Activation of the Keap1/Nrf2 pathway suppresses mitochondrial dysfunction, oxidative stress, and motor phenotypes in C9orf72 ALS/FTD models.

Mitochondrial dysfunction is a common feature of C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD); however, it remains unclear whether this is a cause or consequence of the pathogenic process. Analysing multiple aspects of mitochondrial biology across several Drosophila models of C9orf72-ALS/FTD, we found morphology, oxidative stress, and mitophagy are commonly affected, which correlated with progressive loss of locomotor performance. Notably, only genetic manipulations that reversed the oxidative stress levels were also able to rescue C9orf72 locomotor deficits, supporting a causative link between mitochondrial dysfunction, oxidative stress, and behavioural phenotypes. Targeting the key antioxidant Keap1/Nrf2 pathway, we found that genetic reduction of Keap1 or pharmacological inhibition by dimethyl fumarate significantly rescued the C9orf72-related oxidative stress and motor deficits. Finally, mitochondrial ROS levels were also elevated in C9orf72 patient-derived iNeurons and were effectively suppressed by dimethyl fumarate treatment. These results indicate that mitochondrial oxidative stress is an important mechanistic contributor to C9orf72 pathogenesis, affecting multiple aspects of mitochondrial function and turnover. Targeting the Keap1/Nrf2 signalling pathway to combat oxidative stress represents a therapeutic strategy for C9orf72-related ALS/FTD.

From use of omics to systems biology: Identifying therapeutic targets for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a heterogeneous progressive neurodegenerative disorder with available treatments such as riluzole and edaravone extending survival by an average of 3-6 months. The lack of highly effective, widely available therapies reflects the complexity of ALS. Omics technologies, including genomics, transcriptomic and proteomics have contributed to the identification of biological pathways dysregulated and targeted by therapeutic strategies in preclinical and clinical trials. Integrating clinical, environmental and neuroimaging information with omics data and applying a systems biology approach can further improve our understanding of the disease with the potential to stratify patients and provide more personalised medicine. This chapter will review the omics technologies that contribute to a systems biology approach and how these components have assisted in identifying therapeutic targets. Current strategies, including the use of genetic screening and biosampling in clinical trials, as well as the future application of additional technological advances, will also be discussed.

The Role of Scientific Research in Human Papillomavirus Vaccine Discussions on Twitter: Social Network Analysis.

BACKGROUND: Attitudes toward the human papillomavirus (HPV) vaccine and accuracy of information shared about this topic in web-based settings vary widely. As real-time, global exposure to web-based discourse about HPV immunization shapes the attitudes of people toward vaccination, the spread of misinformation and misrepresentation of scientific knowledge contribute to vaccine hesitancy. OBJECTIVE: In this study, we aimed to better understand the type and quality of scientific research shared on Twitter (recently rebranded as X) by vaccine-hesitant and vaccine-confident communities. METHODS: To analyze the use of scientific research on social media, we collected tweets and retweets using a list of keywords associated with HPV and HPV vaccines using the Academic Research Product Track application programming interface from January 2019 to May 2021. From this data set, we identified tweets referring to or sharing scientific literature through a Boolean search for any tweets with embedded links, hashtags, or keywords associated with scientific papers. First, we used social network analysis to build a retweet or reply network to identify the clusters of users belonging to either the vaccine-confident or vaccine-hesitant communities. Second, we thematically assessed all shared papers based on typology of evidence. Finally, we compared the quality of research evidence and bibliometrics between the shared papers in the vaccine-confident and vaccine-hesitant communities. RESULTS: We extracted 250 unique scientific papers (including peer-reviewed papers, preprints, and gray literature) from approximately 1 million English-language tweets. Social network maps were generated for the vaccine-confident and vaccine-hesitant communities sharing scientific research on Twitter. Vaccine-hesitant communities share fewer scientific papers; yet, these are more broadly disseminated despite being published in less prestigious journals compared to those shared by the vaccine-confident community. CONCLUSIONS: Vaccine-hesitant communities have adopted communication tools traditionally wielded by health promotion communities. Vaccine-confident communities would benefit from a more cohesive communication strategy to communicate their messages more widely and effectively.

Individual and Geospatial Determinants of Health Associated With School-Based Human Papillomavirus Immunization in Alberta: Population-Based Cohort Study.

BACKGROUND: Human papillomavirus (HPV) infection causes nearly all cervical cancer cases and is a cause of anogenital and oropharyngeal cancers. The incidence of HPV-associated cancers is inequitable, with an increased burden on marginalized groups in high-income countries. Understanding how immunization status varies by material and social deprivation, health system, and geospatial factors is valuable for prioritizing and planning HPV immunization interventions. OBJECTIVE: The objective of this study was to describe school-based HPV immunization rates by individual and geospatial determinants of health in Alberta, Canada. METHODS: Health administrative data for male and female individuals born in 2004 in Alberta were used to determine HPV immunization status based on age and the number of doses administered in schools during the 2014/2015-2018/2019 school years. Immunization status and its relationship with material and social deprivation and health system factors were assessed by a logistic regression model. Geospatial clustering was assessed using Getis-Ord Gi* hot spot analysis. Mean scores of material and social deprivation and health system factors were compared between hot and cold spots without full HPV immunization using independent samples t tests. A multidisciplinary team comprising researchers and knowledge users formed a co-design team to design the study protocol and review the study results. RESULTS: The cohort consisted of 45,207 youths. In the adjusted model, the odds of those who did not see their general practitioner (GP) within 3 years before turning 10 years old and not being fully immunized were 1.965 times higher (95% CI 1.855-2.080) than those who did see their GP. The odds of health system users with health conditions and health system nonusers not being fully immunized were 1.092 (95% CI 1.006-1.185) and 1.831 (95% CI 1.678-1.998) times higher, respectively, than health system users without health conditions. The odds of those who lived in areas with the most material and social deprivation not being fully immunized were 1.287 (95% CI 1.200-1.381) and 1.099 (95% CI 1.029-1.174) times higher, respectively, than those who lived in areas with the least deprivation. The odds of those who lived in rural areas not being fully immunized were 1.428 times higher (95% CI 1.359-1.501) than those who lived in urban areas. Significant hot spot clusters of individuals without full HPV immunization exist in rural locations on the northern and eastern regions of Alberta. Hot spots had significantly worse mean material deprivation scores (P=.008) and fewer GP visits (P=.001) than cold spots. CONCLUSIONS: Findings suggest that material and social deprivation, health system access, and rural residency impact HPV immunization. Such factors should be considered by public health professionals in other jurisdictions and will be used by the Alberta co-design team when tailoring programs to increase HPV vaccine uptake in priority populations and regions.

Genetic and geographic population structure in the malaria vector, Anopheles farauti, provides a candidate system for pioneering confinable gene-drive releases.

Indoor insecticide applications are the primary tool for reducing malaria transmission in the Solomon Archipelago, a region where Anopheles farauti is the only common malaria vector. Due to the evolution of behavioural resistance in some An. farauti populations, these applications have become less effective. New malaria control interventions are therefore needed in this region, and gene-drives provide a promising new technology. In considering developing a population-specific (local) gene-drive in An. farauti, we detail the species' population genetic structure using microsatellites and whole mitogenomes, finding many spatially confined populations both within and between landmasses. This strong population structure suggests that An. farauti would be a useful system for developing a population-specific, confinable gene-drive for field release, where private alleles can be used as Cas9 targets. Previous work on Anopheles gambiae has used the Cardinal gene for the development of a global population replacement gene-drive. We therefore also analyse the Cardinal gene to assess whether it may be a suitable target to engineer a gene-drive for the modification of local An. farauti populations. Despite the extensive population structure observed in An. farauti for microsatellites, only one remote island population from Vanuatu contained fixed and private alleles at the Cardinal locus. Nonetheless, this study provides an initial framework for further population genomic investigations to discover high-frequency private allele targets in localized An. farauti populations. This would enable the development of gene-drive strains for modifying localised populations with minimal chance of escape and may provide a low-risk route to field trial evaluations.

Practical Guide to Measuring Wetland Carbon Pools and Fluxes.

Wetlands cover a small portion of the world, but have disproportionate influence on global carbon (C) sequestration, carbon dioxide and methane emissions, and aquatic C fluxes. However, the underlying biogeochemical processes that affect wetland C pools and fluxes are complex and dynamic, making measurements of wetland C challenging. Over decades of research, many observational, experimental, and analytical approaches have been developed to understand and quantify pools and fluxes of wetland C. Sampling approaches range in their representation of wetland C from short to long timeframes and local to landscape spatial scales. This review summarizes common and cutting-edge methodological approaches for quantifying wetland C pools and fluxes. We first define each of the major C pools and fluxes and provide rationale for their importance to wetland C dynamics. For each approach, we clarify what component of wetland C is measured and its spatial and temporal representativeness and constraints. We describe practical considerations for each approach, such as where and when an approach is typically used, who can conduct the measurements (expertise, training requirements), and how approaches are conducted, including considerations on equipment complexity and costs. Finally, we review key covariates and ancillary measurements that enhance the interpretation of findings and facilitate model development. The protocols that we describe to measure soil, water, vegetation, and gases are also relevant for related disciplines such as ecology. Improved quality and consistency of data collection and reporting across studies will help reduce global uncertainties and develop management strategies to use wetlands as nature-based climate solutions. Supplementary Information: The online version contains supplementary material available at 10.1007/s13157-023-01722-2.

Evaluation of acute flaccid paralysis surveillance performance before and during the 2014-2015 Ebola virus disease outbreak in Guinea and Liberia.

Introduction: the number of wild poliomyelitis cases, worldwide, dropped from 350,000 cases in 1988 to 33 in 2018. Acute flaccid paralysis (AFP) surveillance is a key strategy toward achieving global polio eradication. The 2014 Ebola virus disease (EVD) epidemic in West Africa infected over 28,000 people and had devastating effects on health systems in Guinea, Liberia, and Sierra Leone. We sought to assess the effects of the 2014 Ebola outbreak on AFP surveillance in Guinea and Liberia. Methods: a retrospective cross-sectional analysis was performed for Guinea and Liberia to evaluate EVD´s impact on World Health Organization (WHO) AFP surveillance performance indicators during 2012-2015. Results: both Guinea and Liberia met the WHO target non-polio AFP incidence rate nationally, and generally sub-nationally, prior to the EVD outbreak; rates decreased substantially during the outbreak in seven of eight regions in Guinea and 11 of 15 counties in Liberia. Throughout the study period, both Guinea and Liberia attained appropriate overall targets nationally for "notification" and "stool adequacy" indicators, but each country experienced periods of poor regional/county-specific indicator performance. Conclusion: these findings mirrored the negative effect of the Ebola outbreak on polio elimination activities in both countries and highlights the need to reinforce this surveillance system during times of crisis.

Peptide-based approaches to directly target alpha-synuclein in Parkinson's disease.

Peptides and their mimetics are increasingly recognised as drug-like molecules, particularly for intracellular protein-protein interactions too large for inhibition by small molecules, and inaccessible to larger biologics. In the past two decades, evidence associating the misfolding and aggregation of alpha-synuclein strongly implicates this protein in disease onset and progression of Parkinson's disease and related synucleinopathies. The subsequent formation of toxic, intracellular, Lewy body deposits, in which alpha-synuclein is a major component, is a key diagnostic hallmark of the disease. To reach their therapeutic site of action, peptides must both cross the blood-brain barrier and enter dopaminergic neurons to prevent the formation of these intracellular inclusions. In this review, we describe and summarise the current efforts made in the development of peptides and their mimetics to directly engage with alpha-synuclein with the intention of modulating aggregation, and importantly, toxicity. This is a rapidly expanding field with great socioeconomic impact; these molecules harbour significant promise as therapeutics, or as early biomarkers during prodromal disease stages, or both. As these are age-dependent conditions, an increasing global life expectancy means disease prevalence is rising. No current treatments exist to either prevent or slow disease progression. It is therefore crucial that drugs are developed for these conditions before health care and social care capacities become overrun.

A critical view of the use of predictive energy equations for the identification of hypermetabolism in motor neuron disease: A pilot study.

BACKGROUND AND AIMS: People living with motor neuron disease (MND) frequently struggle to consume an optimal caloric intake. Often compounded by hypermetabolism, this can lead to dysregulated energy homeostasis, prompting the onset of malnutrition and associated weight loss. This is associated with a poorer prognosis and reduced survival. It is therefore important to establish appropriate nutritional goals to ensure adequate energy intake. This is best done by measuring resting energy expenditure (mREE) using indirect calorimetry. However, indirect calorimetry is not widely available in clinical practice, thus dietitians caring for people living with MND frequently use energy equations to predict resting energy expenditure (pREE) and estimate caloric requirements. Energy prediction equations have previously been shown to underestimate resting energy expenditure in over two-thirds of people living with MND. Hypermetabolism has previously been identified using the metabolic index. The metabolic index is a ratio of mREE to pREE, whereby an increase of mREE by ≥110% indicates hypermetabolism. We aim to critically reflect on the use of the Harris-Benedict (1919) and Henry (2005) energy prediction equations to inform a metabolic index to indicate hypermetabolism in people living with MND. METHODS: mREE was derived using VO2 and VCO2 measurements from a GEMNutrition indirect calorimeter. pREE was estimated by Harris-Benedict (HB) (1919), Henry (2005) and kcal/kg/day predictive energy equations. The REE variation, described as the percentage difference between mREE and pREE, determined the accuracy of pREE ([pREE-mREE]/mREE) x 100), with accuracy defined as ≤ ± 10%. A metabolic index threshold of ≥110% was used to classify hypermetabolism. All resting energy expenditure data are presented as kcal/24hr. RESULTS: Sixteen people living with MND were included in the analysis. The mean mREE was 1642 kcal/24hr ranging between 1110 and 2015 kcal/24hr. When REE variation was analysed for the entire cohort, the HB, Henry and kcal/kg/day equations all overestimated REE, but remained within the accuracy threshold (mean values were 2.81% for HB, 4.51% for Henry and 8.00% for kcal/kg/day). Conversely, inter-individual REE variation within the cohort revealed HB and Henry equations both inaccurately reflected mREE for 68.7% of participants, with kcal/kg/day inaccurately reflecting 41.7% of participants. Whilst the overall cohort was not classified as hypermetabolic (mean values were 101.04% for HB, 98.62% for Henry and 95.64% for kcal/kg/day), the metabolic index ranges within the cohort were 70.75%-141.58% for HB, 72.82%-127.69% for Henry and 66.09%-131.58% for kcal/kg/day, indicating both over- and under-estimation of REE by these equations. We have shown that pREE correlates with body weight (kg), whereby the lighter the individual, the greater the underprediction of REE. When applied to the metabolic index, this underprediction biases towards the classification of hypermetabolism in lighter individuals. CONCLUSION: Whilst predicting resting energy expenditure using the HB, Henry or kcal/kg/day equations accurately reflects derived mREE at group level, these equations are not suitable for informing resting energy expenditure and classification of hypermetabolism when applied to individuals in clinical practice.

Shower thoughts: why scientists should spend more time in the rain.

Stormwater is a vital resource and dynamic driver of terrestrial ecosystem processes. However, processes controlling interactions during and shortly after storms are often poorly seen and poorly sensed when direct observations are substituted with technological ones. We discuss how human observations complement technological ones and the benefits of scientists spending more time in the storm. Human observation can reveal ephemeral storm-related phenomena such as biogeochemical hot moments, organismal responses, and sedimentary processes that can then be explored in greater resolution using sensors and virtual experiments. Storm-related phenomena trigger lasting, oversized impacts on hydrologic and biogeochemical processes, organismal traits or functions, and ecosystem services at all scales. We provide examples of phenomena in forests, across disciplines and scales, that have been overlooked in past research to inspire mindful, holistic observation of ecosystems during storms. We conclude that technological observations alone are insufficient to trace the process complexity and unpredictability of fleeting biogeochemical or ecological events without the shower thoughts produced by scientists' human sensory and cognitive systems during storms.

A Y374X TDP43 truncation leads to an altered metabolic profile in amyotrophic lateral sclerosis fibroblasts driven by pyruvate and TCA cycle intermediate alterations.

A p.Y374X truncation in TARDBP was recently shown to reduce expression of TDP43 in fibroblasts isolated from ALS cases. In this follow up study focused on assessing the downstream phenotypic consequences of loss of TDP43 in the context of the truncation, we have shown a striking effect on the fibroblast metabolic profile. Phenotypic metabolic screening uncovered a distinct metabolic profile in TDP43-Y374X fibroblasts compared to controls, which was driven by alterations in key metabolic checkpoint intermediates including pyruvate, alpha-ketoglutarate and succinate. These metabolic alterations were confirmed using transcriptomics and bioenergetic flux analysis. These data suggest that TDP43 truncation directly compromises glycolytic and mitochondrial function, identifying potential therapeutic targets for mitigating the effects of TDP43-Y374X truncation.

Dengue and chikungunya virus loads in the mosquito Aedes aegypti are determined by distinct genetic architectures.

Aedes aegypti is the primary vector of the arboviruses dengue (DENV) and chikungunya (CHIKV). These viruses exhibit key differences in their vector interactions, the latter moving more quicky through the mosquito and triggering fewer standard antiviral pathways. As the global footprint of CHIKV continues to expand, we seek to better understand the mosquito's natural response to CHIKV-both to compare it to DENV:vector coevolutionary history and to identify potential targets in the mosquito for genetic modification. We used a modified full-sibling design to estimate the contribution of mosquito genetic variation to viral loads of both DENV and CHIKV. Heritabilities were significant, but higher for DENV (40%) than CHIKV (18%). Interestingly, there was no genetic correlation between DENV and CHIKV loads between siblings. These data suggest Ae. aegypti mosquitoes respond to the two viruses using distinct genetic mechanisms. We also examined genome-wide patterns of gene expression between High and Low CHIKV families representing the phenotypic extremes of viral load. Using RNAseq, we identified only two loci that consistently differentiated High and Low families: a long non-coding RNA that has been identified in mosquito screens post-infection and a distant member of a family of Salivary Gland Specific (SGS) genes. Interestingly, the latter gene is also associated with horizontal gene transfer between mosquitoes and the endosymbiotic bacterium Wolbachia. This work is the first to link the SGS gene to a mosquito phenotype. Understanding the molecular details of how this gene contributes to viral control in mosquitoes may, therefore, also shed light on its role in Wolbachia.

An action-oriented public health framework to reduce financial strain and promote financial wellbeing in high-income countries.

BACKGROUND: Perceived financial security impacts physical, mental, and social health and overall wellbeing at community and population levels. Public health action on this dynamic is even more critical now that the COVID-19 pandemic has exacerbated financial strain and reduced financial wellbeing. Yet, public health literature on this topic is limited. Initiatives targeting financial strain and financial wellbeing and their deterministic effects on equity in health and living conditions are missing. Our research-practice collaborative project addresses this gap in knowledge and intervention through an action-oriented public health framework for initiatives targeting financial strain and wellbeing. METHODS: The Framework was developed using a multi-step methodology that involved review of theoretical and empirical evidence alongside input from a panel of experts from Australia and Canada. In an integrated knowledge translation approach, academics (n = 14) and a diverse group of experts from government and non-profit sectors (n = 22) were engaged throughout the project via workshops, one-on-one dialogues, and questionnaires. RESULTS: The validated Framework provides organizations and governments with guidance for the design, implementation, and assessment of diverse financial wellbeing- and financial strain-related initiatives. It presents 17 priority actionable areas (i.e., entry points for action) likely to have long-lasting, positive effects on people's financial circumstances, contributing to improved financial wellbeing and health. The 17 entry points relate to five domains: Government (All Levels), Organizational & Political Culture, Socioeconomic & Political Context, Social & Cultural Circumstances, and Life Circumstances. CONCLUSIONS: The Framework reveals the intersectionality of root causes and consequences of financial strain and poor financial wellbeing, while also reinforcing the need for tailored actions to promote socioeconomic and health equity for all people. The dynamic, systemic interplay of the entry points illustrated in the Framework suggest opportunities for multi-sectoral, collaborative action across government and organizations towards systems change and the prevention of unintended negative impacts of initiatives.

A Policy-Ready Public Health Guidebook of Strategies and Indicators to Promote Financial Well-Being and Address Financial Strain in Response to COVID-19.

INTRODUCTION: The COVID-19 pandemic has adversely affected the financial well-being of populations globally, escalating concerns about links with health care and overall well-being. Governments and organizations need to act quickly to protect population health relative to exacerbated financial strain. However, limited practice- and policy-relevant resources are available to guide action, particularly from a public health perspective, that is, targeting equity, social determinants of health, and health-in-all policies. Our study aimed to create a public health guidebook of strategies and indicators for multisectoral action on financial well-being and financial strain by decision makers in high-income contexts. METHODS: We used a multimethod approach to create the guidebook. We conducted a targeted review of existing theoretical and conceptual work on financial well-being and strain. By using rapid review methodology informed by principles of realist review, we collected data from academic and practice-based sources evaluating financial well-being or financial strain initiatives. We performed a critical review of these sources. We engaged our research-practice team and government and nongovernment partners and participants in Canada and Australia for guidance to strengthen the tool for policy and practice. RESULTS: The guidebook presents 62 targets, 140 evidence-informed strategies, and a sample of process and outcome indicators. CONCLUSION: The guidebook supports action on the root causes of poor financial well-being and financial strain. It addresses a gap in the academic literature around relevant public health strategies to promote financial well-being and reduce financial strain. Community organizations, nonprofit organizations, and governments in high-income countries can use the guidebook to direct initiative design, implementation, and assessment.

Fact or Fiction? The Development and Evaluation of a Tobacco Virtual Health Tool.

The virtual setting is an important setting for health promotion as individuals increasingly go online for health information and support. Yet, users can have difficulty finding valid, trustworthy, and user-friendly health information online. In 2022, we launched an interactive Fact or Fiction Tobacco virtual health tool. The virtual health tool uses evidence-informed tailored content to engage users and refer them to local tobacco cessation resources. The present paper describes the development, user testing, and evaluation of this tool. The Fact or Fiction virtual health tool was designed by tobacco cessation and health marketing experts and informed by health behaviour theories of change. The tool captures data on who is seeking health information, the user's stage of readiness to quit tobacco products, and whether they act by accessing referred resources. In 2021, we conducted two phases of user testing prior to marketing the tool publicly. After 7 weeks of marketing, we collected data on user interactions with the tool and evaluated the reach of the tool. Results from user testing found the tool to be engaging, easy to use, and quick to complete. Adaptations were made to simplify and condense text and include additional animations. During the first seven weeks of the tool being live, it reached 2306 users, and 38.7% of those users were current or occasional tobacco users. Users were classified based on their intention to quit. Bivariate analysis found that the tool was successful in driving tobacco users towards action as 21.2% tobacco users who were looking to quit and 8.8% of tobacco users who were not looking to quit clicked on local tobacco cessation resources. This virtual health tool is reaching the targeted population and providing tailored information needed at each stage of the continuum of health behaviour change. Among tobacco users looking to quit, this virtual health tool acts as a quick referral to local tobacco cessation resources.

Incidence of Loss of Reduction After Open Reduction Internal Fixation of Metacarpal Shaft Fractures.

BACKGROUND: This study compared the incidence of loss of reduction (LOR) between metacarpal fractures fixed with screws alone and those fixed with plates and screws. Secondary aims included identifying patient or fracture characteristics associated with increased risk of LOR. METHODS: We retrospectively reviewed 138 metacarpal fractures in 106 patients treated with open reduction internal fixation with screws (60 fractures) or plates and screws (78 fractures) with a mean radiographic follow-up of 50 days for evidence of LOR. We compared the incidence of LOR between the screw and plate groups using a χ2 test. We performed logistic regression analysis to determine whether patient age, sex, metacarpal location (index, long, ring, small), the presence of multiple metacarpal fractures, or fracture pattern were associated with increased incidence of LOR. RESULTS: Loss of reduction occurred in 19 (13.8%) of 138 fractures, with no statistically significant difference between lag screw (7 of 60, 11.6%) and plate fixation (12 of 78, 15.4%). Neither fracture pattern nor the presence of multiple metacarpal fractures was associated with an increased incidence of LOR, but patients experienced a 7% increase in the risk of LOR for each additional year of age. Loss of reduction occurred most frequently in index metacarpal fractures (4 of 12, 33%), although this did not reach statistical significance. CONCLUSIONS: We found no difference in LOR incidence between lag screw fixation and plate fixation. The overall incidence of LOR was higher in this study than previously reported and increased with increasing patient age.

Atypical TDP-43 protein expression in an ALS pedigree carrying a p.Y374X truncation mutation in TARDBP.

We describe an autosomal dominant, multi-generational, amyotrophic lateral sclerosis (ALS) pedigree in which disease co-segregates with a heterozygous p.Y374X nonsense mutation within TDP-43. Mislocalization of TDP-43 and formation of insoluble TDP-43-positive neuronal cytoplasmic inclusions is the hallmark pathology in >95% of ALS patients. Neuropathological examination of the single case for which CNS tissue was available indicated typical TDP-43 pathology within lower motor neurons, but classical TDP-43-positive inclusions were absent from motor cortex. The mutated allele is transcribed and translated in patient fibroblasts and motor cortex tissue, but overall TDP-43 protein expression is reduced compared to wild-type controls. Despite absence of TDP-43-positive inclusions we confirmed deficient TDP-43 splicing function within motor cortex tissue. Furthermore, urea fractionation and mass spectrometry of motor cortex tissue carrying the mutation revealed atypical TDP-43 protein species but not typical C-terminal fragments. We conclude that the p.Y374X mutation underpins a monogenic, fully penetrant form of ALS. Reduced expression of TDP-43 combined with atypical TDP-43 protein species and absent C-terminal fragments extends the molecular phenotypes associated with TDP-43 mutations and with ALS more broadly. Future work will need to include the findings from this pedigree in dissecting the mechanisms of TDP-43-mediated toxicity.

Factors influencing human papillomavirus school-based immunization in Alberta: A mixed-methods study protocol.

More than 1,300 Canadians are diagnosed with cervical cancer annually, which is nearly preventable through human papillomavirus (HPV) immunization. Across Canada, coverage rates remain below the 90% target set out by the Action Plan for the Elimination of Cervical Cancer in Canada (2020-2030). To support this Plan, the Canadian Partnership Against Cancer has commissioned the Urban Public Health Network (UPHN) to coordinate a quality improvement project with Canada's school-based HPV immunization programs. In Alberta, the UPHN partnered with Alberta Health Services (AHS) for this work. This study has one overarching research question: what are parent/guardian and program stakeholder perceived barriers, enablers and opportunities to immunization for youth as part of the school-based HPV immunization program in Alberta? This study uses a mixed-methods sequential explanatory design. A survey will be emailed to a sample of Albertans with children aged 11-17 years. Questions will be based on a Conceptual Framework of Access to Health Care. Subsequent qualitative work will explore the survey's findings. Parents/guardians identifying as vaccine hesitant in the survey will be invited to participate in virtual, semi-structured, in-depth interviews. Stakeholders of the school-based immunization program will be purposively sampled from AHS' five health zones for virtual focus groups. Quantitative data will be analyzed using SAS Studio 3.6 to carry out descriptive statistics and, using logistic regression, investigate if Framework constructs are associated with parents'/guardians' decision to immunize their children. Qualitative data will be analyzed using NVivo 12 to conduct template thematic analysis guided by the Framework. Study results will provide insights for Alberta's public health practitioners to make evidence-informed decisions when tailoring the school-based HPV immunization program to increase uptake in vaccine hesitant populations. Findings will contribute to the national study, which will culminate in recommendations to increase HPV immunization uptake nationally and progress towards the 90% coverage target.

Accessibility and Inclusion for Families with Children with Autism Spectrum Disorders in Cultural Institutions.

This project aimed to develop a comprehensive set of evaluation tools to assess the accessibility and inclusion of families with children on the autism spectrum in cultural institutions. A stakeholder team conducted interviews, reviewed museum artifacts, and observed museum programming. An evaluation toolkit was constructed by incorporating best practices from current literature and collected data. Tools were piloted and revised after being implemented in the museum context. The Toolkit to Increase Accessibility and Inclusion for Children on the Autism Spectrum and with Sensory Processing Differences in Cultural Institutions was developed with five unique tools, the Dimensions of Accessibility framework, and further resources to provide a self-assessment of cultural institutions. The toolkit can be used broadly across many types of institutions and self-assessment can lead to proactive development of public spaces, institutions, and programming that is accessible and inclusive of diverse groups of people, beyond families with children on the autism spectrum.

The extent to which soil hydraulics can explain ecohydrological separation.

Field measurements of hydrologic tracers indicate varying magnitudes of geochemical separation between subsurface pore waters. The potential for conventional soil physics alone to explain isotopic differences between preferential flow and tightly-bound water remains unclear. Here, we explore physical drivers of isotopic separations using 650 different model configurations of soil, climate, and mobile/immobile soil-water domain characteristics, without confounding fractionation or plant uptake effects. We find simulations with coarser soils and less precipitation led to reduced separation between pore spaces and drainage. Amplified separations are found with larger immobile domains and, to a lesser extent, higher mobile-immobile transfer rates. Nonetheless, isotopic separations remained small (<4‰ for δ2H) across simulations, indicating that contrasting transport dynamics generate limited geochemical differences. Therefore, conventional soil physics alone are unlikely to explain large ecohydrological separations observed elsewhere, and further efforts aimed at reducing methodological artifacts, refining understanding of fractionation processes, and investigating new physiochemical mechanisms are needed.