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Functional connectivity is the statistical association of neuronal activity time courses across distinct brain regions, supporting specific cognitive processes. This coordination of activity is likely to be highly important for complex aspects of cognition, such as the communication of fluctuating task goals from higher-order control regions to lower-order, functionally specific regions. Some of these functional connections are identifiable even when relevant cognitive tasks are not being performed (i.e. at rest). We used magnetoencephalographic recordings projected into source space to demonstrate that resting state networks in childhood have electrophysiological underpinnings that are evident in the spontaneous fluctuations of oscillatory brain activity. Using the temporal structure of these oscillatory patterns we were able to identify a number of functional resting state networks analogous to those reported in the adult literature. In a second analysis we fused this dynamic temporal information with the spatial information from a functional magnetic resonance imaging analysis of functional connectivity, to demonstrate that inter-subject variability in these electrophysiological measures of functional connectivity is correlated with individual differences in cognitive ability: the strength of connectivity between a fronto-parietal network and lower-level processing areas in inferior temporal cortex was associated with spatial working memory capacity, as measured outside the scanner with educationally relevant standardized assessments. This study represents the first exploration of the electrophysiological mechanisms underpinning resting state functional connectivity in source space in childhood, and the extent to which the strength of particular connections is associated with cognitive ability.

Abstract Background The humanities can aid in the development of important skills for trainee physicians. Because of the nature of their work, palliative medicine residents are expected to apply humanities-based skills frequently in their clinical work and are also likely to use humanities-based skills to support their own self-care. Our project explored the role of the humanities in palliative medicine residency programs across Canada. Methods Each priority topic or objective of the current palliative medicine residency training standards in Canada was reviewed to determine whether they relate to the humanities. A cross-sectional survey was subsequently created using Qualtrics, with the target study population being current palliative medicine residents and palliative medicine staff physicians at academic centers in Canada. Results Multiple humanities objectives exist in Canadian palliative medicine training standards, primarily in the ethical, cultural, and spiritual domains. Eighty-seven people completed the cross-sectional survey, for a 17.4% response rate and 94.6% completion rate. The vast majority (90%) of survey participants felt that the humanities had an important role in medical training at the undergraduate and postgraduate levels, and more than 70% of participants felt that the humanities had an important role in palliative medicine residency training. In some areas, the humanities participants felt that their programs would most benefit from ethics, philosophy, and culture. Over 65% agreed or strongly agreed that their own palliative medicine program would benefit from more humanities content. Conclusion Canadian palliative medicine training standards require residents to demonstrate humanities-based skills. Most survey participants state that the humanities have an important role in medical training at the undergraduate and postgraduate levels, and that their own palliative medicine residency program would benefit from more humanities content. These results may guide future studies to better understand why and how more humanities content can be added to palliative medicine residency programs to optimize residents’ learning experiences and better prepare them for careers in palliative medicine.

The immunosuppressive microenvironment in pancreatic ductal adenocarcinoma (PDAC) prevents tumor control and strategies to restore anti-cancer immunity (i.e. by increasing CD8 T-cell activity) have had limited success. Here, we demonstrate how inducing localized physical damage using ionizing radiation (IR) unmasks the benefit of immunotherapy by increasing tissue-resident natural killer (trNK) cells that support CD8 T activity. Our data confirms that targeting mouse orthotopic PDAC tumors with IR together with CCR5 inhibition and PD1 blockade reduces E-cadherin positive tumor cells by recruiting a hypoactive NKG2D-ve NK population, phenotypically reminiscent of trNK cells, that supports CD8 T-cell involvement. We show an equivalent population in human single-cell RNA sequencing (scRNA-seq) PDAC cohorts that represents immunomodulatory trNK cells that could similarly support CD8 T-cell levels in a cDC1-dependent manner. Importantly, a trNK signature associates with survival in PDAC and other solid malignancies revealing a potential beneficial role for trNK in improving adaptive anti-tumor responses and supporting CCR5 inhibitor (CCR5i)/αPD1 and IR-induced damage as a novel therapeutic approach.

BackgroundOlder African American and Black adults are twice as likely to develop Alzheimer disease and related dementias (ADRD) and have the lowest level of ADRD health literacy compared to any other ethnic group in the United States. Low health literacy concerning ADRD negatively impacts African American and Black people in accessing adequate health care. ObjectiveThis study explored how 3 technological modalities—voice assistants, chatbots, and mobile apps—can assist older African American and Black adults in accessing ADRD information to improve ADRD health literacy. By testing each modality independently, the focus could be kept on understanding the unique needs and challenges of this population concerning the use of each modality when accessing ADRD-related information. MethodsUsing the Wizard of Oz usability testing method, we assessed the 3 modalities with a sample of 15 older African American and Black adults aged >55 years. The 15 participants were asked to interact with the 3 modalities to search for information on local events happening in their geographical area and search for ADRD-related health information. ResultsOur findings revealed that, across the 3 modalities, the content should avoid convoluted and complex language and give the possibility to save, store, and share it to be fully accessible by this population. In addition, content should come from credible sources, including information tailored to the participants’ cultural values, as it has to be culturally relevant for African American and Black communities. Finally, the interaction with the tool must be time efficient, and it should be adapted to the user’s needs to foster a sense of control and representation. ConclusionsWe conclude that, when designing ADRD-related interventions for African American and Black older adults, it proves to be crucial to tailor the content provided by the technology to the community’s values and construct an interaction with the technology that is built on African American and Black communities’ needs and demands.

A study involving 200 adults with mental retardation investigated the interrater reliability and internal consistency of the Matson Evaluation of Drug Side Effects (MEDS), a scale designed to evaluate commonly identified side effects with a psychometrically sound checklist. The MEDS had excellent consistency across raters and good internal consistency. (Author/CR)

Humans' sense of the passage of time is subjective and determined by psychophysiological responses to the environment. The passing of time has been perceived to significantly slow in stressful situations, such as accidents or virtual threats. The current study will explore distortions in the perception of passage of time when threat is simulated using virtual reality (VR). 44 participants negotiated a large (13.6 × 8.4 m) virtual environment designed to maximise the realism of a physical threat by exposing participants to a virtual height of 200m. Subjective perception of passage of time and time estimation were used as independent variables, whereas the movement of participants, and ambulatory psychophysiology, e.g., electrodermal activity (EDA), heart rate, served as dependent variables. The independent variables were examined in relation to the dependent variables through a regression analysis, which allowed for the identification of the specific weight of each variable. Our analyses revealed that passage of time was perceived to decrease (i.e., time slowed down) for those participants who exhibited the higher levels of skin conductance (SCL). It is argued that this finding can be explained by individual differences in self-regulatory strategies during the task and the effectiveness of VR as means to simulate threat.

Evolution is an important part of biology education, but many college biology students do not accept important components of evolution, like the evolution of humans. Practices that reduce perceived conflict between religion and evolution have been proposed to increase student evolution acceptance. This study investigates college student experiences of conflict reducing practices in evolution education and how these experiences are related to their gains in acceptance of human evolution during evolution instruction. We measured the natural variation in student experiences of conflict reducing practices among 6,719 college biology students in 55 courses and 14 states including (1) their experiences of an instructor demonstrating religion-evolution compatibility by presenting examples of religious leaders and scientists who accept evolution and (2) their experiences of an instructor emphasizing students' autonomy in their own decision to accept evolution or not. We also measured student acceptance of human evolution before and after instruction so that we could test whether any changes in evolution acceptance were associated with student experiences of the conflict reducing practices. Linear mixed models showed that highly religious Christian students accepted evolution more when they perceived more compatibility practices. Further, students from all religious and non-religious affiliations accepted human evolution more after instruction when they perceived more autonomy practices. These results indicate that integrating examples of religion compatibility in evolution education will positively impact Christian students' views on evolution and that emphasizing students' autonomy over their decision to accept evolution may be important for students more broadly. If instructors incorporate practices that emphasize compatibility and one's personal choice to accept or not accept evolution, then these results suggest that students will leave their college biology classes accepting evolution more. Perhaps by using more conflict reducing practices, instructors can help increase evolution acceptance levels that have remained low in the United States for decades.

Cerebral blood flow at rest declines with age. However, age-related changes in functional measures of cerebrovascular health including cerebrovascular reactivity and neurovascular coupling are not well understood. Additionally, the effect of apolipoprotein E (APOE) ε4, a strong genetic risk factor for Alzheimer's disease, on cerebral blood flow and cerebrovascular function remains unclear. APOEε4 positive (APOEε4+; n = 37, age = 63±4y) and APOEε4 negative (APOEε4-; n = 50, age = 63±4y) cognitively unimpaired adults participated in this study. Macrovascular cerebral blood flow and microvascular cerebral perfusion were measured using 4D flow MRI and pseudo-continuous arterial spin labeling MRI, respectively. Cerebrovascular reactivity and neurovascular coupling were assessed by measuring middle cerebral artery blood velocity in response to hypercapnia and the n-back test, respectively. Neurovascular coupling was lower in APOEε4+ compared with APOEε4- adults (P

Background: Emerging adults with type 1 diabetes (T1D) struggle with glycemic management that can be exacerbated by a disorganized transition process. Substantial gaps in care have been noted during this transition period and have been shown to lead to suboptimal health care utilization, worsening glycemic management, increased incidence of serious complications, and mental health challenges. A formal transition program can help prevent gaps in care, improve disease self-management skills, decrease disease burden, and reduce diabetes complications. Purpose: There is an increased focus within the pediatric community to formally prepare young adults with T1D as they transition to the adult health care setting. The purpose of the quality improvement initiative was to develop a transition program for adolescents with T1D in a pediatric endocrinology clinic within an academic medical center. Methods/interventions: The Institute for Healthcare Improvement Model for Improvement was used to guide this project. Got Transition's® Six Core Elements of Health Care Transition were adapted to the unique needs of the pediatric endocrinology setting by incorporating diabetes-specific transition guidelines recommended by the American Diabetes Association (ADA). A new program was designed to target patients between the ages of 16–18 offering structured transition visits focused on enhancing knowledge and skills related to the management of T1D and improving the transfer of care process between pediatric and adult providers. Key elements of the program were integrated into the electronic health record. A focus group with clinical partners was used to evaluate the acceptability and practicality of the program. Results: Transition activity within the clinic increased from 12/32–28/32 on the Current Assessment of Healthcare Transition Activities tool. Four themes were identified from clinical partner feedback supporting the acceptability and practicality of program design. Conclusions: The integration of the Got Transition® framework and the ADA recommendations supports clinicians in meeting the unique needs of adolescents with T1D. Incorporating the transition activities into the electronic health record facilitated integration into the workflow of the clinic providers. This initiative can serve as a model to expand transition activities across pediatric specialty care settings.

Social visual engagement difficulties are hallmark early signs of autism (ASD) and are easily quantified using eye tracking methods. However, it is unclear how these difficulties are linked to atypical early functional brain organization in ASD. With resting state fMRI data in a large sample of ASD toddlers and other non-ASD comparison groups, we find ASD-related functional hypoconnnectivity between 'social brain' circuitry such as the default mode network (DMN) and visual and attention networks. An eye tracking-identified ASD subtype with pronounced early social visual engagement difficulties (GeoPref ASD) is characterized by marked DMN-occipito-temporal cortex (OTC) hypoconnectivity. Increased DMN-OTC hypoconnectivity is also related to increased severity of social-communication difficulties, but only in GeoPref ASD. Early and pronounced social-visual circuit hypoconnectivity is a key underlying neurobiological feature describing GeoPref ASD and may be critical for future social-communicative development and represent new treatment targets for early intervention in these individuals.

Abstract Background Asthma is the most common chronic disease in children, occurring at higher frequencies and with more severe disease in children with African ancestry. Methods We tested for association with haplotypes at the most replicated and significant childhood-onset asthma locus at 17q12-q21 and asthma in European American and African American children. Following this, we used whole-genome sequencing data from 1060 African American and 100 European American individuals to identify novel variants on a high-risk African American–specific haplotype. We characterized these variants in silico using gene expression and ATAC-seq data from airway epithelial cells, functional annotations from ENCODE, and promoter capture (pc)Hi-C maps in airway epithelial cells. Candidate causal variants were then assessed for correlation with asthma-associated phenotypes in African American children and adults. Results Our studies revealed nine novel African-specific common variants, enriched on a high-risk asthma haplotype, which regulated the expression of GSDMA in airway epithelial cells and were associated with features of severe asthma. Using ENCODE annotations, ATAC-seq, and pcHi-C, we narrowed the associations to two candidate causal variants that are associated with features of T2 low severe asthma. Conclusions Previously unknown genetic variation at the 17q12-21 childhood-onset asthma locus contributes to asthma severity in individuals with African ancestries. We suggest that many other population-specific variants that have not been discovered in GWAS contribute to the genetic risk for asthma and other common diseases.

Abstract Studying the visual system with fMRI often requires using localizer paradigms to define regions of interest (ROIs). However, the considerable interindividual variability of the cerebral cortex represents a crucial confound for group-level analyses. Cortex-based alignment (CBA) techniques reliably reduce interindividual macroanatomical variability. Yet, their utility has not been assessed for visual field localizer paradigms, which map specific parts of the visual field within retinotopically organized visual areas. We evaluated CBA for an attention-enhanced visual field localizer, mapping homologous parts of each visual quadrant in 50 participants. We compared CBA with volume-based alignment and a surface-based analysis, which did not include macroanatomical alignment. CBA led to the strongest increase in the probability of activation overlap (up to 86%). At the group level, CBA led to the most consistent increase in ROI size while preserving vertical ROI symmetry. Overall, our results indicate that in addition to the increased signal-to-noise ratio of a surface-based analysis, macroanatomical alignment considerably improves statistical power. These findings confirm and extend the utility of CBA for the study of the visual system in the context of group analyses. CBA should be particularly relevant when studying neuropsychiatric disorders with abnormally increased interindividual macroanatomical variability.

Abstract Background Central conventional chondrosarcoma (CS) is the most common subtype of primary malignant bone tumour in adults. Treatment options are usually limited to surgery, and prognosis is challenging. These tumours are characterised by the presence and absence of IDH1 and IDH2 mutations, and recently, TERT promoter alterations have been reported in around 20% of cases. The effect of these mutations on clinical outcome remains unclear. The purpose of this study was to determine if prognostic accuracy can be improved by the addition of genomic data, and specifically by examination of IDH1, IDH2, and TERT mutations. Methods In this study, we combined both archival samples and data sourced from the Genomics England 100,000 Genomes Project (n = 356). Mutations in IDH1, IDH2, and TERT were profiled using digital droplet PCR (n = 346), whole genome sequencing (n=68), or both (n = 64). Complex events and other genetic features were also examined, along with methylation array data (n = 84). We correlated clinical features and patient outcomes with our genetic findings. Results IDH2-mutant tumours occur in older patients and commonly present with high-grade or dedifferentiated disease. Notably, TERT mutations occur most frequently in IDH2-mutant tumours, although have no effect on survival in this group. In contrast, TERT mutations are rarer in IDH1-mutant tumours, yet they are associated with a less favourable outcome in this group. We also found that methylation profiles distinguish IDH1- from IDH2-mutant tumours. IDH wild-type tumours rarely exhibit TERT mutations and tend to be diagnosed in a younger population than those with tumours harbouring IDH1 and IDH2 mutations. A major genetic feature of this group is haploidisation and subsequent genome doubling. These tumours evolve less frequently to dedifferentiated disease and therefore constitute a lower risk group. Conclusions Tumours with IDH1 or IDH2 mutations or those that are IDHwt have significantly different genetic pathways and outcomes in relation to TERT mutation. Diagnostic testing for IDH1, IDH2, and TERT mutations could therefore help to guide clinical monitoring and prognostication.

Abstract RT-PCR is the foremost clinical test for diagnosis of COVID-19. Unfortunately, PCR-based testing has limitations and may not result in a positive test early in the course of infection before symptoms develop. Enveloped RNA viruses, such as coronaviruses, alter peripheral blood methylation and DNA methylation signatures may characterize asymptomatic versus symptomatic infection. We used Illumina’s Infinium MethylationEPIC BeadChip array to profile peripheral blood samples from 164 patients who tested positive for SARS-CoV-2 by RT-PCR, of whom 8 had no symptoms. Epigenome-wide association analysis identified 10 methylation sites associated with infection and a quantile–quantile plot showed little inflation. These preliminary results suggest that differences in methylation patterns may distinguish asymptomatic from symptomatic infection.

The aim of this work is to provide an overview of the current state of additive manufacturing (AM), commonly known as 3D printing, within superficial brachytherapy (BT). Several comprehensive database searches were performed to find publications linked to AM in superficial BT. Twenty-eight core publications were found, which can be grouped under general categories of clinical cases, physical and dosimetric evaluations, proof-of-concept cases, design process assessments, and economic feasibility studies. Each study demonstrated a success regarding AM implementation and collectively, they provided benefits over traditional applicator fabrication techniques. Publications of AM in superficial BT have increased significantly in the last 5 years. This is likely due to associated efficiency and consistency benefits; though, more evidences are needed to determine the true extent of these benefits.

Introduction Frailty is a strong predictor of adverse postoperative outcomes. Prehabilitation may improve outcomes after surgery for older people with frailty by addressing physical and physiologic deficits. The objective of this trial is to evaluate the efficacy of home-based multimodal prehabilitation in decreasing patient-reported disability and postoperative complications in older people with frailty having major surgery.Methods and analysis We will conduct a multicentre, randomised controlled trial of home-based prehabilitation versus standard care among consenting patients >60 years with frailty (Clinical Frailty Scale>4) having elective inpatient major non-cardiac, non-neurologic or non-orthopaedic surgery. Patients will be partially blinded; clinicians and outcome assessors will be fully blinded. The intervention consists of >3 weeks of prehabilitation (exercise (strength, aerobic and stretching) and nutrition (advice and protein supplementation)). The study has two primary outcomes: in-hospital complications and patient-reported disability 30 days after surgery. Secondary outcomes include survival, lower limb function, quality of life and resource utilisation. A sample size of 750 participants (375 per arm) provides >90% power to detect a minimally important absolute difference of 8 on the 100-point patient-reported disability scale and a 25% relative risk reduction in complications, using a two-sided alpha value of 0.025 to account for the two primary outcomes. Analyses will follow intention to treat principles for all randomised participants. All participants will be followed to either death or up to 1 year.Ethics and dissemination Ethical approval has been granted by Clinical Trials Ontario (Project ID: 1785) and our ethics review board (Protocol Approval #20190409-01T). Results will be disseminated through presentation at scientific conferences, through peer-reviewed publication, stakeholder organisations and engagement of social and traditional media.Trial registration number NCT04221295.

During mitosis, individual microtubules make attachments to chromosomes via a specialized protein complex called the kinetochore to faithfully segregate the chromosomes to daughter cells. Translocation of kinetochores on the lateral surface of the microtubule has been proposed to contribute to high fidelity chromosome capture and alignment at the mitotic midzone, but has been difficult to observe in vivo because of spatial and temporal constraints. To overcome these barriers, we used total internal reflection fluorescence (TIRF) microscopy to track the interactions between microtubules, kinetochore proteins, and other microtubule-associated proteins in lysates from metaphase-arrested Saccharomyces cerevisiae. TIRF microscopy and cryo-correlative light microscopy and electron tomography indicated that we successfully reconstituted interactions between intact kinetochores and microtubules. These kinetochores translocate on the lateral microtubule surface toward the microtubule plus end and transition to end-on attachment, whereupon microtubule depolymerization commences. The directional kinetochore movement is dependent on the highly processive kinesin-8, Kip3. We propose that Kip3 facilitates stable kinetochore attachment to microtubule plus ends through its abilities to move the kinetochore laterally on the surface of the microtubule and to regulate microtubule plus end dynamics.

BackgroundNeurological complications due to chikungunya virus (CHIKV) infection have been described in different parts of the world, with children being disproportionately affected. However, the burden of CHIKV-associated neurological disease in Africa is currently unknown and given the lack of diagnostic facilities in routine care it is possible that CHIKV is an unrecognized etiology among children with encephalitis or other neurological illness.Methods and findingsWe estimated the incidence of CHIKV infection among children hospitalized with neurological disease in Kilifi County, coastal Kenya. We used reverse transcriptase polymerase chain reaction (RT-PCR) to systematically test for CHIKV in cerebrospinal fluid (CSF) samples from children aged ConclusionsIn this study, we observed that CHIKV infections are relatively more common than cerebral malaria and bacterial meningitis among children hospitalized with neurological disease in coastal Kenya. Given the wide distribution of CHIKV mosquito vectors, studies to determine the geographic extent of CHIKV-associated neurological disease in Africa are essential.

It is clear that learning and attention interact, but it is an ongoing challenge to integrate their psychological and neurophysiological descriptions. Here we introduce LAG-1, a dynamic neural field model of learning, attention and gaze, that we fit to human learning and eye-movement data from two category learning experiments. LAG-1 comprises three control systems: one for visuospatial attention, one for saccadic timing and control, and one for category learning. The model is able to extract a kind of information gain from pairwise differences in simple associations between visual features and categories. Providing this gain as a reentrant signal with bottom-up visual information, and in top-down spatial priority, appropriately influences the initiation of saccades. LAG-1 provides a moment-by-moment simulation of the interactions of learning and gaze, and thus simultaneously produces phenomena on many timescales, from the duration of saccades and gaze fixations, to the response times for trials, to the slow optimization of attention toward task relevant information across a whole experiment. With only three free parameters (learning rate, trial impatience, and fixation impatience) LAG-1 produces qualitatively correct fits for learning, behavioural timing and eye movement measures, and also for previously unmodelled empirical phenomena (e.g., fixation orders showing stimulus-specific attention, and decreasing fixation counts during feedback). Because LAG-1 is built to capture attention and gaze generally, we demonstrate how it can be applied to other phenomena of visual cognition such as the free viewing of visual stimuli, visual search, and covert attention.

We tested the hypothesis that dividing attention would strengthen the ability to detect mild cognitive impairment (MCI) and specific cognitive abilities from Timed Up and Go (TUG) performance in the community setting. While wearing a belt-worn sensor, 757 dementia-free older adults completed TUG during two conditions, with and without a concurrent verbal serial subtraction task. We segmented TUG into its four subtasks (i.e., walking, turning, and two postural transitions), and extracted 18 measures that were summarized into nine validated sensor metrics. Participants also underwent a detailed cognitive assessment during the same visit. We then employed a series of regression models to determine the combinations of subtask sensor metrics most strongly associated with MCI and specific cognitive abilities for each condition. We also compared subtask performances with and without dividing attention to determine whether the costs of divided attention were associated with cognition. While slower TUG walking and turning were associated with higher odds of MCI under normal conditions, these and other subtask associations became more strongly linked to MCI when TUG was performed under divided attention. Walking and turns were also most strongly associated with executive function and attention, particularly under divided attention. These differential associations with cognition were mirrored by performance costs. However, since several TUG subtasks were more strongly associated with MCI and cognitive abilities when performed under divided attention, future work is needed to determine how instrumented dual-task TUG testing can more accurately estimate risk for late-life cognitive impairment in older adults.

Among the many ambitious decarbonization goals globally, the US intends grid decarbonization by 2035, requiring 1 TW of installed photovoltaics (PV), up from ~110 GW in 2021. This unprecedented global scale-up will stress existing PV supply chains with increased material and energy demands. By 2050, 1.75 TW of PV in the US cumulatively demands 97 million metric tonnes of virgin material and creates 8 million metric tonnes of life cycle waste. This analysis leverages the PV in Circular Economy tool (PV ICE) to evaluate two circular economy approaches, lifetime extension and closed-loop recycling, on their ability to reduce virgin material demands and life cycle wastes while meeting capacity goals. Modules with 50-year lifetimes can reduce virgin material demand by 3% through reduced deployment. Modules with 15-year lifetimes require an additional 1.2 TW of replacement modules to maintain capacity, increasing virgin material demand and waste unless >90% of module mass is closed-loop recycled. Currently, no PV technology is more than 90% closed-loop recycled. Glass, the majority of mass in all PV technologies and an energy intensive component with a problematic supply chain, should be targeted for a circular redesign. Our work contributes data-backed insights prioritizing circular PV strategies for a sustainable energy transition.

BackgroundThere is no practical dementia risk score in the clinical setting.ObjectiveTo derive and validate a score obtained by a rapid and simple assessment, which guides primary care providers in predicting the risk of dementia among older adults.DesignA total of 4178 participants from three longitudinal cohorts (mean age at baseline = 76.8 [SD = 7.6] years), without baseline dementia, followed annually for a median of 10 years (IQR: 5 to16 years, Reverse Kaplan-Meier).ParticipantsTo derive the score, we used data from 1,780 participants from the Rush Memory and Aging Project (93% White). To validate the score, we used data from 1,299 participants from the Religious Order Study (92% White), and to assess generalizability, 679 participants from the Minority Aging Research Study (100% Black).MeasurementsClinician-based dementia diagnosis at any time after baseline and predictive variables associated with dementia risk that can be collected in a primary care setting: demographics, clinical indicators, medical history, memory complaints, cognitive and motor tests, and questions to assess functional disability, depressive symptoms, sleep, social isolation, and genetics (APOE e4 and AD polygenic risk score).ResultsAt baseline, age, memory complaint, the ability to handle finances, the recall of the month, recall of the room, and recall of three words, were associated with the cumulative incidence of dementia, in the derivation cohort. The discrimination of the RADaR (Rapid Risk Assessment of Dementia) was good for the derivation and external-validation cohorts (AUC3 years = 0.82-0.86), compared to the overall discrimination of age alone (AUC3 years = 0.73), a major risk factor for dementia. Adding genetic data did not increase discrimination.LimitationsParticipants were volunteers, may not represent the general population.ConclusionsThe RADaR, derived from community-dwelling older persons, is a brief and valid tool to predict dementia risk at 3 years in older White and Black persons.

Background Haemodialysis patients experience significant symptom burden and effects on health-related quality of life. Studies have shown increases in fluid overload, hospitalization and mortality immediately after the long interdialytic interval in thrice weekly in-centre haemodialysis patients, however the relationship between the dialytic interval and patient reported outcome measures (PROMs) has not been quantified and the extent to which dialysis day of PROM completion needs to be standardised is unknown. Methods Three times a week haemodialysis patients participating in a stepped wedge trial to increase patient participation in haemodialysis tasks completed PROMs (POS-S Renal symptom score and EQ-5D-5L) at recruitment, six, 12 and 18 months. Time from the long interdialytic interval, HD day of the week, and HD days vs non-HD days were included in mixed effects Linear Regression, estimating severity (none to overwhelming treated as 0 to 4) of 17 symptoms and EQ-5D-5L, adjusting for age, sex, time on HD, control versus intervention and Charlson Comorbidity Score. Results 517 patients completed 1659 YHS questionnaires that could be assigned HD day (510 on Mon/Tue/Sun, 549 on Wed/Thu/Tue, 308 on Fri/Sat/Thu and 269 on non-HD days). With the exception of restless legs and skin changes, there was no statistically significant change in symptom severity or EQ-5D-5L with increasing time from the long interdialytic interval. Patients who responded on non-HD days had higher severity of poor appetite, constipation, difficulty sleeping, poor mobility and depression (approximately 0.2 severity level), and lower EQ-5D-5L (-0.06, CI -0.09 to -0.03) compared to HD days. Conclusions Measuring symptom severity and EQ-5D-5L in haemodialysis populations does not need to account for dialysis schedule, but completion either on HD or non-HD days could introduce bias that may impact evaluation of interventions. Researchers should ensure completion of these instruments are standardized on either dialysis or non-dialysis days.

Taurine is an essential amino acid. It has been shown to be neuroprotective including protecting against the neurotoxic effects of glutamate. The goal of the current study was to examine the relationship between CB use and taurine measured in brain using magnetic resonance spectroscopy (MRS), and peripherally from a urine sample. Two experiments are presented. The first is a reanalysis of published data that examined taurine and glutamate in the dorsal anterior cingulate of a CB user group and non-user group using MRS. The second experiment, in a separate CB user group, used metabolomics analysis to measure taurine levels in urine. Because body composition has been associated with the pharmacokinetics of cannabis and taurine levels, a moderation model was examined with body composition included as the covariate. The MRS study found taurine levels were correlated with glutamate in both groups and taurine was correlated with frequency of CB use in the CB user group. The moderation model demonstrated significant effects of CB use and BMI; the interaction was marginally significant with lower BMI individuals showing a positive relationship between CB use and taurine. A similar finding was observed for the urine analysis. Both CB use and weight, as well as the interaction were significant. In this case, individuals with higher weight showed an association between CB use and taurine levels. This study shows the feasibility and potential importance of examining the relationship between taurine and CB use as it may shed light on a mechanism that underlies the neuroprotective effects of CB.

The purpose of this study was to explore the association between participation in organized sport and a broad array of mental health difficulties among US children and adolescents. The data (cross-sectional) were from Data Release 3.0 (one-year follow-up visits on the full cohort) of the Adolescent Brain Cognitive Development (ABCD) study-a broadly representative sample of 11,235 US children and adolescents aged 9 to 13 years. Parents/guardians provided self-reports of their child's mental health difficulties using the Child Behavior Checklist. To assess participation in organized sport, children and adolescents were categorized into one of four groups: 1) participation in team sport, 2) participation in individual sport, 3) participation in team and individual sport, and 4) non-sport participation. Participation in team sport compared to non-sport participation was associated with 10% lower anxious/depressed scores, 19% lower withdrawn/depressed scores, 17% lower social problems scores, 17% lower thought problems scores, and 12% lower attention problems scores. Participation in team sport compared to non-sport participation was also associated with 20% lower rule-breaking behavior scores for females (compared to males). Conversely, participation in individual sport compared to non-sport participation was associated with 16% higher anxious/depressed scores, 14% higher withdrawn/depressed scores, 12% higher social problems scores, and 14% higher attention problems scores. Participation in both team and individual sport compared to non-sport participation was associated with 17% lower rule-breaking behavior scores for females (compared to males). Results indicate that team sport participation was associated with fewer mental health difficulties, whereas individual sport participation was associated with greater mental health difficulties. The findings complement previous research suggesting that team sport participation may be a vehicle to support child and adolescent mental health. Additional research is needed to determine to what extent, and under what circumstances, participation in individual sport may be problematic for younger cohorts.

Fluorescence microscopy is a core method for visualizing and quantifying the spatial and temporal dynamics of complex biological processes. While many fluorescent microscopy techniques exist, due to its cost-effectiveness and accessibility, widefield fluorescent imaging remains one of the most widely used. To accomplish imaging of 3D samples, conventional widefield fluorescence imaging entails acquiring a sequence of 2D images spaced along the z-dimension, typically called a z-stack. Oftentimes, the first step in an analysis pipeline is to project that 3D volume into a single 2D image because 3D image data can be cumbersome to manage and challenging to analyze and interpret. Furthermore, z-stack acquisition is often time-consuming, which consequently may induce photodamage to the biological sample; these are major barriers for workflows that require high-throughput, such as drug screening. As an alternative to z-stacks, axial sweep acquisition schemes have been proposed to circumvent these drawbacks and offer potential of 100-fold faster image acquisition for 3D-samples compared to z-stack acquisition. Unfortunately, these acquisition techniques generate low-quality 2D z-projected images that require restoration with unwieldy, computationally heavy algorithms before the images can be interrogated. We propose a novel workflow to combine axial z-sweep acquisition with deep learning-based image restoration, ultimately enabling high-throughput and high-quality imaging of complex 3D-samples using 2D projection images. To demonstrate the capabilities of our proposed workflow, we apply it to live-cell imaging of large 3D tumor spheroid cultures and find we can produce high-fidelity images appropriate for quantitative analysis. Therefore, we conclude that combining axial z-sweep image acquisition with deep learning-based image restoration enables high-throughput and high-quality fluorescence imaging of complex 3D biological samples.

Introduction Grades 2 and 3 gliomas (G2/3 gliomas), when combined, are the second largest group of malignant brain tumours in adults. The outcomes for G2/3 gliomas at progression approach the dismal outcomes for glioblastoma (GBM), yet there is a paucity of trials for Australian patients with relapsed G2/3 gliomas compared with patients with GBM. LUMOS will be a pilot umbrella study for patients with relapsed G2/3 gliomas that aims to match patients to targeted therapies based on molecular screening with contemporaneous tumour tissue. Participants in whom no actionable or no druggable mutation is found, or in whom the matching drug is not available, will form a comparator arm and receive standard of care chemotherapy. The objective of the LUMOS trial is to assess the feasibility of this approach in a multicentre study across five sites in Australia, with a view to establishing a national molecular screening platform for patient treatment guided by the mutational analysis of contemporaneous tissue biopsiesMethods and analysis This study will be a multicentre pilot study enrolling patients with recurrent grade 2/3 gliomas that have previously been treated with radiotherapy and chemotherapy at diagnosis or at first relapse. Contemporaneous tumour tissue at the time of first relapse, defined as tissue obtained within 6 months of relapse and without subsequent intervening therapy, will be obtained from patients. Molecular screening will be performed by targeted next-generation sequencing at the reference laboratory (PathWest, Perth, Australia). RNA and DNA will be extracted from representative formalin-fixed paraffin embedded tissue scrolls or microdissected from sections on glass slides tissue sections following a review of the histology by pathologists. Extracted nucleic acid will be quantified by Qubit Fluorometric Quantitation (Thermo Fisher Scientific). Library preparation and targeted capture will be performed using the TruSight Tumor 170 (TST170) kit and samples sequenced on NextSeq 550 (Illumina) using NextSeq V.2.5 hi output reagents, according to the manufacturer’s instructions. Data analysis will be performed using the Illumina BaseSpace TST170 app v1.02 and a custom tertiary pipeline, implemented within the Clinical Genomics Workspace software platform from PierianDx (also refer to section 3.2). Primary outcomes for the study will be the number of patients enrolled and the number of patients who complete molecular screening. Secondary outcomes will include the proportion of screened patients enrolled; proportion of patients who complete molecular screening; the turn-around time of molecular screening; and the value of a brain tumour specific multi-disciplinary tumour board, called the molecular tumour advisory panel as measured by the proportion of patients in whom the treatment recommendation was refined compared with the recommendations from the automated bioinformatics platform of the reference laboratory testing.Ethics and dissemination The study was approved by the lead Human Research Ethics Committee of the Sydney Local Health District: Protocol No. X19-0383. The study will be conducted in accordance with the principles of the Declaration of Helsinki 2013, guidelines for Good Clinical Practice and the National Health and Medical Research Council National Statement on Ethical Conduct in Human Research (2007, updated 2018 and as amended periodically). Results will be disseminated using a range of media channels including newsletters, social media, scientific conferences and peer-reviewed publications.Trial registration number ACTRN12620000087954; Pre-results.

Introduction Comprehensive geriatric assessment (CGA) is an intervention that has been deployed in the perioperative setting with the aim to improve outcomes for older patients admitted to hospital. Older patients undergoing surgery are more likely to have postoperative complications, a longer hospital stay and be discharged to a care facility. Despite the increasing application of this intervention within surgical services, the evidence for CGA remains limited in this group. The aim of this systematic review is to describe CGA as in intervention applied to surgical populations in randomised controlled trials (RCTs) as well as the outcomes assessed.Methods and analysis A systematic search of RCTs of CGA in surgery will be run in Embase, Medline, CINAHL (Cumulative Index to Nursing and Allied Health Literature) and Cochrane library. Further articles will be identified from reference lists in relevant studies found in the search. A narrative synthesis will be undertaken outlining specialties included, detailed descriptions of the intervention and outcomes.Ethics and dissemination No ethical approval is required. The results of this review will be published and used as the basis of work to optimise this intervention for future trials in surgical populations.PROSPERO registration number This review is registered with PROSPERO CRD42020221797.

Most clinical trials to determine optimal tuberculosis (TB) treatment regimens have been carried out in adults. A recent randomised control clinical trial published in The New England Journal of Medicine compared the response in children following 4 or 6 months of standard first-line anti-TB treatment and found it to be similar.

Abstract Background While regulated WNT activity is required for normal development and stem cell maintenance, mutations that lead to constitutive activation of the WNT pathway cause cellular transformation and drive colorectal cancer. Activation of the WNT pathway ultimately leads to the nuclear translocation of β-catenin which, in complex with TCF/LEF factors, promotes the transcription of genes necessary for growth. The proto-oncogene MYC is one of the most critical genes activated downstream the WNT pathway in colon cancer. Here, we investigate the converse regulation of the WNT pathway by MYC. Methods We performed RNA-seq analyses to identify genes regulated in cells expressing MYC. We validated the regulation of genes in the WNT pathway including LEF1 by MYC using RT-qPCR, Western blotting, and ChIP-seq. We investigated the importance of LEF1 for the viability of MYC-expressing cells in in fibroblasts, epithelial cells, and colon cells. Bioinformatic analyses were utilized to define the expression of MYC-regulated genes in human colon cancer and metabolomics analyses were used to identify pathways regulated by LEF1 in MYC expressing cells. Results MYC regulates the levels of numerous WNT-related genes, including the β-catenin co-transcription factor LEF1. MYC activates the transcription of LEF1 and is required for LEF1 expression in colon cancer cells and in primary colonic cells transformed by APC loss of function, a common mutation in colon cancer patients. LEF1 caused the retention of β-catenin in the nucleus, leading to the activation of the WNT pathway in MYC-expressing cells. Consequently, MYC-expressing cells were sensitive to LEF1 inhibition. Moreover, we describe two examples of genes induced in MYC-expressing cells that require LEF1 activity: the peroxisome proliferator activated receptor delta (PPARδ) and the Acyl CoA dehydrogenase 9 (ACAD9). Conclusions We demonstrated that MYC is a transcriptional regulator of LEF1 in colonic cells. Our work proposes a novel pathway by which MYC regulates proliferation through activating LEF1 expression which in turn activates the WNT pathway. Graphical Abstract

Positive framing has been proposed as an intervention to increase COVID-19 vaccination intentions. However, available research has examined fictitious or unfamiliar treatments. This pre-registered study (aspredicted#78369) compared the effect of standard negatively framed EU patient information leaflets (PILs), with new positively framed PILs, on booster intentions (measured pre- and post-intervention) for AstraZeneca, Pfizer, and Moderna COVID-19 vaccines. A representative sample of 1222 UK-based adults was randomised to one of six groups in a factorial design with framing (Positive vs. Negative) and vaccine familiarity (same (as previous), familiar, unfamiliar) as factors. The benefit of positive framing was hypothesised to be strongest for the least familiar vaccine (Moderna). Framing was moderated by familiarity, where only the unfamiliar vaccine showed a benefit of positive relative to negative Framing. Framing and familiarity also interacted with baseline Intention with the effect of framing on the unfamiliar vaccine especially pronounced at low baseline Intent. Conversely, standard negative framing appeared to increase intentions for familiar vaccines at low baseline intent. Findings provide important evidence that positive framing could improve vaccine uptake globally when switches or new developments require individuals to receive less familiar vaccines. Positive framing of familiar vaccines, however, should be treated with caution until better understood.

Vaccines are powerful tools to develop immune memory to infectious diseases and prevent excess mortality. In older adults, however vaccines are generally less efficacious and the molecular mechanisms that underpin this remain largely unknown. Autophagy, a process known to prevent aging, is critical for the maintenance of immune memory in mice. Here, we show that autophagy is specifically induced in vaccine-induced antigen-specific CD8+ T cells in healthy human volunteers. In addition, reduced IFNγ secretion by RSV-induced T cells in older vaccinees correlates with low autophagy levels. We demonstrate that levels of the endogenous autophagy-inducing metabolite spermidine fall in human T cells with age. Spermidine supplementation in T cells from old donors recovers their autophagy level and function, similar to young donors’ cells, in which spermidine biosynthesis has been inhibited. Finally, our data show that endogenous spermidine maintains autophagy via the translation factor eIF5A and transcription factor TFEB. In summary, we have provided evidence for the importance of autophagy in vaccine immunogenicity in older humans and uncovered two novel drug targets that may increase vaccination efficiency in the aging context.

The internalization of the central nervous system, termed neurulation in vertebrates, is a critical step in embryogenesis. Open questions remain regarding how force propels coordinated tissue movement during the process, and little is known as to how internalization happens in invertebrates. We show that in C. elegans morphogenesis, apical constriction in the retracting pharynx drives involution of the adjacent neuroectoderm. HMR-1/cadherin mediates this process via inter-tissue attachment, as well as cohesion within the neuroectoderm. Our results demonstrate that HMR-1 is capable of mediating embryo-wide reorganization driven by a centrally located force generator, and indicate a non-canonical use of cadherin on the basal side of an epithelium that may apply to vertebrate neurulation. Additionally, we highlight shared morphology and gene expression in tissues driving involution, which suggests that neuroectoderm involution in C. elegans is potentially homologous with vertebrate neurulation and thus may help elucidate the evolutionary origin of the brain.

A small fraction of HIV-1- infected humans develop broadly neutralizing antibodies (bNAbs) against HIV-1 that protect macaques from simian immunodeficiency HIV chimeric virus (SHIV). Similarly, a small number of macaques infected with SHIVs develop broadly neutralizing serologic activity, but less is known about the nature of simian antibodies. Here, we report on a monoclonal antibody, Ab1485, isolated from a macaque infected with SHIVAD8 that developed broadly neutralizing serologic activity targeting the V3-glycan region of HIV-1 Env. Ab1485 neutralizes 38.1% of HIV-1 isolates in a 42-pseudovirus panel with a geometric mean IC50 of 0.055 µg/mLl and SHIVAD8 with an IC50 of 0.028 µg/mLl. Ab1485 binds the V3-glycan epitope in a glycan-dependent manner. A 3.5 Å cryo-electron microscopy structure of Ab1485 in complex with a native-like SOSIP Env trimer showed conserved contacts with the N332gp120 glycan and gp120 GDIR peptide motif, but in a distinct Env-binding orientation relative to human V3/N332gp120 glycan-targeting bNAbs. Intravenous infusion of Ab1485 protected macaques from a high dose challenge with SHIVAD8. We conclude that macaques can develop bNAbs against the V3-glycan patch that resemble human V3-glycan bNAbs.

Seasonal influenza virus A/H3N2 is a major cause of death globally. Vaccination remains the most effective preventative. Rapid mutation of hemagglutinin allows viruses to escape adaptive immunity. This antigenic drift necessitates regular vaccine updates. Effective vaccine strains need to represent H3N2 populations circulating one year after strain selection. Experts select strains based on experimental measurements of antigenic drift and predictions made by models from hemagglutinin sequences. We developed a novel influenza forecasting framework that integrates phenotypic measures of antigenic drift and functional constraint with previously published sequence-only fitness estimates. Forecasts informed by phenotypic measures of antigenic drift consistently outperformed previous sequence-only estimates, while sequence-only estimates of functional constraint surpassed more comprehensive experimentally-informed estimates. Importantly, the best models integrated estimates of both functional constraint and either antigenic drift phenotypes or recent population growth.

The distribution of fitness effects (DFE) defines how new mutations spread through an evolving population. The ratio of non-synonymous to synonymous mutations (dN/dS) has become a popular method to detect selection in somatic cells. However the link, in somatic evolution, between dN/dS values and fitness coefficients is missing. Here we present a quantitative model of somatic evolutionary dynamics that determines the selective coefficients of individual driver mutations from dN/dS estimates. We then measure the DFE for somatic mutant clones in ostensibly normal oesophagus and skin. We reveal a broad distribution of fitness effects, with the largest fitness increases found for TP53 and NOTCH1 mutants (proliferative bias 1–5%). This study provides the theoretical link between dN/dS values and selective coefficients in somatic evolution, and measures the DFE of mutations in human tissues.

Following the introduction of live-attenuated rotavirus vaccines in many countries, a notable reduction in deaths and hospitalisations associated with diarrhoea in children

Filth flies, cockroaches, and dung beetles have been close neighbors with humans and animals throughout our joint histories. However, these insects can also serve as vectors for many zoonotic enteric parasites (ZEPs). Zoonoses by ZEPs remain a paramount public health threat due to our close contact with animals, combined with poor water, sanitation, and hygiene access, services, and behaviors in many global regions. Our objective in this systematic review was to determine which ZEPs have been documented in these vectors, to identify risk factors associated with their transmission, and to provide effectual One Health recommendations for curbing their spread. Using PRISMA guidelines, a total of 85 articles published from 1926 to 2021 were reviewed and included in this study. Qualitative analysis revealed that the most common parasites associated with these insects included, but were not limited to: Ascaris spp., Trichuris spp., Entamoeba spp., and Cryptosporidium spp. Additionally, prominent risk factors discovered in the review, such as poor household and community WASH services, unsafe food handling, and exposure to domestic animals and wildlife, significantly increase parasitic transmission and zoonoses. The risk of insect vector transmission in our shared environments makes it critically important to implement a One Health approach in reducing ZEP transmission.

Brucellosis is a major economic and production-limiting disease for livestock owners and the community in Iraq. A cost–benefit analysis was conducted to evaluate the impact of an expanded annual mass vaccination programme of sheep and goats that involves all female and male sheep and goats over the age of 3 months with Rev. 1 vaccine. The proposed expanded vaccination programme was compared to the current annual vaccination program, which involved only vaccinating female sheep and goats between the ages of 3 and 6 months of age with Rev. 1. The cost-benefit analysis model was developed utilizing data collected in Dohuk Governorate, northern Iraq. The seroprevalence in small ruminants (using Rose Bengal test and ELISA in series) was predicted to decrease from 9.22% to 0.73% after 20 years of implementing the proposed annual mass vaccination program. The net present value of the mass vaccination program was estimated to be US$ 10,564,828 (95% Confidence Interval (CI): −16,203,454 to 37,049,245), the benefit–cost ratio was estimated to be 4.25 (95% CI: −2.71 to 11.22), and the internal rate of return was 91.38% (95% CI:11.71 to 190.62%). The proposed vaccination strategy was predicted to decrease the overall financial loss caused by brucellosis from 1.75 to 0.55 US$ per adult female animal. The results of this economic analysis highlight the benefit of implementing an annual mass vaccination program of small ruminants with Rev. 1 vaccine to reduce the prevalence of brucellosis in northern Iraq.

Abstract Objective This biomechanical study compared the torsional strength and stiffness of a locking compression plate with all locking versus nonlocking screws and examined the effect of placing a locking unicortical or nonlocking bicortical screw nearest the fracture gap in a synthetic bone model. Results Synthetic bone models simulating a diaphyseal fracture without anatomic reduction were tested using four screw configurations: all bicortical locking (ABL), all bicortical nonlocking (ABN), a hybrid construct with a bicortical nonlocking screw nearest the fracture gap (BN), and a unicortical locking screw placed nearest the fracture gap (UL). Torsional stiffness, rotation and torque at failure were compared via ANOVA and post hoc pairwise comparisons (p

Social visual engagement difficulties are hallmark early signs of autism (ASD) and are easily quantified using eye tracking methods. However, it is unclear how these difficulties are linked to atypical early functional brain organization in ASD. With resting state fMRI data in a large sample of ASD toddlers and other non-ASD comparison groups, we find ASD-related functional hypoconnnectivity between ‘social brain’ circuitry such as the default mode network (DMN) and visual and attention networks. An eye tracking-identified ASD subtype with pronounced early social visual engagement difficulties (GeoPref ASD) is characterized by marked DMN-occipito-temporal cortex (OTC) hypoconnectivity. Increased DMN-OTC hypoconnectivity is also related to increased severity of social-communication difficulties, but only in GeoPref ASD. Early and pronounced social-visual circuit hypoconnectivity is a key underlying neurobiological feature describing GeoPref ASD and may be critical for future social-communicative development and represent new treatment targets for early intervention in these individuals.

Introduction Antipsychotic medication is effective in reducing acute symptoms of psychosis, but it has a range of potentially serious and debilitating adverse effects and is often disliked by patients. It is therefore essential it is only used when benefits outweigh harms. Although multiple trials conducted with people with schizophrenia indicate an increased risk of relapse in the short-term following abrupt antipsychotic discontinuation, there is little evidence about the long-term outcome of a gradual process of reduction and discontinuation on social functioning, relapse and other outcomes.Methods and analysis This is a multicentre, randomised controlled trial involving people with schizophrenia and related disorders who have had more than one episode. Participants are randomised to have a clinically-supervised, gradual reduction of antipsychotic medication, leading to discontinuation when possible, or to continue with maintenance treatment. Blinded follow-up assessments are conducted at 6, 12 and 24 months and the primary outcome is social functioning, measured by the Social Functioning Scale at 24 months. A minimum of 134 evaluable participants provides 90% power to detect a five-point difference, and 206 to detect a four-point difference. Secondary outcomes include severe relapse (admission to hospital) and the study is also intended to detect a minimum 10% difference in severe relapse, which requires 402 participants, assuming a 15% loss to follow-up. Other secondary outcomes include all relapses, as identified by an independent and blinded endpoint committee, symptoms measured by the Positive and Negative Syndrome Scale, quality of life, adverse effects, self-rated recovery and neuropsychological measures. Enrolment started in 2016. The trial is scheduled to finish in June 2022.Ethics and dissemination Ethical approval was initially obtained on 27 October 2016 (UK Research Ethics Committee reference 16/LO/1507). Results will be published in peer-reviewed journals and disseminated to the public.Trial registration number ISRCTN90298520. EudraCT: 2016-000709-36. Pre-results.

Objectives To explore what factors shape a service user’s decision to call an emergency ambulance for a ‘primary care sensitive’ condition (PCSC), including contextual factors. Additionally, to understand the function and purpose of ambulance care from the perspective of service users, and the role health professionals may play in influencing demand for ambulances in PCSCs.Design An ethnographic study set in one UK ambulance service. Patient cases were recruited upon receipt of ambulance treatment for a situation potentially manageable in primary care, as determined by a primary care clinician accompanying emergency medical services (EMS) crews. Methods used included: structured observations of treatment episodes; in-depth interviews with patients, relatives and carers and their GPs; purposeful conversations with ambulance clinicians; analysis of routine healthcare records; analysis of the original EMS ‘emergency’ telephone call recording.Results We analysed 170 qualitative data items across 50 cases. Three cross-cutting concepts emerged as central to EMS use for a PCSC: (1) There exists a typology of nine ‘triggers’, which we categorise as either ‘internal’ or ‘external’, depending on how much control the caller feels they have of the situation; (2) Calling an ambulance on behalf of someone else creates a specific anxiety about urgency; (3) Healthcare professionals experience conflict around fuelling demand for ambulances.Conclusions Previous work suggests a range of sociodemographic factors that may be associated with choosing ambulance care in preference to alternatives. Building on established sociological models, this work helps understand how candidacy is displayed during the negotiation of eligibility for ambulance care. Seeking urgent assistance on behalf of another often requires specific support and different strategies. Use of EMS for such problems—although inefficient—is often conceptualised as ‘rational’ by service users. Public health strategies that seek to advise the public about appropriate use of EMS need to consider how individuals conceptualise an ‘emergency’ situation.

Objectives To determine whether neighbourhood-level socioenvironmental factors including deprivation and inequality predict variance in psychotic symptoms after controlling for individual-level demographics.Design A cross-sectional design was employed.Setting Data were originally collected from secondary care services within the UK boroughs of Ealing, Hammersmith and Fulham, Wandsworth, Kingston, Richmond, Merton, Sutton and Hounslow as part of the West London First-Episode Psychosis study.Participants Complete case analyses were undertaken on 319 participants who met the following inclusion criteria: aged 16 years or over, resident in the study’s catchment area, experiencing a first psychotic episode, with fewer than 12 weeks’ exposure to antipsychotic medication and sufficient command of English to facilitate assessment.Outcome measures Symptom dimension scores, derived from principal component analyses of the Scale for the Assessment of Positive Symptoms and Scale for the Assessment of Negative Symptoms, were regressed on neighbourhood-level predictors, including population density, income deprivation, income inequality, social fragmentation, social cohesion, ethnic density and ethnic fragmentation, using multilevel regression. While age, gender and socioeconomic status were included as individual-level covariates, data on participant ethnicity were not available.Results Higher income inequality was associated with lower negative symptom scores (coefficient=−1.66, 95% CI −2.86 to –0.46, p

Hepatitis C virus (HCV) is a highly variable pathogen that frequently establishes chronic infection. This genetic variability is affected by the adaptive immune response but the contribution of other host factors is unclear. Here, we examined the role played by interferon lambda-4 (IFN-λ4) on HCV diversity; IFN-λ4 plays a crucial role in spontaneous clearance or establishment of chronicity following acute infection. We performed viral genome-wide association studies using human and viral data from 485 patients of white ancestry infected with HCV genotype 3a. We demonstrate that combinations of host genetic variants, which determine IFN-λ4 protein production and activity, influence amino acid variation across the viral polyprotein - not restricted to specific viral proteins or HLA restricted epitopes - and modulate viral load. We also observed an association with viral di-nucleotide proportions. These results support a direct role for IFN-λ4 in exerting selective pressure across the viral genome, possibly by a novel mechanism.

Cellular differentiation requires both activation of target cell transcriptional programs and repression of non-target cell programs. The Myt1 family of zinc finger transcription factors contributes to fibroblast to neuron reprogramming in vitro. Here, we show that ztf-11 (Zinc-finger Transcription Factor-11), the sole Caenorhabditis elegans Myt1 homolog, is required for neurogenesis in multiple neuronal lineages from previously differentiated epithelial cells, including a neuron generated by a developmental epithelial-to-neuronal transdifferentiation event. ztf-11 is exclusively expressed in all neuronal precursors with remarkable specificity at single-cell resolution. Loss of ztf-11 leads to upregulation of non-neuronal genes and reduced neurogenesis. Ectopic expression of ztf-11 in epidermal lineages is sufficient to produce additional neurons. ZTF-11 functions together with the MuvB corepressor complex to suppress the activation of non-neuronal genes in neurons. These results dovetail with the ability of Myt1l (Myt1-like) to drive neuronal transdifferentiation in vitro in vertebrate systems. Together, we identified an evolutionarily conserved mechanism to specify neuronal cell fate by repressing non-neuronal genes.

Objective To summarise the incidental findings detected on brain imaging and blood tests during the first wave of data collection for the Insight 46 study.Design Prospective observational sub-study of a birth cohort.Setting Single-day assessment at a research centre in London, UK.Participants 502 individuals were recruited from the MRC National Survey of Health and Development (NSHD), the 1946 British birth cohort, based on pre-specified eligibility criteria; mean age was 70.7 (SD: 0.7) and 49% were female.Outcome measures Data regarding the number and types of incidental findings were summarised as counts and percentages, and 95% confidence intervals were calculated.Results 93.8% of participants completed a brain scan (n=471); 4.5% of scanned participants had a pre-defined reportable abnormality on brain MRI (n=21); suspected vascular malformations and suspected intracranial mass lesions were present in 1.9% (n=9) and 1.5% (n=7) respectively; suspected cerebral aneurysms were the single most common vascular abnormality, affecting 1.1% of participants (n=5), and suspected meningiomas were the most common intracranial lesion, affecting 0.6% of participants (n=3); 34.6% of participants had at least one abnormality on clinical blood tests (n=169), but few reached the prespecified threshold for urgent action (n=11).Conclusions In older adults, aged 69-71 years, potentially serious brain MRI findings were detected in around 5% of participants, and clinical blood test abnormalities were present in around one third of participants. Knowledge of the expected prevalence of incidental findings in the general population at this age is useful in both research and clinical settings.

In humans, a first-degree family history of dementia (FH) is a well-documented risk factor for Alzheimer’s disease (AD); however, the influence of FH on cognition across the lifespan is poorly understood. To address this issue, we developed an internet-based paired-associates learning (PAL) task and tested 59,571 participants between the ages of 18–85. FH was associated with lower PAL performance in both sexes under 65 years old. Modifiers of this effect of FH on PAL performance included age, sex, education, and diabetes. The Apolipoprotein E ε4 allele was also associated with lower PAL scores in FH positive individuals. Here we show, FH is associated with reduced PAL performance four decades before the typical onset of AD; additionally, several heritable and non-heritable modifiers of this effect were identified.