C3d-Targeted factor H inhibits tissue complement in disease models and reduces glomerular injury without affecting circulating complement.

Complement-mediated diseases can be treated using systemic inhibitors. However, complement components are abundant in circulation, affecting systemic inhibitors' exposure and efficacy. Furthermore, because of complement's essential role in immunity, systemic treatments raise infection risk in patients. To address these challenges, we developed antibody fusion proteins combining the alternative-pathway complement inhibitor factor H (fH1-5) with an anti-C3d monoclonal antibody (C3d-mAb-2fH). Because C3d is deposited at sites of complement activity, this molecule localizes to tissue complement while minimizing circulating complement engagement. These fusion proteins bind to deposited complement in diseased human skin sections and localize to activated complement in a primate skin injury model. We further explored the pharmacology of C3d-mAb-2fH proteins in rodent models with robust tissue complement activation. Doses of C3d-mAb-2fH >1 mg/kg achieved >75% tissue complement inhibition in mouse and rat injury models while avoiding circulating complement blockade. Glomerular-specific complement inhibition reduced proteinuria and preserved podocyte foot-process architecture in rat membranous nephropathy, indicating disease-modifying efficacy. These data indicate that targeting local tissue complement results in durable and efficacious complement blockade in skin and kidney while avoiding systemic inhibition, suggesting broad applicability of this approach in treating a range of complement-mediated diseases.

The information required by people with inflammatory arthritis when taking Methotrexate: a mixed-methods systematic review.

OBJECTIVES: This mixed-methods systematic review aimed to identify and synthesize knowledge of the characteristics, content, and preferred format of information to support people with inflammatory arthritis (IA) to take MTX. METHODS: A literature search using MEDLINE, The Cochrane Library, EMBASE, CINAHL, PsychInfo, GreyEU, Web of Science and Open Dissertation was conducted to identify all studies published from 2000 to December 2022. Included studies detailed factors related to MTX information needs of people aged ≥18 years with IA published in English. The Joanna Briggs Institute Guidelines (JBI) for convergent integrated mixed-methods systematic reviews were followed using validated tools for data extraction and quality. The data was analysed using reflexive thematic analysis. RESULTS: Thirteen studies (seven quantitative, two mixed-methods and four qualitative) were included, involving 3425 adults, mainly female n = 2434 (71%), age 20-84 years. An overarching theme of a requirement for person-centred care was developed, with three interlinking themes: (1) accepting the need for treatment with MTX, (2) concerns about taking MTX, and (3) a need for tailored information and support. Limitations of the evidence included the use of heterogeneous outcome measures and instruments for measuring information needs. CONCLUSION: People with IA have individual, multifaceted information and support needs about MTX that are often unresolved when a one-size-fits-all approach is used. The findings of this review can inform rheumatology training to support a person-centred approach to identifying and addressing the specific needs and concerns and development of consistent easy-to-understand accessible MTX information.

Children's physical activity and sedentary behaviour in before school care: An observational study.

OBJECTIVE: In Australia, less than one quarter of children aged 5-12 years meet national physical activity (PA) guidelines. Before school care operates as part of Out of School Hours Care (OSHC) services and provide opportunities for children to meet their daily PA recommendations. The aim of this study was to explore factors associated with children meeting 15 min of moderate-to-vigorous-intensity physical activity (MVPA) while attending before school care. METHODS: A cross-sectional study was conducted in 25 services in New South Wales, Australia. Each service was visited twice between March and June 2021. Staff behaviours and PA type and context were captured using staff interviews and the validated System for Observing Staff Promotion of Physical Activity and Nutrition (SOSPAN) time sampling tool. Child PA data were collected using Actigraph accelerometers and associations between program practices and child MVPA analysed. RESULTS: PA data were analysed for 654 children who spent an average of 39.2% (±17.6) of their time sedentary; 45.4% (±11.4) in light PA; and 14.9% (±11.7) in MVPA. Only 17% of children (n = 112) reached ≥15 min MVPA, with boys more likely to achieve this. Children were more likely to meet this recommendation in services where staff promoted and engaged in PA; PA equipment was available; children were observed in child-led free play; and a written PA policy existed. CONCLUSIONS: Before school care should be supported to improve physical activity promotion practices by offering staff professional development and guidance on PA policy development and implementation practices.

Barriers and facilitators in diagnosing axial spondyloarthritis: a qualitative study.

INTRODUCTION: Diagnosis of axial spondyloarthritis (axSpA) is frequently delayed for years after symptom onset. However, little is known about patient and healthcare professional (HCP) perspectives on barriers and facilitators in axSpA diagnosis. This study explored the experiences and perceptions of both groups regarding the factors affecting the timely diagnosis of axSpA. METHOD: Semi-structured interviews with patients with axSpA and axSpA-interested HCPs from the United Kingdom (UK) were performed by telephone or Microsoft Teams and focussed on the individuals' perspective of the diagnostic journey for axSpA. Interview transcripts were thematically analysed. RESULTS: Fourteen patients with axSpA (10 female, 4 male) and 14 UK based HCPs were recruited, the latter comprising of 5 physiotherapists, 4 General Practitioners, 3 rheumatologists, a nurse, and an occupational therapist. Barriers to diagnosis identified by patients and HCPs were: difficult to diagnose, a lack of awareness, unclear referral pathways, patient behaviour and patient/HCP communication. Patient-identified facilitators of diagnosis were patient advocacy, clear referral processes and pathways, increased awareness, and serendipity. HCPs identified promoting awareness as a facilitator of diagnosis, along with symptom recognition, improvements to healthcare practice and patient/HCP communications. CONCLUSION: Poor communication and a lack of understanding of axSpA in the professional and public spheres undermine progress towards timely diagnosis of axSpA. Improving communication and awareness for patients and HCPs, along with systemic changes in healthcare (such as improved referral pathways) could reduce diagnostic delay.

Investigating Substance Use as a Coping Strategy Among Adolescent Psychiatric Inpatients: A Comparative Analysis Before and During the COVID-19 Pandemic.

The COVID-19 pandemic resulted in significant changes in daily life, potentially impacting mental health and substance use behavior. Research on COVID-related changes in adolescent substance use have yielded mixed findings. The current cross-sectional chart review study compared rates of past-year substance use before and during COVID-19 among adolescent psychiatric inpatients, and investigated how motives for coping with COVID-19 changes were related to psychiatric acuity, and past-year substance use. Count models assessed if the number of past-year days of alcohol and cannabis use was higher among adolescents (n = 491, 11-18 years, 61% female) hospitalized during COVID-19 (3/14/20 to 4/5/21) versus adolescents hospitalized before COVID-19 (8/30/2019 to 3/13/20). For a subsample of COVID-19 inpatients (n = 124; 75% female), we evaluated psychiatric correlates of endorsing substances to cope with COVID-19 changes/rules. Results indicated adolescents admitted during COVID-19 reported significantly more past-year alcohol and cannabis use days than adolescents admitted before COVID-19. Adolescents endorsed using alcohol (19%), cannabis (33%), and e-cigarettes/vaping (25%) to cope with COVID-19. E-cigarette/vaping to cope with COVID-19 was significantly related to lifetime suicide attempt. Endorsing alcohol or cannabis to cope with COVID-19 was associated with a significantly greater number of past-year use days for each respective substance. Adolescent psychiatric inpatients admitted during COVID-19 reported more substance use days than adolescents admitted before COVID-19. Using substances to cope was linked to psychiatric correlates (e.g., suicidality). Assessing the presence and function of substance use in this population may be important to identify, treat, and prevent compounding negative outcomes during times of community stress.

Nutrition and physical activity practices in family day care: A cross-sectional survey of Australian family day care educators.

ISSUE ADDRESSED: Munch & Move is a New South Wales (NSW) Ministry of Health program offering family day care (FDC) educators training to support children's healthy behaviours. This study examined educators' nutrition, physical activity and screen time practices and relationships between Munch & Move training and professional development (PD) on these practices. METHODS: NSW FDC educators (n = 186) completed an online survey from July 2020-June 2021. Differences between groups based on Munch & Move training (trained; not trained) and PD (those who completed PD ≥1 time per year; those who completed PD <1 time per year or never) were tested using bivariate analyses. RESULTS: A significantly higher proportion of educators trained in Munch & Move offered information to families regarding food serving sizes, nutrition policies, and children's physical activity and screen time. Over one-third in both groups did not meet the guideline of no screen time for children under 2 years old. Compared with those who completed PD ≥1 time per year, a significantly higher proportion of educators who completed PD <1 time per year or never did not provide families with nutrition guidelines or resources. CONCLUSIONS: Educators trained in Munch & Move, and those who completed PD more frequently, demonstrated better nutrition, physical activity and screen time practices in several areas. SO WHAT?: This study demonstrated benefits of the Munch & Move program, implemented with support from Local Health District health promotion officers, and highlighted key areas for improvement in healthy practices in FDC.

Awareness and use of the Eat Smart Play Smart resources in Out of School Hours Care services: A staff survey in New South Wales, Australia.

ISSUE ADDRESSED: Out of School Hours Care (OSHC) is an important setting to promote healthy eating and physical activity. Between 2017 and 2018, The Eat Smart Play Smart (ESPS) resources were disseminated to OSHC services across New South Wales (NSW), Australia. The aim of this study was to evaluate the awareness and usability of ESPS to support OSHC healthy eating and physical activity practices. METHODS: All NSW OSHC services (approximately 1700) were invited to complete an online survey to assess awareness and use of the ESPS resources (manual and online modules). Data were analysed using SPSS (Version 29). RESULTS: A total of 393 OSHC staff responded to the survey. Most (75%) had used the ESPS resources. Of the 25% who had not used the resources, 63% indicated it was because they did not receive the manual and 52% were not aware of the resources. Of the OSHC services that knew about the resources, 69% indicated that ESPS contributed to their service's ability to meet the Australian National Quality Standards. Respondents identified additional support was required regarding physical activity educational materials and professional learning. Suggestions for improvements included offering content in different formats (e.g., digital). CONCLUSION: This evaluation identified factors influencing the uptake of the ESPS resources and will inform future interventions for OSHC staff to improve knowledge and practices in healthy eating and physical activity promotion. SO WHAT?: Our findings will support the optimisation of ESPS resources and inform future development of future healthy eating and physical activity interventions in the OSHC setting.

Occupational hand dermatitis secondary to methacrylates-The 'manual tray' sign.

A case report of a dentist presenting with allergic contact dermatitis to methacrylates present in dental bonding agent applied on the dorsum of a gloved hand. The patient presented with a localized dermatitis to the dorsum of the non-dominant hand which can be described as a 'manual tray sign'.

Spatial Bayesian GLM on the cortical surface produces reliable task activations in individuals and groups.

The general linear model (GLM) is a widely popular and convenient tool for estimating the functional brain response and identifying areas of significant activation during a task or stimulus. However, the classical GLM is based on a massive univariate approach that does not explicitly leverage the similarity of activation patterns among neighboring brain locations. As a result, it tends to produce noisy estimates and be underpowered to detect significant activations, particularly in individual subjects and small groups. A recently proposed alternative, a cortical surface-based spatial Bayesian GLM, leverages spatial dependencies among neighboring cortical vertices to produce more accurate estimates and areas of functional activation. The spatial Bayesian GLM can be applied to individual and group-level analysis. In this study, we assess the reliability and power of individual and group-average measures of task activation produced via the surface-based spatial Bayesian GLM. We analyze motor task data from 45 subjects in the Human Connectome Project (HCP) and HCP Retest datasets. We also extend the model to multi-run analysis and employ subject-specific cortical surfaces rather than surfaces inflated to a sphere for more accurate distance-based modeling. Results show that the surface-based spatial Bayesian GLM produces highly reliable activations in individual subjects and is powerful enough to detect trait-like functional topologies. Additionally, spatial Bayesian modeling enhances reliability of group-level analysis even in moderately sized samples (n=45). Notably, the power of the spatial Bayesian GLM to detect activations above a scientifically meaningful effect size is nearly invariant to sample size, exhibiting high power even in small samples (n=10). The spatial Bayesian GLM is computationally efficient in individuals and groups and is convenient to implement with the open-source BayesfMRI R package.

Correlates of physical activity and sedentary behaviour in children attending before and after school care: a systematic review.

BACKGROUND: Out of School Hours Care (OSHC) offers structured care to elementary/primary-aged children before and after school, and during school holidays. The promotion of physical activity in OSHC is important for childhood obesity prevention. The aim of this systematic review was to identify correlates of objectively measured physical activity and sedentary behaviour in before and after school care. METHODS: A systematic search was conducted in Scopus, ERIC, MEDLINE (EBSCO), PsycINFO and Web of Science databases up to December 2021. Study inclusion criteria were: written in English; from a peer-reviewed journal; data from a centre-based before and/or after school care service; children with a mean age < 13 years; an objective measure of physical activity or sedentary behaviour; reported correlations and significance levels; and if an intervention study design these correlates were reported at baseline. Study quality was assessed using the Office of Health Assessment and Translation Risk of Bias Rating Tool for Human and Animal Studies. The PRISMA guidelines informed the reporting, and data were synthesised according to shared correlations and a social ecological framework. RESULTS: Database searches identified 4559 papers, with 18 cross-sectional studies meeting the inclusion criteria.There were a total of 116 physical activity correlates and 64 sedentary behaviour correlates identified. The most frequently reported correlates of physical activity were child sex (males more active), staff engaging in physical activity, an absence of elimination games, and scheduling physical activity in daily programming (all more positively associated). The most frequently reported correlates of sedentary behaviour were child sex (females more sedentary) and age (older children more sedentary). CONCLUSIONS: Encouraging physical activity engagement of female children, promoting positive staff behaviours, removing elimination elements from games, and scheduling more time for physical activity should be priorities for service providers. Additional research is needed in before school care services.

Foods and beverages provided in out of school hours care services: an observational study.

INTRODUCTION: Out of school hours care (OSHC) is a fast-growing childcare setting in Australia, however the types of foods and beverages offered are relatively unknown. This study describes the food and beverages offered and investigates sector-level and setting-level factors which may impact OSHC in meeting the Australian Dietary Guidelines (ADG). METHODS: This cross-sectional, observational study was conducted in 89 OSHC services (between 2018 and 2019). Food and beverages offered, kitchen facilities and menus were captured via direct observation. Foods were categorised into five food groups or discretionary foods, based on the ADG, and frequencies determined. Short interviews with OSHC directors ascertained healthy eating policies, staff training, food quality assessment methods and food budgets. Fisher's exact test explored the influence of sector-level and setting-level factors on food provision behaviours. RESULTS: Discretionary foods (1.5 ± 0.68) were offered more frequently than vegetables (0.82 ± 0.80) (p < .001), dairy (0.97 ± 0.81) (p = .013) and lean meats (0.22 ± 0.54) (p < .001). OSHC associated with long day care and reported using valid food quality assessment methods offered more lean meats (p= .002, and p= .004). Larger organisations offered more vegetables (p = .015) and discretionary foods (p= .007). Menus with clearly worded instructions to provide fruits and vegetables daily offered more fruit (p= .009), vegetables (p < .001) and whole grains (p= .003). No other sector or setting-level factors were associated with services aligning with the ADG. CONCLUSION: Future interventions could benefit from trialling menu planning training and tools to assist OSHC services in NSW meet the ADG requirements.

Acceptability of, and preferences for, remote consulting during COVID-19 among older patients with two common long-term musculoskeletal conditions: findings from three qualitative studies and recommendations for practice.

BACKGROUND: Guidance for choosing face-to-face vs remote consultations (RCs) encourages clinicians to consider patient preferences, however, little is known about acceptability of, and preferences for RCs, particularly amongst patients with musculoskeletal conditions. This study aimed to explore the acceptability of, and preferences for, RC among patients with osteoporosis and rheumatoid arthritis. METHODS: Three UK qualitative studies, exploring patient experiences of accessing and receiving healthcare, undertaken during the pandemic, with people with osteoporosis and rheumatoid arthritis. Study team members agreed a consistent approach to conduct rapid deductive analysis using the Theoretical Framework of Acceptability (TFA) on transcripts from each data set relating to RC, facilitated by group meetings to discuss interpretations. Findings from the three studies were pooled. RESULTS: Findings from 1 focus group and 64 interviews with 35 people were included in the analysis. Participants' attitudes to RC, views on fairness (ethicality) and sense-making (intervention coherence) varied according to their needs within the consultation and views of the pandemic. Some participants valued the reduced burden associated with RC, while others highly valued non-verbal communication and physical examination associated with face-to-face consults (opportunity costs). Some participants described low confidence (self-efficacy) in being able to communicate in RCs and others perceived RCs as ineffective, in part due to suboptimal communication. CONCLUSIONS: Acceptability of, and preferences for RC appear to be influenced by societal, healthcare provider and personal factors and in this study, were not condition-dependant. Remote care by default has the potential to exacerbate health inequalities and needs nuanced implementation.

Estimation of Multiple Sclerosis lesion age on magnetic resonance imaging.

We introduce the first-ever statistical framework for estimating the age of Multiple Sclerosis (MS) lesions from magnetic resonance imaging (MRI). Estimating lesion age is an important step when studying the longitudinal behavior of MS lesions and can be used in applications such as studying the temporal dynamics of chronic active MS lesions. Our lesion age estimation models use first order radiomic features over a lesion derived from conventional T1 (T1w) and T2 weighted (T2w) and fluid attenuated inversion recovery (FLAIR), T1w with gadolinium contrast (T1w+c), and Quantitative Susceptibility Mapping (QSM) MRI sequences as well as demographic information. For this analysis, we have a total of 32 patients with 53 new lesions observed at 244 time points. A one or two step random forest model for lesion age is fit on a training set using a lesion volume cutoff of 15 mm3 or 50 mm3. We explore the performance of nine different modeling scenarios that included various combinations of the MRI sequences and demographic information and a one or two step random forest models, as well as simpler models that only uses the mean radiomic feature from each MRI sequence. The best performing model on a validation set is a model that uses a two-step random forest model on the radiomic features from all of the MRI sequences with demographic information using a lesion volume cutoff of 50 mm3. This model has a mean absolute error of 7.23 months (95% CI: [6.98, 13.43]) and a median absolute error of 5.98 months (95% CI: [5.26, 13.25]) in the validation set. For this model, the predicted age and actual age have a statistically significant association (p-value <0.001) in the validation set.

Physical activity in out of school hours care: an observational study.

BACKGROUND: Opportunities for physical activity within out of school hours care (OSHC) are not well documented in Australia. This study explored factors associated with children (5-12 years) meeting 30 min of moderate to vigorous physical activity (MVPA) while attending OSHC in the afternoon period. METHODS: A cross-sectional study, conducted in 89 OSHC services in New South Wales, Australia, serving 4,408 children. Each service was visited twice between 2018-2019. Physical activity promotion practices were captured via short interviews and System for Observing Staff Promotion of Physical Activity and Nutrition (SOSPAN). Physical activity spaces was measured (m2) and physical activity of 3,614 child days (42% girls), were collected using Acti-Graph accelerometers. Association between program practices and children accumulation of MVPA was tested using mixed effects logistic regression, adjusted by OSHC service and child. RESULTS: Twenty-six percent of children (n = 925) accumulated 30 min or more of MVPA. Factors associated with children reaching MVPA recommendations included: services scheduling greater amounts of child-led free play, both 30-59 min (OR 2.6, 95%CI 1.70, 3.98) and ≥ 60 min (OR 6.4, 95%CI 3.90, 10.49); opportunities for staff-led organised play of ≥ 30 min (OR 2.3, 95%CI 1.47, 3.83); and active games that engaged the majority of children (OR 1.7, 95%CI 1.11, 2.61). Children were less likely to meet MVPA recommendations if services played games with elimination components (OR 0.56, 95%CI 0.37, 0.86). CONCLUSION: Improvements to service-level physical activity promotion practices, specifically the type of physical activity scheduled and the structure of games, may be an effective strategy to increase MVPA of children attending OSHC afterschool in NSW, Australia.

Foods provided to children in family day care: an observational study.

OBJECTIVE: To assess the quality and quantity of foods and beverages provided to children aged 0-5 years in family day care and identify structural and sociodemographic factors associated with the nutritional quality of food provided. DESIGN: A cross-sectional study measured the food and beverages provided to children using weighed food records. The number of serves from different food groups was calculated according to the Australian Guide to Healthy Eating, and a healthy food provision index score was created. Associations between structural and sociodemographic factors and healthy food provision index scores were analysed using linear mixed models. SETTING: Family day care services in two large geographic areas in New South Wales, Australia. PARTICIPANTS: One hundred and four children in thirty-three family day care services. RESULTS: During attendance at childcare, most children met recommended servings of fruit but not dairy, vegetables, lean meat and meat alternatives and wholegrains. Discretionary foods exceeded recommendations. Children's age, socio-economic status and the type of main meal provided were significantly associated with the healthy food provision index score. CONCLUSIONS: Foods provided to children in family day care are aligned with dietary recommendations for fruit but not vegetables, dairy, lean meat and meat alternatives, wholegrains or discretionary foods. Interventions to promote healthy eating are needed to support families and educators to improve the nutritional quality of food provided to children.

Catalytic Synthesis of Potassium Acyltrifluoroborates (KATs) from Boronic Acids and the Thioimidate KAT Transfer Reagent.

We report the synthesis of potassium acyltrifluoroborates (KATs) by a palladium-catalyzed cross-coupling of boronic acids and the thioimidate KAT transfer reagent. The combination of widely available aryl- and vinylboronic acids with commercially available thioimidate 1 using catalytic PdII and a CuII additive enables the preparation of KATs in high yields and with good functional group tolerance. This formal insertion of CO into organoboronic acids can also be applied to boronic acid pinacol esters and potassium organotrifluoroborates using a slightly modified procedure. The cross-coupling can be telescoped into the one-pot synthesis of amides and α-aminotrifluoroborates by exploiting the unique chemistry of KATs and their trifluoroborate iminium (TIM) derivatives.

Expression of C9orf72-related dipeptides impairs motor function in a vertebrate model.

Large expansions of hexanucleotide GGGGCC (G4C2) repeats (hundreds to thousands) in the first intron of the chromosome 9 open reading frame 72 (C9orf72) locus are the strongest known genetic factor associated with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Different hypotheses exist about the underlying disease mechanism including loss of function by haploinsufficiency, toxicity arising as a result of RNA or dipeptide repeats (DPRs). Five different DPRs are produced by repeat-associated non-ATG-initiated translation of the G4C2 repeats. Though earlier studies have indicated toxicity of the DPRs in worms, flies, primary cultured cells and cell lines, the effect of expressing DPRs of amyotrophic lateral sclerosis-relevant length has not been tested on motor behaviour in vertebrate models. In this study, by expressing constructs with alternate codons encoding different lengths of each DPR (40, 200 and 1000) in the vertebrate zebrafish model, the GR DPR was found to lead to the greatest developmental lethality and morphological defects, and GA, the least. However, expressing 1000 repeats of any DPR, including the 'non-toxic' GA DPR led to locomotor defects. Based on these observations, a transgenic line stably expressing 100 GR repeats was generated to allow specific regional and temporal expression of GR repeats in vivo. Expression of GR DPRs ubiquitously resulted in severe morphological defects and reduced swimming. However, when expressed specifically in motor neurons, the developmental defects were significantly reduced, but the swimming phenotype persisted, suggesting that GR DPRs have a toxic effect on motor neuron function. This was validated by the reduction in motor neuron length even in already formed motor neurons when GR was expressed in these. Hence, the expression of C9orf72-associated DPRs can cause significant motor deficits in vertebrates.

Genetic compendium of 1511 human brains available through the UK Medical Research Council Brain Banks Network Resource.

Given the central role of genetic factors in the pathogenesis of common neurodegenerative disorders, it is critical that mechanistic studies in human tissue are interpreted in a genetically enlightened context. To address this, we performed exome sequencing and copy number variant analysis on 1511 frozen human brains with a diagnosis of Alzheimer's disease (AD, n = 289), frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS, n = 252), Creutzfeldt-Jakob disease (CJD, n = 239), Parkinson's disease (PD, n = 39), dementia with Lewy bodies (DLB, n = 58), other neurodegenerative, vascular, or neurogenetic disorders (n = 266), and controls with no significant neuropathology (n = 368). Genomic DNA was extracted from brain tissue in all cases before exome sequencing (Illumina Nextera 62 Mb capture) with variants called by FreeBayes; copy number variant (CNV) analysis (Illumina HumanOmniExpress-12 BeadChip); C9orf72 repeat expansion detection; and APOE genotyping. Established or likely pathogenic heterozygous, compound heterozygous, or homozygous variants, together with the C9orf72 hexanucleotide repeat expansions and a copy number gain of APP, were found in 61 brains. In addition to known risk alleles in 349 brains (23.9% of 1461 undergoing exome sequencing), we saw an association between rare variants in GRN and DLB. Rare CNVs were found in <1.5% of brains, including copy number gains of PRPH that were overrepresented in AD. Clinical, pathological, and genetic data are available, enabling the retrieval of specific frozen brains through the UK Medical Research Council Brain Banks Network. This allows direct access to pathological and control human brain tissue based on an individual's genetic architecture, thus enabling the functional validation of known genetic risk factors and potentially pathogenic alleles identified in future studies.

Evolutionarily conserved transcription factors drive the oxidative stress response in Drosophila.

As organisms are constantly exposed to the damaging effects of oxidative stress through both environmental exposure and internal metabolic processes, they have evolved a variety of mechanisms to cope with this stress. One such mechanism is the highly conserved p38 MAPK (p38K) pathway, which is known to be post-translationally activated in response to oxidative stress, resulting in the activation of downstream antioxidant targets. However, little is known about the role of p38K transcriptional regulation in response to oxidative stress. Therefore, we analyzed the p38K gene family across the genus Drosophila to identify conserved regulatory elements. We found that oxidative stress exposure results in increased p38K protein levels in multiple Drosophila species and is associated with increased oxidative stress resistance. We also found that the p38Kb genomic locus includes conserved AP-1 and lola-PT transcription factor consensus binding sites. Accordingly, over-expression of these transcription factors in D. melanogaster is sufficient to induce transcription of p38Kb and enhances resistance to oxidative stress. We further found that the presence of a putative lola-PT binding site in the p38Kb locus of a given species is predictive of the species' survival in response to oxidative stress. Through our comparative genomics approach, we have identified biologically relevant putative transcription factor binding sites that regulate the expression of p38Kb and are associated with resistance to oxidative stress. These findings reveal a novel mode of regulation for p38K genes and suggest that transcription may play as important a role in p38K-mediated stress responses as post-translational modifications.

Radiomic measures from chest high-resolution computed tomography associated with lung function in sarcoidosis.

INTRODUCTION: Pulmonary sarcoidosis is a rare heterogeneous lung disease of unknown aetiology, with limited treatment options. Phenotyping relies on clinical testing including visual scoring of chest radiographs. Objective radiomic measures from high-resolution computed tomography (HRCT) may provide additional information to assess disease status. As the first radiomics analysis in sarcoidosis, we investigate the potential of radiomic measures as biomarkers for sarcoidosis, by assessing 1) differences in HRCT between sarcoidosis subjects and healthy controls, 2) associations between radiomic measures and spirometry, and 3) trends between Scadding stages. METHODS: Radiomic features were computed on HRCT in three anatomical planes. Linear regression compared global radiomic features between sarcoidosis subjects (n=73) and healthy controls (n=78), and identified associations with spirometry. Spatial differences in associations across the lung were investigated using functional data analysis. A subanalysis compared radiomic features between Scadding stages. RESULTS: Global radiomic measures differed significantly between sarcoidosis subjects and controls (p<0.001 for skewness, kurtosis, fractal dimension and Geary's C), with differences in spatial radiomics most apparent in superior and lateral regions. In sarcoidosis subjects, there were significant associations between radiomic measures and spirometry, with a large association found between Geary's C and forced vital capacity (FVC) (p=0.008). Global radiomic measures differed significantly between Scadding stages (p<0.032), albeit nonlinearly, with stage IV having more extreme radiomic values. Radiomics explained 71.1% of the variability in FVC compared with 51.4% by Scadding staging alone. CONCLUSIONS: Radiomic HRCT measures objectively differentiate disease abnormalities, associate with lung function and identify trends in Scadding stage, showing promise as quantitative biomarkers for pulmonary sarcoidosis.