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Abstract Background Most Canadians receive their care in community hospitals, yet most clinical research is conducted in academic hospitals. This study aims to compare patients with community acquired pneumonia (CAP) treated in academic and community hospitals with respect to their demographics, clinical characteristics, treatments and outcomes. Methods This nested observational cohort substudy of the Community Acquired Pneumonia: Toward InnoVAtive Treatment (CAPTIVATE) trial included 1,329 hospitalized adults with CAP recruited between March 1st, 2018 and September 31st, 2023 from 15 Canadian hospitals. Unadjusted and adjusted analyses for age, sex and co-morbidities using logistic, Cox and censored quantile regressions were conducted. Results Patients in community hospitals were older (mean [SD] 75.0 [15.7] years vs. 68.3 [16.2] years; p

Abstract Background The prevention of type 2 diabetes (T2DM) is recognised as a health care priority in the UK. In people living with T2DM, lifestyle changes (e.g. increasing physical activity) have been shown to slow disease progression and protect from the development of associated comorbidities. The use of digital health technologies provides a strategy to increase physical activity in patients with chronic disease. Furthermore, behaviour economics suggests that financial incentives may be a useful strategy for increasing the maintenance and effectiveness of behaviour change intervention, including physical activity intervention using digital health technologies. The Milton Keynes Activity Rewards Programme (MKARP) is a 24-month intervention which combines the use of a mobile health app, smartwatch (Fitbit or Apple watch) and financial incentives to encourage people living with T2DM to increase physical activity to improve health. Therefore, this randomised controlled trial aims to examine the long-term acceptability, health effects and cost-effectiveness of the MKARP on HbA1c in patients living with T2DM versus a waitlist usual care comparator. Methods A two-arm, single-centre, randomised controlled trial aiming to recruit 1018 participants with follow-up at 12 and 24 months. The primary outcome is the change in HbA1c at 12 months. Secondary outcomes included changes in markers of metabolic, cardiovascular, anthropometric, and psychological health along with cost-effectiveness. Recruitment will be via annual diabetes review in general practices, retinal screening services and social media. Participants aged 18 or over, with a diagnosis of type 2 diabetes and a valid HbA1c measurement in the last 2 months are invited to take part in the trial. Participants will be individually randomised (1:1 ratio) to receive either the Milton Keynes Activity Rewards Programme or usual care. The intervention will last for 24 months with assessment for outcomes at baseline, 12 and 24 months. Discussion This study will provide new evidence of the long-term effectiveness of an activity rewards scheme focused on increasing physical activity conducted within routine care in patients living with type 2 diabetes in Milton Keynes, UK. It will also investigate the cost-effectiveness of the intervention. Trial registration ISRCTN 14925701. Registered on 30 October 2023.

Abstract Background Efficient and scalable solutions are needed to identify patients who qualify for germline cancer genetic testing. We evaluated the clinical validity of a brief, patient-administered hereditary cancer risk assessment digital tool programmed to assess if patients meet criteria for germline genetic testing, based on personal and family history, and in line with national guidelines. Methods We applied the tool to cases seen in a nationwide telehealth genetic counseling practice. Validity of the tool was evaluated by comparing the tool’s assessment to that of the genetic counselor who saw the patient. Patients’ histories were extracted from genetic counselor-collected pedigrees and input into the tool by the research team to model how a patient would complete the tool. We also validated the tool’s assessment of which specific aspects of the personal and family history met criteria for genetic testing. Descriptive statistics were used. Results Of the 152 cases (80% female, mean age 52.3), 56% had a personal history of cancer and 66% met genetic testing criteria. The tool and genetic counselor agreed in 96% of cases. Most disagreements (4/6; 67%) occurred because the genetic counselor’s assessment relied on details the tool was not programmed to collect since patients typically don’t have access to the relevant information (pathology details, risk models). We also found complete agreement between the tool and research team on which specific aspects of the patient’s history met criteria for genetic testing. Conclusion We observed a high level of agreement with genetic counselor assessments, affirming the tool’s clinical validity in identifying individuals for hereditary cancer predisposition testing and its potential for increasing access to hereditary cancer risk assessment.

Abstract Parkinson’s disease (PD) is characterized by neuroinflammation, progressive loss of dopaminergic neurons, and accumulation of α-synuclein (α-Syn) into insoluble aggregates called Lewy pathology. The Line 61 α-Syn mouse is an established preclinical model of PD; Thy-1 is used to promote human α-Syn expression, and features of sporadic PD develop at 9–18 months of age. To accelerate the PD phenotypes, we injected sonicated human α-Syn preformed fibrils (PFFs) into the striatum, which produced phospho-Syn (p-α-Syn) inclusions in the substantia nigra pars compacta and significantly increased MHC Class II-positive immune cells. Additionally, there was enhanced infiltration and activation of innate and adaptive immune cells in the midbrain. We then used this new model, Line 61-PFF, to investigate the effect of inhibiting the JAK/STAT signaling pathway, which is critical for regulation of innate and adaptive immune responses. After administration of the JAK1/2 inhibitor AZD1480, immunofluorescence staining showed a significant decrease in p-α-Syn inclusions and MHC Class II expression. Flow cytometry showed reduced infiltration of CD4+ T-cells, CD8+ T-cells, CD19+ B-cells, dendritic cells, macrophages, and endogenous microglia into the midbrain. Importantly, single-cell RNA-Sequencing analysis of CD45+ cells from the midbrain identified 9 microglia clusters, 5 monocyte/macrophage (MM) clusters, and 5 T-cell (T) clusters, in which potentially pathogenic MM4 and T3 clusters were associated with neuroinflammatory responses in Line 61-PFF mice. AZD1480 treatment reduced cell numbers and cluster-specific expression of the antigen-presentation genes H2-Eb1, H2-Aa, H2-Ab1, and Cd74 in the MM4 cluster and proinflammatory genes such as Tnf, Il1b, C1qa, and C1qc in the T3 cluster. Together, these results indicate that inhibiting the JAK/STAT pathway suppresses the activation and infiltration of innate and adaptive cells, reducing neuroinflammation in the Line 61-PFF mouse model.

Abstract Background The Multi-System Inflammatory Syndrome in Children (MIS-C) can develop several weeks after SARS-CoV-2 infection and requires a distinct treatment protocol. Distinguishing MIS-C from SARS-CoV-2 negative sepsis (SCNS) patients is important to quickly institute the correct therapies. We performed targeted proteomics and machine learning analysis to identify novel plasma proteins of MIS-C for early disease recognition. Methods A case-control study comparing the expression of 2,870 unique blood proteins in MIS-C versus SCNS patients, measured using proximity extension assays. The 2,870 proteins were reduced in number with either feature selection alone or with a prior COMBAT-Seq batch effect adjustment. The leading proteins were correlated with demographic and clinical variables. Organ system and cell type expression patterns were analyzed with Natural Language Processing (NLP). Results The cohorts were well-balanced for age and sex. Of the 2,870 unique blood proteins, 58 proteins were identified with feature selection (FDR-adjusted P

Abstract Background Sepsis is a dysregulated systemic inflammatory response triggered by infection, resulting in organ dysfunction. A major challenge in clinical pediatrics is to identify sepsis early and then quickly intervene to reduce morbidity and mortality. As blood biomarkers hold promise as early sepsis diagnostic tools, we aimed to measure a large number of blood inflammatory biomarkers from pediatric sepsis patients to determine their predictive ability, as well as their correlations with clinical variables and illness severity scores. Methods Pediatric patients that met sepsis criteria were enrolled, and clinical data and blood samples were collected. Fifty-eight inflammatory plasma biomarker concentrations were determined using immunoassays. The data were analyzed with both conventional statistics and machine learning. Results Twenty sepsis patients were enrolled (median age 13 years), with infectious pathogens identified in 75%. Vasopressors were administered to 85% of patients, while 55% received invasive ventilation and 20% were ventilated non-invasively. A total of 24 inflammatory biomarkers were significantly different between sepsis patients and age/sex-matched healthy controls. Nine biomarkers (IL-6, IL-8, MCP-1, M-CSF, IL-1RA, hyaluronan, HSP70, MMP3, and MMP10) yielded AUC parameters > 0.9 (95% CIs: 0.837-1.000; p

Abstract Background Physical inactivity is associated with feelings of burnout and fatigue, which in turn are associated with reduced performance among healthcare practitioners. This study explored movement behaviours of general practitioners (GPs) and the association between these behaviours with burnout and fatigue. Methods GPs in Northern Ireland were asked to wear a thigh-worn accelerometer for seven days and complete validated questionnaires to assess the association between daily number of steps, time spent sitting and standing with feelings of burnout and fatigue. Results Valid accelerometer data were obtained from 47 (77.0%) participants. Average workday sitting time, standing time and number of steps were 10.6 h (SD 1.5), 3.8 h (SD 1.3), and 7796 steps (SD 3116) respectively. Participants were less sedentary (8.0 h (SD 1.6)) and more active (4.7 h (SD 1.4) standing time and 12,408 steps (SD 4496)) on non-workdays. Fourteen (30.4%) participants reported burnout and sixteen (34.8%) reported severe fatigue. There were no significant associations between sitting, standing and step counts with burnout or fatigue (p > 0.05). Conclusion GPs were less active on workdays compared to non-workdays and exhibited high levels of sitting. Feelings of burnout and fatigue were highly prevalent, however movement behaviours were not found to be associated with burnout and fatigue. Given the increased sedentariness among GPs on workdays compared to non-workdays, GPs should consider how they can improve their movement behaviours on workdays to help optimise their wellbeing.

Abstract Autosomal dominant pathogenic mutations in Leucine-rich repeat kinase 2 (LRRK2) cause Parkinson’s disease (PD). The most common mutation, G2019S-LRRK2, increases the kinase activity of LRRK2 causing hyper-phosphorylation of its substrates. One of these substrates, Rab10, is phosphorylated at a conserved Thr73 residue (pRab10), and is one of the most abundant LRRK2 Rab GTPases expressed in various tissues. The involvement of Rab10 in neurodegenerative disease, including both PD and Alzheimer’s disease makes pinpointing the cellular and subcellular localization of Rab10 and pRab10 in the brain an important step in understanding its functional role, and how post-translational modifications could impact function. To establish the specificity of antibodies to the phosphorylated form of Rab10 (pRab10), Rab10 specific antisense oligonucleotides were intraventricularly injected into the brains of mice. Further, Rab10 knock out induced neurons, differentiated from human induced pluripotent stem cells were used to test the pRab10 antibody specificity. To amplify the weak immunofluorescence signal of pRab10, tyramide signal amplification was utilized. Rab10 and pRab10 were expressed in the cortex, striatum and the substantia nigra pars compacta. Immunofluorescence for pRab10 was increased in G2019S-LRRK2 knockin mice. Neurons, astrocytes, microglia and oligodendrocytes all showed Rab10 and pRab10 expression. While Rab10 colocalized with endoplasmic reticulum, lysosome and trans-Golgi network markers, pRab10 did not localize to these organelles. However, pRab10, did overlap with markers of the presynaptic terminal in both mouse and human cortex, including α-synuclein. Results from this study suggest Rab10 and pRab10 are expressed in all brain areas and cell types tested in this study, but pRab10 is enriched at the presynaptic terminal. As Rab10 is a LRRK2 kinase substrate, increased kinase activity of G2019S-LRRK2 in PD may affect Rab10 mediated membrane trafficking at the presynaptic terminal in neurons in disease.

Abstract Background People with intellectual disabilities are a marginalized group whose health experiences and outcomes are poor. Lack of skill and knowledge in the healthcare workforce is a contributing factor. In England, there is a new legislative requirement for mandatory intellectual disability training to be given to the existing healthcare workforce, including doctors. There is a lack of evidence about effective models of educational delivery of such training in medical schools. We undertook a scoping review to assess the range of intellectual disabilities educational interventions and their effectiveness. Methods We included any study from 1980 onwards which reported an educational intervention on intellectual disability, or intellectual disability and autism, for medical students from any year group. Databases searched included PUBMED, ERIC, Scopus and Web of Science as well as searches of grey literature and hand searching two journals (Medical Education and Journal of Learning Disabilities). 2,020 records were extracted, with 1,992 excluded from initial screening, and a further 12 excluded from full-text review, leaving 16 studies for inclusion. Data was extracted, quality assessed, and findings collated using narrative analysis. Results We found a variety of intervention types: classroom-based teaching, simulation, placement, home visits, and panel discussions. There was substantial variation in content. Most studies involved lived experience input. Across studies, interventions had different learning outcomes which made it difficult to assess effectiveness. Overall study quality was poor, with high use of non-validated measures, making further assessment of effectiveness problematic. Conclusions There is a need for more consistency in intervention design, and higher quality evaluation of teaching in this area. Our review has drawn attention to the variety in teaching on this topic area and further research should focus on updating this review as curriculum changes are implemented over time.

Abstract Background Standardization of post-cardiac arrest care between emergency department arrival and intensive care unit admission can be challenging, particularly for rural centers, which can experience significant delays in interfacility transfer. One approach to addressing this issue is to form a post-cardiac arrest learning community (P-CALC) consisting of emergency department (ED) and intensive care unit (ICU) physicians and nurses who use data, shared resources, and collaboration to improve post-cardiac arrest care. MaineHealth, the largest regional health system in Maine, launched its P-CALC in 2022. Objective To explore P-CALC participants’ perspectives on current post-cardiac arrest care, attitudes toward implementing a P-CALC intervention, perceived barriers and facilitators to intervention implementation, and implementation strategies. Methods We conducted semi-structured, individual, qualitative interviews with 16 staff from seven system EDs spanning the rural–urban spectrum. Directed content analysis was used to discern key themes in transcribed interviews. Results Participants highlighted site- and system-level factors influencing current post-cardiac arrest care. They expressed both positive attitudes and concerns about the P-CALC intervention. Multiple facilitators and barriers were identified in regard to the intervention implementation. Five proposed implementation strategies emerged as important factors to move the intervention forward. Conclusions Implementation of a P-CALC intervention to effect system-wide improvements in post-cardiac arrest care is complex. Understanding providers’ perspectives on current care practices, feasibility of quality improvement, and potential intervention impacts is essential for program development.

Abstract Background Peer support relates to the provision of social/emotional support that is delivered by individuals with lived experience of a key characteristic that is shared with clients. Although the main objective of peer support is to enhance client outcomes, through their involvement, peers derive a secondary benefit to their own personal development. This study applied a hybrid participatory-realist approach to identify what works, for whom, why and in what circumstances within the LOFT Transitional Age Youth (TAY) peer services. This paper presents findings related to the processes and possible benefits of being involved in peer work for the peer supporters themselves. Methods Semi-structured interviews and focus groups were completed with peer and non-peer staff from the TAY program. A qualitative analysis applied a retroductive approach that involved both inductive and deductive processes to identify relevant themes. Results Four program theories and one over-arching context were identified through the analyses. Program theories were related to: (1) enhancing self-efficacy and self-determination through peer involvement in program design, (2) increasing peer resiliency and self-care through effective supervision, (3) developing professional skills and opportunities for career advancement through peer practice and (4) overcoming stigma through the recognition of the value of peer lived experience. Conclusions Peer practice holds significant potential for the enhancement of the mental health system as well as to increase our understanding of stigma. The findings from this study offer critical new insights into the dynamics of how professional peer practice can support the personal development of youth peers and how programming can be intentionally designed to enhance these benefits.

Abstract Background Poor oral health during pregnancy has significant implications across the life course, including increased risk for adverse pregnancy, birth outcomes, and the development of early childhood caries. In efforts to improve perinatal oral health in the United States, a set of national interprofessional guidelines were developed that include recommended practice behaviors for both oral health providers and prenatal providers. The purpose of this study was to examine guideline awareness, familiarity, beliefs, and practice behaviors among both provider types. Methods Prenatal providers and oral health providers in Florida were recruited via random and convenience sampling to complete an online survey guided by the Consolidated Framework for Implementation Research (CFIR) and the Cabana Framework. The present analysis focused on the Individuals Involved domain (CFIR), awareness and familiarity with the guidelines (Cabana Framework), confidence, and practice behaviors as recommended by prenatal oral health guidelines (assess, advise, refer, share/coordinate). Data were analyzed using chi-square tests, independent samples t-tests, Pearson correlation coefficients, and one-way analysis of variance (ANOVA) and analyses were conducted in SPSS. Results Prenatal and oral health providers did not differ significantly in their awareness of the guidelines, but awareness was significantly associated with three of the four practice behaviors for prenatal providers. Familiarity with the guidelines was significantly higher among oral health providers and was associated with all four practice behaviors for both provider types. Five out of ten oral health belief items were significantly associated with practicing the guidelines among prenatal providers, but only two among oral health providers. Confidence in performing the practice behaviors was significantly associated with guideline implementation among both groups. Years in practice was significantly associated with performing practice behaviors for prenatal providers, but not for oral health providers. Conclusions Our findings highlight the importance of professional organizations and the role of clinical guidelines on practice behaviors. Although provider education is a key implementation strategy, organizational and policy-level system changes could also be critical in supporting practice behaviors.

Abstract Background The efficient production of sustainable biofuels is important for the reduction of greenhouse gas emissions. Clostridium thermocellum ATCC 27405 is a candidate for ethanol production from lignocellulosic biomass using consolidated bioprocessing. Fermentation of cellulosic biomass goes through an atypical glycolytic pathway in this thermophilic bacterium, with various glycolytic enzymes capable of utilizing different phosphate donors, including GTP and inorganic pyrophosphate (PPi), in addition to or in place of the usual ATP. C. thermocellum contains three annotated phosphofructokinases (PFK) genes, the expression of which have all been detected through proteomics and transcriptomics. Pfp (Cthe_0347) was previously characterized as pyrophosphate dependent with fructose-6-phosphate (F6P) as its substrate. Results We now demonstrate that this enzyme can also phosphorylate sedoheptulose-7-phosphate (an intermediate in the pentose phosphate pathway), with the V max and K m of F6P being approximately 15 folds higher and 43 folds lower, respectively, in comparison to sedoheptulose-7-phosphate. Purified PfkA shows preference for GTP as the phosphate donor as opposed to ATP with a 12.5-fold difference in K m values while phosphorylating F6P. Allosteric regulation is a factor at play in PfkA activity, with F6P exhibiting positive cooperativity, and an apparent requirement for ammonium ions to attain maximal activity. Phosphoenolpyruvate and PPi were the only inhibitors for PfkA determined from the study, which corroborates what is known about enzymes from this subfamily. The activation or inhibition by these ligands lends support to the argument that glycolysis is regulated by metabolites such as PPi and NH4 + in the organism. PfkB, showed no activity with F6P, but had significant activity with fructose, while utilizing either ATP or GTP, making it a fructokinase. Rounding out the upper glycolysis pathway, the identity of the fructose-1,6-bisphosphate aldolase in the genome was verified and reported to have substantial activity with fructose-1,6-bisphosphate, in the presence of the divalent ion, Zn2+. Conclusion These findings along with previous proteomic data suggest that Pfp, plays a role in both glycolysis and the pentose phosphate pathway, while PfkA and PfkB may phosphorylate sugars in glycolysis but is responsible for sugar metabolism elsewhere under conditions outside of growth on sufficient cellobiose.

Abstract Background Childhood obesity is a public health challenge in many countries. Food labelling may help children make healthier food choices. Food is typically labelled using the traffic light label system but this is complex to understand. Physical activity calorie equivalent (PACE) labelling may be easier for children to understand and more appealing because it contextualises the energy content of food/drinks. Methods A cross-sectional online questionnaire was completed by 808 adolescents aged 12–18 years in England. The questionnaire investigated participants’ views and understanding of traffic light and PACE labels. Participants were also asked about their understanding of the meaning of calories. The questionnaire explored participants’ views about the potential frequency of use of PACE labels and their perceived usefulness in influencing purchasing and consumption decisions. Questions that explored participants’ views about the possible implementation of PACE labelling, preferences for food settings and types of food/drinks they may like such labelling implemented, and whether PACE labels would encourage physical activity were included. Descriptive statistics were explored. Analyses assessed associations between variables and tested differences in the proportions of views about the labels. Results More participants reported PACE labels as easier to understand than traffic light labels (69% vs 31%). Of participants who had seen traffic light labels, 19% looked at them often/always. Forty-two percent of participants would look at PACE labels often/always. The most common reason why participants never/would never look at food labels is because they are not interested in making healthy choices. Fifty-two percent of participants said PACE labels would make it easier for them to choose healthy food and drinks. Fifty percent of participants reported PACE labels would encourage them to be physically active. It was perceived that PACE labels could be useful in a range of food settings and on a range of food/drinks. Conclusions PACE labelling may be easier for young people to understand and more appealing/useful to them than traffic light labelling. PACE labelling may help young people choose healthier food/drinks and reduce excess energy consumption. Research is now needed to understand the impact of PACE labelling on food choice among adolescents in real eating settings.

Abstract Detection of respiratory viruses requires testing of the upper respiratory tract to obtain specimens for analysis. However, nasal and throat swabs can cause discomfort and procedural anxiety in children. Respiratory sampling methods which are accurate and less invasive are needed. We aim to determine the positive and negative percentage agreement of a novel anterior nasal swab (ANS) compared with the combined throat and anterior nasal swab (CTN), the reference standard, for detection of respiratory viruses. Children 5 – 18 years of age presenting to a tertiary paediatric hospital with respiratory symptoms were tested with both swabs in randomised order. Respiratory samples were tested on a multiplex RT-PCR panel. Viral detections, RT-PCR cycle-threshold values and child/parent/clinician experience of the swab were recorded. There were 157 viral detections from 249 participant CTN swabs. In comparison with the CTN, the overall positive and negative percentage agreement of ANS for detection of respiratory viruses was 96.2% (95% CI, 91.8–98.3%) and 99.8% (95% CI, 99.6–99.9%), respectively. The ANS was “extremely comfortable”, or only a “little uncomfortable” for 90% of children compared with 48% for CTN. 202 children (84%) rated the ANS as the preferred swab, and 208 (87%) indicated they would prefer ANS for future testing. The ANS required additional laboratory handling processes compared to the CTN. The ANS has high positive percentage agreement and is comparable to the current standard of care. The high acceptability from the less invasive ANS provides a more comfortable method for respiratory virus testing in children. Trial registration ClinicalTrials.gov ID NCT05043623.

Abstract Background In many Westernised countries, children do not consume a sufficient amount of vegetables for optimal health and development. Child-feeding guidelines have been produced to address this, but often only promote offering vegetables at midday/evening meals and snack times. With guidance having limited success in increasing children’s vegetable intake at a population level, novel approaches to address this must be developed. Offering vegetables to children at breakfast time in nursery/kindergarten settings has the potential to increase children’s overall daily vegetable consumption as children typically attend nursery/kindergarten and many routinely eat breakfast there. However, the feasibility and acceptability of this intervention (Veggie Brek) to children and nursery staff has not been investigated. Methods A feasibility and acceptability cluster randomised controlled trial (RCT) was undertaken in eight UK nurseries. All nurseries engaged in one-week baseline and follow-up phases before and after an intervention/control period. Staff in intervention nurseries offered three raw carrot batons and three cucumber sticks alongside children’s main breakfast food each day for three weeks. Control nurseries offered children their usual breakfast. Feasibility was assessed by recruitment data and nursery staff's ability to follow the trial protocol. Acceptability was assessed by children’s willingness to eat the vegetables at breakfast time. All primary outcomes were assessed against traffic-light progression criteria. Staff preference for collecting data via photographs versus using paper was also assessed. Further views about the intervention were obtained through semi-structured interviews with nursery staff. Results The recruitment of parents/caregivers willing to provide consent for eligible children was acceptable at 67.8% (within the amber stop–go criterion) with 351 children taking part across eight nurseries. Both the feasibility and acceptability of the intervention to nursery staff and the willingness of children to consume the vegetables met the green stop–go criteria, with children eating some part of the vegetables in 62.4% (745/1194) of instances where vegetables were offered. Additionally, staff preferred reporting data using paper compared to taking photographs. Conclusions Offering vegetables to children at breakfast time in nursery/kindergarten settings is feasible and acceptable to children and nursery staff. A full intervention evaluation should be explored via a definitive RCT. Trial registration NCT05217550.

Abstract Background Many people do not regularly participate in physical activity, which may negatively impact their health. Current physical activity guidelines are focused on promoting weekly accumulation of at least 150 min of moderate to vigorous intensity physical activity (MVPA). Whilst revised guidance now recognises the importance of making small changes to physical activity behaviour, guidance still focuses on adults needing to achieve at least 150 min of MVPA per week. An alternative ‘whole day’ approach that could motivate the public to be more physically active, is a concept called Snacktivity™. Instead of focusing on achieving 150 min per week of physical activity, for example 30 min of MVPA over 5 days, Snacktivity™ encourages the public to achieve this through small, but frequent, 2–5 min ‘snacks’ of MVPA throughout the whole day. Methods The primary aim is to undertake a feasibility trial with nested qualitative interviews to assess the feasibility and acceptability of the Snacktivity™ intervention to inform the design of a subsequent phase III randomised trial. A two-arm randomised controlled feasibility trial aiming to recruit 80 inactive adults will be conducted. Recruitment will be from health and community settings and social media. Participants will be individually randomised (1:1 ratio) to receive either the Snacktivity™ intervention or usual care. The intervention will last 12 weeks with assessment of outcomes completed before and after the intervention in all participants. We are interested in whether the Snacktivity™ trial is appealing to participants (assessed by the recruitment rate) and if the Snacktivity™ intervention and trial methods are acceptable to participants (assessed by Snacktivity™/physical activity adherence and retention rates). The intervention will be delivered by health care providers within health care consultations or by researchers. Participants’ experiences of the trial and intervention, and health care providers’ views of delivering the intervention within health consultations will be explored. Discussion The development of physical activity interventions that can be delivered at scale are needed. The findings from this study will inform the viability and design of a phase III trial to assess the effectiveness and cost-effectiveness of Snacktivity™ to increase physical activity. Trial registration ISRCTN: 64851242.

Abstract Background Survivors of acute COVID-19 often suffer prolonged, diffuse symptoms post-infection, referred to as “Long-COVID”. A lack of Long-COVID biomarkers and pathophysiological mechanisms limits effective diagnosis, treatment and disease surveillance. We performed targeted proteomics and machine learning analyses to identify novel blood biomarkers of Long-COVID. Methods A case–control study comparing the expression of 2925 unique blood proteins in Long-COVID outpatients versus COVID-19 inpatients and healthy control subjects. Targeted proteomics was accomplished with proximity extension assays, and machine learning was used to identify the most important proteins for identifying Long-COVID patients. Organ system and cell type expression patterns were identified with Natural Language Processing (NLP) of the UniProt Knowledgebase. Results Machine learning analysis identified 119 relevant proteins for differentiating Long-COVID outpatients (Bonferonni corrected P

Abstract Background Stigma associated with mental health challenges is a major barrier to service seeking among youth. Understanding how stigma impacts service-seeking decisions from the perspectives of youth remains underexplored. Such research is necessary to inform effective stigma reduction. Objective This study aims to understand how stigma influences service seeking among youth with mental health challenges. Methods Qualitative inquiry was taken using youth engagement, underpinned by pragmatism. Data were collected via 4 virtual focus groups with 22 purposively selected youth participants with lived experience of mental health challenges in Ontario, Canada. Focus group guides were developed collaboratively among research team members, including youth co-researchers. Data were analyzed inductively using reflexive thematic analysis. Results Three main themes were constructed from the data: point of entry into the system, being biomedicalized or trivialized, and paving the way for non-stigmatizing services. Initial contact with the mental healthcare system was seen to be affected by stigma, causing participants to delay contact or be refused services if they do not fit with an expected profile. Participants described a constant negotiation between feeling ‘sick enough’ and ‘not sick enough’ to receive services. Once participants accessed services, they perceived the biomedicalization or trivialization of their challenges to be driven by stigma. Lastly, participants reflected on changes needed to reduce stigma’s effects on seeking and obtaining services. Conclusion A constant negotiation between being ‘sick enough’ or ‘not sick enough’ is a key component of stigma from the perspectives of youth. This tension influences youth decisions about whether to seek services, but also service provider decisions about whether to offer services. Building awareness around the invisibility of mental health challenges and the continuum of wellness to illness may help to break down stigma’s impact as a barrier to service seeking. Early intervention models of care that propose services across the spectrum of challenges may prevent the sense of stigma that deters youth from accessing and continuing to access services.

Abstract Background Hyaluronic acid (HA) promotes cancer metastasis; however, the currently approved treatments do not target HA. Metastatic renal carcinoma (mRCC) is an incurable disease. Sorafenib (SF) is a modestly effective antiangiogenic drug for mRCC. Although only endothelial cells express known SF targets, SF is cytotoxic to RCC cells at concentrations higher than the pharmacological-dose (5-µM). Using patient cohorts, mRCC models, and SF combination with 4-methylumbelliferone (MU), we discovered an SF target in RCC cells and targeted it for treatment. Methods We analyzed HA-synthase (HAS1, HAS2, HAS3) expression in RCC cells and clinical (n = 129), TCGA-KIRC (n = 542), and TCGA-KIRP (n = 291) cohorts. We evaluated the efficacy of SF and SF plus MU combination in RCC cells, HAS3-transfectants, endothelial-RCC co-cultures, and xenografts. Results RCC cells showed increased HAS3 expression. In the clinical and TCGA-KIRC/TCGA-KIRP cohorts, higher HAS3 levels predicted metastasis and shorter survival. At > 10-µM dose, SF inhibited HAS3/HA-synthesis and RCC cell growth. However, at ≤ 5-µM dose SF in combination with MU inhibited HAS3/HA synthesis, growth of RCC cells and endothelial-RCC co-cultures, and induced apoptosis. The combination inhibited motility/invasion and an HA-signaling-related invasive-signature. We previously showed that MU inhibits SF inactivation in RCC cells. While HAS3-knockdown transfectants were sensitive to SF, ectopic-HAS3-expression induced resistance to the combination. In RCC models, the combination inhibited tumor growth and metastasis with little toxicity; however, ectopic-HAS3-expressing tumors were resistant. Conclusion HAS3 is the first known target of SF in RCC cells. In combination with MU (human equivalent-dose, 0.6–1.1-g/day), SF targets HAS3 and effectively abrogates mRCC.

Abstract Background Children referred for attention-deficit/hyperactivity disorder (ADHD) often present with a broader pattern of conduct problems including oppositionality and defiance. This combination can be extremely stressful to parents, lower parents’ self-esteem and negatively impact family life. The National Institute for Health and Care Excellence (NICE) recommends that families receive support as soon as possible after their referral. However, as clinical services are overstretched, and traditional in-person parenting intervention programmes are expensive, families often must wait times a long time prior to receiving this vital input. To address this, we have created a digital parenting programme called STEPS. It is delivered as a mobile phone app providing a set of tools and resources that can be easily accessed at parents’ convenience. This study aims to evaluate the clinical and cost-effectiveness of STEPS in supporting parents of children with high levels of hyperactivity/impulsivity, inattention and conduct problems, who are waiting to be assessed by specialist children’s clinical services. Methods Online Parent Training for The Initial Management of ADHD referrals (OPTIMA) is a two-arm superiority parallel randomised controlled trial with an internal pilot study. We aim to recruit 352 parents and their children, who have been accepted onto a waitlist in Child and Adolescent Mental Health Services or similar child health services. Parents who consent will be randomised 1:1 to either the STEPS or wait-as-usual (WAU) group. The trial will be conducted remotely (online and telephone) with measures taken at baseline and 3, 6, 9 and 12 months post-randomisation. The primary objective is to evaluate whether STEPS reduces the severity of children’s oppositional and defiant behaviour, as rated by parents, measured at 3 months post-randomisation compared to WAU. Discussion Digital solutions, such as mobile phone apps, have potential for delivering psychological support for parents of children with clinical-level needs in a timely and inexpensive manner. This trial will provide data on the clinical and cost-effectiveness of the STEPS app, which could support the implementation of this scalable parenting intervention programme into standard clinical care and, ultimately, improve the outcomes for families of children referred to specialist child and adolescent health services. Trial registration ISRCTN 16523503. Prospectively registered on 18 November 2021. https://www.isrctn.com/ISRCTN16523503

Abstract Background Interventions that provide pregnant women with opportunities to access and participate in physical activity have been shown to be beneficial to their health. Much of this evidence however has been based on self-reported physical activity data, which may be prone to inflated effects due to recall bias and social desirability bias. No previous synthesis of randomised controlled trials has assessed the effectiveness of these interventions using only device measured data, to assess their health benefits more accurately in pregnant women. This systematic review and meta-analysis aimed to address this evidence gap. Data sources Cochrane Central Register of Controlled Trials, Medline, SportDiscus, APA PsycINFO, Embase and Web of Science databases were queried from inception up to December 2, 2021. An updated search of PubMed was conducted on May 16, 2022. Study eligibility criteria Randomised controlled trials that recruited pregnant women, participating in any physical activity intervention (excluding interventions aimed entirely at body conditioning), compared with standard antenatal care (comparators), using device-measured total physical activity as an outcome were eligible for inclusion. Methods 3144 titles and abstracts were screened for eligibility, and 18 met the inclusion criteria. Data were analysed using random effect models, (standardised mean difference and mean difference), using data from baseline to last available follow-up (primary end point), and until between 24 to 30 weeks gestation. Gestational weight gain was also assessed at these timepoints in the included trials. Results No significant differences between the groups were found for total physical activity at last available follow-up or 24 to 30 weeks gestation (95% CI 0.03 to 0.27, p = 0.10: 95% CI -0.05 to 0.33, p = 0.15) respectively. On average, pregnant women randomised to a physical activity intervention completed 435 and 449 more steps per day than comparators at last available follow-up and at 24 to 30 weeks gestation (95% CI -0.5-870.6, p = 0.05: 95% CI 5.5-892.7, p = 0.05) respectively. Intervention participants also gained 0.69 kg less (95% CI -1.30 to -0.08, p = 0.03) weight than comparators. Conclusion Based on device-measured data, interventions to promote physical activity during pregnancy have small but important effects on increasing physical activity and managing excessive gestational weight gain.

Abstract Background Pregnancy presents an opportune time for oral health promotion and intervention; however, implementation of the prenatal oral health guidelines remains a challenge among prenatal and oral health providers. The purpose of this study was twofold: To employ a theory-based approach to identify high-priority Consolidated Framework for Implementation Research (CFIR) constructs with the greatest potential to impact prenatal oral health guideline implementation, and to operationalize and pre-test survey items based on the prioritized CFIR constructs. Identifying barriers and facilitators to guideline implementation will inform the development of targeted interventions that address gaps in adherence which can positively impact oral-systemic health. Methods The online survey development process employed three rounds of a modified-Delphi technique with prenatal (i.e., MD/DO, CNM) and oral health (i.e., DMD) Practice Advisory Board Members, cognitive interviews with prenatal and oral health providers, and deliberations among the research team and a Scientific Advisory Board (OBGYN, pediatric dentist, and researchers). High-impact CFIR constructs were identified and translated into survey items that were subsequently piloted and finalized. Results During three modified-Delphi rounds, a total of 39 CFIR constructs were evaluated with final input and deliberations with the Practice Advisory Board, Scientific Advisory Board, and the research team achieving consensus on 19 constructs. The instrument was pre-tested with four prenatal and two oral health providers. Overall, participants reported that the survey items were feasible to respond to, took an appropriate length of time to complete, and were well-organized. Participants identified specific areas of improvement to clarify CFIR items. The final survey instrument included 21 CFIR items across four domains, with five constructs included from the intervention characteristics domain, two from the process domain, two from the outer setting domain, and 12 from the inner setting domain. Conclusions Lessons learned from the survey development process include the importance of soliciting diverse scientific and practice-based input, distinguishing between importance/impact and direction of impact (barrier/facilitator), and the need for additional qualitative methods during interdisciplinary collaborations. Overall, this study illustrated an iterative approach to identifying high-priority CFIR constructs that may influence the implementation of the prenatal oral health guidelines into practice settings.

Abstract Background Youth peer support, as a practice that aligns youth engagement and participatory approaches, has become increasingly popular in the context of youth mental health services. However, there is a need for more evidence that describes how and why youth peer support practice might be effective. This study was designed to examine a peer support service for youth experiencing complex challenges with mental health, physical health and/or substance use to better understand key features and underlying mechanisms that lead to improved client outcomes. Methods We applied a hybrid realist-participatory approach to explore key issues and underlying theoretical assumptions within a youth peer support approach for young people (age 14–26) experiencing complex mental health and substance use challenges. We used semi-structured interviews and focus groups with staff, including peers (N = 8), clinical service providers and administrative staff (N = 15), to develop the theories and a client survey to validate them. Our qualitative thematic analysis applied a retroductive approach that involved both inductive and deductive processes. For the client survey (N = 77), we calculated descriptive statistics to examine participant profiles and usage patterns. Pearson correlations were examined to determine relationships among concepts outlined in the program theories, including context, mechanism and outcome variables. Results Our analyses resulted in one over-arching context, one over-arching outcome and four program theories. Program theories were focused on mechanisms related to 1) positive identity development through identification with peers, 2) enhanced social connections, 3) observational learning and 4) enhanced autonomy and empowerment. Conclusions This study serves as a unique example of a participatory-realist hybrid approach. Findings highlight possible key components of youth peer practice and shed light on the functional mechanisms that underlie successful peer practice. These key components can be examined in other settings to develop more comprehensive theories of change with respect to youth peer support and can eventually be used to develop guidelines and standards to strengthen practice. This research contributes to an expanding body of literature on youth peer support in mental health and connects peer practice with several social theories. This research begins to lay a foundation for enhanced youth peer support program design and improved outcomes for young people experiencing complex mental health and substance use challenges.

Abstract Background Since its introduction to the Anglophone Caribbean in 1793, breadfruit has had a diverse history in the region, and there is a considerable repository of traditional knowledge about the crop, that is undocumented. Consequently, it remains underutilized as a food source, despite recognition of its potential to contribute to food and nutrition security. Understanding the folk taxonomy and traditional knowledge associated with its diversity and uses is a prerequisite to develop programs for its commercial production and utilization. Method This study was conducted among 170 respondents who were selected across four Anglophone Caribbean countries and provided information on the ethnobotany and traditional knowledge associated with breadfruit biodiversity, including systems of naming, identification and classification of breadfruit cultivars or types. Results Breadfruit has socio-cultural and economic value and is produced for both home use and sale by most respondents (68%). The genetic diversity of breadfruit managed by the respondents is also important, as a total of 51 vernacular names were identified, with nine of those names recorded for the first time in this study. Breadfruit types were identified by morphological and agronomical characteristics, with other important traits relating to use and cooking quality. Classification of breadfruit cultivars or types was based on eating-quality, most suitable methods of preparation and ease of cooking. Conclusion The ethnobotanical and traditional knowledge obtained from this study may be useful in assessing the genetic diversity of breadfruit and guiding future community-based conservation and classification studies of this important crop resource in the Caribbean. This is crucial to support the commercialization of breadfruit to improve its contribution to food and nutrition security.

Abstract Background Long-COVID is characterized by prolonged, diffuse symptoms months after acute COVID-19. Accurate diagnosis and targeted therapies for Long-COVID are lacking. We investigated vascular transformation biomarkers in Long-COVID patients. Methods A case–control study utilizing Long-COVID patients, one to six months (median 98.5 days) post-infection, with multiplex immunoassay measurement of sixteen blood biomarkers of vascular transformation, including ANG-1, P-SEL, MMP-1, VE-Cad, Syn-1, Endoglin, PECAM-1, VEGF-A, ICAM-1, VLA-4, E-SEL, thrombomodulin, VEGF-R2, VEGF-R3, VCAM-1 and VEGF-D. Results Fourteen vasculature transformation blood biomarkers were significantly elevated in Long-COVID outpatients, versus acutely ill COVID-19 inpatients and healthy controls subjects (P

Abstract Background Taking advantage of the rapidly increasing access to digital technology in low- and middle-income countries, the World Health Organization has launched an electronic version of the mental health Gap Action Programme intervention guide (emhGAP-IG). This is suitable for use on smartphones or tablets by non-specialist primary healthcare providers (PHCWs) to deliver evidence-based intervention for priority mental, neurological and substance use disorders. We assessed the perceptions of PHCWs on the feasibility, acceptability, and benefits of using smartphone-based clinical guidance and the emhGAP-IG in the management of people with mental health conditions in Nigeria. Methods Exploration of the views of PHCWs from 12 rural and urban primary health clinics (PHCs) in South-Western Nigeria were carried out using 34 in-depth key informant qualitative interviews with nurses (n = 10), community health officers (n = 13) and community health extension workers (n = 11). An additional two focus group discussions, each comprising eight participants drawn from across the range of characteristics of PHCWs, were also conducted. Thematic analysis was conducted using a three-staged constant comparison technique to refine and categorise the data. Results Three overall themes were identified around the use of clinical guidance and mobile applications (apps) in PHCs. Apps were deployed for purposes other than clinical consultation and decision making. Although paper-based guidance was the expected practice, its utilization is not fully embedded in routine care. An app-based decision-making tool was preferred to paper by PHCWs. Future usage of the emhGAP-IG would be facilitated by training and supporting of staff, helpful design features, and obtaining patients’ buy-in. Conclusion Our findings suggest that the emhGAP-IG could be a viable way to embed clinical guidance and decision-making tools in the management of people with mental health conditions in Nigerian PHCs.

Abstract Background Fluticasone furoate/vilanterol trifenatate (FF/VI) is an inhaled therapy for the treatment of asthma, with a prolonged duration of anti-inflammatory and bronchodilatory action. This study investigated the global metabolomic and lipidomic profile following treatment with FF/VI or placebo and assessed whether changes correlated with exhaled nitric oxide levels as a measure of airway inflammation. Methods This was a single-center, randomized, double-blind, placebo-controlled, two-period, crossover, repeat-dose study. Adults with asthma (forced expiratory volume in 1 s ≥ 60% predicted; fraction of exhaled nitric oxide [FeNO] > 40 parts per billion) received once-daily FF/VI 100 µg/25 µg or placebo for 14 days, followed by a 21-day washout period. Serum samples were taken at pre-dose (T1), and 15 and 21 days (T2 and T3, respectively) post dose in each period. The metabolomic and lipidomic profiles were analyzed by liquid chromatography with tandem mass spectrometry and polar liquid chromatography platforms, and ions were matched to a library of standards for metabolite identification and quantification. FeNO values at each timepoint were evaluated for correlations with the biochemical data. Results Of 27 randomized participants (mean age 24.5 years, 63% male), 26 provided serum samples for metabolomic analysis. A total of 1969 metabolites were identified, 1634 of which corresponded to a named structure in a reference library. Treatment-related changes in the metabolome were generally subtle, with a modest increase in metabolite perturbations across timepoints. The percentage of metabolites with significant changes (p

Abstract Background To report a case of a subretinal, unilateral, peripapillary granuloma that was diagnosed as sarcoidosis by a 27-gauge pars plana vitrectomy subretinal biopsy. Sarcoidosis is a chronic idiopathic granulomatous inflammatory disease, that has ocular involvement in 10–80% of patients. It is often mistaken for many other primary ocular diseases because the condition can involve any structure in or around the eye. Previous case reports of peripapillary sarcoidosis have either been limited to the choroid or presented with additional ocular and systemic signs, hence have not required an intraocular biopsy. Case presentation A 54-year-old Filipino male presented with a 6-month history of painless blurred vision in his right eye. Fundus examination revealed a large white peripapillary lesion. Enhanced-depth imaging optical coherence tomography confirmed the subretinal location of the mass. Indocyanine green angiography demonstrated absolute hypofluorescent blockage with satellite lesions. A whole-body positron emission tomography scan demonstrated widespread lymphadenopathy, but investigations including an inguinal lymph node biopsy were inconclusive. Following growth of the peripapillary lesion and worsening vision, a 27-gauge pars plana vitrectomy subretinal biopsy was performed which confirmed sarcoidosis. He was treated with oral corticosteroids and transitioned to long term immunotherapy with methotrexate. Conclusions Sarcoidosis can present in the subretinal space, around the optic nerve without other ocular findings.

Abstract Background Healthcare-associated infections (HAI) are one of significant causes of morbidity and mortality. Evaluating risk factors associated with HAI are important to improve clinical outcomes. We aimed to evaluate the risk factors of HAI in children in a low-to middle-income country. Methods A prospective cohort study was conducted during 43 months at a teaching hospital in Yogyakarta, Indonesia. All consecutive patients admitted to pediatric ICU and pediatric wards > 48 h were eligible. Those eligible patients were observed daily to identify the presence of HAI based on CDC criteria. The risk factors of HAI were identified. Multivariable logistic regression was used to identify independent risk factors. Results Total of 2612 patients were recruited. Of 467 were diagnosed as HAI. The cumulative incidence of HAI was 17.9%. In the multivariable analysis; length of stay > 7 days, severe sepsis, use of urine catheter, central venous catheter (CVC), non-standardized antibiotics, and aged 7 days, use of urine catheter and CVC, non-standardized antibiotic use, aged

Abstract Background Many people do not meet the recommended health guidance of participation in a minimum of 150–300 min of moderate intensity physical activity per week, often promoted as at least 30 min of physical activity on 5 days of the week. This is concerning and highlights the importance of finding innovative ways to help people to be physically active each day. Snacktivity™ is a novel approach that aims to encourage people to do small, 2–5 min bouts of physical activity ‘snacks’ throughout the whole day, such that they achieve at least 150 min of moderate intensity activity per week. However, before it can be recommended, there is a need to explore whether the concept is acceptable to the public. Methods A survey to assess the views of the public about Snacktivity™ was distributed to adult patients registered at six general practices in the West Midlands, UK and to health care employees in the same region. Results A total of 5989 surveys were sent to patients, of which 558 were returned (9.3%). A further 166 surveys were completed by health care employees. A total of 85% of respondents liked the Snacktivity™ concept. The flexibility of the approach was highly rated. A high proportion of participants (61%) reported that the ability to self-monitor their behaviour would help them to do Snacktivity™ throughout their day. Physically inactive participants perceived that Snacktivity™ would help to increase their physical activity, more than those who were physically active (OR = 0.41, 95% CI: 0.25–0.67). Approximately 90% of respondents perceived that Snacktivity™ was easy to do on a non-working day compared to 60% on a working day. Aerobic activity ‘snacks’ were preferred to those which were strength based. Conclusions The Snacktivity™ approach to promoting physical activity was viewed positively by the public and interventions to test the merits of such an approach now need to be developed and tested in a variety of everyday contexts.

Abstract Background Imaging features obtained with Fourier-domain optical coherence tomography (FD-OCT) and in vivo confocal microscopy (IVCM) for corneal stromal disorders have been sparsely reported in dogs. This case report is a compilation of imaging features for three cases of different stromal disorders of the canine cornea which have not yet been reported elsewhere. Case presentation Lipid deposition in case 1 appeared as needle-shaped hyperreflective lines along the collagen lamellae, which correlated histologically with lipid clefts. In case 2, glycosaminoglycan accumulation by mucopolysaccharidosis type 1 caused diffuse stromal hyperreflectivity and depletion of keratocytes on IVCM and was associated with secondary corneal degeneration presumed to be calcium deposition. In case 3, posterior corneal stromal opacities in the absence of ocular inflammation were identified. Hyperreflective particles were scattered in the middle and posterior corneal stroma on FD-OCT. With IVCM, hyperreflective deposits were identified within keratocytes and the number of enlarged keratocytes containing hyperreflective deposits increased towards the posterior stroma. The bilateral, non-inflammatory nature and unique appearance with IVCM is most consistent with a posterior stromal dystrophy reminiscent of pre-Descemet corneal dystrophy described in humans. Conclusions In vivo multimodal corneal imaging facilitated instantaneous microstructural analysis and may be valuable in the differential diagnosis of corneal stromal disorders in veterinary clinical practice. The non-specific nature of imaging findings occurs in some conditions such as mucopolysaccharidosis, thus in vivo corneal imaging should be complemented with other gold standard methods of definitive diagnosis.

Abstract Background Cerebrospinal fluid (CSF) tau and beta-amyloid levels in chronic traumatic encephalopathy (CTE), a disease which can be clinically indistinguishable from Alzheimer’s disease (AD), are largely unknown. We examined postmortem CSF analytes among participants with autopsy confirmed CTE and AD. Methods In this cross-sectional study 192 participants from the Boston University AD Research Center, VA-BU-CLF Center, and Framingham Heart Study (FHS) had post-mortem CSF collected at autopsy. Participants were divided into pathological groups based on AD and CTE criteria, with 61 CTE participants (18 low, 43 high stage), 79 AD participants (23 low, 56 intermediate to high), 11 participants with CTE combined with AD, and 41 participants lacking both CTE and AD neuropathology. The Meso Scale Discovery immunoassay system was utilized to measure amyloid-beta (Aβ1-40, Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau181 and p-tau231). CSF analytes were then compared across the pathological groups: no CTE/no AD (control), Low CTE, Low AD, High CTE, Intermediate/High AD, and AD+CTE. Results Among the Low disease state groups, the Low CTE group had significantly higher levels of p-tau231 versus the control group and compared to the Low AD group. The Low CTE group was also found to have significantly lower levels of Aβ1-42 compared to the control group. The high CTE group had higher levels of p-tau231 and lower levels of Aβ1-42 compared to Intermediate/High AD group. Conclusions Importantly, p-tau231 and Aβ1-42 were predictors of diagnosis of CTE vs. control and CTE vs. AD. Increased CSF p-tau231 is a promising potentially sensitive biomarker of CTE, and CSF Aβ1-42 needs further investigation in CTE.

Abstract Background In the UK, children with high levels of hyperactivity, impulsivity and inattention referred to clinical services with possible attention-deficit/hyperactivity disorder (ADHD) often wait a long time for specialist diagnostic assessment. Parent training (PT) has the potential to support parents during this difficult period, especially regarding the management of challenging and disruptive behaviours that often accompany ADHD. However, traditional face-to-face PT is costly and difficult to organise in a timely way. We have created a low-cost, easily accessible PT programme delivered via a phone app, Structured E-Parenting Support (STEPS), to address this problem. The overall OPTIMA programme will evaluate the efficacy and cost-effectiveness of STEPS as a way of helping parents manage their children behaviour while on the waitlist. To ensure the timely and efficient evaluation of STEPS in OPTIMA, we have worked with children’s health services to implement a remote strategy for recruitment, screening and assessment of recently referred families. Part of this strategy is incorporated into routine clinical practice and part is OPTIMA specific. Here, we present the protocol for Phase 1 of OPTIMA—a study of the feasibility of this remote strategy, as a basis for a large-scale STEPS randomised controlled trial (RCT). Methods This is a single arm observational feasibility study. Participants will be parents of up to 100 children aged 5-11 years with high levels of hyperactivity/impulsivity, inattention and challenging behaviour who are waiting for assessment in one of five UK child and adolescent mental health or behavioural services. Recruitment, consenting and data collection will occur remotely. The primary outcome will be the rate at which the families, who meet inclusion criteria, agree in principle to take part in a full STEPS RCT. Secondary outcomes include acceptability of remote consenting and online data collection procedures; the feasibility of collecting teacher data remotely within the required timeframe, and technical difficulties with completing online questionnaires. All parents in the study will receive access to STEPS. Discussion Establishing the feasibility of our remote recruitment, consenting and assessment strategy is a pre-requisite for the full trial of OPTIMA. It can also provide a model for future trials conducted remotely.

Abstract Background Infective endocarditis (IE) caused by Streptococcus agalactiae (GBS) is increasingly reported and associated with an aggressive course and high mortality rate. Existing literature on GBS IE is limited to case series; we compared the characteristics of patients with GBS IE to patients with GBS bacteremia without IE to identify risk factors for development of IE. Methods A nested case–control study in a cohort of adult patients with GBS bacteremia over a 18-year period was conducted across seven centres in three Canadian cities. A chart review identified patients with possible or definite IE (per Modified Duke Criteria) and patients with IE were matched to those without endocarditis in a 1:3 fashion. Multivariate analyses were completed using logistic regression. Results Of 520 patients with GBS bacteremia, 28 cases of possible or definite IE were identified (5.4%). 68% (19/28) met criteria for definite IE, surgery was performed in 29% (8/28), and the overall in-hospital mortality rate was 29% (8/28). Multivariate analysis demonstrated that IE was associated with injection drug use (OR = 19.6, 95% CI = 3.39–111.11, p = 0.001), prosthetic valve (OR = 11.5, 95% CI = 1.73–76.92, p = 0.011) and lack of identified source of bacteremia (OR = 3.81, 95% CI = 1.24–11.65, p = 0.019). Conclusions GBS bacteremia, especially amongst people who inject drugs, those with prosthetic valves, and those with no apparent source of infection, should increase clinical suspicion for IE.

Abstract Background Leucine rich repeat kinase 2 (LRRK2) and SNCA are genetically linked to late-onset Parkinson’s disease (PD). Aggregated α-synuclein pathologically defines PD. Recent studies identified elevated LRRK2 expression in pro-inflammatory CD16+ monocytes in idiopathic PD, as well as increased phosphorylation of the LRRK2 kinase substrate Rab10 in monocytes in some LRRK2 mutation carriers. Brain-engrafting pro-inflammatory monocytes have been implicated in dopaminergic neurodegeneration in PD models. Here we examine how α-synuclein and LRRK2 interact in monocytes and subsequent neuroinflammatory responses. Methods Human and mouse monocytes were differentiated to distinct transcriptional states resembling macrophages, dendritic cells, or microglia, and exposed to well-characterized human or mouse α-synuclein fibrils. LRRK2 expression and LRRK2-dependent Rab10 phosphorylation were measured with monoclonal antibodies, and myeloid cell responses to α-synuclein fibrils in R1441C-Lrrk2 knock-in mice or G2019S-Lrrk2 BAC mice were evaluated by flow cytometry. Chemotaxis assays were performed with monocyte-derived macrophages stimulated with α-synuclein fibrils and microglia in Boyden chambers. Results α-synuclein fibrils robustly stimulate LRRK2 and Rab10 phosphorylation in human and mouse macrophages and dendritic-like cells. In these cells, α-synuclein fibrils stimulate LRRK2 through JAK-STAT activation and intrinsic LRRK2 kinase activity in a feed-forward pathway that upregulates phosphorylated Rab10. In contrast, LRRK2 expression and Rab10 phosphorylation are both suppressed in microglia-like cells that are otherwise highly responsive to α-synuclein fibrils. Corroborating these results, LRRK2 expression in the brain parenchyma occurs in pro-inflammatory monocytes infiltrating from the periphery, distinct from brain-resident microglia. Mice expressing pathogenic LRRK2 mutations G2019S or R1441C have increased numbers of infiltrating pro-inflammatory monocytes in acute response to α-synuclein fibrils. In primary cultured macrophages, LRRK2 kinase inhibition dampens α-synuclein fibril and microglia-stimulated chemotaxis. Conclusions Pathologic α-synuclein activates LRRK2 expression and kinase activity in monocytes and induces their recruitment to the brain. These results predict that LRRK2 kinase inhibition may attenuate damaging pro-inflammatory monocyte responses in the brain.

Abstract Pathologic inclusions composed of α-synuclein called Lewy pathology are hallmarks of Parkinson’s Disease (PD). Dominant inherited mutations in leucine rich repeat kinase 2 (LRRK2) are the most common genetic cause of PD. Lewy pathology is found in the majority of individuals with LRRK2-PD, particularly those with the G2019S-LRRK2 mutation. Lewy pathology in LRRK2-PD associates with increased non-motor symptoms such as cognitive deficits, anxiety, and orthostatic hypotension. Thus, understanding the relationship between LRRK2 and α-synuclein could be important for determining the mechanisms of non-motor symptoms. In PD models, expression of mutant LRRK2 reduces membrane localization of α-synuclein, and enhances formation of pathologic α-synuclein, particularly when synaptic activity is increased. α-Synuclein and LRRK2 both localize to the presynaptic terminal. LRRK2 plays a role in membrane traffic, including axonal transport, and therefore may influence α-synuclein synaptic localization. This study shows that LRRK2 kinase activity influences α-synuclein targeting to the presynaptic terminal. We used the selective LRRK2 kinase inhibitors, MLi-2 and PF-06685360 (PF-360) to determine the impact of reduced LRRK2 kinase activity on presynaptic localization of α-synuclein. Expansion microscopy (ExM) in primary hippocampal cultures and the mouse striatum, in vivo, was used to more precisely resolve the presynaptic localization of α-synuclein. Live imaging of axonal transport of α-synuclein-GFP was used to investigate the impact of LRRK2 kinase inhibition on α-synuclein axonal transport towards the presynaptic terminal. Reduced LRRK2 kinase activity increases α-synuclein overlap with presynaptic markers in primary neurons, and increases anterograde axonal transport of α-synuclein-GFP. In vivo, LRRK2 inhibition increases α-synuclein overlap with glutamatergic, cortico-striatal terminals, and dopaminergic nigral-striatal presynaptic terminals. The findings suggest that LRRK2 kinase activity plays a role in axonal transport, and presynaptic targeting of α-synuclein. These data provide potential mechanisms by which LRRK2-mediated perturbations of α-synuclein localization could cause pathology in both LRRK2-PD, and idiopathic PD.

Abstract Background Insights from behavioral economics, or how individuals’ decisions and behaviors are shaped by finite cognitive resources (e.g., time, attention) and mental heuristics, have been underutilized in efforts to increase the use of evidence-based practices in implementation science. Using the example of firearm safety promotion in pediatric primary care, which addresses an evidence-to-practice gap in universal suicide prevention, we aim to determine: is a less costly and more scalable behavioral economic-informed implementation strategy (i.e., “Nudge”) powerful enough to change clinician behavior or is a more intensive and expensive facilitation strategy needed to overcome implementation barriers? Methods The Adolescent and child Suicide Prevention in Routine clinical Encounters (ASPIRE) hybrid type III effectiveness-implementation trial uses a longitudinal cluster randomized design. We will test the comparative effectiveness of two implementation strategies to support clinicians’ use of an evidence-based firearm safety practice, S.A.F.E. Firearm, in 32 pediatric practices across two health systems. All pediatric practices in the two health systems will receive S.A.F.E. Firearm materials, including training and cable locks. Half of the practices (k = 16) will be randomized to receive Nudge; the other half (k = 16) will be randomized to receive Nudge plus 1 year of facilitation to target additional practice and clinician implementation barriers (Nudge+). The primary implementation outcome is parent-reported clinician fidelity to the S.A.F.E Firearm program. Secondary implementation outcomes include reach and cost. To understand how the implementation strategies work, the primary mechanism to be tested is practice adaptive reserve, a self-report practice-level measure that includes relationship infrastructure, facilitative leadership, sense-making, teamwork, work environment, and culture of learning. Discussion The ASPIRE trial will integrate implementation science and behavioral economic approaches to advance our understanding of methods for implementing evidence-based firearm safety promotion practices in pediatric primary care. The study answers a question at the heart of many practice change efforts: which strategies are sufficient to support change, and why? Results of the trial will offer valuable insights into how best to implement evidence-based practices that address sensitive health matters in pediatric primary care. Trial registration ClinicalTrials.gov, NCT04844021 . Registered 14 April 2021.

Abstract Background High mobility group box 1 protein (HMGB1) is an alarmin following its release by immune cells upon cellular activation or stress. High levels of extracellular HMGB1 play a critical role in impairing the clearance of invading pulmonary pathogens and dying neutrophils in the injured lungs of cystic fibrosis (CF) and acute respiratory distress syndrome (ARDS). A heparin derivative, 2-O, 3-O desulfated heparin (ODSH), has been shown to inhibit HMGB1 release from a macrophage cell line and is efficacious in increasing bacterial clearance in a mouse model of pneumonia. Thus, we hypothesized that ODSH can attenuate the bacterial burden and inflammatory lung injury in CF and we conducted experiments to determine the underlying mechanisms. Methods We determined the effects of ODSH on lung injury produced by Pseudomonas aeruginosa (PA) infection in CF mice with the transmembrane conductance regulator gene knockout (CFTR −/− ). Mice were given ODSH or normal saline intraperitoneally, followed by the determination of the bacterial load and lung injury in the airways and lung tissues. ODSH binding to HMGB1 was determined using surface plasmon resonance and in silico docking analysis of the interaction of the pentasaccharide form of ODSH with HMGB1. Results CF mice given 25 mg/kg i.p. of ODSH had significantly lower PA-induced lung injury compared to mice given vehicle alone. The CF mice infected with PA had decreased levels of nitric oxide (NO), increased levels of airway HMGB1 and HMGB1-impaired macrophage phagocytic function. ODSH partially attenuated the PA-induced alteration in the levels of NO and airway HMGB1 in CF mice. In addition, ODSH reversed HMGB1-impaired macrophage phagocytic function. These effects of ODSH subsequently decreased the bacterial burden in the CF lungs. In a surface plasmon resonance assay, ODSH interacted with HMGB1 with high affinity (KD = 3.89 × 10–8 M) and induced conformational changes that may decrease HMGB1’s binding to its membrane receptors, thus attenuating HMGB1-induced macrophage dysfunction. Conclusions The results suggest that ODSH can significantly decrease bacterial infection-induced lung injury in CF mice by decreasing both HMGB1-mediated impairment of macrophage function and the interaction of HMGB1 with membrane receptors. Thus, ODSH could represent a novel approach for treating CF and ARDS patients that have HMGB1-mediated lung injury. Graphic abstract

Abstract Background Despite numerous benefits for both mom and baby, few infants are exclusively breastfed for the recommended first six months. Additionally, infants are given solids too early. Prenatal education increases rates of breastfeeding initiation and we hypothesize it can also improve exclusive breastfeeding rates and prevent the early introduction of solids. We conducted a randomized controlled pilot and feasibility trial to understand the feasibility and maternal acceptance of a prenatal behavioral lifestyle intervention (PBLI) delivered via group based phone counseling (GBPC) and its effectiveness on rates of exclusive breastfeeding up to six months postpartum. Secondary aims included rates of any breastfeeding up to six months, rates of early introduction of solids, and infant feeding progression. Methods Forty-one pregnant women were recruited from a Kansas City Metropolitan Obstetrics and Gynecology office and randomly assigned to a usual care group or a PBLI. Women in the PBLI participated in six GBPC sessions where they learned about breastfeeding and introducing solids. Feeding questionnaires to assess breastfeeding and introduction of solids were sent at two weeks, two months, four months, and six months postpartum. Structured interviews were also conducted after the intervention and at six months postpartum to assess maternal acceptance and intervention feasibility. Results Participants overwhelmingly found the intervention acceptable and beneficial. Rates of exclusive breastfeeding and any breastfeeding did not differ between groups at any time point. No between group differences were found for early introduction of solids or infant feeding progression. Conclusions Mothers discontinue breastfeeding earlier than recommended despite high rates of initiation. A PBLI delivered via GBP is feasible, acceptable to participants, and showed positive impacts such as maternal empowerment for both breastfeeding and introducing solids. Future interventions should incorporate both prenatal and postpartum components. Trial registration Study protocols were approved by the University of Kansas Medical Center’s Human Subjects Committee (STUDY00140506) and registered at ClinicalTrials.gov on 02/22/2018 ( NCT03442517 , retrospectively registered). All participants gave written informed consent prior to data collection.

Abstract Background The global emergence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has seen the dominance of specific clones in different regions around the world with the PVL-positive ST93-IV as the predominant CA-MRSA clone in Australia. In this study we applied a genome-wide association study (GWAS) approach on a collection of Australian ST93-IV MRSA genomes to screen for genetic traits that might have assisted the ongoing transmission of ST93-IV in Australia. We also compared the genomes of ST93-IV bacteraemia and non-bacteraemia isolates to search for potential virulence genes associated with bacteraemia. Results Based on single nucleotide polymorphism phylogenetics we revealed two distinct ST93-IV clades circulating concurrently in Australia. One of the clades contained isolates primarily isolated in the northern regions of Australia whilst isolates in the second clade were distributed across the country. Analyses of the ST93-IV genome plasticity over a 15-year period (2002–2017) revealed an observed gain in accessory genes amongst the clone’s population. GWAS analysis on the bacteraemia isolates identified two gene candidates that have previously been associated to this kind of infection. Conclusions Although this hypothesis was not tested here, it is possible that the emergence of a ST93-IV clade containing additional virulence genes might be related to the high prevalence of ST93-IV infections amongst the indigenous population living in the northern regions of Australia. More importantly, our data also demonstrated that GWAS can reveal candidate genes for further investigations on the pathogenesis and evolution of MRSA strains within a same lineage.

Abstract Background After childbirth, most women do not lose the extra weight gained during pregnancy. This is important because postnatal weight retention contributes to the development of obesity in later life. Research shows that postnatal women living with overweight would prefer to weigh less, are interested in implementing weight loss strategies, and would like support. Without evidence for the benefit of weight management interventions during pregnancy, postnatal interventions are increasingly important. Research has focused on intensive weight loss programmes, which cannot be offered to all postnatal women. Instead, we investigated the feasibility of a brief intervention delivered to postnatal women at child immunisation appointments. This qualitative study explored the views of women who received the intervention and healthcare professionals who delivered it. Methods The intervention was delivered within the context of the national child immunisation programme. The intervention group were offered brief support encouraging self-management of weight when attending general practices to have their child immunised at two, three and four months of age. The intervention involved motivation and support from practice nurses to encourage women to make healthier lifestyle choices through self-monitoring of weight and signposting to an online weight management programme. Nurses provided external accountability for weight loss. Women were asked to weigh themselves weekly and record this on a weight record card. Nested within this trial, semi-structured interviews explored the experiences of postnatal women who received the intervention and nurses who delivered it. Results The intervention was generally acceptable to participants and child immunisation appointments considered a suitable intervention setting. Nurses were hesitant to discuss maternal weight, viewing the postnatal period as a vulnerable time. Whilst some caveats to implementation were discussed by nurses, they felt the intervention was easy to deliver and would motivate postnatal women to lose weight. Conclusions Participants were keen to lose weight after childbirth. Overall, they reported that the intervention was acceptable, convenient, and, appreciated support to lose weight after childbirth. Although nurses, expressed concerns about raising the topic of weight in the early postnatal period, they felt the intervention was easy to deliver and would help to motivate women to lose weight.

Abstract Background As the numbers of people with dementia worldwide rises, there is a need for improved knowledge and awareness about the condition across the healthcare workforce. There are concerns that traditional models of healthcare education, which focus on short-term episodes of care, limit student understanding of long-term conditions. We therefore designed and delivered the Time for Dementia programme at five Universities in the UK. Through longitudinal contact with families living with dementia, healthcare students gain increased understanding about the experiences of living with dementia. However, implementing new educational models brings challenges. To enable implementation of similar programmes in other educational institutions, this study aimed to identify the common barriers and facilitators of implementing these types of longitudinal programmes at scale. Methods To understand the facilitators and barriers of implementing a longitudinal dementia educational programme, a qualitative study was completed. Between October and December 2018, twelve in-depth semi-structured interviews were completed with university teaching staff (n = 6), programme administrators (n = 4), and Alzheimer’s Society staff (n = 2) that had key responsibilities for implementing Time for Dementia. Interview questions explored participants experiences, the facilitators, and the challenges encountered when implementing the programme. Interviews were audio recorded, transcribed verbatim, and analysed using inductive thematic analysis. Results The analysis identified five key themes: “Leadership characteristics”, “Organisational and student buy-in”, “Perceived value and motivating factors”, “Team coalition and support”, and “Time and fit”. Implementation of the programme was enhanced by resilient leaders managing the challenges of curricular change. Their belief in the value of the programme, stakeholder buy-in, and supportive team working enabled challenges to be overcome. Workload was reduced and student buy-in increased as time progressed and as more resources became available. A flexible approach to implementation was recommended to ensure the programme fits within the established curriculum. Conclusion Curricular change is a challenging task, yet necessary, if we are to improve care for people with long term conditions such as dementia. This study highlights the common barriers and facilitators experienced when implementing a longitudinal educational programme at scale. The findings presented in this study can be used by other educational institutions to manage curricular change efforts.

Abstract We have previously reported long-term changes in the brains of non-concussed varsity rugby players using magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI) and functional magnetic imaging (fMRI). Others have reported cognitive deficits in contact sport athletes that have not met the diagnostic criteria for concussion. These results suggest that repetitive mild traumatic brain injuries (rmTBIs) that are not severe enough to meet the diagnostic threshold for concussion, produce long-term consequences. We sought to characterize the neuroimaging, cognitive, pathological and metabolomic changes in a mouse model of rmTBI. Using a closed-skull model of mTBI that when scaled to human leads to rotational and linear accelerations far below what has been reported for sports concussion athletes, we found that 5 daily mTBIs triggered two temporally distinct types of pathological changes. First, during the first days and weeks after injury, the rmTBI produced diffuse axonal injury, a transient inflammatory response and changes in diffusion tensor imaging (DTI) that resolved with time. Second, the rmTBI led to pathological changes that were evident months after the injury including: changes in magnetic resonance spectroscopy (MRS), altered levels of synaptic proteins, behavioural deficits in attention and spatial memory, accumulations of pathologically phosphorylated tau, altered blood metabolomic profiles and white matter ultrastructural abnormalities. These results indicate that exceedingly mild rmTBI, in mice, triggers processes with pathological consequences observable months after the initial injury.

Abstract Background Task-shifting and technology in psychological interventions are two solutions to increasing access to mental health intervention and overcoming the treatment gap in low and middle-income countries. The CONEMO intervention combines a smartphone app with support from non-specialized professionals, aiming to treat depression in patients with diabetes and/or hypertension. The aim of this paper is to describe the process of recruitment, training and supervision of the non-specialized professionals who participated in the CONEMO task-shifting intervention in Brazil and Peru. Methods We described and analyzed data related to the recruitment, training and supervision of 62 nurse assistants from the health system in Sao Paulo, Brazil, and three hired nurses in Lima, Peru. The data were collected from information provided by nurses and nurse assistants, supervisor records from supervision meetings and the CONEMO platform database. Results We found that task-shifting was feasible using existing resources in Sao Paulo and additional human resources in Lima. Training and supervision were found to be crucial and well received by the staff; however, time was a limitation when using existing human resources. Ensuring technological competence prior to the start of the intervention was essential. Group supervision meetings allowed non-specialized professionals to learn from each other’s experiences. Conclusion Carefully considering recruitment, training and supervision of non-specialized professionals is important for effective task-shifting when delivering an mHealth intervention for depression. Opportunities and challenges of working in different health systems are described, which should be considered in future implementation, either for research or real settings. Trial registration NCT028406662 (Sao Paulo), NCT03026426 (Peru).

Abstract Background Our objective was to determine the impacts of artificial intelligence (AI) on public health practice. Methods We used a fundamental qualitative descriptive study design, enrolling 15 experts in public health and AI from June 2018 until July 2019 who worked in North America and Asia. We conducted in-depth semi-structured interviews, iteratively coded the resulting transcripts, and analyzed the results thematically. Results We developed 137 codes, from which nine themes emerged. The themes included opportunities such as leveraging big data and improving interventions; barriers to adoption such as confusion regarding AI’s applicability, limited capacity, and poor data quality; and risks such as propagation of bias, exacerbation of inequity, hype, and poor regulation. Conclusions Experts are cautiously optimistic about AI’s impacts on public health practice, particularly for improving disease surveillance. However, they perceived substantial barriers, such as a lack of available expertise, and risks, including inadequate regulation. Therefore, investment and research into AI for public health practice would likely be beneficial. However, increased access to high-quality data, research and education regarding the limitations of AI, and development of rigorous regulation are necessary to realize these benefits.

Abstract Background Neuroinflammation has been implicated in the pathogenesis of chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disease association with exposure to repetitive head impacts (RHI) received though playing contact sports such as American football. Past work has implicated early and sustained activation of microglia as a potential driver of tau pathology within the frontal cortex in CTE. However, the RHI induced signals required to recruit microglia to areas of damage and pathology are unknown. Methods Postmortem brain tissue was obtained from 261 individuals across multiple brain banks. Comparisons were made using cases with CTE, cases with Alzheimer’s disease (AD), and cases with no neurodegenerative disease and lacked exposure to RHI (controls). Recruitment of Iba1+ cells around the CTE perivascular lesion was compared to non-lesion vessels. TMEM119 staining was used to characterize microglia or macrophage involvement. The potent chemoattractant CCL2 was analyzed using frozen tissue from the dorsolateral frontal cortex (DLFC) and the calcarine cortex. Finally, the amounts of hyperphosphorylated tau (pTau) and Aβ42 were compared to CCL2 levels to examine possible mechanistic pathways. Results An increase in Iba1+ cells was found around blood vessels with perivascular tau pathology compared to non-affected vessels in individuals with RHI. TMEM119 staining revealed the majority of the Iba1+ cells were microglia. CCL2 protein levels in the DLFC were found to correlate with greater years of playing American football, the density of Iba1+ cells, the density of CD68+ cells, and increased CTE severity. When comparing across multiple brain regions, CCL2 increases were more pronounced in the DLFC than the calcarine cortex in cases with RHI but not in AD. When examining the individual contribution of pathogenic proteins to CCL2 changes, pTau correlated with CCL2, independent of age at death and Aβ42 in AD and CTE. Although levels of Aβ42 were not correlated with CCL2 in cases with CTE, in males in the AD group, Aβ42 trended toward an inverse relationship with CCL2 suggesting possible gender associations. Conclusion Overall, CCL2 is implicated in the pathways recruiting microglia and the development of pTau pathology after exposure to RHI, and may represent a future therapeutic target in CTE.

Abstract Background Attention deficit hyperactivity disorder (ADHD) is underdiagnosed in the UK and the assessment and diagnosis pathway often involves a general practitioner (GP) referral to secondary care services. GPs’ levels of knowledge and understanding about ADHD is often a significant barrier in patients accessing care. The development of an online education resource could improve GPs knowledge of ADHD and optimise appropriate referrals. Involving end-users in co-creating interventions may enhance their clinical utility and impact routine clinical practice. However, there is limited published evidence describing how to meaningfully involve stakeholders in both the design and development components of co-production. Method We report a step wise, co-production approach towards developing an online ADHD education intervention for GPs. Preparatory work highlighted the relevant topics to be included in the intervention, from which educational videos were then developed. Workshops were then conducted with GPs, leading to further refinement of the video content and subsequently the final intervention. A pilot usability study (n = 10 GPs) was then conducted to assess the intervention’s acceptability, feasibility and accessibility. Results The development of the online intervention was greatly facilitated by the involvement of GPs. Having a co-production development process ensured the consistent adaptation of the intervention to meet GPs’ needs. The usability study showed that the content of the intervention was suitable, easily accessible, engaging and delivered at an acceptable level of intensity, validating the development approach taken. Conclusion While further studies are needed to evaluate the efficacy of the developed intervention, preliminary findings demonstrated that it was acceptable and well received. The importance of co-development was highlighted in developing an intervention that addresses specific needs for GPs. This development approach may be useful for other researchers and developers of clinical interventions.

Abstract The most common genetic cause of amyotrophic lateral sclerosis (ALS) is a GGGGCC (G4C2) hexanucleotide repeat expansions in first intron of the C9orf72 gene. The accumulation of repetitive RNA sequences can mediate toxicity potentially through the formation of intranuclear RNA foci that sequester key RNA-binding proteins (RBPs), and non-ATG mediated translation into toxic dipeptide protein repeats. However, the contribution of RBP sequestration to the mechanisms underlying RNA-mediated toxicity remain unknown. Here we show that the ALS-associated RNA-binding protein, Matrin-3 (MATR3), colocalizes with G4C2 RNA foci in patient tissues as well as iPSC-derived motor neurons harboring the C9orf72 mutation. Hyperexpansion of C9 repeats perturbed subcellular distribution and levels of endogenous MATR3 in C9-ALS patient-derived motor neurons. Interestingly, we observed that ectopic expression of human MATR3 strongly mitigates G4C2-mediated neurodegeneration in vivo. MATR3-mediated suppression of C9 toxicity was dependent on the RNA-binding domain of MATR3. Importantly, we found that expression of MATR3 reduced the levels of RAN-translation products in mammalian cells in an RNA-dependent manner. Finally, we have shown that knocking down endogenous MATR3 in C9-ALS patient-derived iPSC neurons decreased the presence of G4C2 RNA foci in the nucleus. Overall, these studies suggest that MATR3 genetically modifies the neuropathological and the pathobiology of C9orf72 ALS through modulating the RNA foci and RAN translation.

Abstract Background The prevalence of obesity in women continues to rise and pregnancy is a high-risk time for excessive weight gain. The period after childbirth represents an opportunity to offer women support to manage their weight. The primary aim here was to investigate the acceptability and feasibility of delivering a self-management intervention to postnatal women to support weight loss, embedded within the national child immunisation programme. Methods The research involved a randomised controlled cluster feasibility trial. Data were collected at baseline and 3 months later. Twenty-eight postnatal women living with overweight or obesity were recruited via Birmingham Women Hospital or general practices. Babies are routinely immunised at 2, 3 and 4 months of age; the intervention was embedded within these appointments. The intervention involved brief motivation/support by practice nurses to encourage participants to make healthier lifestyle choices through self-monitoring of weight and signposting to an online weight management programme, when they attended their practice to have their child immunised. The role of the nurse was to provide external accountability for weight loss. Participants were asked to weigh themselves weekly and record this on a record card or using the online programme. The weight goal was for participants to lose 0.5 to 1 kg per week. Usual care received a healthy lifestyle leaflet. The primary outcome was the feasibility of a phase III trial to test the subsequent effectiveness of the intervention, as assessed against three stop-go traffic light criteria (recruitment, adherence to regular self-weighing and registration with an online weight management programme). Results The traffic light stop-go criteria results were red for recruitment (28/80, 35% of target), amber for registration with the online weight loss programme (9/16, 56%) and green for adherence to weekly self-weighing (10/16, 63%). Nurses delivered the intervention with high fidelity. Discussion Whilst participants and nurses followed the trial protocol well and adherence to self-weighing was acceptable, recruitment was challenging and there is scope to improve engagement with the online weight management programme component of the intervention. Trial registration ISRCTN 12209332 . Registration date is 04/12/18.