A cautionary tale of pyridoxine toxicity in cystathionine beta‐synthase deficiency detected by two‐tier newborn screening highlights the need for clear pyridoxine dosing guidelines

Classic homocystinuria is due to deficiency of cystathionine beta‐synthase (CBS), a pyridoxine‐dependent enzyme that, depending on the molecular variants, may be co‐factor responsive. Elevated methionine is often used as the primary analyte to detect CBS deficiency (CBSD) on newborn screening (NBS), but is limited by increased detection of other biochemical disorders with less clear clinical significance such as methionine aminotransferase (MAT) I/III heterozygotes. Our state has implemented a two‐tier NBS algorithm for CBSD that successfully reduced the number of MATI/III heterozygotes, yet effectively detected a mild, co‐factor responsive form of CBSD. After initial diagnosis, newborns with CBSD often undergo a pyridoxine challenge with high‐dose pyridoxine to determine responsiveness. Here we describe our NBS‐identified patient with a mild form of pyridoxine responsive CBSD who developed respiratory failure and rhabdomyolysis consistent with pyridoxine toxicity during a pyridoxine challenge. This case highlights the need for weight‐based dosing and duration recommendations for pyridoxine challenge in neonates.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163455/2/ajmga61815.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163455/1/ajmga61815_am.pd

Gene regulatory network analysis predicts cooperating transcription factor regulons required for FLT3-ITD+ AML growth

Acute myeloid leukemia (AML) is a heterogeneous disease caused by different mutations. Previously, we showed that each mutational subtype develops its specific gene regulatory network (GRN) with transcription factors interacting within multiple gene modules, many of which are transcription factor genes themselves. Here, we hypothesize that highly connected nodes within such networks comprise crucial regulators of AML maintenance. We test this hypothesis using FLT3-ITD-mutated AML as a model and conduct an shRNA drop-out screen informed by this analysis. We show that AML-specific GRNs predict crucial regulatory modules required for AML growth. Furthermore, our work shows that all modules are highly connected and regulate each other. The careful multi-omic analysis of the role of one (RUNX1) module by shRNA and chemical inhibition shows that this transcription factor and its target genes stabilize the GRN of FLT3-ITD+ AML and that its removal leads to GRN collapse and cell death.</p

The ChatGPT Artificial Intelligence Chatbot: How Well Does It Answer Accounting Assessment Questions?

ChatGPT, a language-learning model chatbot, has garnered considerable attention for its ability to respond to users’ questions. Using data from 14 countries and 186 institutions, we compare ChatGPT and student performance for 28,085 questions from accounting assessments and textbook test banks. As of January 2023, ChatGPT provides correct answers for 56.5 percent of questions and partially correct answers for an additional 9.4 percent of questions. When considering point values for questions, students significantly outperform ChatGPT with a 76.7 percent average on assessments compared to 47.5 percent for ChatGPT if no partial credit is awarded and 56.5 percent if partial credit is awarded. Still, ChatGPT performs better than the student average for 15.8 percent of assessments when we include partial credit. We provide evidence of how ChatGPT performs on different question types, accounting topics, class levels, open/closed assessments, and test bank questions. We also discuss implications for accounting education and research

Is healthy neuroticism associated with health behaviors? A coordinated integrative data analysis

Current literature suggests that neuroticism is positively associated with maladaptive life choices, likelihood of disease, and mortality. However, recent research has identified circumstances under which neuroticism is associated with positive outcomes. The current project examined whether “healthy neuroticism”, defined as the interaction of neuroticism and conscientiousness, was associated with the following health behaviors: smoking, alcohol consumption, and physical activity. Using a pre-registered multi-study coordinated integrative data analysis (IDA) approach, we investigated whether “healthy neuroticism” predicted the odds of engaging in each of the aforementioned activities. Each study estimated identical models, using the same covariates and data transformations, enabling optimal comparability of results. These results were then meta-analyzed in order to estimate an average (N-weighted) effect and to ascertain the extent of heterogeneity in the effects. Overall, these results suggest that neuroticism alone was not related to health behaviors, while individuals higher in conscientiousness were less likely to be smokers or drinkers, and more likely to engage in physical activity. In terms of the healthy neuroticism interaction of neuroticism and conscientiousness, significant interactions for smoking and physical activity suggest that the association between neuroticism and health behaviors was smaller among those high in conscientiousness. These findings lend credence to the idea that healthy neuroticism may be linked to certain health behaviors and that these effects are generalizable across several heterogeneous samples

Is healthy neuroticism associated with longevity? A coordinated integrative data analysis

Early investigations of the neuroticism by conscientiousness interaction with regards to health have been promising, but to date, there have been no systematic investigations of this interaction that account for the various personality measurement instruments, varying populations, or aspects of health. The current study - the second of three - uses a coordinated analysis approach to test the impact of the neuroticism by conscientiousness interaction on the prevalence and incidence of chronic conditions. Using 15 pre-existing longitudinal studies (N > 49,375), we found that conscientiousness did not moderate the relationship between neuroticism and having hypertension (OR = 1.00,95%CI[0.98,1.02]), diabetes (OR = 1.02[0.99,1.04]), or heart disease (OR = 0.99[0.97,1.01]). Similarly, we found that conscientiousness did not moderate the prospective relationship between neuroticism and onset of hypertension (OR = 0.98,[0.95,1.01]), diabetes (OR = 0.99[0.94,1.05]), or heart disease (OR = 0.98[0.94,1.03]). Heterogeneity of effect sizes was largely nonsignificant, with one exception, indicating that the effects are consistent between datasets. Overall, we conclude that there is no evidence that healthy neuroticism, operationalized as the conscientiousness by neuroticism interaction, buffers against chronic conditions

The fitness for the Ageing Brain Study II (FABS II): protocol for a randomized controlled clinical trial evaluating the effect of physical activity on cognitive function in patients with Alzheimer's disease

Background: Observational studies have documented a potential protective effect of physical exercise in older adults who are at risk for developing Alzheimer's disease. The Fitness for the Ageing Brain II (FABS II) study is a multicentre randomized controlled clinical trial (RCT) aiming to determine whether physical activity reduces the rate of cognitive decline among individuals with Alzheimer's disease. This paper describes the background, objectives of the study, and an overview of the protocol including design, organization and data collection methods

The acceptability and feasibility of using the Adult Social Care Outcomes Toolkit (ASCOT) to inform practice in care homes

Background: The Adult Social Care Outcomes Toolkit (ASCOT) measures social care related quality of life (SCRQoL) and can be used to measure outcomes and demonstrate impact across different social care settings. This exploratory study built on previous work by collecting new inter-rater reliability data on the mixed-methods version of the toolkit and exploring how it might be used to inform practice in four case study homes. Method: We worked with two care home providers to agree an in-depth study collecting SCRQoL data in four case-study homes. Data was collected about residents’ age, ethnicity, cognitive impairment, ability to perform activities of daily living and SCRQoL in the four homes. Feedback sessions with staff and managers were held in the homes two weeks after baseline and follow-up data collected three months later. Interviews with managers explored their views of the feedback and recorded any changes that had been made because of it. Results: Participant recruitment was challenging, despite working in partnership with the homes. Resident response rates ranged from 23 to 54 % with 58 residents from four care homes taking part in the research. 53 % lacked capacity to consent. Inter-rater reliability for the ASCOT ratings of SCRQoL were good at time one (IRR = 0.72) and excellent at time two (IRR = 0.76). During the study, residents’ ability to perform activities of daily living declined significantly (z = -2.67, p < .01), as did their expected needs in the absence of services (z = -2.41, p < .05). Despite these rapid declines in functionings, residents’ current SCRQoL declined slightly but not significantly (Z = -1.49, p = .14). Staff responded positively to the feedback given and managers reported implementing changes in practice because of it. Conclusion: This exploratory study faced many challenges in the recruitment of residents, many of whom were cognitively impaired. Nevertheless, without a mixed-methods approach many of the residents living in the care homes would have been excluded from the research altogether or had their views represented only by a representative or proxy. The value of the mixed-methods toolkit and its potential for use by providers is discussed

Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning

Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.Peer reviewe

Cerebral small vessel disease genomics and its implications across the lifespan

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.Peer reviewe