text review, and data extraction. Primary outcome was reduction in pain. Secondary outcomes included adverse events, need for rescue analgesia, and patient and provider satisfaction. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. A meta-analysis was not performed due to heterogeneity. RESULTS: Of 1120 unique citations, four studies (3 ED and 1 pre-hospital) met full inclusion criteria (n = 467 participants). The overall quality of the included studies was high. Intranasal (IN) sufentanil was superior to placebo for pain relief at 30 min (difference 20.8%, 95% CI 4.0-36.2%, p = 0.01). Both IN (two studies) and IV sufentanil (one study) were comparable to IV morphine. Mild adverse events were common and there was a higher propensity for minor sedation in patients receiving sufentanil. There were no serious adverse events requiring advanced interventions. CONCLUSION: Sufentanil was comparable to IV morphine and was superior to placebo for rapid relief of acute pain in the ED setting. The safety profile of sufentanil is similar to IV morphine in this setting, with minimal concern for serious adverse events. The intranasal formulation may provide an alternative, rapid, non-parenteral route that could benefit our unique emergency department and pre-hospital patient population. Due to the overall small sample size of this review, larger studies are required to confirm safety.

Genomic answers for children: Dynamic analyses of >1000 pediatric rare disease genomes.

PURPOSE: This study aimed to provide comprehensive diagnostic and candidate analyses in a pediatric rare disease cohort through the Genomic Answers for Kids program. METHODS: Extensive analyses of 960 families with suspected genetic disorders included short-read exome sequencing and short-read genome sequencing (srGS); PacBio HiFi long-read genome sequencing (HiFi-GS); variant calling for single nucleotide variants (SNV), structural variant (SV), and repeat variants; and machine-learning variant prioritization. Structured phenotypes, prioritized variants, and pedigrees were stored in PhenoTips database, with data sharing through controlled access the database of Genotypes and Phenotypes. RESULTS: Diagnostic rates ranged from 11% in patients with prior negative genetic testing to 34.5% in naive patients. Incorporating SVs from genome sequencing added up to 13% of new diagnoses in previously unsolved cases. HiFi-GS yielded increased discovery rate with >4-fold more rare coding SVs compared with srGS. Variants and genes of unknown significance remain the most common finding (58% of nondiagnostic cases). CONCLUSION: Computational prioritization is efficient for diagnostic SNVs. Thorough identification of non-SNVs remains challenging and is partly mitigated using HiFi-GS sequencing. Importantly, community research is supported by sharing real-time data to accelerate gene validation and by providing HiFi variant (SNV/SV) resources from >1000 human alleles to facilitate implementation of new sequencing platforms for rare disease diagnoses.

Barriers and facilitators to nursing delirium screening in older emergency patients: a qualitative study using the theoretical domains framework.

BACKGROUND: delirium is common in older emergency department (ED) patients, but vastly under-recognised, in part due to lack of standardised screening processes. Understanding local context and barriers to delirium screening are integral for successful implementation of a delirium screening protocol. OBJECTIVES: we sought to identify barriers and facilitators to delirium screening by nurses in older ED patients. METHODS: we conducted 15 semi-structured, face-to-face interviews based on the Theoretical Domains Framework with bedside nurses, nurse educators and managers at two academic EDs in 2017. Two research assistants independently coded transcripts. Relevant domains and themes were identified. RESULTS: a total of 717 utterances were coded into 14 domains. Three dominant themes emerged: (i) lack of clinical prioritisation because of competing demands, lack of time and heavy workload; (ii) discordance between perceived capabilities and knowledge and (iii) hospital culture. CONCLUSION: this qualitative study explored nursing barriers and facilitators to delirium screening in older ED patients. We found that delirium was recognised as an important clinical problem; however, it was not clinically prioritised; there was a false self-perception of knowledge and ability to recognise delirium and hospital culture was a strong influencer of behaviour. Successful adoption of a delirium screening protocol will only be realised if these issues are addressed.

Ready, set, go! Evaluating readiness to implement competency-based medical education.

PURPOSE: Organizational readiness is critical for successful implementation of an innovation. We evaluated program readiness to implement Competence by Design (CBD), a model of Competency-Based Medical Education (CBME), among Canadian postgraduate training programs. METHODS: A survey of program directors was distributed 1 month prior to CBD implementation in 2019. Questions were informed by the R = MC2 framework of organizational readiness and addressed: program motivation, general capacity for change, and innovation-specific capacity. An overall readiness score was calculated. An ANOVA was conducted to compare overall readiness between disciplines. RESULTS: Survey response rate was 42% (n = 79). The mean overall readiness score was 74% (30-98%). There was no difference in scores between disciplines. The majority of respondents agreed that successful implementation of CBD was a priority (74%), and that their leadership (94%) and faculty and residents (87%) were supportive of change. Fewer perceived that CBD was a move in the right direction (58%) and that implementation was a manageable change (53%). Curriculum mapping, competence committees and programmatic assessment activities were completed by >90% of programs, while <50% had engaged off-service disciplines. CONCLUSION: Our study highlights important areas where programs excelled in their preparation for CBD, as well as common challenges that serve as targets for future intervention to improve program readiness for CBD implementation.

Implementation of competence committees during the transition to CBME in Canada: A national fidelity-focused evaluation.

PURPOSE: This study evaluated the fidelity of competence committee (CC) implementation in Canadian postgraduate specialist training programs during the transition to competency-based medical education (CBME). METHODS: A national survey of CC chairs was distributed to all CBME training programs in November 2019. Survey questions were derived from guiding documents published by the Royal College of Physicians and Surgeons of Canada reflecting intended processes and design. RESULTS: Response rate was 39% (113/293) with representation from all eligible disciplines. Committee size ranged from 3 to 20 members, 42% of programs included external members, and 20% included a resident representative. Most programs (72%) reported that a primary review and synthesis of resident assessment data occurs prior to the meeting, with some data reviewed collectively during meetings. When determining entrustable professional activity (EPA) achievement, most programs followed the national specialty guidelines closely with some exceptions (53%). Documented concerns about professionalism, EPA narrative comments, and EPA entrustment scores were most highly weighted when determining resident progress decisions. CONCLUSIONS: Heterogeneity in CC implementation likely reflects local adaptations, but may also explain some of the variable challenges faced by programs during the transition to CBME. Our results offer educational leaders important fidelity data that can help inform the larger evaluation and transformation of CBME.

Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture.

The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1(cre/flox) mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 × 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.

Does the public feel prepared to be substitute decision-makers? Gaps in preparedness and support for a high school curriculum: a national survey.

BACKGROUND: Substitute decision-makers (SDMs) make decisions on behalf of patients who do not have capacity, in line with previously expressed wishes, values and beliefs. However, miscommunications and poor awareness of previous wishes often lead to inappropriate care. Increasing public preparedness to communicate on behalf of loved ones may improve care in patients requiring an SDM. METHODS: We conducted an online survey in January 2019 with a representative sample of the Canadian population. The primary outcome was self-reported preparedness to be an SDM. The secondary outcome was support for a high school curriculum on the role of SDMs. The effect of socio-demographics, known enablers and barriers to acting as an SDM, and attitudes towards a high school curriculum were assessed using multivariate analysis. RESULTS: Of 1,000 participants, 53.1% felt prepared to be an SDM, and 75.4% stated they understood their loved one's values. However, only 55.6% reported having had a meaningful conversation with their loved one about values and wishes, and only 61.7% reported understanding the SDM role. Engagement in advance care planning for oneself was low (23.1%). Age, experience, training and comfort with communication were associated with preparedness in our multivariate analysis. A high school curriculum was supported by 61.1% of respondents, with 28.3% neutral and 10.6% against it. INTERPRETATION: There is a gap between perceived and actual preparedness to be an SDM. Many report understanding their loved one's values yet have not asked them about wishes in illness or end of life. The majority of respondents support high school education to improve preparedness.

Exploring the use of rating scales with entrustment anchors in workplace-based assessment.

PURPOSE: Competency-based medical education (CBME) has prompted widespread implementation of workplace-based assessment (WBA) tools using entrustment anchors. This study aimed to identify factors that influence faculty's rating choices immediately following assessment and explore their experiences using WBAs with entrustment anchors, specifically the Ottawa Surgical Competency Operating Room Evaluation scale. METHOD: A convenience sample of 50 semi-structured interviews with Emergency Medicine (EM) physicians from a single Canadian hospital were conducted between July and August 2019. All interviews occurred within two hours of faculty completing a WBA of a trainee. Faculty were asked what they considered when rating the trainee's performance and whether they considered an alternate rating. Two team members independently analysed interview transcripts using conventional content analysis with line-by-line coding to identify themes. RESULTS: Interviews captured interactions between 70% (26/37) of full-time EM faculty and 86% (19/22) of EM trainees. Faculty most commonly identified the amount of guidance the trainee required as influencing their rating. Other variables such as clinical context, trainee experience, past experiences with the trainee, perceived competence and confidence were also identified. While most faculty did not struggle to assign ratings, some had difficulty interpreting the language of entrustment anchors, being unsure whether their assessment should be retrospective or prospective in nature, and if/how the assessment should change whether they were 'in the room' or not. CONCLUSIONS: By going to the frontline during WBA encounters, this study captured authentic and honest reflections from physicians immediately engaged in assessment using entrustment anchors. While many of the factors identified are consistent with previous retrospective work, we highlight how some faculty consider factors outside the prescribed approach and struggle with the language of entrustment anchors. These results further our understanding of 'in-the-moment' assessments using entrustment anchors and may facilitate effective faculty development regarding WBA in CBME.

Twelve tips for learners to succeed in a CBME program.

The international movement to competency-based medical education (CBME) marks a major transition in medical education that requires a shift in educators' and learners' approach to clinical experiences, the way assessment data are collected and integrated, and in learners' mindsets. Learners entering a CBME curriculum must actively drive their learning experiences and education goals. For some, this expectation may be a significant change from their previous approach to learning in medicine. This paper highlights 12 tips to help learners succeed within a CBME model.

Diagnosing conflict: Conflicting data, interpersonal conflict, and conflicts of interest in clinical competency committees.

Clinical competency committees (CCCs) are increasingly used within health professions education as their decisions are thought to be more defensible and fairer than those generated by previous training promotion processes. However, as with most group-based processes, it is inevitable that conflict will arise. In this paper the authors explore three ways conflict may arise within a CCC: (1) conflicting data submissions that are presented to the committee, (2) conflicts between members of the committee, and (3) conflicts of interest between a specific committee member and a trainee. The authors describe each of these conflict situations, dissect out the underlying problems, and explore possible solutions based on the current literature.

Mutations in THAP11 cause an inborn error of cobalamin metabolism and developmental abnormalities.

CblX (MIM309541) is an X-linked recessive disorder characterized by defects in cobalamin (vitamin B12) metabolism and other developmental defects. Mutations in HCFC1, a transcriptional co-regulator which interacts with multiple transcription factors, have been associated with cblX. HCFC1 regulates cobalamin metabolism via the regulation of MMACHC expression through its interaction with THAP11, a THAP domain-containing transcription factor. The HCFC1/THAP11 complex potentially regulates genes involved in diverse cellular functions including cell cycle, proliferation, and transcription. Thus, it is likely that mutation of THAP11 also results in biochemical and other phenotypes similar to those observed in patients with cblX. We report a patient who presented with clinical and biochemical phenotypic features that overlap cblX, but who does not have any mutations in either MMACHC or HCFC1. We sequenced THAP11 by Sanger sequencing and discovered a potentially pathogenic, homozygous variant, c.240C > G (p.Phe80Leu). Functional analysis in the developing zebrafish embryo demonstrated that both THAP11 and HCFC1 regulate the proliferation and differentiation of neural precursors, suggesting important roles in normal brain development. The loss of THAP11 in zebrafish embryos results in craniofacial abnormalities including the complete loss of Meckel's cartilage, the ceratohyal, and all of the ceratobranchial cartilages. These data are consistent with our previous work that demonstrated a role for HCFC1 in vertebrate craniofacial development. High throughput RNA-sequencing analysis reveals several overlapping gene targets of HCFC1 and THAP11. Thus, both HCFC1 and THAP11 play important roles in the regulation of cobalamin metabolism as well as other pathways involved in early vertebrate development.

Entrustment Checkpoint: Clinical Supervisors' Perceptions of the Emergency Department Oral Case Presentation.

Phenomenon: The oral case presentation represents a unique method of communication and forms the foundation for trainee-supervisor interactions in the clinical setting. Recently, entrustment has been highlighted as an essential element of trainee-supervisor interactions. Despite the growing body of knowledge concerning entrustment in medical education, how supervisors conceptualize the oral case presentation as a contributor to entrustment decision making during clinical supervision remains unknown. Given their widespread use, oral case presentations may represent a potential tool for future frameworks of workplace-based assessment. This study sought to explore what factors influence supervisors' expectations of oral case presentation content and how the oral case presentation may contribute to entrustment decision making. Approach: Using qualitative methodology, semistructured interviews were conducted from a purposive sample of attending emergency medicine physicians at an academic medical center from 2015 to 2016. Thematic analysis of the semistructured interview transcripts was conducted by 2 investigators using line-by-line coding and constant comparative analysis. Key themes were identified through consensus. Theoretical sampling occurred until thematic saturation was reached. Findings: Twenty-one attending physicians were interviewed. Four factors were found to influence supervisor expectations pertaining to oral case presentation content (trainee level, trainee familiarity, clinical context, and clinical task). Further, the oral case presentation was found to serve as a means of indirect observation and an entrustment check point informing future decisions relating to trainee supervision. Insights: The oral case presentation represents a core activity within the trainee-supervisor relationship in which entrustment plays a central role. Given the numerous factors influencing oral case presentation content, we caution supervisors against relying solely on the oral case presentation as an entrustment check point, as this may lead to inaccurate judgments of trainee competence. We recommend that the oral case presentation be used in conjunction with other means of direct and indirect observation to assist with entrustment decisions relating to trainee supervision.

Barriers and enablers that influence guideline-based care of geriatric fall patients presenting to the emergency department.

BACKGROUND: Geriatric patients commonly present to the ED after a fall. Recent evidence suggests that ED physicians are poorly adherent to published ED-specific geriatric fall guidelines. This study applied a theoretical domains framework (TDF) approach to systematically investigate barriers and enablers in the provision of guideline-based care to ED geriatric fall patients. METHODS: From June to September 2017, semistructured interviews of staff ED physicians practising in Ontario, Canada, were conducted and analysed. An interview guide based on the TDF was used to capture 14 domains influencing provision of guideline-based care. Relevant domains were identified based on frequencies of beliefs, existence of conflicting beliefs and evidence of strong beliefs that would influence provision of guideline-based care. RESULTS: Eleven interviews were conducted with practising ED physicians. Thirty belief statements were identified across 13 relevant TDF domains (all except Optimism). Prominent themes included lack of knowledge, paucity of evidence, heterogeneous self-perceived skills, perceived increased time and workload, importance of allied health support, inconsistently available allied health workers, lack of positive reinforcement, emotions negatively impacting these clinical encounters and support for memory aids. Overall, ED physicians were supportive of guideline implementation, and believe it will lead to better outcomes for geriatric fall patients. CONCLUSION: This study identified important barriers and enablers to provision of guideline-based care in geriatric ED fall patients. Based on these findings, future implementation of guidelines nationally and internationally should focus on improving knowledge and training on guidelines, improving positive reinforcement for guideline-appropriate management, greater allied health support and further research to support guidelines.

Supervisor-trainee continuity and the quality of work-based assessments.

CONTEXT: Work-based assessments (WBAs) represent an increasingly important means of reporting expert judgements of trainee competence in clinical practice. However, the quality of WBAs completed by clinical supervisors is of concern. The episodic and fragmented interaction that often occurs between supervisors and trainees has been proposed as a barrier to the completion of high-quality WBAs. OBJECTIVES: The primary purpose of this study was to determine the effect of supervisor-trainee continuity on the quality of assessments documented on daily encounter cards (DECs), a common form of WBA. The relationship between trainee performance and DEC quality was also examined. METHODS: Daily encounter cards representing three differing degrees of supervisor-trainee continuity (low, intermediate, high) were scored by two raters using the Completed Clinical Evaluation Report Rating (CCERR), a previously published nine-item quantitative measure of DEC quality. An analysis of variance (anova) was performed to compare mean CCERR scores among the three groups. Linear regression analysis was conducted to examine the relationship between resident performance and DEC quality. RESULTS: Differences in mean CCERR scores were observed between the three continuity groups (p = 0.02); however, the magnitude of the absolute differences was small (partial eta-squared = 0.03) and not educationally meaningful. Linear regression analysis demonstrated a significant inverse relationship between resident performance and CCERR score (p < 0.001, r2  = 0.18). This inverse relationship was observed in both groups representing on-service residents (p = 0.001, r2  = 0.25; p = 0.04, r2  = 0.19), but not in the Off-service group (p = 0.62, r2  = 0.05). CONCLUSIONS: Supervisor-trainee continuity did not have an educationally meaningful influence on the quality of assessments documented on DECs. However, resident performance was found to affect assessor behaviours in the On-service group, whereas DEC quality remained poor regardless of performance in the Off-service group. The findings suggest that greater attention should be given to determining ways of improving the quality of assessments reported for off-service residents, as well as for those residents demonstrating appropriate clinical competence progression.

Inborn Error of Cobalamin Metabolism Associated with the Intracellular Accumulation of Transcobalamin-Bound Cobalamin and Mutations in ZNF143, Which Codes for a Transcriptional Activator.

Vitamin B12 (cobalamin, Cbl) cofactors adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl) are required for the activity of the enzymes methylmalonyl-CoA mutase (MCM) and methionine synthase (MS). Inborn errors of Cbl metabolism are rare Mendelian disorders associated with hematological and neurological manifestations, and elevations of methylmalonic acid and/or homocysteine in the blood and urine. We describe a patient whose fibroblasts had decreased functional activity of MCM and MS and decreased synthesis of AdoCbl and MeCbl (3.4% and 1.0% of cellular Cbl, respectively). The defect in cultured patient fibroblasts complemented those from all known complementation groups. Patient cells accumulated transcobalamin-bound-Cbl, a complex which usually dissociates in the lysosome to release free Cbl. Whole-exome sequencing identified putative disease-causing variants c.851T>G (p.L284*) and c.1019C>T (p.T340I) in transcription factor ZNF143. Proximity biotinylation analysis confirmed the interaction between ZNF143 and HCFC1, a protein that regulates expression of the Cbl trafficking enzyme MMACHC. qRT-PCR analysis revealed low MMACHC expression levels both in patient fibroblasts, and in control fibroblasts incubated with ZNF143 siRNA.