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Huntington disease (HD) reflects the dominant consequences of a CAG-repeat expansion in HTT. Analysis of common SNP-based haplotypes has revealed that most European HD subjects have distinguishable HTT haplotypes on their normal and disease chromosomes and that ∼50% of the latter share the same major HD haplotype. We reasoned that sequence-level investigation of this founder haplotype could provide significant insights into the history of HD and valuable information for gene-targeting approaches. Consequently, we performed whole-genome sequencing of HD and control subjects from four independent families in whom the major European HD haplotype segregates with the disease. Analysis of the full-sequence-based HTT haplotype indicated that these four families share a common ancestor sufficiently distant to have permitted the accumulation of family-specific variants. Confirmation of new CAG-expansion mutations on this haplotype suggests that unlike most founders of human disease, the common ancestor of HD-affected families with the major haplotype most likely did not have HD. Further, availability of the full sequence data validated the use of SNP imputation to predict the optimal variants for capturing heterozygosity in personalized allele-specific gene-silencing approaches. As few as ten SNPs are capable of revealing heterozygosity in more than 97% of European HD subjects. Extension of allele-specific silencing strategies to the few remaining homozygous individuals is likely to be achievable through additional known SNPs and discovery of private variants by complete sequencing of HTT. These data suggest that the current development of gene-based targeting for HD could be extended to personalized allele-specific approaches in essentially all HD individuals of European ancestry.

OBJECTIVES Participants in faculty development workshops often comment that 'those who need faculty development the most attend the least'. The goals of this study were to explore the reasons why some clinical teachers do not participate in centralised faculty development activities and to learn how we can make faculty development programmes more relevant to teachers' needs. METHODS In 2006, we conducted focus groups with 16 clinical teachers, who had not participated in faculty development activities, to ascertain their perceptions of faculty development, reasons for non-participation and perceived barriers to involvement. Content analysis and team consensus guided the data interpretation. RESULTS Focus group participants were aware of faculty development offerings and valued the goals of these activities. Important reasons for non-participation emerged: clinical reality, which included volume of work and lack of (protected) time; logistical issues, such as timing and the central location of organised activities; a perceived lack of financial reward and recognition for teaching, and a perceived lack of direction from, and connection to, the university. CONCLUSIONS Clinical reality and logistical issues appeared to be greater deterrents to participation than faculty development goals, content or strategies. Moreover, when asked to discuss faculty development, teachers referred to their development as faculty members in the broadest sense, which included personal and career development. They also expressed the desire for clear guidance from the university, financial rewards and recognition for teaching, and a sense of 'belonging'. Faculty development programmes should try to address these organisational issues as well as teachers' personal and professional needs. [ABSTRACT FROM AUTHOR]

Abstract Background Although motor deficits are gaining attention in autism research much less attention has been paid to the physical activity patterns in this group of children. The participants in this study were a group of children with autism spectrum disorder (N = 72) between the ages of 9-18 years. This cross-sectional study explored the physical activity patterns of seventy-two children with autism spectrum disorder as they aged. Findings Results indicated significant differences between the mean time spent in moderate to vigorous physical activity and the mean time spent in sedentary activity. Older children with autism spectrum disorder are significantly more physically inactive, compared to younger children. Conclusions Physical activity programs and interventions need to address this deficit, in physical activity. Children with autism have a similar trend in physical activity patterns compared to their peers without autism; associated benefits and future research will be discussed.

Abstract Background The efficacy of natural products (NPs) is being evaluated using randomized controlled trials (RCTs) with increasing frequency, yet a search of the literature did not identify a widely accepted critical appraisal instrument developed specifically for use with NPs. The purpose of this project was to develop and evaluate a critical appraisal instrument that is sufficiently rigorous to be used in evaluating RCTs of conventional medicines, and also has a section specific for use with single entity NPs, including herbs and natural sourced chemicals. Methods Three phases of the project included: 1) using experts and a Delphi process to reach consensus on a list of items essential in describing the identity of an NP; 2) compiling a list of non-NP items important for evaluating the quality of an RCT using systematic review methodology to identify published instruments and then compiling item categories that were part of a validated instrument and/or had empirical evidence to support their inclusion and 3) conducting a field test to compare the new instrument to a published instrument for usefulness in evaluating the quality of 3 RCTs of a NP and in applying results to practice. Results Two Delphi rounds resulted in a list of 15 items essential in describing NPs. Seventeen item categories fitting inclusion criteria were identified from published instruments for conventional medicines. The new assessment instrument was assembled based on content of the two lists and the addition of a Reviewer's Conclusion section. The field test of the new instrument showed good criterion validity. Participants found it useful in translating evidence from RCTs to practice. Conclusion A new instrument for the critical appraisal of RCTs of NPs was developed and tested. The instrument is distinct from other available assessment instruments for RCTs of NPs in its systematic development and validation. The instrument is ready to be used by pharmacy students, health care practitioners and academics and will continue to be refined as required.

OBJECTIVE: The research findings reported here describe the importance and various functions of physician listening according to patients. METHODS: Fifty-eight patients of the McGill University Health Centre were interviewed using a qualitative, interpretive design approach. RESULTS: Patients explained why listening was important to them and these findings were organized into three themes: (a) listening as an essential component of clinical data gathering and diagnosis; (b) listening as a healing and therapeutic agent; and (c) listening as a means of fostering and strengthening the doctor-patient relationship. The findings are presented along with a conceptual model on the functions of physician listening. CONCLUSION: Elucidating the multiple functions of listening in the clinical encounter from patient perspectives can assist physicians in improving their listening approach. PRACTICE IMPLICATIONS: For training purposes, we recommend that a module on listening should lead to a discussion not only about the skill required in listening attentively, but also to the values, beliefs, attitudes, and intentions of physicians who choose to listen to their patients. This teaching objective may be facilitated by future research that explores the concept of 'authenticity' in a physician's listening approach, which we argue is central to successful clinical outcomes. [ABSTRACT FROM AUTHOR]

Purpose: External physiological monitoring is the primary approach to measure and remove effects of low-frequency respiratory variation from BOLD-fMRI signals. However, the acquisition of clean external respiratory data during fMRI is not always possible, so recent research has proposed using machine learning to directly estimate respiratory variation (RV), potentially obviating the need for external monitoring. In this study, we propose an extended method for reconstructing RV waveforms directly from resting state BOLD-fMRI data in healthy adult participants with the inclusion of both BOLD signals and derived head motion parameters., Methods: In the proposed method, 1D convolutional neural networks (1D-CNNs) used BOLD signals and head motion parameters to reconstruct the RV waveform for the whole fMRI scan time. Resting-state fMRI data and associated respiratory records from the Human Connectome Project in Young Adults (HCP-YA) dataset are used to train and test the proposed method., Results: Compared to using only BOLD-fMRI data for a CNN input, this approach yielded improvements of 14% in mean absolute error, 24% in mean square error, 14% in correlation, and 12% in dynamic time warping. When tested on independent datasets, the method demonstrated generalizability, even in data with different TRs and physiological conditions., Conclusion: This study shows that the respiratory variations could be reconstructed from BOLD-fMRI data in the young adult population, and its accuracy could be improved using supportive data such as head motion parameters. The method also performed well on independent datasets with different experimental conditions., (© 2024 The Author(s). Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

The concept of childhood has evolved over the years, inspired by the United Nations Convention on the Rights of the Child in 1989, shifting from developmental models to a conception of childhood that recognizes children as moral agents. This evolution highlights the importance of respecting children's agency and their right to be heard in matters that are related to them. In conventional health research, however, children's voices are often inadequately accessed. In this commentary, we discuss the imperative to recognize children's agency in dental research and a shift from research on children to research with and by children. Moreover, we underscore the importance of actively seeking and listening to children's voices and recognizing their agency in shaping research and healthcare practices in the field of dentistry. Further, we explore the application of participatory research approaches in dental research and provide examples of studies that have involved children in various capacities. We conclude this commentary by emphasizing the potential benefits of participatory research in both qualitative and quantitative dental studies to promote deeper understanding, clearer communication, and stronger advocacy regarding children's interests. Primarily, we call for greater recognition of children's agency in dental research and advocate for more inclusive and child-centred research methodologies., (© 2024 The Authors. Community Dentistry and Oral Epidemiology published by John Wiley & Sons Ltd.)

Cardiovascular mortality is particularly high and increasing in patients with chronic kidney disease, with vascular calcification (VC) as a major pathophysiologic feature. VC is a highly regulated biological process similar to bone formation involving osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs). We have previously demonstrated that loss of T-cell death-associated gene 51 (TDAG51) expression leads to an attenuation of medial VC. We now show a significant induction of circulating levels of growth differentiation factor 10 (GDF10) in TDAG51 -/- mice, which was of interest due to its established role as an inhibitor of osteoblast differentiation. The objective of this study was to examine the role of GDF10 in the osteogenic transdifferentiation of VSMCs. Using primary mouse and human VSMCs, as well as ex vivo aortic ring cultures, we demonstrated that treatment with recombinant human (rh) GDF10 mitigated phosphate-mediated hydroxyapatite (HA) mineral deposition. Furthermore, ex vivo aortic rings from GDF10 -/- mice exhibited increased HA deposition compared to C57BL/6J controls. To explain our observations, we identified that rhGDF10 treatment reduced protein expression of runt-related transcription factor 2, a key driver of osteogenic transdifferentiation of VSMCs and VC. In support of these findings, in vivo treatment with rhGDF10 attenuated VD 3 -induced VC. Furthermore, we demonstrated an increase in circulating GDF10 in patients with chronic kidney disease with clinically defined severe VC, as assessed by coronary artery calcium score. Thus, our studies identify GDF10 as a novel inhibitor of mineral deposition and as such, may represent a potential novel biomarker and therapeutic target for the detection and management of VC., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Neuropalliative care as a clinical speciality aims to address the unique end-of-life needs and concerns of patients with neurologic disease. Although literature has outlined clinical hurdles, a more nuanced understanding of how neuropalliative care was experienced, conceptualized, and enacted could provide context and depth to better outline practice and research priorities. This article presents findings from an ethnographic study of neuropalliative care conducted in a university-affiliated, tertiary care neurological hospital in Canada with a dedicated neuropalliative consultation service. Specifically, this article examines how clinical hurdles outlined in the neuropalliative literature were experienced and addressed by multiple stakeholders, including patients, families, and clinicians. These clinical hurdles include locating the scope of neuropalliative care, ascertaining the impact of prognostic uncertainty and poor recognition of the dying patient, and navigating the tensions between curative and palliative philosophies. In the discussion, the implications of these clinical hurdles are addressed, concluding with reflections on the role of ethnography, palliative care in the context of functional changes, and broadening approaches to uncertainty., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 by The Hospice and Palliative Nurses Association. All rights reserved.)

Huntington's disease (HD) is a neurodegenerative genetic disorder caused by an expansion in the CAG repeat tract of the huntingtin (HTT) gene resulting in behavioural, cognitive, and motor defects. Current knowledge of disease pathogenesis remains incomplete, and no disease course-modifying interventions are in clinical use. We have previously reported the development and characterisation of the OVT73 transgenic sheep model of HD. The 73 polyglutamine repeat is somatically stable and therefore likely captures a prodromal phase of the disease with an absence of motor symptomatology even at 5-years of age and no detectable striatal cell loss. To better understand the disease-initiating events we have undertaken a single nuclei transcriptome study of the striatum of an extensively studied cohort of 5-year-old OVT73 HD sheep and age matched wild-type controls. We have identified transcriptional upregulation of genes encoding N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors in medium spiny neurons, the cell type preferentially lost early in HD. Further, we observed an upregulation of astrocytic glutamate uptake transporters and medium spiny neuron GABAA receptors, which may maintain glutamate homeostasis. Taken together, these observations support the glutamate excitotoxicity hypothesis as an early neurodegeneration cascade-initiating process but the threshold of toxicity may be regulated by several protective mechanisms. Addressing this biochemical defect early may prevent neuronal loss and avoid the more complex secondary consequences precipitated by cell death., (© The Author(s) 2024. Published by Oxford University Press.)

Neuropalliative care developed to address the needs of patients living with life-limiting neurologic disease. One critical consideration is that disease-related changes to cognition, communication, and function challenge illness experiences and care practices. We conducted an ethnography to understand neuropalliative care as a phenomenon; how it was experienced, provided, conceptualized. Personhood served as our conceptual framework; with its long philosophical history and important place in nursing theory, we examined the extent to which it captured neuropalliative experiences and concerns. Personhood contextualized complex losses, aligning the impact of functional and relational changes. Cognition, communication, and functional alterations stretched conceptions of personhood, insinuating it can be relational, fluid, adaptive. Although normative conceptions of personhood guided research and decision-making, ethical considerations suggested personhood could be transformed, remade. We consider the implications of our findings through three themes. First, we examine how literature on illness experience fails to integrate the realities of people living with and dying from neurologic disease; we counter this by interrogating the concept of experience. Second, we turn to Ricoeur's work on recognition to illuminate relational conceptions of personhood to inform care practices. Finally, we reflect on how personhood can bridge the gap left by functional changes, enhance relational engagement, and promote dignity at the end of life., (© 2024 The Author(s). Nursing Inquiry published by John Wiley & Sons Ltd.)

Huntington's disease (HD), due to expansion of a CAG repeat in HTT , is representative of a growing number of disorders involving somatically unstable short tandem repeats. We find that overlapping and distinct genetic modifiers of clinical landmarks and somatic expansion in blood DNA reveal an underlying complexity and cell-type specificity to the mismatch repair-related processes that influence disease timing. Differential capture of non-DNA-repair gene modifiers by multiple measures of cognitive and motor dysfunction argues additionally for cell-type specificity of pathogenic processes. Beyond trans modifiers, differential effects are also illustrated at HTT by a 5'-UTR variant that promotes somatic expansion in blood without influencing clinical HD, while, even after correcting for uninterrupted CAG length, a synonymous sequence change at the end of the CAG repeat dramatically hastens onset of motor signs without increasing somatic expansion. Our findings are directly relevant to therapeutic suppression of somatic expansion in HD and related disorders and provide a route to define the individual neuronal cell types that contribute to different HD clinical phenotypes.

Huntington's disease (HD), one of >50 inherited repeat expansion disorders (Depienne and Mandel, 2021), is a dominantly-inherited neurodegenerative disease caused by a CAG expansion in HTT (The Huntington's Disease Collaborative Research Group, 1993). Inherited CAG repeat length is the primary determinant of age of onset, with human genetic studies underscoring that the property driving disease is the CAG length-dependent propensity of the repeat to further expand in brain (Swami et al ., 2009; GeM-HD, 2015; Hensman Moss et al ., 2017; Ciosi et al ., 2019; GeM-HD, 2019; Hong et al ., 2021). Routes to slowing somatic CAG expansion therefore hold great promise for disease-modifying therapies. Several DNA repair genes, notably in the mismatch repair (MMR) pathway, modify somatic expansion in HD mouse models (Wheeler and Dion, 2021). To identify novel modifiers of somatic expansion, we have used CRISPR-Cas9 editing in HD knock-in mice to enable in vivo screening of expansion-modifier candidates at scale. This has included testing of HD onset modifier genes emerging from human genome-wide association studies (GWAS), as well as interactions between modifier genes, thereby providing new insight into pathways underlying CAG expansion and potential therapeutic targets.

While protein activity is traditionally studied with a major focus on the active site, the activity of enzymes has been hypothesized to be linked to the flexibility of adjacent regions, warranting more exploration into how the dynamics in these regions affects catalytic turnover. One such enzyme is Xylanase A (XylA), which cleaves hemicellulose xylan polymers by hydrolysis at internal β-1,4-xylosidic linkages. It contains a "thumb" region whose flexibility has been suggested to affect the activity. The double mutation D11F/R122D was previously found to affect activity and potentially bias the thumb region to a more open conformation. We find that the D11F/R122D double mutation shows substrate-dependent effects, increasing activity on the non-native substrate ONPX2 but decreasing activity on its native xylan substrate. To characterize how the double mutant causes these kinetics changes, nuclear magnetic resonance (NMR) and molecular dynamics (MD) simulations were used to probe structural and flexibility changes. NMR chemical shift perturbations revealed structural changes in the double mutant relative to the wild-type, specifically in the thumb and fingers regions. Increased slow-timescale dynamics in the fingers region was observed as intermediate-exchange line broadening. Lipari-Szabo order parameters show negligible changes in flexibility in the thumb region in the presence of the double mutation. To help understand if there is increased energetic accessibility to the open state upon mutation, alchemical free energy simulations were employed that indicated thumb opening is more favorable in the double mutant. These studies aid in further characterizing how flexibility in adjacent regions affects the function of XylA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

The de novo design of miniprotein inhibitors has recently emerged as a new technology to create proteins that bind with high affinity to specific therapeutic targets. Their size, ease of expression, and apparent high stability makes them excellent candidates for a new class of protein drugs. However, beyond circular dichroism melts and hydrogen/deuterium exchange experiments, little is known about their dynamics, especially at the elevated temperatures they seemingly tolerate quite well. To address that and gain insight for future designs, we have focused on identifying unintended and previously overlooked heat-induced structural and chemical changes in a particularly stable model miniprotein, EHEE_rd2_0005. Nuclear magnetic resonance (NMR) studies suggest the presence of dynamics on multiple time and temperature scales. Transiently elevating the temperature results in spontaneous chemical deamidation visible in the NMR spectra, which we validate using both capillary electrophoresis and mass spectrometry (MS) experiments. High temperatures also result in greatly accelerated intrinsic rates of hydrogen exchange and signal loss in NMR heteronuclear single quantum coherence spectra from local unfolding. These losses are in excellent agreement with both room temperature hydrogen exchange experiments and hydrogen bond disruption in replica exchange molecular dynamics simulations. Our analysis reveals important principles for future miniprotein designs and the potential for high stability to result in long-lived alternate conformational states., (© 2024 The Protein Society.)

Many Mendelian disorders, such as Huntington's disease (HD) and spinocerebellar ataxias, arise from expansions of CAG trinucleotide repeats. Despite the clear genetic causes, additional genetic factors may influence the rate of those monogenic disorders. Notably, genome-wide association studies discovered somewhat expected modifiers, particularly mismatch repair genes involved in the CAG repeat instability, impacting age at onset of HD. Strikingly, FAN1 , previously unrelated to repeat instability, produced the strongest HD modification signals. Diverse FAN1 haplotypes independently modify HD, with rare genetic variants diminishing DNA binding or nuclease activity of the FAN1 protein, hastening HD onset. However, the mechanism behind the frequent and the most significant onset-delaying FAN1 haplotype lacking missense variations has remained elusive. Here, we illustrated that a microRNA acting on 3'-UTR (untranslated region) SNP rs3512, rather than transcriptional regulation, is responsible for the significant FAN1 expression quantitative trait loci signal and allelic imbalance in FAN1 messenger ribonucleic acid (mRNA), accounting for the most significant and frequent onset-delaying modifier haplotype in HD. Specifically, miR-124-3p selectively targets the reference allele at rs3512, diminishing the stability of FAN1 mRNA harboring that allele and consequently reducing its levels. Subsequent validation analyses, including the use of antagomir and 3'-UTR reporter vectors with swapped alleles, confirmed the specificity of miR-124-3p at rs3512. Together, these findings indicate that the alternative allele at rs3512 renders the FAN1 mRNA less susceptible to miR-124-3p-mediated posttranscriptional regulation, resulting in increased FAN1 levels and a subsequent delay in HD onset by mitigating CAG repeat instability., Competing Interests: Competing interests statement:J.-M.L. consults for Life Edit Therapeutics and serves on the scientific advisory board of GenEdit Inc. J.F.G. was a Founder and Scientific Advisory Board member with a financial interest in Triplet Therapeutics Inc. His NIH-funded project is using genetic and genomic approaches to uncover other genes that significantly influence when diagnosable symptoms emerge and how rapidly they worsen in HD. The company was developing new therapeutic approaches to address triplet repeat disorders such as HD, myotonic dystrophy, and SCAs. J.F.G.’s interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. J.F.G. also consults for Transine Therapeutics Ltd and has been a consultant for Wave Life Sciences USA Inc., Biogen Inc., and Pfizer Inc. V.C.W. was a Scientific Advisory Board member of Triplet Therapeutics, Inc., a company developing new therapeutic approaches to address triplet repeat disorders such HD and myotonic dystrophy. Her financial interests in Triplet Therapeutics were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. She is a scientific advisory board member of LoQus23 Therapeutics and has provided paid consulting services to Alnylam, Acadia Pharmaceuticals Inc., Alnylam Inc., Biogen Inc. and Passage Bio. S.L. is currently employee of Illumina, Inc., a public company that develops and markets systems for genetic analysis. Within the last 5 y D.G.M. has been a scientific consultant and/or received an honoraria/grants from AMO Pharma, Dyne, F. Hoffman-La Roche, LoQus23, MOMA Therapeutics, Novartis, Ono Pharmaceuticals, Pfizer Pharmaceuticals, Rgenta Therpeutics, Sanofi, Sarepta Therapeutics Inc, Script Biosciences, Triplet Therapeutics, and Vertex Pharmaceuticals. D.G.M. also had research contracts with AMO Pharma and Vertex Pharmaceuticals. T.H.M. is an associate member of the scientific advisory board of LoQus23 Therapeutics Ltd.

Huntington's disease (HD) is a dominant neurological disorder caused by an expanded HTT exon 1 CAG repeat that lengthens huntingtin's polyglutamine tract. Lowering mutant huntingtin has been proposed for treating HD, but genetic modifiers implicate somatic CAG repeat expansion as the driver of onset. We find that branaplam and risdiplam, small molecule splice modulators that lower huntingtin by promoting HTT pseudoexon inclusion, also decrease expansion of an unstable HTT exon 1 CAG repeat in an engineered cell model. Targeted CRISPR-Cas9 editing shows this effect is not due to huntingtin lowering, pointing instead to pseudoexon inclusion in PMS1. Homozygous but not heterozygous inactivation of PMS1 also reduces CAG repeat expansion, supporting PMS1 as a genetic modifier of HD and a potential target for therapeutic intervention. Although splice modulation provides one strategy, genome-wide transcriptomics also emphasize consideration of cell-type specific effects and polymorphic variation at both target and off-target sites., (© 2024. The Author(s).)

Background: Amyloid-beta and brain atrophy are hallmarks for Alzheimer's Disease that can be targeted with positron emission tomography (PET) and MRI, respectively. MRI is cheaper, less-invasive, and more available than PET. There is a known relationship between amyloid-beta and brain atrophy, meaning PET images could be inferred from MRI., Purpose: To build an image translation model using a Conditional Generative Adversarial Network able to synthesize Amyloid-beta PET images from structural MRI., Study Type: Retrospective., Population: Eight hundred eighty-two adults (348 males/534 females) with different stages of cognitive decline (control, mild cognitive impairment, moderate cognitive impairment, and severe cognitive impairment). Five hundred fifty-two subjects for model training and 331 for testing (80%:20%)., Field Strength/sequence: 3 T, T1-weighted structural (T1w)., Assessment: The testing cohort was used to evaluate the performance of the model using the Structural Similarity Index Measure (SSIM) and Peak Signal-to-Noise Ratio (PSNR), comparing the likeness of the overall synthetic PET images created from structural MRI with the overall true PET images. SSIM was computed in the overall image to include the luminance, contrast, and structural similarity components. Experienced observers reviewed the images for quality, performance and tried to determine if they could tell the difference between real and synthetic images., Statistical Tests: Pixel wise Pearson correlation was significant, and had an R 2 greater than 0.96 in example images. From blinded readings, a Pearson Chi-squared test showed that there was no significant difference between the real and synthetic images by the observers (P = 0.68)., Results: A high degree of likeness across the evaluation set, which had a mean SSIM = 0.905 and PSNR = 2.685. The two observers were not able to determine the difference between the real and synthetic images, with accuracies of 54% and 46%, respectively., Conclusion: Amyloid-beta PET images can be synthesized from structural MRI with a high degree of similarity to the real PET images., Evidence Level: 3 TECHNICAL EFFICACY: Stage 1., (© 2023 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: Little is known about the clinical knowledge and skills that are acquired by physicians through teaching, how such learning occurs, or the factors that influence this process. This study explored how physicians acquire clinical knowledge and skills through clinical teaching and examined the contextual elements that influence this learning., Method: Two theoretical frameworks informed this interpretive description study: situated learning and cognitive apprenticeship. From March to November 2021, semistructured interviews and follow-up discussions were conducted at McGill University with clinician-teachers who regularly supervise internal medicine residents. Participants were asked to describe how they learned clinical medicine through spontaneous clinical teaching, guided by questions relating to what they learned, memorable teaching moments, and factors influencing this learning. Data were analyzed iteratively, using both a deductive and inductive approach., Results: Of the 87 contacted physicians, 45 responded, expressing interest (n = 22) or declining participation (n = 23), and 42 did not respond. All 22 clinicians who responded positively were interviewed, with 7 follow-up discussions. Results suggested that clinician-teachers encountered myriad opportunities to learn clinical medicine during spontaneous interactions with trainees. These interactions, embedded in authentic patient care, were influenced by clinician-teacher characteristics, trainee characteristics, and contextual affordances. Clinician-teachers were stimulated to learn by trainee presence and through discrete interactions with trainees. These stimuli often led to feelings of "performative pressure" to role model and teach effectively or "slowing down" in thinking, prompting clinician-teachers to engage in learning processes (e.g., reflection, collaboration, and articulation), which resulted in knowledge acquisition, reinforcement, and refinement., Conclusions: Learning through teaching is an underappreciated strategy that can help clinician-teachers improve their clinical knowledge and skills. This study uncovered some of the processes through which clinicians learn during spontaneous clinical teaching and the factors that modulate this learning., (Copyright © 2024 the Association of American Medical Colleges.)

Expansions of glutamine-coding CAG trinucleotide repeats cause a number of neurodegenerative diseases, including Huntington's disease and several of spinocerebellar ataxias. In general, age-at-onset of the polyglutamine diseases is inversely correlated with the size of the respective inherited expanded CAG repeat. Expanded CAG repeats are also somatically unstable in certain tissues, and age-at-onset of Huntington's disease corrected for individual HTT CAG repeat length (i.e. residual age-at-onset), is modified by repeat instability-related DNA maintenance/repair genes as demonstrated by recent genome-wide association studies. Modification of one polyglutamine disease (e.g. Huntington's disease) by the repeat length of another (e.g. ATXN3, CAG expansions in which cause spinocerebellar ataxia 3) has also been hypothesized. Consequently, we determined whether age-at-onset in Huntington's disease is modified by the CAG repeats of other polyglutamine disease genes. We found that the CAG measured repeat sizes of other polyglutamine disease genes that were polymorphic in Huntington's disease participants but did not influence Huntington's disease age-at-onset. Additional analysis focusing specifically on ATXN3 in a larger sample set ( n = 1388) confirmed the lack of association between Huntington's disease residual age-at-onset and ATXN3 CAG repeat length. Additionally, neither our Huntington's disease onset modifier genome-wide association studies single nucleotide polymorphism data nor imputed short tandem repeat data supported the involvement of other polyglutamine disease genes in modifying Huntington's disease. By contrast, our genome-wide association studies based on imputed short tandem repeats revealed significant modification signals for other genomic regions. Together, our short tandem repeat genome-wide association studies show that modification of Huntington's disease is associated with short tandem repeats that do not involve other polyglutamine disease-causing genes, refining the landscape of Huntington's disease modification and highlighting the importance of rigorous data analysis, especially in genetic studies testing candidate modifiers., Competing Interests: J.F.G. was a Scientific Advisory Board member and had a financial interest in Triplet Therapeutics, Inc. His NIH-funded project is using genetic and genomic approaches to uncover other genes that significantly influence when diagnosable symptoms emerge and how rapidly they worsen in Huntington disease. The company is developing new therapeutic approaches to address triplet repeat disorders such Huntington's disease, myotonic dystrophy and SCAs. His interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. J.F.G. has also been a consultant for Wave Life Sciences USA, Inc., Biogen, Inc. and Pfizer, Inc. Within the last five years D.G.M. has been a scientific consultant and/or received an honoraria/stock options from AMO Pharma, Dyne, F. Hoffman-La Roche, LoQus23, Novartis, Ono Pharmaceuticals, Rgenta Therapeutics, Sanofi, Sarepta Therapeutics Inc, Script Biosciences, Triplet Therapeutics, and Vertex Pharmaceuticals and held research contracts with AMO Pharma and Vertex Pharmaceuticals. J.D.L. is a paid Advisory Board member for F. Hoffmann-La Roche Ltd and uniQure biopharma B.V., and he is a paid consultant for Vaccinex Inc, Wave Life Sciences USA Inc, Genentech Inc, Triplet Inc, and PTC Therapeutics Inc. T.H.M. is an associate member of the scientific advisory board of LoQus23 Therapeutics. L.J. was a member of the scientific advisory boards of LoQus23 Therapeutics and Triplet Therapeutics. V.C.W. was a Scientific Advisory Board member of Triplet Therapeutics, Inc., a company developing new therapeutic approaches to address triplet repeat disorders such Huntington's disease and myotonic dystrophy. Her financial interests in Triplet Therapeutics were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. She is a scientific advisory board member of LoQus23 Therapeutics and has provided paid consulting services to Alnylam, Acadia Pharmaceuticals Inc., Alnylam Inc., Biogen Inc. and Passage Bio. J.M.L consults for Life Edit Therapeutics and serves in the scientific advisory board of GenEdit, Inc., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Brain imaging and genomics are critical tools enabling characterization of the genetic basis of brain disorders. However, imaging large cohorts is expensive and may be unavailable for legacy datasets used for genome-wide association studies (GWASs). Using an integrated feature selection/aggregation model, we developed an image-mediated association study (IMAS), which utilizes borrowed imaging/genomics data to conduct association mapping in legacy GWAS cohorts. By leveraging the UK Biobank image-derived phenotypes (IDPs), the IMAS discovered genetic bases underlying four neuropsychiatric disorders and verified them by analyzing annotations, pathways, and expression quantitative trait loci (eQTLs). A cerebellar-mediated mechanism was identified to be common to the four disorders. Simulations show that, if the goal is identifying genetic risk, our IMAS is more powerful than a hypothetical protocol in which the imaging results were available in the GWAS dataset. This implies the feasibility of reanalyzing legacy GWAS datasets without conducting additional imaging, yielding cost savings for integrated analysis of genetics and imaging., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Somatic instability of the huntingtin (HTT) CAG repeat mutation modifies age-at-onset of Huntington's disease (HD). Understanding the mechanism and pathogenic consequences of instability may reveal therapeutic targets. Using small-pool PCR we analyzed CAG instability in the OVT73 sheep model which expresses a full-length human cDNA HTT transgene. Analyses of five- and ten-year old sheep revealed the transgene (CAG)69 repeat was remarkably stable in liver, striatum, and other brain tissues. As OVT73 sheep at ten years old have minimal cell death and behavioral changes, our findings support instability of the HTT expanded-CAG repeat as being required for the progression of HD.

Purpose/objectives: Evidence-based caries management (EBCM) has developed into an internationally recognized tool for integration of comprehensive non-surgical caries treatment in dental education. However, uptake of the EBCM approach remains uneven across Canadian dental schools. Our project sought to understand how dental instructors perceive the challenges and solutions to the integration of the EBCM approach in undergraduate clinical education., Methods: Using a qualitative descriptive design, we recruited a purposeful sample of clinical instructors supervising undergraduate dental students in caries-related dental care. Semi-structured, online interviews focused on the main characteristics of EBCM. Interviews were analyzed using the awareness, desire, knowledge, ability, and reinforcement (ADKAR) change management model to understand challenges with EBCM implementation in undergraduate education. The analysis process started with verbatim transcription; then, transcripts were coded deductively based on the interview guide and the ADKAR model domains, and inductively to generate emergent codes. Finally, thematic analysis was used to develop themes and subthemes., Results: We interviewed 11 dental instructors with a wide range of clinical experience. Our results show that participants had sufficient awareness regarding the need for the EBCM approach and portrayed a strong desire to participate in bringing curricular changes. Knowledge and ability of participants depended on their training, experience, and involvement in continuing education courses. A lack of standardized caries management practices, less chairside time, and poor remuneration for instructors were major barriers in EBCM clinical implementation. Potential solutions suggested included providing continuing education courses, credits for students for non-surgical caries management, and remunerating instructors for implementation., Conclusions: In conclusion, most participants were aware of the need for a substantive change toward EBCM and demonstrated the desire to participate and improve its implementation. Our analysis showed that to facilitate full integration of the EBCM approach into the undergraduate dental clinics, organizational focus needs to be placed on the individual's knowledge and ability, with tailored efforts toward reinforcement., (© 2023 The Authors. Journal of Dental Education published by Wiley Periodicals LLC on behalf of American Dental Education Association.)

This paper is the fourth of a series of narrative reviews to critically rethink underexplored concepts in oral health research. The series commenced with an initial commissioned framework of Inclusion Oral Health, which spawned further exploration into the social forces that undergird social exclusion and othering. The second review challenged unidimensional interpretations of the causes of inequality by bringing intersectionality theory to oral health. The third exposed how language, specifically labels, can perpetuate and (re)produce vulnerability by eclipsing the agency and power of vulnerabilised populations. In this fourth review, we revisit othering, depicted in the concept of stigma. We specifically define and conceptualize oral health-related stigma, bringing together prior work on stigma to advance the robustness and utility of this theory for oral health research., (© 2023 The Authors. Community Dentistry and Oral Epidemiology published by John Wiley & Sons Ltd.)

This article presents an overview of past and current grief rituals and practices and existing grassroots and institutional initiatives seeking to address the complex, prolonged, and traumatic grief experienced by many Inuit living in Quebec. While conducting a study seeking to identify the strengths, resources, and challenges for Nunavik's Inuit communities related to end-of-life care, results emerged concerning how family caregivers' grief related to the dying process was compounded by the sequelae of historic loss experiences (e.g., losses related to Canada's federal policies, including residential schools, forced relocations, and dog slaughters) and by present loss experiences (e.g., tragic and sudden deaths in local communities). To better support caregivers, an understanding of these grief experiences and a vision of bereavement care inclusive of community mobilization efforts to develop bereavement training and support is needed. We conclude with a discussion of a community capacity approach to bereavement care., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Cancer treatments can damage healthy tissues and organs, and leave harmful impacts on cancer survivors, especially on children and adolescents. The oral effects of cancer treatment can occur during or soon after treatment, or months-even years-later. Cancer treatments can also affect the child, psychologically and socially by hindering their speech, eating, sleeping, and social interactions. These effects can have profound impacts on children's quality of life. Building on a previous review published in 2012, this scoping review aims to identify and map the current evidence base underpinning the oral health-related impacts of cancer treatment on the quality of life of children with cancer., Methodology and Methods: Our methodology is guided by Arksey and O'Malley's methodological framework for scoping reviews, Levac's additions to the framework, and follows the Joanna Briggs Institute Reviewer's Manual. Five electronic databases and grey literature will be systematically searched using a predefined search strategy. Two reviewers will independently screen the retrieved articles using Rayyan software and chart data from included articles. One of the team's senior research members will act as a third reviewer and make the final decision on disputed documents. We will include literature with a focus on oral health-related quality of life of children undergoing cancer treatments. Following the selection of studies, data will be extracted, synthesized, and reported thematically and the relevant stakeholder's insight will be added to our results., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Attaran et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Poor oral health affects the health and well-being of older adults in many ways. Despite years of international research investigating poor oral health among older adults, it has remained a largely unresolved problem. The aim of this article is to explore the combination of 2 key frameworks, ecosocial theory and intersectionality, to guide our exploration and understanding of oral health and aging and help inform research, education, policy, and services. Proposed by Krieger, ecosocial theory is concerned with the symbiotic relationship among embodied biological processes and social, historical, and political contexts. Building on the work of Crenshaw, intersectionality explores how social identities such as race, gender, socioeconomic status, and age interconnect in ways that can enhance privilege or compound discrimination and social disadvantage. Intersectionality offers a layered understanding of how power relations reflected in systems of privilege or oppression influence an individual's multiple intersecting social identities. Understanding this complexity and the symbiotic relationships offers an opportunity to reconsider how inequities in oral health for older adults can be addressed in research, education, and practice and increase the focus on equity, prevention, interdisciplinary care, and use of innovative technology.

Children with medical complexity have been defined within the literature as chronically ill and medically fragile children with complex care needs. Care for these children raises significant ethical and moral considerations. Therefore, this participatory ethnographic study conducted with eight children and their families aimed to better understand the moral experiences of children with medical complexity, based on views of children as moral agents and capable of understanding and expressing interpretations about their lived experiences. Through our participatory hermeneutical ethnographic research, we were able to shed light on how children with medical complexity express their moral experiences within a complex sociopolitical context, perpetuating dominant outlooks on what is considered a "normal" child. Children with medical complexity described their resistance to these dominant views as they strive to be included in discussions about matters that affect them, reacting to painful medical procedures and treatments, and expressing their concerns about their future aspirations. The knowledge advanced by this study about moral experiences of children with medical complexity can inform understandings of children's interests based on their own interpretations within complex sociopolitical contexts that value their lives differently.

Objective: Metabolic Syndrome (MetS) affects hundreds of millions of individuals and constitutes a major cause of morbidity and mortality worldwide. Obesity is believed to be at the core of metabolic abnormalities associated with MetS, including dyslipidemia, insulin resistance, fatty liver disease and vascular dysfunction. Although previous studies demonstrate a diverse array of naturally occurring antioxidants that attenuate several manifestations of MetS, little is known about the (i) combined effect of these compounds on hepatic health and (ii) molecular mechanisms responsible for their effect., Methods: We explored the impact of a metabolic enhancer (ME), consisting of 7 naturally occurring antioxidants and mitochondrial enhancing agents, on diet-induced obesity, hepatic steatosis and atherogenic serum profile in mice., Results: Here we show that a diet-based ME supplementation and exercise have similar beneficial effects on adiposity and hepatic steatosis in mice. Mechanistically, ME reduced hepatic ER stress, fibrosis, apoptosis, and inflammation, thereby improving overall liver health. Furthermore, we demonstrated that ME improved HFD-induced pro-atherogenic serum profile in mice, similar to exercise. The protective effects of ME were reduced in proprotein convertase subtilisin/kexin 9 (PCSK9) knock out mice, suggesting that ME exerts it protective effect partly in a PCSK9-dependent manner., Conclusions: Our findings suggest that components of the ME have a positive, protective effect on obesity, hepatic steatosis and cardiovascular risk and that they show similar effects as exercise training.