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BACKGROUNDAutoimmune diseases often have strong genetic associations with specific HLA-DR alleles. The synovial lesion in chronic inflammatory forms of arthritis shows marked upregulation of HLA-DR molecules, including in postinfectious Lyme arthritis (LA). However, the identity of HLA-DR-presented peptides, and therefore the reasons for these associations, has frequently remained elusive.METHODSUsing immunopeptidomics to detect HLA-DR-presented peptides from synovial tissue, we identified T cell epitopes from 3 extracellular matrix (ECM) proteins in patients with postinfectious LA, identified potential Borreliella burgdorferi-mimic (Bb-mimic) epitopes, and characterized T and B cell responses to these peptides or proteins.RESULTSOf 24 postinfectious LA patients, 58% had CD4+ T cell responses to at least 1 epitope of 3 ECM proteins, fibronectin-1, laminin B2, and/or collagen Vα1, and 17% of 52 such patients had antibody responses to at least 1 of these proteins. Patients with autoreactive T cell responses had significantly increased frequencies of HLA-DRB1*04 or -DRB1*1501 alleles and more prolonged arthritis. When tetramer reagents were loaded with ECM or corresponding Bb-mimic peptides, binding was only with the autoreactive T cells. A high percentage of ECM-autoreactive CD4+ T cells in synovial fluid were T-bet-expressing Th1 cells, a small percentage were RoRγt-expressing Th17 cells, and a minimal percentage were FoxP3-expressing Tregs.CONCLUSIONAutoreactive, proinflammatory CD4+ T cells and autoantibodies develop to ECM proteins in a subgroup of postinfectious LA patients who have specific HLA-DR alleles. Rather than the traditional molecular mimicry model, we propose that epitope spreading provides the best explanation for this example of infection-induced autoimmunity.FUNDINGSupported by National Institute of Allergy and Infectious Diseases R01-AI101175, R01-AI144365, and F32-AI125764; National Institute of Arthritis and Musculoskeletal and Skin Diseases K01-AR062098 and T32-AR007258; NIH grants P41-GM104603, R24-GM134210, S10-RR020946, S10-OD010724, S10-OD021651, and S10-OD021728; and the G. Harold and Leila Y. Mathers Foundation, the Eshe Fund, and the Lyme Disease and Arthritis Research Fund at Massachusetts General Hospital.

With the current trends of wind energy already playing a major part in the Scottish energy supply, the capacity of wind farms is predicted to grow exponentially and reach further depths offshore. However, a key challenge that presents itself is the integration of large producing assets into the current UK grid. One potential solution to this is green hydrogen production, which is being heavily researched in industry, with many concepts being investigated for large-scale purposes. However, the operations and maintenance (O&M) costs and availability of green hydrogen systems need to be quantified to ensure economical and technical viability, which is sparse in the available literature. The study presented in this paper investigated the availability and O&M costs of coupled wind–hydrogen systems by attempting to quantify the failure rates, repair times, repair costs and number of technicians required for key green hydrogen components. This study also utilised an O&M model created by the University of Strathclyde, which uses Monte Carlo Markov chain simulations to produce the O&M outputs. A number of assumptions were made throughout the study in relation to the O&M model inputs, and the baseline availability for the coupled wind–hydrogen system was 85.24%. Whilst the wind turbine still contributed a major part to the downtime seen in the simulations, the combined hydrogen system also contributed a significant amount, a total of 37%, which could have been due to the technology readiness levels of some the components included in the hydrogen system.

Introduction Coding has become burdensome to healthcare systems due to patient complexity and resource requirements. In Alberta, Intelligent Medical Objects (IMO), an interface terminology mapping product, is integrated within the new province-wide Clinical Information System, named Connect Care (CC), to support documentation by clinicians and map clinical terminologies to ICD-10. This study evaluates comparability of terminologies mapped ICD-10 codes to the ICD-10 codes in DAD. Approach We conducted a retrospective analysis by linking acute care hospital DAD with CC between April 2021 and December 2023. The primary outcome was the level of agreement between ‘hospital problem list’ of CC and DAD for ICD-10-CA codes at a 3-digit level. The number of diagnoses and rate of unspecified codes were also compared. The outcome measures were stratified by physician specialty, hospital type and location, and length-of-stay (LOS). Results A total of 498,834 unique hospital records were linked. The average level of agreement between CC and DAD at 3-digit level of ICD-10-CA code was 43.4%. The average number of diagnoses captured in CC (3.91) was slightly lower than DAD (4.06), and the average rate of unspecified codes was higher in CC (26.4%) compared to DAD (23.0%). The level of agreement varied by specialty and length-of-stay with specialties with more complex patients and longer lengths-of-stay having the lowest agreement (43% for generalists and internal medicine and 33% for LOS >3 months). Conclusion Level of agreement between CC and DAD for ICD-10 data was identified as low, indicating significant disparities between terminology mappings and the coding process.

IntroductionBritish Muslim School Children (BMSC) are required to follow special halal dietary requirements in accordance with their religion, which is often not accounted for in British schools. This often leaves BMSC limited to a vegetarian diet while at school, despite this not being their chosen diet or preference. This study explores the perceptions of key stakeholders regarding fairness and accessibility of school meals for BMSC, as well as discussing school food provision for those maintaining a religious diet in light of social justice. This is in the context of limited knowledge previously being explored in the North East of England regarding procurement and decision-making at a systems level to cater for BMSC.MethodsA qualitative research design was conducted. A total of 62 participants (39 BMSC, 15 parents, and 8 school and catering staff) took part in a semi-structured interview or focus group. Participants were recruited from six schools, with these schools selected based on their differing levels of BMSC in attendance. This project took place between March 2022 and October 2023.Results/discussionResults suggested that where schools already catered for diverse food requirements, inclusive of BMSC dietary needs, food choices were still limited in the options and amount available. School and catering staff stated that cost implications contributed to their menu development process. Despite this, there was an evident willingness to learn about the cultural food options and how these can be implemented in future school menus. Suggestions discussed included an increase in the use of halal meat in order to provide a more inclusive school food experience for BMSC.

Abstract Objectives Peptidoglycan (PG) is an arthritogenic bacterial cell wall component whose role in human osteoarthritis is poorly understood. The purpose of this study was to determine if PG is present in synovial tissue of osteoarthritis patients at the time of primary total knee arthroplasty (TKA), and if its presence is associated with inflammation and patient reported outcomes. Methods Intraoperative synovial tissue and synovial fluid samples were obtained from 56 patients undergoing primary TKA, none of whom had history of infection. PG in synovial tissue was detected by immunohistochemistry (IHC) and immunofluorescence microscopy (IFM). Synovial tissue inflammation and fibrosis were assessed by histopathology and synovial fluid cytokine quantification. Primary human fibroblasts isolated from arthritis synovial tissue were stimulated with PG to determine inflammatory cytokine response. Results A total of 33/56 (59%) of primary TKA synovial tissue samples were positive for PG by IHC, and PG staining colocalized with markers of synovial macrophages and fibroblasts by IFM. Synovial tissue inflammation and elevated IL-6 in synovial fluid positively correlated with PG positivity. Primary human fibroblasts stimulated with PG secreted high levels of IL-6, consistent with ex vivo findings. Interestingly, we observed a significant inverse correlation between PG and age at time of TKA, indicating younger age at time of TKA was associated with higher PG levels. Conclusion Peptidoglycan is commonly found in synovial tissue from patients undergoing TKA. Our data indicate that PG may play an important role in inflammatory synovitis, particularly in patients who undergo TKA at a relatively younger age.

Eccrine carcinoma, a subtype of which is ductal eccrine adenocarcinoma (DEA), is a rare cutaneous malignancy. For metastatic eccrine carcinoma, there are very limited data to guide treatment. Conventional chemotherapy is of limited benefit and there is only a small body of evidence for the use of immunotherapy in non-DEA eccrine carcinomas. We report the first case of metastatic DEA treated with a multimodality approach including surgery, radiotherapy, and immunotherapy, with an excellent prolonged response to pembrolizumab, and provide a review of the literature on pathological and management aspects for this rare tumour subtype. A 60-year-old male with a history of pT1N0M0 left scalp DEA, managed 2 years prior with excision and adjuvant radiotherapy, represented with a symptomatic right pontine metastasis. Imaging demonstrated intracranial, pulmonary, and hilar disease; biopsy of the cranial and lung lesions showed metastatic adenocarcinoma, morphologically similar to the previously resected scalp DEA. The patient was treated with stereotactic resections of his pontine metastases and adjuvant cranial radiotherapy, then commenced on immunotherapy with pembrolizumab. The patient has completed 21 months of pembrolizumab with a significant radiological response of the pulmonary and hilar disease and nil evidence of intracranial recurrence or further metastases. In this case report, we provide the first evidence of efficacy of immunotherapy in metastatic DEA, demonstrating an excellent and prolonged response of metastatic DEA to pembrolizumab. Further research is required to better establish the role of immunotherapy within the management protocol for this uncommon but aggressive tumour subtype.

Abstract Introduction With the purpose of supporting scientific professionals and helping them to better integrate the expertise of users in their work, a users' and relatives' panel (URP) was set up at the National Institute for Excellence in Health and Social Services in Quebec (INESSS), Canada for the social services and mental health directorate. URPs are advisory structures that mobilise the experiential knowledge of people affected by various issues. Objectives The objective of this study is to assess from a diverse stakeholders' perceptions: (1) the experience of developing and implementing the URP within the context of an Agencies for Health Technology Assessment and Assessment of Social Services (AHTAASS), (2) the contribution of such a URP, (3) the challenges encountered and (4) the perspectives of improvement for the following years. Methodology We conducted a qualitative descriptive evaluation study. Nineteen interviews were conducted: six with URP members and 13 with staff representatives. The documents related to the creation of the panel, the URP minutes summarising the discussions and the reports published during that period were collected and analysed. Following a preliminary round of data analysis, a debriefing meeting was conducted with a few participants to validate the results. Results The panel was set up as part of the INESSS' desire to better integrate experiential knowledge into its recommendations. Twelve projects were presented to the panel on various themes. The URP enabled health professionals to consider dimensions they had not identified, to better integrate the experiential data collected from users into their work and to develop recommendations that made more sense to users. Panel members and INESSS professionals learned to work together, moving the working methods from consultation to collaboration and even coconstruction. Based on the panel's significant contribution, the INESSS decided to maintain it and to strengthen its place in its system to better integrate the experiential knowledge of users into its work. Conclusion This research illustrates how AHTAASS can set up a URP composed exclusively of users, and how it can contribute and be evaluated. It shows that URPs are structures that value the sharing of experiential knowledge of its members, humanise decision‐making and give meaning to the work done by scientific professionals. Patient or Public Contribution One patient–researcher has contributed to the preparation and writing of this manuscript.

Background and Aims: Informed consent should allow patients the appropriate time and conditions to make decisions about their care. However, consent is often obtained immediately prior to a colonoscopy. We conducted a quality improvement study to assess how a preprocedure consent video 2 days prior to an outpatient colonoscopy impacts patient satisfaction. Methods: Patients undergoing outpatient colonoscopy at a large academic medical center opted in to a text messaging platform for procedural information. Our intervention was an informed consent video 2 days before the colonoscopy. Our primary outcome was a composite patient satisfaction score. Pre and postintervention scores were compared using ordinal or multinomial logistic models to calculate odds ratios (OR) or relative risk ratios and 95% confidence intervals (CI), adjusting for age and sex. Results: 1109 and 1452 patients completed ≥1 survey question in the pre and postintervention phases, respectively. Overall patient satisfaction did not differ between groups [OR for a 1-point increment in satisfaction score between post- vs preintervention groups = 1.05; 95% CI: 0.90–1.22; P = .51]. Compared to preintervention, postintervention respondents were more likely to report higher satisfaction with time available to talk with their physician (OR of a 1-point increase in individual question response = 1.29; 95% CI: 1.09–1.54; P = .004). Compared to preintervention, more physicians in the postintervention phase rated satisfaction with consent process efficiency as “very satisfied” or “satisfied” (P < .001). Conclusion: An informed consent video prior to colonoscopy resulted in similar overall patient satisfaction. However, post-intervention, patients were more likely to report sufficient time to talk with their physician, and physicians reported higher satisfaction with consent efficiency.

BACKGROUND Autoimmune diseases often have strong genetic associations with specific HLA-DR alleles. The synovial lesion in chronic inflammatory forms of arthritis shows marked upregulation of HLA-DR molecules, including in postinfectious Lyme arthritis (LA). However, the identity of HLA-DR–presented peptides, and therefore the reasons for these associations, has frequently remained elusive.METHODS Using immunopeptidomics to detect HLA-DR–presented peptides from synovial tissue, we identified T cell epitopes from 3 extracellular matrix (ECM) proteins in patients with postinfectious LA, identified potential Borreliella burgdorferi–mimic (Bb-mimic) epitopes, and characterized T and B cell responses to these peptides or proteins.RESULTS Of 24 postinfectious LA patients, 58% had CD4+ T cell responses to at least 1 epitope of 3 ECM proteins, fibronectin-1, laminin B2, and/or collagen Vα1, and 17% of 52 such patients had antibody responses to at least 1 of these proteins. Patients with autoreactive T cell responses had significantly increased frequencies of HLA-DRB1*04 or -DRB1*1501 alleles and more prolonged arthritis. When tetramer reagents were loaded with ECM or corresponding Bb-mimic peptides, binding was only with the autoreactive T cells. A high percentage of ECM-autoreactive CD4+ T cells in synovial fluid were T-bet–expressing Th1 cells, a small percentage were RoRγt-expressing Th17 cells, and a minimal percentage were FoxP3-expressing Tregs.CONCLUSION Autoreactive, proinflammatory CD4+ T cells and autoantibodies develop to ECM proteins in a subgroup of postinfectious LA patients who have specific HLA-DR alleles. Rather than the traditional molecular mimicry model, we propose that epitope spreading provides the best explanation for this example of infection-induced autoimmunity.FUNDING Supported by National Institute of Allergy and Infectious Diseases R01-AI101175, R01-AI144365, and F32-AI125764; National Institute of Arthritis and Musculoskeletal and Skin Diseases K01-AR062098 and T32-AR007258; NIH grants P41-GM104603, R24-GM134210, S10-RR020946, S10-OD010724, S10-OD021651, and S10-OD021728; and the G. Harold and Leila Y. Mathers Foundation, the Eshe Fund, and the Lyme Disease and Arthritis Research Fund at Massachusetts General Hospital.

Summary: Background: Statin use has been linked to a reduced risk of advanced colorectal adenomas, but its association with colorectal cancer (CRC) in patients with inflammatory bowel disease (IBD) - a high risk population for CRC - remains inconclusive. Methods: From a nationwide IBD cohort in Sweden, we identified 5273 statin users and 5273 non-statin users (1:1 propensity score matching) from July 2006 to December 2018. Statin use was defined as the first filled prescription for ≥30 cumulative defined daily doses and followed until December 2019. Primary outcome was incident CRC. Secondary outcomes were CRC-related mortality and all-cause mortality. Cox regression estimated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). Findings: During a median follow-up of 5.6 years, 70 statin users (incidence rate (IR): 21.2 per 10,000 person-years) versus 90 non-statin users (IR: 29.2) were diagnosed with incident CRC (rate difference (RD), −8.0 (95% CIs: −15.8 to −0.2 per 10,000 person-years); aHR = 0.76 (95% CIs: 0.61 to 0.96)). The benefit for incident CRC was duration-dependent in a nested case-control design: as compared to short-term use (30 days to

BackgroundStuttering, also known as childhood-onset fluency disorder, is a chronic neurodevelopmental disorder that affects 1% of the population and can greatly impact an individual's social, occupational, and academic functioning. Prior research has shown dopamine D2 antagonists are effective in reducing the severity of stuttering symptoms, but these compounds can be associated with metabolic and movement disorder adverse effects. Ecopipam is an investigational medication that acts as a selective dopamine D1 receptor antagonist. This mechanism should reduce the likelihood of metabolic and movement disorder adverse effects of D2 antagonists.MethodThis open-label pilot study investigated ecopipam in the treatment of adults who stutter.ResultsThe results showed that a majority of participants demonstrated improvement in their stuttering. The medication was well tolerated.ConclusionsThese positive, preliminary findings suggest that a doubleblind, randomized controlled clinical trial to examine the efficacy of ecopipam in the treatment of stuttering is warranted.

Defective angiogenesis remains a high source of morbidity in multiple disorders. Here they show that βIV-spectrin, a membrane-associated cytoskeletal protein, is essential for regulation of endothelial tip cell populations and VEGF signaling during sprouting angiogenesis.

The RAS-regulated RAF-MEK1/2-ERK1/2 signalling pathway is frequently de-regulated in human cancer. Melanoma in particular exhibits a high incidence of activating BRAFV600E/K and NRASQ61L/K mutations and such cells are addicted to the activity of these mutant oncoproteins. As a result three different BRAF inhibitors (BRAFi) have now been approved for BRAFV600E/K- mutant melanoma and have transformed the treatment of this disease. Despite this, clinical responses are typically transient as tumour cells develop resistance. These resistance mechanisms frequently involve reinstatement of ERK1/2 signalling and BRAFi are now deployed in combination with one of three approved MEK1/2 inhibitors (MEKi) to provide more durable, but still transient, clinical responses. Furthermore, inhibitors to ERK1/2 (ERK1/2i) have also been developed to counteract ERK1/2 signalling. However, recent studies have suggested that BRAFi/MEKi and ERK1/2i resistance can arise through activation of a parallel signalling pathway leading to activation of ERK5, an unusual protein kinase that contains both a kinase domain and a transcriptional transactivation domain. Here we review the evidence supporting ERK5 as a mediator of BRAFi/MEKi and ERK1/2i resistance. We also review the challenges in targeting ERK5 signalling with small molecules, including paradoxical activation of the transcriptional transactivation domain, and discuss new therapeutic modalities that could be employed to target ERK5.

Natural killer (NK) cells can be divided into phenotypic subsets based on expression of receptors that bind self-MHC-I molecules, a concept termed licensing or education. Here we show NK cell subsets with different migratory, effector, and immunoregulatory functions in dendritic cell and antigen (ag)-specific CD8+ T cell responses during influenza and murine cytomegalovirus infections. Shortly after infection, unlicensed NK cells localized in draining lymph nodes and produced GM-CSF, which correlated with the expansion and activation of dendritic cells, and resulted in greater and sustained ag-specific T cell responses. In contrast, licensed NK cells preferentially migrated to infected tissues and produced IFN-γ. Importantly, human NK cell subsets exhibited similar phenotypic characteristics. Collectively, our studies demonstrate a critical demarcation between the functions of licensed and unlicensed NK cell subsets, with the former functioning as the classical effector subset and the latter as the stimulator of adaptive immunity helping to prime immune responses.

In mammals, CENP-A, a histone H3 variant found in the centromeric chromatin, is critical for faithful chromosome segregation and genome integrity maintenance through cell divisions. Specifically, it has dual functions, enabling to define epigenetically the centromere position and providing the foundation for building up the kinetochore. Regulation of its dynamics of synthesis and deposition ensures to propagate proper centromeres on each chromosome across mitosis and meiosis. However, CENP-A overexpression is a feature identified in many cancers. Importantly, high levels of CENP-A lead to its mislocalization outside the centromere. Recent studies in mammals have begun to uncover how CENP-A overexpression can affect genome integrity, reprogram cell fate and impact 3D nuclear organization in cancer. Here, we summarize the mechanisms that orchestrate CENP-A regulation. Then we review how, beyond its centromeric function, CENP-A overexpression is linked to cancer state in mammalian cells, with a focus on the perturbations that ensue at the level of chromatin organization. Finally, we review the clinical interest for CENP-A in cancer treatment.

The neurovascular unit (NVU) is an anatomical group of cells that establishes the blood–brain barrier (BBB) and coordinates cerebral blood flow in association with neuronal function. In cerebral gray matter, cellular constituents of the NVU include endothelial cells and associated pericytes, astrocytes, neurons, and microglia. Dysfunction of the NVU is a common feature of diseases that affect the CNS, such as ischemic stroke. High-level evaluation of these NVU changes requires the use of imaging modalities that can enable the visualization of various cell types under disease conditions. In this study, we applied our confocal microscopy strategy using commercially available labeling reagents to, for the first time, simultaneously investigate associations between endothelial cells, the vascular basal lamina, pericytes, microglia, astrocytes and/or astrocyte end-feet, and neurites in both healthy and ischemic brain tissue. This allowed us to demonstrate ischemia-induced astrocyte activation, neurite loss, and microglial migration toward blood vessels in a single confocal image. Furthermore, our labeling cocktail enabled a precise quantification of changes in neurites and astrocyte reactivity, thereby showing the relationship between different NVU cellular constituents in healthy and diseased brain tissue. The application of our imaging approach for the simultaneous visualization of multiple NVU cell types provides an enhanced understanding of NVU function and pathology, a state-of-the-art advancement that will facilitate the development of more effective treatment strategies for diseases of the CNS that exhibit neurovascular dysfunction, such as ischemic stroke.

Advancements in extended reality (XR) have inspired new uses and users of advanced visualization interfaces, transforming geospatial data visualization and consumption by enabling interactive 3D geospatial data experiences in 3D. Conventional metrics (e.g., mental rotations test (MRT)) are often used to assess and predict the appropriateness of these visualizations without accounting for the effect the interface has on those metrics. We developed the Immersive MRT (IMRT) to evaluate the impact that virtual reality (VR) based visualizations and 3D virtual environments have on mental rotation performance. Consistent with previous work, the results of our pilot study suggest that mental rotation tasks are performed more accurately and rapidly with stereo 3D stimuli than with 2D images of those stimuli.

The gut microbiome is increasingly recognized to play a role in cognition and dementia. Antibiotic use impacts the gut microbiome and has been linked with chronic disease. Despite these data, there is no evidence supporting an association between long-term antibiotic use in adults and cognitive function. We conducted a prospective population-based cohort study among 14,542 participants in the Nurses’ Health Study II who completed a self-administered computerized neuropsychological test battery between 2014–2018. Multivariate linear regression models were used to assess if chronic antibiotic use in midlife was associated with cognitive impairment assessed later in life. Women who reported at least 2 months of antibiotic exposure in midlife (mean age 54.7, SD 4.6) had lower mean cognitive scores seven years later, after adjustment for age and educational attainment of the spouse and parent, with a mean difference of -0.11 standard units for the global composite score (Ptrend

This paper reports on Intertidal – a collaborative project to demonstrate integrated workflows to 3D spatial data infrastructure (SDI), simulations and geovisual interfaces - as integrated approaches to support the 3D characterization of coastal morphology, intertidal dynamics, potential sea level rise, and mitigation responses to them. Specifically, this project emphasized the potential of emerging 3D data, new analytical visualization methods, and emerging 3D interface technologies as ingredients of emerging and future environmental data science and visualization practice of coastal/intertidal environments.

Structure-from-motion (SfM) has emerged as a popular method of characterizing marine benthos in tropical marine environments and could be of tremendous value to glass sponge monitoring and management efforts in the Northeast Pacific Ocean. However, temperate marine environments present a unique set of challenges to SfM workflows, and the combined impact that cold, dark, and turbid waters have on the veracity of SfM derived data must be critically evaluated in order for SfM to become a meaningful tool for ongoing glass sponge research. This paper discusses the design, development, testing, and deployment of an innovative underwater SfM workflow for generating high-resolution 3D models in temperate marine environments. This multi-phase research project (dry-lab, wet-lab, and field), while possibly seen as unconventional, was designed to innovate in two ways. First to build an operational data capture platform to support low-cost SfM-based seafloor surveys. And second, to enable systematic isolation and evaluation of SfM data capture parameters and their implications for representational veracity and data quality. This paper reports the challenges and outcomes from a series of field surveys conducted in Howe Sound, BC, one of which serves as the first of two data sets in a temporal analysis of 3D morphometric change. This research demonstrates that accurate, high-resolution morphometric characterization, of all benthic species and habitats, is dependent on a range of equipment, procedural, and environmental variables. It is also intended to share our applied problem-solving path to successful 3D capture, backed up by robust data science.

Music is often described as having magical powers to enchant listeners, but it has an equally and often unremarked magical effect on performers and scholars contemplating music. North American music theory has done little to address music’s enchantments, preferring to frame its discourse around empiricism and objectivity. Since the 1990s various postmodern and post-structuralist perspectives have brought about changes of content – what music is considered – and methodology, including a consideration of music’s “magical” powers. These new perspectives have, in part, resulted in an increased diversity in the demographics of musicology, but there have not been changes of sufficient significance in either content or methodology in North American music theory and the demographics of music theory remain dominated by white, male practitioners. In this short essay, I propose two ways that music-theoretical practice can be transformed in order to overcome the “epistemic injustices” of past work in music theory. First, music-theoretical work should address the complicity of the scholar’s perspective, and second, it should recognize the authorial work of diverse creators. To exemplify the latter, I offer a short analysis of Eliza Brown’s The Body of the State (2017). Musik wird zwar häufig eine „magische Kraft“ zugeschrieben, Zuhörer*innen zu bezaubern, aber sie hat ebenso eine häufig unbeachtete magische Wirkung auf Interpret*innen und Musikforscher*innen, die über Musik nachdenken. Die gegenwärtige nordamerikanische Musiktheorie hat wenig dazu beigetragen, diese „Verzauberung“ durch Musik zu thematisieren, stattdessen verortet sie sich diskursiv in Empirismus und Objektivität. Seit den 1990er Jahren haben unterschiedliche postmoderne und poststrukturalistische Perspektiven einen Wandel bezüglich der Inhalte – welcher Musikbegriff wird zugrunde gelegt – und Methoden angestoßen, einschließlich einer Berücksichtigung der „magischen Kräfte“ von Musik. Diese neuen Perspektiven haben innerhalb der Musikwissenschaft zumindest teilweise zu einer größeren demographischen Diversität geführt, aber in der nordamerikanischen Musiktheorie hat kein grundlegender Wandel von Inhalten oder Methoden stattgefunden und sie wird nach wie vor von weißen und männlichen Fachvertretern dominiert. In diesem kurzen Essay zeige ich zwei Möglichkeiten auf, wie musiktheoretische Praxis so verändert werden kann, dass sie die „epistemischen Ungerechtigkeiten“ vergangener musiktheoretischer Arbeit überwindet. Erstens sollte Musiktheorie die Abhängigkeit der Forscher*innen von ihrer jeweiligen Perspektive reflektieren und zweitens sollte Musiktheorie die Werke verschiedenster Künstler*innen anerkennen. Als ein Beispiel dafür dient eine kurze Analyse von Eliza Browns The Body of the State (2017).

Selective ERK5 inhibitors target ERK5 kinase activity, but they do not phenocopy the effects of ERK5 genetic depletion. Here, the authors demonstrate that the direct interaction of these inhibitors to ERK5 kinase domain induces conformational changes that promote ERK5 nuclear translocation and transcriptional activities.

Since the beginning of the COVID-19 pandemic, numerous studies have been conducted to identify interventions that could contribute to alleviating the burden it has caused. The Institut national d'excellence en santé et en services sociaux (INESSS) has played a key role in informing the government of Québec regarding the evaluation of specific pandemic-related interventions. This process took place in a context characterized by a sense of urgency to assess and recommend potential interventions that could save lives and reduce the effects of the disease on populations and healthcare systems, which increased the pressure on the regulatory agencies leading these evaluations. While some of the interventions examined were considered promising, results from COVID-19 studies often led to uncertainty regarding their efficacy or safety. Regulatory agencies evaluating the value of promising interventions thus face challenges in deciding whether these should be made available to the population, particularly when assessing their benefit-risk balance. To shed light on these challenges, we identified underlying ethical considerations that can influence such an assessment. A rapid literature review was conducted in February 2021, to identify the main challenges associated with the benefit-risk balance assessment of promising interventions. To reinforce our understanding of the underlying ethical considerations, we initiated a discussion among various social actors involved in critical thinking surrounding the evaluation of promising interventions, including ethicists, clinicians and researchers involved in clinical or public health practice, as well as patients and citizens. This discussion allowed us to create a space for exchange and mutual understanding among these various actors who contributed equally to the identification of ethical considerations. The knowledge and perspectives stemming from the scientific literature and those consulted were integrated in a common reflection on these ethical considerations. This allowed patients and citizens, directly affected by the evaluation of pandemic-related interventions and the resulting social choices, to contribute to the identification of the relevant ethical considerations. It also allowed for reflection on the responsibilities of the various actors involved in the development, evaluation, and distribution of promising interventions in a setting of urgency and uncertainty, such as that brought about by the COVID-19 pandemic.

An understanding of the pathogenesis and pathophysiology of Lyme disease is key to the ultimate care of patients with Lyme disease. To better understand the various mechanisms underlying the infection caused by Borrelia burgdorferi, the Pathogenesis and Pathophysiology of Lyme Disease Subcommittee was formed to review what is currently known about the pathogenesis and pathophysiology of Lyme disease, from its inception, but also especially about its ability to persist in the host. To that end, the authors of this report were assembled to update our knowledge about the infectious process, identify the gaps that exist in our understanding of the process, and provide recommendations as to how to best approach solutions that could lead to a better means to manage patients with persistent Lyme disease.

Computer-based evacuation simulations are important tools for emergency managers. These simulations vary in complexity and include 2D and 3D GIS-based network analyses, agent-based models, and sophisticated models built on documented human behaviour and particle dynamics. Despite the influential role of built environments in determining human movement, a disconnect often exists between the features of the real world and the way they are represented within these simulation environments. The proliferation of emergency management location-aware mobile devices, along with a recent infatuation for augmented reality (AR), has resulted in new wayfinding and hazard assessment tools that bridge this gap, allowing users to visualize geospatial information superimposed on the real world. In this paper, we report research and development that has produced AR geovisual analytical systems, enabling visual analysis of human dynamics in multi-level built environments with complex thoroughfare network infrastructure. We demonstrate prototypes that show how mixed reality visual analysis of intelligent human movement simulations built in virtual spaces can become part of real space. This research introduces a fundamentally new way to view and link simulations of people with the real-world context of the built environment: mixed reality crowd simulation in real space.

Background & Aims: Colorectal cancer is an epigenetically heterogeneous disease, however, the extent and spectrum of the CpG island methylator phenotype (CIMP) is not clear. Methods: Genome-scale methylation and transcript expression were measured by DNA Methylation and RNA expression microarray in 216 unselected colorectal cancers, and findings were validated using The Cancer Genome Atlas 450K and RNA sequencing data. Mutations in epigenetic regulators were assessed using CIMP-subtyped Cancer Genome Atlas exomes. Results: CIMP-high cancers dichotomized into CIMP-H1 and CIMP-H2 based on methylation profile. KRAS mutation was associated significantly with CIMP-H2 cancers, but not CIMP-H1 cancers. Congruent with increasing methylation, there was a stepwise increase in patient age from 62 years in the CIMP-negative subgroup to 75 years in the CIMP-H1 subgroup (P < .0001). CIMP-H1 predominantly comprised consensus molecular subtype 1 cancers (70%) whereas consensus molecular subtype 3 was over-represented in the CIMP-H2 subgroup (55%). Polycomb Repressive Complex-2 (PRC2)-marked loci were subjected to significant gene body methylation in CIMP cancers (P < 1.6 × 10-78). We identified oncogenes susceptible to gene body methylation and Wnt pathway antagonists resistant to gene body methylation. CIMP cluster–specific mutations were observed in chromatin remodeling genes, such as in the SWItch/Sucrose Non-Fermentable and Chromodomain Helicase DNA-Binding gene families. Conclusions: There are 5 clinically and molecularly distinct subgroups of colorectal cancer. We show a striking association between CIMP and age, sex, and tumor location, and identify a role for gene body methylation in the progression of serrated neoplasia. These data support our recent findings that CIMP is uncommon in young patients and that BRAF mutant polyps in young patients may have limited potential for malignant progression. Keywords: DNA Methylation, CIMP, Colorectal Cancer, Epigenetics, BRAF, KRAS

The consumption of acetaminophen (APAP) can induce neurological changes in human subjects; however, effects of APAP on blood–brain barrier (BBB) integrity are unknown. BBB changes by APAP can have profound consequences for brain delivery of co-administered drugs. To study APAP effects, female Sprague–Dawley rats (12–16 weeks old) were administered vehicle (i.e., 100% dimethyl sulfoxide (DMSO), intraperitoneally (i.p.)) or APAP (80 mg/kg or 500 mg/kg in DMSO, i.p.; equivalent to a 900 mg or 5600 mg daily dose for a 70 kg human subject). BBB permeability was measured via in situ brain perfusion using [14C]sucrose and [3H]codeine, an opioid analgesic drug that is co-administered with APAP (i.e., Tylenol #3). Localization and protein expression of tight junction proteins (i.e., claudin-5, occludin, ZO-1) were studied in rat brain microvessels using Western blot analysis and confocal microscopy, respectively. Paracellular [14C]sucrose “leak” and brain [3H]codeine accumulation were significantly enhanced in rats treated with 500 mg/kg APAP only. Additionally, claudin-5 localization and protein expression were altered in brain microvessels isolated from rats administered 500 mg/kg APAP. Our novel and translational data show that BBB integrity is altered following a single high APAP dose, results that are relevant to patients abusing or misusing APAP and/or APAP/opioid combination products.

The blood-brain barrier (BBB) allows the brain to selectively import nutrients and energy critical to neuronal function while simultaneously excluding neurotoxic substances from the peripheral circulation. In contrast to the highly permeable vasculature present in most organs that reside outside of the central nervous system (CNS), the BBB exhibits a high transendothelial electrical resistance (TEER) along with a low rate of transcytosis and greatly restricted paracellular permeability. The property of low paracellular permeability is controlled by tight junction (TJ) protein complexes that seal the paracellular route between apposing brain microvascular endothelial cells. Although tight junction protein complexes are principal contributors to physical barrier properties, they are not static in nature. Rather, tight junction protein complexes are highly dynamic structures, where expression and/or localization of individual constituent proteins can be modified in response to pathophysiological stressors. These stressors induce modifications to tight junction protein complexes that involve de novo synthesis of new protein or discrete trafficking mechanisms. Such responsiveness of BBB tight junctions to diseases indicates that these protein complexes are critical for maintenance of CNS homeostasis. In fulfillment of this vital role, BBB tight junctions are also a major obstacle to therapeutic drug delivery to the brain. There is an opportunity to overcome this substantial obstacle and optimize neuropharmacology via acquisition of a detailed understanding of BBB tight junction structure, function, and regulation. In this review, we discuss physiological characteristics of tight junction protein complexes and how these properties regulate delivery of therapeutics to the CNS for treatment of neurological diseases. Specifically, we will discuss modulation of tight junction structure, function, and regulation both in the context of disease states and in the setting of pharmacotherapy. In particular, we will highlight how these properties can be potentially manipulated at the molecular level to increase CNS drug levels via paracellular transport to the brain.

Emergency preparedness is a fundamental component of a successful emergency management strategy. This includes a proactive communication strategy that informs all stakeholders of the emergency plan and helps translate that knowledge to real spaces. Communicating multilevel built environments can be difficult, as the architectural complexity creates problems for both visual and mental representations of networks in 3D space. Modern mobile technology offers emerging opportunities for emergency managers to develop and deploy 3D visualizations of multilevel spaces that preserve the topology of those spaces while adding the spatial context that allows the individual to better understand their position within it. In this paper, we present a collection of mixed reality (specifically augmented reality) geovisualizations that overcome the visual limitations associated with the traditional static 2D methods of communicating the evacuation plans of multilevel structures. We demonstrate how this technology can provide spatially contextualized 3D geovisualizations that promote spatial knowledge acquisition and support cognitive mapping. These geovisualizations are designed as a proactive emergency management tool to educate and prepare at risk populations prior to the occurrence of a hazardous event.

Abstract Background Silicone oil tamponade is more frequently reserved for cases of complex retinal detachment. We describe the effects of different variations in oil ratios with the relatively unknown technique of double oil tamponade. Methods Retrospective case note review of nine patients with complex rhegmatogenous retinal detachment (RD). All cases had both superior and inferior breaks, mostly with associated proliferative vitreoretinopathy (PVR). All cases were treated with pars plana vitrectomy (PPV) and a double silicone oil endotamponade (DSOE) of both heavy silicone oil and conventional ‘light’ silicone oil. Ratios were varied to suit different RD configurations. In vitro observations were studied to help direct these decisions. Results Anatomical success was achieved in all cases. Common complications were the same as those seen in single oil tamponade (elevated intraocular pressure, cystoid macular oedema (CMO), cataract and posterior capsule opacification. No single case of recurrent RD was seen whilst mixed oil remained in situ. Conclusions Double silicone oil endotamponade is a safe and effective treatment for complex retinal detachments with superior and inferior breaks. Differences in oil ratios can be tailored to best fit the distribution of retinal pathology. In vitro observations may help to inform these choices.