Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.

Pathogenic heterozygous loss of function variants in CTNNB1 are associated with CTNNB1 neurodevelopmental disorder. We report the clinical phenotype of individuals with CTNNB1 neurodevelopmental disorder using both caregiver-reported data (medical history, adaptive function, quality of life, and behavior issues) and in-person clinical assessments (neurological, motor, and cognitive function) in 32 individuals with likely pathogenic or pathogenic CTNNB1 variants. Most individuals had truncal hypotonia, muscle weakness, hypertonia, dystonia, microcephaly, and many had a history of tethered cord. Visual problems included strabismus, hyperopia, and familial exudative vitreoretinopathy. Half of individuals walked without an assistive device. The mean Gross Motor Functional Measure-66 score was 56.6 (SD = 14.8). Average time to complete Nine-Hole Peg Test was slower than norms. Mean general conceptual ability composite scores from Differential Ability Scales Second Edition were very low (M = 58.3, SD = 11.3). Fifty-five percent of individuals had low adaptive functioning based on the Vineland Adaptive Behavioral Scales. Based upon the Child Behavior Checklist total problems score, the majority (65%) of individuals had behavioral challenges. The mean overall Quality of Life Inventory-Disability score was 81.7 (SD = 11.9). These data provide a detailed characterization of clinical features in individuals with CTNNB1 neurodevelopmental disorder.

Rare predicted deleterious FEZF2 variants are associated with a neurodevelopmental phenotype.

FEZF2 encodes a transcription factor critical to neurodevelopment that regulates other neurodevelopment genes. Rare variants in FEZF2 have previously been suggested to play a role in autism, and cases of 3p14 microdeletions that include FEZF2 share a neurodevelopmental phenotype including mild dysmorphic features and intellectual disability. We identified seven heterozygous predicted deleterious variants in FEZF2 (three frameshifts, one recurrent missense in two independent cases, one nonsense, and one complete gene deletion) in unrelated individuals with neurodevelopmental disorders including developmental delay/intellectual disability, autism, and/or attention-deficit/hyperactivity. Variants were confirmed to be de novo in five of seven cases and paternally inherited from an affected father in one. Predicted deleterious variants in FEZF2 may affect the expression of genes that are involved in fate choice pathways in developing neurons, and thus contribute to the neurodevelopmental phenotype. Future studies are needed to clarify the mechanism by which FEZF2 leads to this neurodevelopmental disorder.

Providers' and Patients' Perspectives on Diagnostic Errors in the Acute Care Setting.

BACKGROUND: Diagnostic errors (DEs) have been studied extensively in ambulatory care, but less work has been done in the acute care setting. In this study, the authors examined health care providers' and patients' perspectives about the classification of DEs, the main causes and scope of DEs in acute care, the main gaps in current systems, and the need for innovative solutions. METHODS: A qualitative mixed methods study was conducted, including semistructured interviews with health care providers and focus groups with patient advisors. Using grounded theory approach, thematic categories were derived from the interviews and focus groups. RESULTS: The research team conducted interviews with 17 providers and two focus groups with seven patient advisors. Both providers and patient advisors struggled to define and describe DEs in acute care settings. Although participants agreed that DEs pose a significant risk to patient safety, their perception of the frequency of DEs was mixed. Most participants identified communication failures, lack of comfort with diagnostic uncertainty, incorrect clinical evaluation, and cognitive load as key causes of DEs. Most respondents believed that non-information technology (IT) tools and processes (for example, communication improvement strategies) could significantly reduce DEs. CONCLUSION: The study findings represent an important supplement to our understanding of DEs in acute care settings and the advancement of a culture of patient safety in the context of patient-centered care and patient engagement. Health care organizations should consider the key factors identified in this study when trying to create a culture that engages clinicians and patients in reducing DEs.

Developing, pilot testing, and refining requirements for 3 EHR-integrated interventions to improve diagnostic safety in acute care: a user-centered approach.

Objective: To describe a user-centered approach to develop, pilot test, and refine requirements for 3 electronic health record (EHR)-integrated interventions that target key diagnostic process failures in hospitalized patients. Materials and Methods: Three interventions were prioritized for development: a Diagnostic Safety Column (DSC) within an EHR-integrated dashboard to identify at-risk patients; a Diagnostic Time-Out (DTO) for clinicians to reassess the working diagnosis; and a Patient Diagnosis Questionnaire (PDQ) to gather patient concerns about the diagnostic process. Initial requirements were refined from analysis of test cases with elevated risk predicted by DSC logic compared to risk perceived by a clinician working group; DTO testing sessions with clinicians; PDQ responses from patients; and focus groups with clinicians and patient advisors using storyboarding to model the integrated interventions. Mixed methods analysis of participant responses was used to identify final requirements and potential implementation barriers. Results: Final requirements from analysis of 10 test cases predicted by the DSC, 18 clinician DTO participants, and 39 PDQ responses included the following: DSC configurable parameters (variables, weights) to adjust baseline risk estimates in real-time based on new clinical data collected during hospitalization; more concise DTO wording and flexibility for clinicians to conduct the DTO with or without the patient present; and integration of PDQ responses into the DSC to ensure closed-looped communication with clinicians. Analysis of focus groups confirmed that tight integration of the interventions with the EHR would be necessary to prompt clinicians to reconsider the working diagnosis in cases with elevated diagnostic error (DE) risk or uncertainty. Potential implementation barriers included alert fatigue and distrust of the risk algorithm (DSC); time constraints, redundancies, and concerns about disclosing uncertainty to patients (DTO); and patient disagreement with the care team's diagnosis (PDQ). Discussion: A user-centered approach led to evolution of requirements for 3 interventions targeting key diagnostic process failures in hospitalized patients at risk for DE. Conclusions: We identify challenges and offer lessons from our user-centered design process.

Supporting addiction affected families effectively: a feasibility randomised controlled trial of a psychosocial intervention delivered by lay counsellors in Goa, India.

Background: Despite evidence of the burden of alcohol use on families, there is a lack of adequate and targeted support. We aimed to examine the feasibility, acceptability and impact of Supporting Addiction Affected Families Effectively (SAFE), a brief lay counsellor-delivered intervention for affected family members (AFMs). Methods: Parallel arm feasibility randomised controlled trial [1:1 allocation to SAFE or enhanced usual care (EUC)]. The primary outcome was mean difference in symptom score assessed by the Symptom Rating Test and secondary outcomes were difference in coping, impact and social support scores measured by the Coping Questionnaire, Family Member Impact Questionnaire, and Alcohol, Drugs and the Family Social Support Scale. Process data examining feasibility and acceptability were also collected. The primary analysis was intention to treat at the 3-month endpoint. Results: In total, 115 AFMs were referred to the trial, and 101 (87.8%) consenting participants were randomised to the two arms (51 SAFE arm and 50 EUC arm). Seventy-eight per cent completed treatment, with the mean number of sessions being 4.25 sessions and mean duration being 53 min. Ninety-five per cent completed outcome assessment. There were no statistically significant differences between SAFE and EUC on any of the outcome measures, except for the between-group adjusted mean differences for social support scores (AMD -6.05, 95% CI -10.98 to -1.12, p = 0.02). Conclusion: Our work indicates that it is possible to identify AFMs through community networking, and have high rates of participation for lay counsellor-delivered psychosocial care. Nevertheless, there is a need for further intervention development to ensure its contextual relevance and appropriateness.

A structured approach to EHR surveillance of diagnostic error in acute care: an exploratory analysis of two institutionally-defined case cohorts.

OBJECTIVES: To test a structured electronic health record (EHR) case review process to identify diagnostic errors (DE) and diagnostic process failures (DPFs) in acute care. METHODS: We adapted validated tools (Safer Dx, Diagnostic Error Evaluation Research [DEER] Taxonomy) to assess the diagnostic process during the hospital encounter and categorized 13 postulated e-triggers. We created two test cohorts of all preventable cases (n=28) and an equal number of randomly sampled non-preventable cases (n=28) from 365 adult general medicine patients who expired and underwent our institution's mortality case review process. After excluding patients with a length of stay of more than one month, each case was reviewed by two blinded clinicians trained in our process and by an expert panel. Inter-rater reliability was assessed. We compared the frequency of DE contributing to death in both cohorts, as well as mean DPFs and e-triggers for DE positive and negative cases within each cohort. RESULTS: Twenty-seven (96.4%) preventable and 24 (85.7%) non-preventable cases underwent our review process. Inter-rater reliability was moderate between individual reviewers (Cohen's kappa 0.41) and substantial with the expert panel (Cohen's kappa 0.74). The frequency of DE contributing to death was significantly higher for the preventable compared to the non-preventable cohort (56% vs. 17%, OR 6.25 [1.68, 23.27], p<0.01). Mean DPFs and e-triggers were significantly and non-significantly higher for DE positive compared to DE negative cases in each cohort, respectively. CONCLUSIONS: We observed substantial agreement among final consensus and expert panel reviews using our structured EHR case review process. DEs contributing to death associated with DPFs were identified in institutionally designated preventable and non-preventable cases. While e-triggers may be useful for discriminating DE positive from DE negative cases, larger studies are required for validation. Our approach has potential to augment institutional mortality case review processes with respect to DE surveillance.

Analyzing diagnostic errors in the acute setting: a process-driven approach.

OBJECTIVES: We describe an approach for analyzing failures in diagnostic processes in a small, enriched cohort of general medicine patients who expired during hospitalization and experienced medical error. Our objective was to delineate a systematic strategy for identifying frequent and significant failures in the diagnostic process to inform strategies for preventing adverse events due to diagnostic error. METHODS: Two clinicians independently reviewed detailed records of purposively sampled cases identified from established institutional case review forums and assessed the likelihood of diagnostic error using the Safer Dx instrument. Each reviewer used the modified Diagnostic Error Evaluation and Research (DEER) taxonomy, revised for acute care (41 possible failure points across six process dimensions), to characterize the frequency of failure points (FPs) and significant FPs in the diagnostic process. RESULTS: Of 166 cases with medical error, 16 were sampled: 13 (81.3%) had one or more diagnostic error(s), and a total of 113 FPs and 30 significant FPs were identified. A majority of significant FPs (63.3%) occurred in "Diagnostic Information and Patient Follow-up" and "Patient and Provider Encounter and Initial Assessment" process dimensions. Fourteen (87.5%) cases had a significant FP in at least one of these dimensions. CONCLUSIONS: Failures in the diagnostic process occurred across multiple dimensions in our purposively sampled cohort. A systematic analytic approach incorporating the modified DEER taxonomy, revised for acute care, offered critical insights into key failures in the diagnostic process that could serve as potential targets for preventative interventions.

Auditing the AUDIT: A systematic review of cut-off scores for the Alcohol Use Disorders Identification Test (AUDIT) in low- and middle-income countries.

INTRODUCTION: The World Health Organization's (WHO) Alcohol Use Disorders Identification Test (AUDIT) is used extensively across the world, with cut-off scores recommended by the WHO. We reviewed the use and validity of AUDIT cut-off scores in low- and middle-income countries as cultural contexts are expected to influence the detection of alcohol use disorders. MATERIALS AND METHODS: The systematic review was guided by an a priori defined protocol consistent with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. We searched Cochrane library, Medline, EMBASE, PsycINFO, CINAHL, Indmed, LILACS, and AJOL databases using appropriate search terms. We conducted a narrative synthesis of the data. RESULTS: We identified 54 distinct studies that used AUDIT cut-off scores which were not in alignment with those recommended by the WHO. India (n = 10), Nigeria (n = 9), and Brazil (n = 9) produced most of these included studies. Most of the studies (n = 42) did not conduct psychometric evaluations of AUDIT cut-off scores. Of the twelve studies which did report psychometric results, a wide range of cut-off scores performed well. In these studies the cut-off scores to detect hazardous drinking ranged from >3 to >5, for harmful drinking from >5 to >16, and for dependent drinking from >7 to >24. DISCUSSION: AUDIT is being widely used in LMICs and non-recommended cut-off scores are considered to be appropriate in these countries. It is important to systematically evaluate the psychometric properties of those cut-off scores to ensure the internal validity of the studies in which they are used.