Huntington disease (HD) is a progressive neurodegenerative disease that is debilitating for families worldwide. Inherited in an autosomal dominant manner, HD results from a CAG expansion in the gene encoding the huntingtin protein. This mutation leads to a host of motor, cognitive, and psychiatric symptoms that generally appear in middle age. While spiny projection neurons in the striatum are the most vulnerable cell type in HD, notable atrophy occurs throughout the brain, including the white matter; for this reason, HD is now considered to be a brain-wide disease. The clinical features, ethics, and neurobiology of HD are discussed in this chapter. The chapter also reviews the exciting approaches being employed today to advance understanding of underlying mechanisms in an effort to develop therapies that would delay the onset and slow progression of this disease.
Current design standards for steel structures in North America use a structural reliability model that employs first-order probability methods. This approach yields interpretable safety indexes and corresponding probabilities of failure, based on a log-normality assumption for the load and resistance probability distributions. In this work, the suitability of a log-normal assumption for the resistance distribution is assessed numerically by constructing approximate distributions of the ultimate limit state resistance of various welded steel connections between rectangular hollow section (RHS) members. Raw data from material surveys and experimental results are combined to produce approximate resistance distributions for RHS X-connections, under branch axial compression and for a variety of geometric scenarios. It is empirically shown that resistance distributions are often well represented by log-normal distributions, despite deviations in laboratory results. This suggests that current reliability analyses, as prescribed by first-order methods such as in CSA S408-11, are adequate for a wide range of resistance models for steel members and connections, even for moderate violations of assumptions in experimental or numerical data.
Mass timber has proven to be a sustainable alternative to steel and concrete and its use in construction has increased significantly in the last decade. With building codes relaxing height limitations, there is a need for novel connection solutions for the next generation of tall timber buildings. There is also a need to ensure that mass timber products are being used responsibly and sustainably, with deconstruction and reuse being identified as important factors in this pursuit. This paper presents and discusses a new hybrid shear connection for mass timber buildings that allows for easy construction, deconstruction, and reuse of the structural elements. The connection consists of a fully threaded steel rod embedded into a CLT panel and reinforced with a layer of epoxy-based grout. The structural performance of shear connections with varying rod diameter and steel strength-grade, grout thickness, and CLT grade is analyzed. An insight into the behaviour under quasi-static monotonic incremental loads is given based on a comprehensive experimental campaign, with a total of 84 push-out tests performed on squared CLT specimens. Experiments show that strong and stiff behaviour can be achieved and that the yield point is clearly identifiable, supporting optimum capacity design strategies. This allows for the connection to be protected from damage and therefore reusable. Observed failure modes suggest that load-carrying capacity and stiffness models, as per common wood bolted connections, can be developed. This high-performance shear connection has great potential for deconstruction and reuse and supports prefabricated hybrid CLT-based structural solutions for large-scale building construction.
Several art scholars have recently doubted the prudence of thinking about the nature of aesthetic value. The problem is that traditional thinking about aesthetic value fails to capture the specificities with which empirical art scholars must grapple. This paper diagnoses how the tradition came to think in this problematic way about aesthetic value. It then sketches an approach to aesthetic value that boosts the refractive power of the tools that scholars of the arts can use to bring into focus some of the specificities they care about. The path to that goal skirts the troublesome features of traditional approaches.
In classical Hodgkin lymphoma (cHL), the highly abundant CD4+ T cells in the vicinity of tumor cells are considered essential for tumor cell survival, but are ill-defined. Although they are activated, they consistently lack expression of activation marker CD26. In this study, we compared sorted CD4+CD26- and CD4+CD26+ T cells from cHL lymph node cell suspensions by RNA sequencing and T cell receptor variable gene segment usage analysis. This revealed that although CD4+CD26- T cells are antigen experienced, they have not clonally expanded. This may well be explained by the expression of exhaustion associated transcription factors TOX and TOX2, immune checkpoints PDCD1 and CD200, and chemokine CXCL13, which were amongst the 100 significantly enriched genes in comparison with the CD4+CD26+ T cells. Findings were validated in single-cell RNA sequencing data from an independent cohort. Interestingly, immunohistochemistry revealed predominant and high frequency of staining for TOX and TOX2 in the T cells attached to the tumor cells. In conclusion, the dominant CD4+CD26- T cell population in cHL is antigen experienced, polyclonal, and exhausted. This population is likely a main contributor to the very high response rates to immune checkpoint inhibitors in cHL.
Spare-parts surgery in traumatic amputation sources tissue from the amputated part to cover the residual amputation defect. This case describes a trauma patient requiring below-elbow amputation. Stump closure was accomplished with a pedicled fillet flap derived from the still-attached hand, avoiding donor site morbidity and maximizing stump length.
Background Despite the growing utility of cardiovascular magnetic resonance (CMR) for cardiac morphology and function, sex and age-specific normal reference values derived from large, multi-ethnic data sets are lacking. Furthermore, most available studies use a simplified tracing methodology. Using a large cohort of participants without history of cardiovascular disease (CVD) or risk factors from the Canadian Alliance for Healthy Heart and Minds, we sought to establish a robust set of reference values for ventricular and atrial parameters using an anatomically correct contouring method, and to determine the influence of age and sex on ventricular parameters. Methods and results Participants (n = 3206, 65% females; age 55.2 ± 8.4 years for females and 55.1 ± 8.8 years for men) underwent CMR using standard methods for quantitative measurements of cardiac parameters. Normal ventricular and atrial reference values are provided: (1) for males and females, (2) stratified by four age categories, and (3) for different races/ethnicities. Values are reported as absolute, indexed to body surface area, or height. Ventricular volumes and mass were significantly larger for males than females (p < 0.001). Ventricular ejection fraction was significantly diminished in males as compared to females (p < 0.001). Indexed left ventricular (LV) end-systolic, end-diastolic volumes, mass and right ventricular (RV) parameters significantly decreased as age increased for both sexes (p < 0.001). For females, but not men, mean LV and RVEF significantly increased with age (p < 0.001). Conclusion Using anatomically correct contouring methodology, we provide accurate sex and age-specific normal reference values for CMR parameters derived from the largest, multi-ethnic population free of CVD to date. Clinical trial registration ClinicalTrials.gov, NCT02220582. Registered 20 August 2014—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02220582 .
Self-regulated promoting practices foster students’ development of metacognition, motivation and strategic action. These underlying learning competencies improve students' academic, social, emotional and career outcomes. Although beneficial, the development of self-regulated promoting practices is challenging, particularly for teacher candidates. This article describes self-regulated learning practices and how motivational supports for teacher candidates' self-determined motivation creates contextual conditions that foster teacher candidates’ development of these practices. The article concludes with suggestions for future research.
Accelerometers measure the acceleration of the body part they are attached and allow to estimate time spent in activity levels (sedentary behaviour, light, and moderate-to-vigorous physical activity) and sleep over a 24-h period for several consecutive days. These advantages come with the challenges to analyse the large amount of data while integrating dimensions of both physical activity/sedentary behaviour and sleep domains. This commentary raises the questions of 1) how to classify sleep breaks (i.e. wake after sleep onset) during the night within the 24-h movement behaviour framework and 2) how to assess their impact on health while also accounting for night time sleep duration and time in sedentary behaviour and physical activity during the day. The authors advocate for future collaborations between researchers from the physical activity/sedentary behaviour and sleep research fields to ensure appropriate analysis and interpretation of the tremendous amount of data recorded by the newer generation accelerometers. This is the only way forward to provide meaningfully accurate evidence to inform future 24-h movement behaviour guidelines.
Background Chronic obstructive pulmonary disease (COPD) causes 3 million deaths each year, yet 38% of COPD patients continue to smoke. Despite proof of effectiveness and universal guideline recommendations, smoking cessation interventions are underused in practice. We sought to develop an infographic featuring personalized biomedical risk assessment through future lung function decline prediction (with vs without ongoing smoking) to both prompt and enhance clinician delivery of smoking cessation advice and pharmacotherapy, and augment patient motivation to quit. Methods We recruited patients with COPD and pulmonologists from a quaternary care center in Toronto, Canada. Infographic prototype content and design was based on best evidence. After face validation, the prototype was optimized through rapid-cycle design. Each cycle consisted of: (1) infographic testing in a moderated focus group and a clinician interview (recorded/transcribed) (with questionnaire completion); (2) review of transcripts for emergent/critical findings; and (3) infographic modifications to address findings (until no new critical findings emerged). We performed iterative transcript analysis after each cycle and a summative qualitative transcript analysis with quantitative (descriptive) questionnaire analysis. Results Stopping criteria were met after 4 cycles, involving 20 patients (58% male) and 4 pulmonologists (50% male). The following qualitative themes emerged: Tool content (infographic content preferences); Tool Design (infographic design preferences); Advantages of Infographic Messaging (benefits of an infographic over other approaches); Impact of Tool on Determinants of Smoking Cessation Advice Delivery (impact on barriers and enablers to delivery of smoking cessation advice in practice); and Barriers and Enablers to Quitting (impact on barriers and enablers to quitting). Patient Likert scale ratings of infographic content and format/usability were highly positive, with improvements in scores for 20/21 questions through the design process. Providers scored the infographic at 77.8% (“superior”) on the Suitability Assessment of Materials questionnaire. Conclusions We developed a user preference-based personalized biomedical risk assessment infographic to drive smoking cessation in patients with COPD. Our findings suggest that this tool could impact behavioural determinants of provider smoking-cessation advice delivery, while increasing patient quit motivation. Impacts of the tool on provider care, patient motivation to quit, and smoking cessation success should now be evaluated in real-world settings.
Facial attractiveness in humans signals an individual’s genetic condition, underlying physiology and health status, serving as a cue to one’s mate value. The practice of wearing face masks for prevention of transmission of airborne infections may disrupt one’s ability to evaluate facial attractiveness, and with it, cues to an individual's health and genetic condition. The current research investigated the effect of face masks on the perception of face attractiveness. Across four studies, we tested if below- and above-average attractive full faces are equally affected by wearing facial masks. The results reveal that for young faces (Study 1) and old faces (Study 2) a facial mask increases the perceived attractiveness of relatively unattractive faces, but there is no effect of wearing a face mask for highly attractive faces. Study 3 shows that the same pattern of ratings emerged when the bottom-half of the faces are cropped rather than masked, indicating that the effect is not mask-specific. Our final Study 4, in which information from only the lower half of the faces was made available, showed that contrary to our previous findings, highly attractive half-faces are perceived to be less attractive than their full-face counterpart; but there is no such effect for the less attractive faces. This demonstrates the importance of the eye-region in the perception of attractiveness, especially for highly attractive faces. Collectively these findings suggest that a positivity-bias enhances the perception of unattractive faces when only the upper face is visible, a finding that may not extend to attractive faces because of the perceptual weight placed on their eye-region.
The generation of T-cells from stem cells in vitro could provide an alternative source of cells for immunotherapies. T-cell development from hematopoietic stem and progenitor cells (HSPCs) is tightly regulated through Notch pathway activation by Delta-like (DL) ligands 1 and 4. Other molecules, such as stem cell factor (SCF) and interleukin (IL)-7, play a supportive role in regulating the survival, differentiation, and proliferation of developing T-cells. Numerous other signaling molecules influence T-lineage development in vivo, but little work has been done to understand and optimize their use for T-cell production. Using a defined engineered thymic niche system, we undertook a multi-stage statistical learning-based optimization campaign and identified IL-3 and tumor necrosis factor α (TNFα) as a stage- and dose-specific enhancers of cell proliferation and T-lineage differentiation. We used this information to construct an efficient three-stage process for generating conventional TCRαβ ⁺ CD8 ⁺ T-cells expressing a diverse TCR repertoire from blood stem cells. Our work provides new insight into T-cell development and a robust system for generating T-cells to enable clinical therapies for treating cancer and immune disorders.
The accurate simulation of additional interactions at the ATLAS experiment for the analysis of proton–proton collisions delivered by the Large Hadron Collider presents a significant challenge to the computing resources. During the LHC Run 2 (2015–2018), there were up to 70 inelastic interactions per bunch crossing, which need to be accounted for in Monte Carlo (MC) production. In this document, a new method to account for these additional interactions in the simulation chain is described. Instead of sampling the inelastic interactions and adding their energy deposits to a hard-scatter interaction one-by-one, the inelastic interactions are presampled, independent of the hard scatter, and stored as combined events. Consequently, for each hard-scatter interaction, only one such presampled event needs to be added as part of the simulation chain. For the Run 2 simulation chain, with an average of 35 interactions per bunch crossing, this new method provides a substantial reduction in MC production CPU needs of around 20%, while reproducing the properties of the reconstructed quantities relevant for physics analyses with good accuracy.
Synaptic abnormalities are a cardinal feature of Alzheimer’s disease (AD) that are known to arise as the disease progresses. A growing body of evidence suggests that pathological alterations to neuronal circuits and synapses may provide a mechanistic link between amyloid β (Aβ) and tau pathology and thus may serve as an obligatory relay of the cognitive impairment in AD. Brain-derived neurotrophic factors (BDNFs) play an important role in maintaining synaptic plasticity in learning and memory. Considering AD as a synaptic disorder, BDNF has attracted increasing attention as a potential diagnostic biomarker and a therapeutical molecule for AD. Although depletion of BDNF has been linked with Aβ accumulation, tau phosphorylation, neuroinflammation and neuronal apoptosis, the exact mechanisms underlying the effect of impaired BDNF signaling on AD are still unknown. Here, we present an overview of how BDNF genomic structure is connected to factors that regulate BDNF signaling. We then discuss the role of BDNF in AD and the potential of BDNF-targeting therapeutics for AD.
Background The importance of patient-centered measurement in cancer care has led to recognition of the potential for caregiver-reported outcomes to improve caregiver, patient and healthcare system outcomes. Yet, there is limited evidence to inform caregiver-reported outcome implementation. Our purpose was to generate evidence to inform the meaningful and constructive integration of caregiver-reported outcomes into cancer care to benefit caregivers, including exploration of the question of the extent to which these assessments should be shared with patients. We focused on caregivers of patients with colorectal cancer (CRC) because CRC is common, and associated caregiving can be complex. Results From our Interpretive Description analysis of qualitative interview data from 78 participants (25 caregivers, 37 patients, and 16 healthcare providers [HCPs]), we identified contrasting perspectives about the sharing of caregiver-reported outcome assessments with patients with CRC. Those who preferred open communication with both the patient and caregiver present considered this essential for supporting the caregiver. The participants who preferred private communication without the patient, cited concern about caregiver- and patient-burden and guilt. Recognizing these perspectives, HCPs described strategies used to navigate sensitivities inherent in preferences for open versus private communication. Conclusions The integration of caregiver-reported outcomes into cancer care will require careful consideration of caregiver and patient preferences regarding the communication of caregiver assessments to prevent additional burden.
Background: To evaluate how an international one-year intensive research training program for addiction medicine physicians contributed to subsequent research involvement and productivity. Methods: We prospectively compared addiction medicine physician fellows admitted to a one-year training program with non-admitted controls, using baseline questionnaire and peer-reviewed publication data. Participants' publication activity was assessed from fellowship application date onwards using biomedical databases (e.g., PubMed, Embase). Results: Between July 2014 and June 2020, which is six years of cohorts, 56 (39 women) physicians, both fellows (n = 25) and non-admitted applicants (n = 31), were observed and included in the study, contributing 261 person-years of observation. At baseline, in the fellows' cohort: 76% of participants (19/25) reported past research involvement, 24% (6/25) had one or more advanced graduate degrees (e.g., MPH), and the median number of peer-reviewed, first author publications was one (Interquartile Range [IQR] = 0-2). At baseline, in the controls' cohort: 84% of participants (26/31) reported past research involvement, 39% (12/31) had one or more advanced graduate degrees, and the median number of peer-reviewed, first author publications was zero. The physicians' training included internal medicine (n = 8), family medicine (n = 33), psychiatry (n = 5) and others (n = 4). At follow up, there was a significant difference between fellows (n = 25) and controls (n = 31) in total number of publications (Rate Ratio [RR] = 13.09, 95% Confidence Interval [CI], 5.01 - 34.21, p < 0.001), as well as first author publications (RR = 5.59, 95% CI, 2.23 - 14.06, p < 0.001). Conclusion: In the six-year observation period, fellows' productivity indicates undertaking this fellowship was associated with significant research outputs in comparison to controls, signaling successful training of addiction physicians to help recruit addiction medicine physicians to participate in addiction research.
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