Laboratory Practice Guidelines for Detecting and Reporting BCR-ABL Drug Resistance Mutations in Chronic Myelogenous Leukemia and Acute Lymphoblastic Leukemia

The BCR-ABL tyrosine kinase produced by the t(9;22)(q34;q11) translocation, also known as the Philadelphia chromosome, is the initiating event in chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL). Targeting of BCR-ABL with tyrosine kinase inhibitors (TKIs) has resulted in rapid clinical responses in the vast majority of patients with CML and Philadelphia chromosome+ ALL. However, long-term use of TKIs occasionally results in emergence of therapy resistance, in part through the selection of clones with mutations in the BCR-ABL kinase domain. We present here an overview of the current practice in monitoring for such mutations, including the methods used, the clinical and laboratory criteria for triggering mutational analysis, and the guidelines for reporting BCR-ABL mutations. We alsopresent a proposal for a public database for correlating mutational status with in vitro and in vivo responses to different TKIs to aid in the interpretation of mutation studies

Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus

Objectives: Motor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial. Here, we detail a systematic and structured evidence-based approach to inform consensus decision making to select the first two drugs for evaluation in Motor Neuron Disease-Systematic Multi-arm Adaptive Randomised Trial (MND-SMART: NCT04302870), an adaptive platform trial. We aim to identify and prioritise candidate drugs which have the best available evidence for efficacy, acceptable safety profiles and are feasible for evaluation within the trial protocol. Methods: We conducted a two-stage systematic review to identify potential neuroprotective interventions. First, we reviewed clinical studies in MND, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and multiple sclerosis, identifying drugs described in at least one MND publication or publications in two or more other diseases. We scored and ranked drugs using a metric evaluating safety, efficacy, study size and study quality. In stage two, we reviewed efficacy of drugs in MND animal models, multicellular eukaryotic models and human induced pluripotent stem cell (iPSC) studies. An expert panel reviewed candidate drugs over two shortlisting rounds and a final selection round, considering the systematic review findings, late breaking evidence, mechanistic plausibility, safety, tolerability and feasibility of evaluation in MND-SMART. Results: From the clinical review, we identified 595 interventions. 66 drugs met our drug/disease logic. Of these, 22 drugs with supportive clinical and preclinical evidence were shortlisted at round 1. Seven drugs proceeded to round 2. The panel reached a consensus to evaluate memantine and trazodone as the first two arms of MND-SMART. Discussion: For future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human iPSCs

MRI-derived g-ratio and lesion severity in newly diagnosed multiple sclerosis

Myelin loss is associated with axonal damage in established multiple sclerosis. This relationship is challenging to study in vivo in early disease. Here, we ask whether myelin loss is associated with axonal damage at diagnosis, by combining non-invasive neuroimaging and blood biomarkers. We performed quantitative microstructural MRI and single molecule ELISA plasma neurofilament measurement in 73 patients with newly diagnosed, immunotherapy naïve relapsing-remitting multiple sclerosis. Myelin integrity was evaluated using aggregate g-ratios, derived from magnetization transfer saturation (MTsat) and neurite orientation dispersion and density imaging (NODDI) diffusion data. We found significantly higher g-ratios within cerebral white matter lesions (suggesting myelin loss) compared with normal-appearing white matter (0.61 vs 0.57, difference 0.036, 95% CI 0.029 to 0.043, p < 0.001). Lesion volume (Spearman’s rho rs= 0.38, p < 0.001) and g-ratio (rs= 0.24 p < 0.05) correlated independently with plasma neurofilament. In patients with substantial lesion load (n = 38), those with higher g-ratio (defined as greater than median) were more likely to have abnormally elevated plasma neurofilament than those with normal g-ratio (defined as less than median) (11/23 [48%] versus 2/15 [13%] p < 0.05). These data suggest that, even at multiple sclerosis diagnosis, reduced myelin integrity is associated with axonal damage. MRI-derived g-ratio may provide useful additional information regarding lesion severity, and help to identify individuals with a high degree of axonal damage at disease onset. York, Martin et al. simultaneously measured g-ratio and plasma neurofilament in 73 relapsing-remitting multiple sclerosis patients at diagnosis using advanced MRI and single molecule ELISA. They demonstrate that g-ratio of cerebral white matter lesions varies at diagnosis, and show that high g-ratio of lesions is associated with elevated plasma neurofilament

Quickstart for toddlers with autism spectrum disorder: A preliminary report of an adapted community-based early intervention program

Background and Aims: Early intervention (EI) for young children with autism spectrum disorder (ASD) must be resource-efficient while remaining effective; thus, clinicians are challenged to create and implement useful methods. Clinical evidence from community-based interventions that include reliable diagnoses, individual EI programs, along with comprehensive descriptions of participants, procedures, and participant outcomes can inform practice, translational research, and local policy. Parent-mediated EI for toddlers with ASD can promote positive developmental outcomes and lifelong well-being, but evidence of successful community uptake of research-based EIs is somewhat limited. The community-based, parent-mediated, evidence-informed QuickStart EI program aims to encourage toddlers’ early social communication, social interactions, and relationship-building, in a community clinic setting. We aim to (1) describe our adaptations to the evidence-based Parent-Delivered Early Start Denver Model and (2) present promising findings for toddlers with or at risk for ASD and their families who received QuickStart. We also intend to motivate a similar study of EI in real-world situations to advance evidence-based practice and create relevant dialogue and questions for research. Methods: Complete data were identified and analyzed for up to 89 toddlers diagnosed with, or at risk of, ASD. Pre- and post-intervention parent- or self-report data were analyzed using descriptive statistics and paired-sample t-tests, as appropriate. Pre-intervention measures included demographic information (n = 89) and the Early Screening of Autism and Communication (ESAC; n = 89). Measures taken pre- and post-intervention included the Adaptive Behavior Assessment System-II (n = 60), MacArthur-Bates Communication Development Inventories (n = 58), and the parental sense of competence scale (n = 62). The Measure of Processes of Care (n = 60) was taken post-intervention. On enrollment, parents signed standard clinical agreements that included statements allowing their anonymous data to be analyzed for research. Results: Using standardized parent/self-report measures, toddler gains were noted for social interaction, language, communication skills, and ASD symptoms, but not for parents’ feelings of competence. Parents identified QuickStart procedures as family centered (Measure of Processes of Care). Conclusions: The QuickStart EI program, provided to toddlers and their families over 20 weeks in a community clinic, resulted in promising positive behavior and communication changes, as indicated on the parent-response measures, for a moderately large sample of toddlers. Implications: This study adds to the literature by describing a new EI program with clear procedures by which clinicians can create, provide, and evaluate a readily accessible, community-based EI for toddlers with or at risk of ASD. Methodological limitations inherent to our study design that precluded a control group and necessitated a reliance on available parent-report data are carefully critiqued and discussed

Third age usability and safety - an ergonomics contribution to design

Third age usability and safety - an ergonomics contribution to desig

The Patient Health Questionnaire (PHQ-9) as a tool to screen for depression in people with multiple sclerosis: a cross-sectional validation study

Abstract Background: Depression has a point prevalence of 25% and lifetime prevalence of 50% in people with multiple sclerosis (pwMS). Due to accessibility and brevity, the 9-item Patient Health Questionnaire (PHQ-9) may be a useful tool in clinical practice for screening and monitoring of depressive symptoms in people with MS (pwMS). Methods: The objective of this study was to evaluate the reliability, validity and acceptability of the PHQ-9 as a screening tool for depressive symptoms in pwMS. PwMS completed online questionnaires at 3 time-points over 4-weeks. The PHQ-9, Multiple Sclerosis Impact Scale (MSIS-29), Centre for Disease Control Health-Related Quality of Life Measure (CDC-HQOL-4) and clinical history. Results: 103 participants completed the PHQ-9 at three time points, 43% were categorised as depressed on at least one response. The PHQ-9 exhibited high internal reliability (Cronbach’s α = 0.89), and test-re-test agreement (ICC 0.89, 95% CI 0.85–0.91). Convergent validity was indicated through positive correlation with the mental health items on the MSIS-29 (r = 0.46 and r = 0.50) and CDC-HQOL-4 (r = 0.79 and r = 0.73) at both assessment points. Positive correlations between the PHQ-9 and the MSIS-29 (r = 0.86 and r = 0.84) and CDC-HQOL-4 (r = 0.55 and r = 0.37) physical symptom sub-scores did not indicate divergent validity. 93% of ratings evaluated the PHQ-9 as “Very” or “Completely” acceptable. Conclusion: The PHQ-9 is a reliable and valid measure of depressive symptoms in people with MS. Given its accessibility, ease of administration, and acceptability, we recommend the PHQ-9 as a tool to screen for depressive symptoms in people with MS