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Meningiomas are the most common primary intracranial tumors in adults and are increasing in incidence due to the aging population and increased access to neuroimaging. While most exhibit nonmalignant behavior, a subset of meningiomas are biologically aggressive and are associated with treatment resistance, resulting in significant neurologic morbidity and even mortality. In recent years, meaningful advances in our understanding of the biology of these tumors have led to the incorporation of molecular biomarkers into their grading and prognostication. However, unlike other central nervous system (CNS) tumors, a unified molecular taxonomy for meningiomas has not yet been established and remains an overarching goal of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy-Not Official World Health Organization (cIMPACT-NOW) working group. Additionally, clinical equipoise still remains on how specific meningioma cases and patient populations should be optimally managed. To address these existing gaps, members of the International Consortium on Meningiomas including field-leading experts, have prepared this comprehensive consensus narrative review directed toward clinicians, researchers, and patients. Included in this manuscript are detailed overviews of proposed molecular classifications, novel biomarkers, contemporary treatment strategies, trials on systemic therapies, health-related quality-of-life studies, and management strategies for unique meningioma patient populations. In each section, we discuss the current state of knowledge as well as ongoing clinical and research challenges to road map future directions for further investigation.

The global panzootic lineage (GPL) of the pathogenic fungus Batrachochytrium dendrobatidis (Bd) has caused severe amphibian population declines, yet the drivers underlying the high frequency of GPL in regions of amphibian decline are unclear. Using publicly available Bd genome sequences, we identified multiple non-GPL Bd isolates that contain a circular Rep-encoding single-stranded (CRESS)-like DNA virus, which we named Bd DNA virus 1 (BdDV-1). We further sequenced and constructed genome assemblies with long read sequences to find that the virus is integrated into the nuclear genome in some strains. Attempts to cure virus-positive isolates were unsuccessful; however, phenotypic differences between naturally virus-positive and virus-negative Bd isolates suggested that BdDV-1 decreases the growth of its host in vitro but increases the virulence of its host in vivo. BdDV-1 is the first-described CRESS DNA mycovirus of zoosporic true fungi, with a distribution inversely associated with the emergence of the panzootic lineage.

Maturation of the human fetal brain should follow precisely scheduled structural growth and folding of the cerebral cortex for optimal postnatal function1. We present a normative digital atlas of fetal brain maturation based on a prospective international cohort of healthy pregnant women2, selected using World Health Organization recommendations for growth standards3. Their fetuses were accurately dated in the first trimester, with satisfactory growth and neurodevelopment from early pregnancy to 2 years of age4,5. The atlas was produced using 1,059 optimal quality, three-dimensional ultrasound brain volumes from 899 of the fetuses and an automated analysis pipeline6-8. The atlas corresponds structurally to published magnetic resonance images9, but with finer anatomical details in deep grey matter. The between-study site variability represented less than 8.0% of the total variance of all brain measures, supporting pooling data from the eight study sites to produce patterns of normative maturation. We have thereby generated an average representation of each cerebral hemisphere between 14 and 31 weeks gestation with quantification of intracranial volume variability and growth patterns. Emergent asymmetries were detectable from as early as 14 weeks, with peak asymmetries in regions associated with language development and functional lateralization between 20 and 26 weeks gestation. These patterns were validated in 1,487 three-dimensional brain volumes from 1,295 different fetuses in the same cohort. We provide a unique spatiotemporal benchmark of fetal brain maturation from a large cohort with normative postnatal growth and neurodevelopment.

Abstract Background Collaboration between physicians and pharmacists facilitates the conduct of medication optimisation efforts. In the context of deprescribing, pharmacists’ roles are often described as making deprescribing recommendations to physicians. Little is known about factors associated with pharmacists’ willingness to make deprescribing recommendations and their interprofessional collaboration with physicians in Swiss primary care settings. Objective To explore pharmacists' perspectives on medication optimisation and deprescribing in older adults, and their preferences for interprofessional collaboration in Swiss primary care settings. Methods In this cross-sectional study, a random sample of 1000 pharmacist members of the Swiss Pharmacists Association pharmaSuisse was invited to participate in a survey on medication optimisation, deprescribing, and interprofessional collaboration. The survey contained three case vignettes of multimorbid patients with polypharmacy aged ≥ 80 years old, with different levels of dependency in activities in daily living (ADL) and cardiovascular disease (CVD). For each case vignette, pharmacists were asked if and which medications they would deprescribe. We calculated proportions of pharmacists’ willingness to deprescribe by case vignette and performed a multilevel logistic regression to assess associations between CVD, ADL, and willingness to deprescribe. Results One hundred thirty-eight (14%) pharmacists responded to the survey: 113 (82%) were female, their mean age was 44 years (SD = 11), and 66% (n = 77) reported having never received any specific training on how to conduct structured medication reviews. Eighty-three (72%) pharmacists reported to be confident in identifying deprescribing opportunities. All pharmacists were willing to deprescribe ≥ 1 medication in all vignettes. Patients with CVD were at lower odds of having medications deprescribed (OR = 0.27, 95%CI 0.21 to 0.36). Willingness to deprescribe was lower with higher dependency in ADL (medium versus low dependency: OR = 0.68, 95%CI 0.54 to 0.87, high versus low dependency: OR = 0.72, 95%CI 0.56 to 0.91). However, the effect of dependency in ADL on willingness to deprescribe was significantly modified by the history of CVD. One hundred five pharmacists (97%) reported to interact with physicians to clarify questions regarding prescriptions at least once a week and 88 (81%) wished to be more involved in deprescribing and medication review. Conclusion Pharmacists were willing to make deprescribing suggestions for older patients with polypharmacy, but two-thirds reported having received no formal training on how to perform structured medication reviews. Pharmacists would like to be more involved in the process of medication review and deprescribing, which should be leveraged in the context of Swiss primary care settings.

Abstract Background Patients from socioeconomically disadvantaged backgrounds are underserved in randomised controlled trials, yet they experience a much greater burden of disease compared with patients from socioeconomically advantaged areas. It is crucial to make trials more inclusive to ensure that treatments and interventions are safe and effective in real-world contexts. Improving how information about trials is verbally communicated is an unexplored strategy to make trials more inclusive. This study examined how trials are communicated verbally, comparing consultations involving patients from the most and least socioeconomically disadvantaged areas. Methods Secondary qualitative analysis of 55 trial consultation transcripts from 41 patients, sampled from 3 qualitative studies embedded in their respective UK multi-site, cancer-related randomised controlled trials. Patients living in the most and least socioeconomically disadvantaged areas, defined using English Indices of Multiple Deprivation decile scores, were purposively sampled. Analysis was largely thematic and drew on the constant comparison method. Results Recruiters communicated clinical uncertainty in a similar way for patients living in different socioeconomic areas. Consultations with disadvantaged patients were, on average, half the duration of those with advantaged patients, and tended to involve recruiters providing less in-depth explanations of trial concepts, used phrasing that softened trial arm risks, and described trial processes (e.g. randomisation) using informal or metaphorical phrasing. Disadvantaged and advantaged patients differed in the concerns they expressed; disadvantaged patients voiced fewer concerns and asked fewer questions but were also less likely to be invited to do so by recruiters. Conclusion Interactions about trials unfolded in different ways between patients living in different socioeconomic areas, likely due to both patient- and recruiter-related factors. We present considerations for recruiters when discussing trials with patients from socioeconomically disadvantaged backgrounds, aimed at enhancing trial communication. Future research should examine disadvantaged patients’ and recruiters’ experiences of verbal trial communication to inform guidance that addresses the needs and preferences of underserved groups.

Central nervous system (CNS) tumor patients commonly undergo multimodality treatment in the course of their disease. Adverse effects and complications from these interventions have not been systematically studied, but pose significant challenges in clinical practice and impact function and quality of life, especially in the management of long-term brain tumor survivors. Here, the European Association of Neuro-Oncology (EANO) has developed recommendations to prevent, diagnose, and manage adverse effects and complications in the adult primary brain CNS tumor (except lymphomas) patient population with a specific focus on surgery, radiotherapy, and pharmacotherapy. Specifically, we also provide recommendations for dose adaptations, interruptions, and reexposure for pharmacotherapy that may serve as a reference for the management of standard of care in clinical trials. We also summarize which interventions are unnecessary, inactive or contraindicated. This consensus paper should serve as a reference for the conduct of standard therapy within and outside of clinical trials.

Background Current National Health Service policy in England encourages enhanced digital access in primary care service provision. In this study, we investigate ‘digital facilitation’ – that range of processes, procedures and personnel which seeks to support National Health Service primary care patients in their uptake and use of online services. Objectives Identify, characterise and explore the potential benefits and challenges associated with different models of digital facilitation currently in use in general practice which are aimed at improving patient access to online services in general practice in England. Use the resulting intelligence to design a framework for future evaluations of the effectiveness and cost effectiveness of such interventions. Explore how patients with mental health conditions experience digital facilitation and gauge their need for this support. Design Observational mixed-methods study (literature review, surveys, ethnographic observation and interviews); formal synthesis of findings. Setting General practice in four regions of England. Participants Practice survey: 156 staff. Patient survey: 3051 patients. Mental health survey: 756 patients. General practitioner patient survey: 3 million responders. Ethnographic case-studies: 8 practices; interviews with 36 staff, 33 patients and 10 patients with a mental health condition. Stakeholder interviews: 19 participants. Intervention Digital facilitation as undertaken in general practice. Main outcome measures Patient and practice staff reported use of, and views of, digital facilitation. Data sources Surveys, qualitative research; national General Practitioner Patient Survey (2019–22). Review methods Scoping-review methodology applied to academic and grey literature published 2015–20. Results While we did find examples of digital facilitation in routine practice, these often involved using passive or reactive modes of support. The context of COVID, and the necessary acceleration (at that time) of the move to a digital-first model of primary care, shaped the way digital facilitation was delivered. There was lack of clarity over where the responsibility for facilitation efforts lay; it was viewed as the responsibility of ‘others’. Patients living with mental health conditions had similar needs and experiences regarding digital facilitation to other patients. Limitations The context of the COVID pandemic placed limitations on the project. Fewer practices responded to the practice survey than anticipated; reconfiguration of general practices to support COVID measures was a key consideration during non-participant observation with social distancing and other measures still in place during fieldwork. Conclusions Digital facilitation, while not a widely recognised concept, is important in supporting the move to a National Health Service with enhanced digital opportunities and enhanced digital access. General practice staff are allocating resources to provide such efforts in general practices in England. The establishment of clear lines of responsibility, the development of digital tools and platforms that work for patients and practice staff, and investment in staff time and training are needed if digital facilitation is to support the intended digital revolution. Future work We did not find one single dominant or preferred model of digital facilitation which might reasonably be considered to form the basis of an intervention to be tested. Rather, there is a need to co-develop such an intervention with patients, general practice staff and relevant policy experts. We outline a framework for a future evaluation of such an intervention. Study registration This study is registered as ResearchRegistry6523 (www.researchregistry.com/browse-the-registry#home/?view_2_search=Di-Facto&view_2_page=1) and PROSPERO CRD42020189019 (www.crd.york.ac.uk/prospero/display_record.php?RecordID=189019). Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: NIHR128268) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 32. See the NIHR Funding and Awards website for further award information. Plain language summary Background Online services are common in the National Health Service. This research looked at ‘digital facilitation’ in general practices. Digital facilitation is about supporting National Health Service patients in their use of online services. We aimed to understand how much digital facilitation is being used by general practices. We also looked at how digital facilitation happens and if it affects the number of people using online services. Methods We looked at previous research to help us understand what approaches have been used to support patients to use online services. We used surveys to ask staff at general practices what they were already doing, and to ask patients about their experiences. We observed digital facilitation in general practices and spoke to patients and staff to help us understand the benefits and challenges of different approaches. We combined findings from the three stages outlined above to identify key aspects of digital facilitation. All stages of our research included discussions with the project’s patient advisory group. Key findings We found that digital facilitation is seen as important and has many forms. Most general practices are using passive and reactive types of facilitation. An example of passive facilitation, initiated by the service but not involving direct inter-personal interaction, is the use of text messaging relating to ordering of repeat prescriptions online. An example of reactive facilitation is providing a response to a patient-initiated query regarding online access. There is clear scope to develop a more proactive approach to facilitation that actively engages patients. Our research highlights a lack of clarity over who is responsible for digital facilitation. Different people (patients, staff, policy-makers) often think that the responsibility lies with others. Investment in digital facilitation is needed. Tools and platforms for digital facilitation that meet patients’ and general practices’ needs should be developed. Scientific summary Background The NHS is facing the increasing demands of a growing and ageing population, technological progress and changing public expectations. Current NHS policy in England encourages enhanced digital opportunities and enhanced digital access in primary care provision. Drivers behind this move include the assumption that online services lead to improved choice, convenience, and ease of access for users, improved triage systems and streamlining of service delivery. In this research, we addressed ‘digital facilitation’ [digital facilitation (DF)] – ‘that range of processes, procedures and personnel which seeks to support NHS patients in their uptake and use of online services’. We investigated the provision by general practices to support access to NHS online primary care services by their registered patients and carers of those patients. Support in accessing and using services is required at all stages: initial registration for online services; subsequent continued use; and navigating the wide range of NHS online provision. Hence, it is important to understand the extent to which approaches to DF are applied, how they are applied, the impact such efforts have on uptake of online services, and how such uptake may affect patient health and access to healthcare information and services. Aims Identify, characterise and explore the potential benefits and challenges associated with different models of DF currently in use in general practice in England which are aimed at improving patient access to online primary care services. Use the resulting intelligence to design a framework for future evaluations of the effectiveness and cost effectiveness of such interventions. Explore how patients with mental health conditions experience DF and gauge their need for this support. Methods The project comprised four interlinked elements. Initially we undertook a scoping review and narrative synthesis of published literature, seeking to understand and characterise the range, effectiveness and cost effectiveness of models of DF for improving access to online services within health. Searches of academic databases and grey literature published between 2015 and 2020 were undertaken, including snowballing from the publications they cited. We surveyed general practice staff and patients (with an additional boost sample of patients living with mental health conditions, which was in direct response to a National Institute for Health and Care Research commissioning brief) and undertook analyses of data from the national General Practice Patient Survey (GPPS). The practice staff questionnaire included items addressing which online services were being used and what steps had been implemented in practices to promote and support the use of such services. We implemented a sequential mixed mode when inviting staff from 500 general practices to complete the survey online or on paper. The patient questionnaire addressed patients’ familiarity and confidence with information technology (IT) and internet use, their awareness and uptake of online services, and their experiences of any support provided by their practice. Questionnaires were sent by post with the option of replying online or by post. We also analysed responses to questions from the English national GPPSs (2019–22) concerning awareness and use of online booking of appointments, ordering repeat prescriptions and accessing medical records, and additionally the use of online consultations. Logistic regression models were used to examine how the awareness and use of online services, the awareness and use of facilitation efforts, and experience of other support varied by patient characteristics. We undertook a qualitative exploration of DF comprising two elements: focused ethnographic case studies in general practices, and an interview study with key stakeholders. Focused ethnography was used to explore, in-depth, the use of DF in general practices. Eight general practice case study sites were recruited to provide variation in terms of their DF offering, and in terms of a range of practice characteristics (practice setting, deprivation status and size, and the age profile of registered patients). We undertook: non-participant observation of the process of DF and how practice staff and patients/carers interact with different types of DF, semistructured interviews with staff members and patients in each practice, and collected secondary analysis of documentation pertaining to digital services or facilitation within the practice. This was augmented by 10 interviews with patients living with mental health conditions from the case study sites; these sought to explore their experiences of DF. The interview study with key stakeholders sought understanding of the broader context and wider drivers of DF in primary care. We conducted semistructured interviews with stakeholders providing a level of insight beyond individual practices, including policy-makers, commissioners and third- sector organisations. Data from the focused ethnographic case studies and stakeholder interviews were analysed together using thematic analysis. We conducted a synthesis of the evidence generated by each element of the study. We employed Weiss’s approach to theory-based evaluation as a theoretical framework. A pragmatic, iterative and cumulative approach was applied to synthesising the findings from all elements and to developing programme and implementation theories. We triangulated findings, summarising the results in a matrix, which evolved into thematic groupings as the study progressed and as evidence from our work packages (WPs) became available. Findings were brought together in a series of three workshop meetings of researchers and patient/public participants as individual WPs were completed. The synthesis process concluded following an online discussion with national and regional stakeholders. We used the synthesised findings to identify the key aspects of a framework aimed at informing future research on DF. Patient and public involvement and engagement (PPIE) was embedded throughout this research, from the original conception through to the design and conduct of the research, and the synthesis and interpretation of findings. Our team has benefited from a patient co-investigator, a dedicated PPIE co-ordinator, and an actively engaged Patient Advisory Group (PAG). All WPs have worked with the PAG to ensure the research is patient focused and addresses patient needs. The PAG was augmented with additional members with lived experience of mental health conditions to ensure that the additional work focused on patients living with mental health conditions was appropriately framed. Members of the PAG were fully involved as equal voices alongside the research team in the synthesis workshops. Results The synthesis of findings from the literature review, surveys and qualitative work resulted in the identification of 11 thematic groups (distinct from, but incorporating, the results of the qualitative thematic analysis): 3 scene-setting themes relating to the context in which DF takes place, and 8 themes related to types of DF, their implementation and effectiveness. Scene-setting themes: The first theme related to the value and purpose of digital services. The qualitative exploration found that the need for, and value of, digital services are not always clear and that there is a lack of shared understanding or belief about what digital services should achieve. The second theme related to conflation of the digital environment with other routes to access. For example, the qualitative exploration found that digital services can both enable access and be a barrier to access, and that patient priorities are often to navigate the system to access health care, making access a more important concept than DF to many. The third theme related to the impact of the COVID pandemic. Many practices responding to the practice survey reported increased digital service offerings and reduced provision of traditional forms of access. The exception to this was in relation to online appointment booking, where 44% of responding practices reported that they had offered this service pre-pandemic but did not do so at the time of the survey. Furthermore, in the qualitative exploration we found that the pandemic was associated with some initiatives being halted that have not subsequently resumed. Digital facilitation themes: The fourth theme related to how people define and identify DF. While, as a research team, we proposed a definition of digital facilitation, it is not yet a widely recognised concept and the qualitative exploration found that it was often difficult to have a working definition for DF given that it is movable and relative to a person’s circumstance. The fifth theme related to the types of DF. In our literature review, we found a focus on interventions that require practices to actively support patients to use digital services. This was in striking contrast with our practice survey where we found that the majority of practices reported passive and reactive modes of facilitation (e.g. 88% of practices used text messages or e-mails for DF and 91% provided ad hoc support to patients). The sixth theme relates to the differing foci of DF on initial sign-up versus supporting sustained use over time. The majority of research found in our review focused on initial sign-up. While in the patient survey we did find that registration was a substantial barrier (20% of responders to the patient survey cited not knowing how to register or finding registration too difficult as a reason for not using online services), the qualitative exploration found that supporting patients to register was often still reactive. Furthermore, although recognising that DF could go beyond initial sign-up, some practices felt that this was their only required contribution to the task of extending digital access. The seventh theme relates to who delivers facilitation. There was a mismatch between existing evidence identified in WP1, which suggested that general practitioners (GPs) and nurses undertake most facilitation, and our survey and qualitative findings that most facilitation efforts were conducted by receptionists and administrative staff. We also found a ‘bystander effect’, with patients, different staff groups and stakeholders all assuming that responsibility for DF lies elsewhere. The eighth and ninth themes related to the enablers and barriers of DF, respectively. Findings from our qualitative work were consistent with much of what emerged from the literature review. Enablers of DF include someone having specific responsibility for such efforts, with associated funding, time and other resources, platforms that enable easy registration and use, and a clear rationale for the digital services that can be understood by practice and patient (i.e. products that have a ‘good fit’ with what is needed). Barriers to effective facilitation include confusion about who is responsible for DF and why; practices using a variety of digital platforms; lack of consideration for the individual circumstances of patients; and assumptions being made about what people can and cannot do digitally based on stereotypes. In our patient survey, we found very low awareness of DF activities (apart from use of e-mail and text messages). Few (13%) responders to the patient survey reported being given help to use online services, but when that help was given, it was generally rated as useful. The 10th theme focuses on digital access and DF for patient subgroups. Age emerged as a common important dimension across the WPs. The literature review identified that older people may particularly benefit from direct, human support in accessing digital services. In the practice survey, most practices reported targeting older adults. However, in the patient survey we found that older patients were less likely to be aware of or make use of DF and were less likely to be told about or receive help to use digital services. In the qualitative work we found that the age of the individual is perceived to have an impact on both staff and patients’ digital knowledge, understanding, experience and confidence. Responders to the patient survey who were from ethnic minorities had long-term health conditions, did not speak English as a first language, or were in receipt of repeat prescriptions, were more likely to report awareness of and use of (passive) facilitation than other patients. But these groups were also less likely to be told about online services or to have received help to use them. The findings of our work focusing on patients living with mental health conditions were largely concordant with the findings of the main patient survey and qualitative research. There were some differences in the way that specific mental health conditions impacted on individuals’ contact with their practice, and consequently in the use by such individuals of digital services and in their need for DF. Responders in the patient survey mental health sample were more likely to report using digital services and to being aware of DF efforts than were responders to the main survey, but this was largely explained by differences in the sample demographics. The final theme considered the effectiveness of DF. There was no evidence around the cost effectiveness of DF, and the limited existing evidence on effectiveness almost entirely focused on initial sign-up of services. Reflecting this, our qualitative exploration found that some practices focused on the number of patients signed up to a service as evidence of the effectiveness of their facilitation efforts. Conclusions Digital facilitation is important in the context of the move to an NHS-enhanced digital opportunities and enhanced digital access in primary care service provision. Staff are spending time and effort to provide DF in general practices in England. Digital facilitation is viewed to have value and potential to increase the uptake of online services. Digital facilitation can take many forms, though most such efforts are reactive and passive. There is clear scope to develop a more proactive approach to facilitation that actively engages patients. There is currently a disconnect between the expectations and perceptions of what DF is happening and its potential effectiveness, and the reality seen in everyday practice. This is related to a lack of clarity over the responsibility for delivering DF and pressures on the time of general practice staff. Establishing clear lines of responsibility, and the development of digital tools and platforms that work for patients and practice staff, will both be needed, alongside investment in staff time and training, if DF is to deliver on the intended digital revolution. This project set out to explore DF that was already underway, with the potential of identifying good practice. However, we did not find an example of what might form a complete, practical intervention package. Future research should therefore focus on: co-development, involving patients and general practice staff, of DF, seeking to ensure a responsive and adaptive approach improving the presentation of practice websites for patient engagement with the intent of increasing uptake of digital tools and reducing the need for DF the best approaches to tailoring DF to different patient groups and identifying which patient groups are most likely to benefit from such efforts ensuring that the digital exclusion of certain groups, including, but not limited to, older patients, is investigated monitoring the sustained use of online services, not merely initial sign-up. Study registration This study is registered as ResearchRegistry6523 (www.researchregistry.com/browse-the-registry#home/?view_2_search=Di-Facto&view_2_page=1) and PROSPERO CRD42020189019 (www.crd.york.ac.uk/prospero/display_record.php?RecordID=189019). Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: NIHR128268) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 32. See the NIHR Funding and Awards website for further award information.

Objectives To pilot test a co-designed intervention that enhances patient participation in hospital discharge medication communication.Design Pilot randomised controlled trial.Setting One tertiary hospital.Participants Patients who were ≥45 years of age; ≥1 chronic illness and ≥1 regularly prescribed medication that they manage at home were recruited between October 2022 and May 2023. Healthcare professionals on participating units completed surveys.Intervention The co-designed intervention included three websites: a medication search engine, a medication question builder and tools to facilitate medication management at home. Inpatient posters contained QR codes to provide access to these websites.Primary and secondary outcome measures The primary outcomes were the feasibility of study processes and intervention acceptability. Feasibility of study processes was measured in terms of recruitment, fidelity, retention, missing data and contamination. Patients in the intervention group and healthcare professionals on the wards self-reported intervention acceptability. Secondary outcomes were medication understanding, use, self-efficacy and healthcare utilisation.Results 60 patients were recruited and randomised; half in each study group. The intervention was largely delivered as intended, and 99.7% of data collected was complete. In total, 16/59 (27.1%) patients were lost to follow-up 28 days after hospital discharge, and 3 patients in the usual care group reported that they saw the intervention poster prior to hospital discharge. 21 of 24 intervention group patients (87.5%) deemed the intervention acceptable, while half of the healthcare professionals (n=5, 50%) thought it was acceptable.Conclusions We demonstrated that in a future definitive trial, intervention fidelity would be high with little missing data, and patients would likely find the intervention acceptable. Thus, a larger trial may be warranted, as the intervention is implementable and approved by patients. However, additional strategies to increase recruitment and retention of eligible participants are needed. Healthcare professionals may require more preparation for the intervention to enhance their perceptions of intervention acceptability.Trial registration number ACTRN12622001028796.

Background: Falls are common among people with intellectual disabilities. Many falls happen within the home. Our scoping review aimed to identify evidence for falls-risk factors and falls-prevention interventions for this population. Method: We conducted a multi-database search to identify any type of published study that explored falls-risk factors or falls-prevention interventions for people with intellectual disabilities. Following a process of (i) title & abstract and (ii) full-text screening, data was extracted from the included studies and described narratively. Results: Forty-one studies were included. Risks are multifactorial. There was limited evidence of medical, behavioural/psychological, or environmental interventions to address modifiable risk factors, and no evidence of the interventions' cost-effectiveness. Conclusions: Clinically and cost effective, acceptable and accessible falls-prevention pathways should be available for people with intellectual disabilities who are at risk of falls from an earlier age than the general population.

Abstract Background X-chromosome inactivation (XCI) is an epigenetic process that occurs during early development in mammalian females by randomly silencing one of two copies of the X chromosome in each cell. The preferential inactivation of either the maternal or paternal copy of the X chromosome in a majority of cells results in a skewed or non-random pattern of X inactivation and is observed in over 25% of adult females. Identifying skewed X inactivation is of clinical significance in patients with suspected rare genetic diseases due to the possibility of biased expression of disease-causing genes present on the active X chromosome. The current clinical test for the detection of skewed XCI relies on the methylation status of the methylation-sensitive restriction enzyme (Hpall) binding site present in proximity of short tandem polymorphic repeats on the androgen receptor (AR) gene. This approach using one locus results in uninformative or inconclusive data for 10–20% of tests. Further, recent studies have shown inconsistency between methylation of the AR locus and the state of inactivation of the X chromosome. Herein, we develop a method for estimating X inactivation status, using exome and transcriptome sequencing data derived from blood in 227 female samples. We built a reference model for evaluation of XCI in 135 females from the GTEx consortium. We tested and validated the model on 11 female individuals with different types of undiagnosed rare genetic disorders who were clinically tested for X-skew using the AR gene assay and compared results to our outlier-based analysis technique. Results In comparison to the AR clinical test for identification of X inactivation, our method was concordant with the AR method in 9 samples, discordant in 1, and provided a measure of X inactivation in 1 sample with uninformative clinical results. We applied this method on an additional 81 females presenting to the clinic with phenotypes consistent with different hereditary disorders without a known genetic diagnosis. Conclusions This study presents the use of transcriptome and exome sequencing data to provide an accurate and complete estimation of X-inactivation and skew status in a cohort of female patients with different types of suspected rare genetic disease.

Motor sequence learning gradually quickens reaction time, suggesting that sequence learning alters motor preparation processes. Interestingly, evidence has shown that preparing sequence movements decreases short intracortical inhibition (SICI) in the contralateral motor cortex (M1), but also that sequence learning alters motor preparation processes in both the contralateral and ipsilateral M1s. Therefore, one possibility is that sequence learning alters the SICI decreases occurring during motor preparation in bilateral M1s. To examine this, two novel hypotheses were tested: unilateral sequence preparation would decrease SICI in bilateral M1s, and sequence learning would alter such bilateral SICI responses. Paired-pulse transcranial magnetic stimulation was delivered over the contralateral and ipsilateral M1s to assess SICI in an index finger muscle during the preparation of sequences initiated by either the right index or little finger. In the absence of sequence learning, SICI decreased in both the contralateral and ipsilateral M1s during the preparation of sequences initiated by the right index finger, suggesting that SICI decreases in bilateral M1s during unilateral motor preparation. As sequence learning progressed, SICI decreased in the contralateral M1 whilst it increased in the ipsilateral M1. Moreover, these bilateral SICI responses were observed at the onset of motor preparation, suggesting that sequence learning altered baseline SICI levels rather than the SICI decreases occurring during motor preparation per se. Altogether, these results suggest that SICI responses in bilateral M1s reflect two motor processes: an acute decrease of inhibition during motor preparation, and a cooperative but bidirectional shift of baseline inhibition levels as sequence learning progresses.

The Global Panzootic Lineage (GPL) of the pathogenic fungus Batrachochytrium dendrobatidis ( Bd ) has caused severe amphibian population declines, yet the drivers underlying the high frequency of GPL in regions of amphibian decline are unclear. Using publicly available Bd genome sequences, we identified multiple non-GPL Bd isolates that contain a circular Rep-encoding single stranded DNA-like virus which we named BdDV-1. We further sequenced and constructed genome assemblies with long read sequences to find that the virus is likely integrated into the nuclear genome. Attempts to cure virus positive isolates were unsuccessful, however, phenotypic differences between naturally virus positive and virus negative Bd isolates suggested that BdDV-1 decreases the growth of its host in vitro but increases the virulence of its host in vivo . BdDV-1 is the first described CRESS DNA mycovirus to increase host virulence with a distribution inversely associated with the emergence of the panzootic lineage.

Background As diagnostic tests for COVID-19 were broadly deployed under Emergency Use Authorization, there emerged a need to understand the real-world utilization and performance of serological testing across the United States. Methods Six health systems contributed electronic health records and/or claims data, jointly developed a master protocol, and used it to execute the analysis in parallel. We used descriptive statistics to examine demographic, clinical, and geographic characteristics of serology testing among patients with RNA positive for SARS-CoV-2. Results Across datasets, we observed 930,669 individuals with positive RNA for SARS-CoV-2. Of these, 35,806 (4%) were serotested within 90 days; 15% of which occurred 30%) in some datasets—limiting our ability to examine differences in serological testing by race. In datasets where race/ethnicity information was available, we observed a greater distribution of White individuals among those serotested; however, the time between RNA and serology tests appeared shorter in Black compared to White individuals. Test manufacturer data was available in half of the datasets contributing to the analysis. Conclusion Our results inform the underlying context of serotesting during the first year of the COVID-19 pandemic and differences observed between claims and EHR data sources–a critical first step to understanding the real-world accuracy of serological tests. Incomplete reporting of race/ethnicity data and a limited ability to link test manufacturer data, lab results, and clinical data challenge the ability to assess the real-world performance of SARS-CoV-2 tests in different contexts and the overall U.S. response to current and future disease pandemics.

Background Real-world performance of COVID-19 diagnostic tests under Emergency Use Authorization (EUA) must be assessed. We describe overall trends in the performance of serology tests in the context of real-world implementation. Methods Six health systems estimated the odds of seropositivity and positive percent agreement (PPA) of serology test among people with confirmed SARS-CoV-2 infection by molecular test. In each dataset, we present the odds ratio and PPA, overall and by key clinical, demographic, and practice parameters. Results A total of 15,615 people were observed to have at least one serology test 14–90 days after a positive molecular test for SARS-CoV-2. We observed higher PPA in Hispanic (PPA range: 79–96%) compared to non-Hispanic (60–89%) patients; in those presenting with at least one COVID-19 related symptom (69–93%) as compared to no such symptoms (63–91%); and in inpatient (70–97%) and emergency department (93–99%) compared to outpatient (63–92%) settings across datasets. PPA was highest in those with diabetes (75–94%) and kidney disease (83–95%); and lowest in those with auto-immune conditions or who are immunocompromised (56–93%). The odds ratios (OR) for seropositivity were higher in Hispanics compared to non-Hispanics (OR range: 2.59–3.86), patients with diabetes (1.49–1.56), and obesity (1.63–2.23); and lower in those with immunocompromised or autoimmune conditions (0.25–0.70), as compared to those without those comorbidities. In a subset of three datasets with robust information on serology test name, seven tests were used, two of which were used in multiple settings and met the EUA requirement of PPA ≥87%. Tests performed similarly across datasets. Conclusion Although the EUA requirement was not consistently met, more investigation is needed to understand how serology and molecular tests are used, including indication and protocol fidelity. Improved data interoperability of test and clinical/demographic data are needed to enable rapid assessment of the real-world performance of in vitro diagnostic tests.

Objectives . The role of race in late preterm respiratory morbidity has not been adequately described. We aimed to determine whether neonatal respiratory morbidity differs between Black and White late preterm infants. Methods . Single-centre retrospective cohort study at King’s College Hospital NHS Foundation Trust, London, UK of infants born at 34 to

Molecular visualization is a powerful way to represent the complex structure of molecules and their higher order assemblies, as well as the dynamics of their interactions. Although conventions for depicting static molecular structures and complexes are now well established and guide the viewer’s attention to specific aspects of structure and function, little attention and design classification has been devoted to how molecular motion is depicted. As we continue to probe and discover how molecules move - including their internal flexibility, conformational changes and dynamic associations with binding partners and environments - we are faced with difficult design challenges that are relevant to molecular visualizations both for the scientific community and students of cell and molecular biology. To facilitate these design decisions, we have identified twelve molecular animation design principles that are important to consider when creating molecular animations. Many of these principles pertain to misconceptions that students have primarily regarding the agency of molecules, while others are derived from visual treatments frequently observed in molecular animations that may promote misconceptions. For each principle, we have created a pair of molecular animations that exemplify the principle by depicting the same content in the presence and absence of that design approach. Although not intended to be prescriptive, we hope this set of design principles can be used by the scientific, education, and scientific visualization communities to facilitate and improve the pedagogical effectiveness of molecular animation.

Summary: Research has examined the relationship between interoception and anxiety, depression, and psychosis; however, it is unclear which aspects of interoception have been systematically examined, what the combined findings are, and which areas require further research. To answer these questions, we systematically searched and narratively synthesised relevant reviews, meta-analyses, and theory papers (total n = 34). Existing systematic reviews and meta-analyses (anxiety n = 2; depression n = 2; psychosis n = 0), focus on cardiac interoceptive accuracy (heartbeat perception), and indicate that heartbeat perception is not systematically impaired in anxiety or depression. Heartbeat perception might be poorer in people with psychosis, but further evidence is needed. Other aspects of interoception, such as different body systems and processing levels, have been studied but not systematically reviewed. We highlight studies examining these alternative bodily domains and levels, review the efficacy of interoception-based psychological interventions, and make suggestions for future research. Funding: Wellcome Trust UK.

Aims This re-audit of rapid tranquillisation (RT) practices in patients over the age of 65 at a district general hospital took place as part of a wider quality improvement project to assess whether practices had improved following previous audits. Methods Data was accessed using the hospital's electronic patient record system. Drug charts for patients over 65 admitted to six wards (total n = 172) were reviewed. The wards comprised three geriatric wards, two medical wards, and one surgical ward. Drug charts were reviewed using the audit tool developed in previous audits, which has been designed to collect relevant data according to the recognised standard (in this case the local mental health trust's RT guidance). Data was collected on RT type, RT frequency of RT, RT route, indication documentation, post-RT monitoring, nature of prescription (PRN, stat, or regular), underlying diagnosis of delirium or dementia, and involvement of specialist teams. Results •Of the 172 audited patients, 9 (5.2%) received RT, compared with 13 out of 297 (4.3%) in the previous 2022 audit. •PRN remained the most common prescription pattern, with two designated as stat and the remaining three mostly stat but occasionally incorporating PRN. Intramuscular administration continued to be the most common route in both cycles. •In the current cycle, the maximum frequency was indicated in 55.5% of cases, whereas it was not indicated in the previous cycle. •In the current cycle, indications were documented for 88.8% of prescriptions, a significant increase from 50% in the previous cycle. Furthermore, there was almost 100% compliance in nursing/medical documentation of RT administration in patient notes, which was lacking in the previous audit. •Psych liaison or dementia team involvement was observed in around 33% of cases in the current cycle, whereas it was not evident in the previous cycle. •Post-sedation monitoring in line with policy was not evident in either cycle. Conclusion Overall, both audits highlighted consistent challenges in prescription practices and post-administration monitoring, albeit with variations in compliance levels and team involvement. Since the completion of this re-audit, a new RT policy has been approved which has much clearer guidance for the general hospital. This RT policy will be launched with a programme of teaching and training for the hospital. We aim to track progress by conducting a re-audit within 6–12 months.

Patients with anorexia nervosa (AN) typically hold altered beliefs about their body that they struggle to update, including global, prospective beliefs about their ability to know and regulate their body and particularly their interoceptive states. While clinical questionnaire studies have provided ample evidence on the role of such beliefs in the onset, maintenance, and treatment of AN, psychophysical studies have typically focused on perceptual and ‘local’ beliefs. Across two experiments, we examined how women at the acute AN (N = 86) and post-acute AN state (N = 87), compared to matched healthy controls (N = 180) formed and updated their self-efficacy beliefs retrospectively (Experiment 1) and prospectively (Experiment 2) about their heartbeat counting abilities in an adapted heartbeat counting task. As preregistered, while AN patients did not differ from controls in interoceptive accuracy per se, they hold and maintain ‘pessimistic’ interoceptive, metacognitive self-efficacy beliefs after performance. Modelling using a simplified computational Bayesian learning framework showed that neither local evidence from performance, nor retrospective beliefs following that performance (that themselves were suboptimally updated) seem to be sufficient to counter and update pessimistic, self-efficacy beliefs in AN. AN patients showed lower learning rates than controls, revealing a tendency to base their posterior beliefs more on prior beliefs rather than prediction errors in both retrospective and prospective belief updating. Further explorations showed that while these differences in both explicit beliefs, and the latent mechanisms of belief updating, were not explained by general cognitive flexibility differences, they were explained by negative mood comorbidity, even after the acute stage of illness.

Background: In recent years, there has been increasing research in the applications of Artificial Intelligence in the medical industry. Digital pathology has seen great success in introducing the use of technology in the digitisation and analysis of pathology slides to ease the burden of work on pathologists. Digitised pathology slides, otherwise known as whole slide images, can be analysed by pathologists with the same methods used to analyse traditional glass slides. Methods: The digitisation of pathology slides has also led to the possibility of using these whole slide images to train machine learning models to detect tumours. Patch-based methods are common in the analysis of whole slide images as these images are too large to be processed using normal machine learning methods. However, there is little work exploring the effect that the size of the patches has on the analysis. A patch-based whole slide image analysis method was implemented and then used to evaluate and compare the accuracy of the analysis using patches of different sizes. In addition, two different patch sampling methods are used to test if the optimal patch size is the same for both methods, as well as a downsampling method where whole slide images of low resolution images are used to train an analysis model. Results: It was discovered that the most successful method uses a patch size of 256 × 256 pixels with the informed sampling method, using the location of tumour regions to sample a balanced dataset. Conclusion: Future work on batch-based analysis of whole slide images in pathology should take into account our findings when designing new models.

Abstract Background Glioblastoma (GBM) brain tumors lacking IDH1 mutations (IDHwt) have the worst prognosis of all brain neoplasms. Patients receive surgery and chemoradiotherapy but tumors almost always fatally recur. Results Using RNA sequencing data from 107 pairs of pre- and post-standard treatment locally recurrent IDHwt GBM tumors, we identify two responder subtypes based on longitudinal changes in gene expression. In two thirds of patients, a specific subset of genes is upregulated from primary to recurrence (Up responders), and in one third, the same genes are downregulated (Down responders), specifically in neoplastic cells. Characterization of the responder subtypes indicates subtype-specific adaptive treatment resistance mechanisms that are associated with distinct changes in the tumor microenvironment. In Up responders, recurrent tumors are enriched in quiescent proneural GBM stem cells and differentiated neoplastic cells, with increased interaction with the surrounding normal brain and neurotransmitter signaling, whereas Down responders commonly undergo mesenchymal transition. ChIP-sequencing data from longitudinal GBM tumors suggests that the observed transcriptional reprogramming could be driven by Polycomb-based chromatin remodeling rather than DNA methylation. Conclusions We show that the responder subtype is cancer-cell intrinsic, recapitulated in in vitro GBM cell models, and influenced by the presence of the tumor microenvironment. Stratifying GBM tumors by responder subtype may lead to more effective treatment.

Abstract Background DNA methylation is one of the most stable and well-characterized epigenetic alterations in humans. Accordingly, it has already found clinical utility as a molecular biomarker in a variety of disease contexts. Existing methods for clinical diagnosis of methylation-related disorders focus on outlier detection in a small number of CpG sites using standardized cutoffs which differentiate healthy from abnormal methylation levels. The standardized cutoff values used in these methods do not take into account methylation patterns which are known to differ between the sexes and with age. Results Here we profile genome-wide DNA methylation from blood samples drawn from within a cohort composed of healthy controls of different age and sex alongside patients with Prader–Willi syndrome (PWS), Beckwith–Wiedemann syndrome, Fragile-X syndrome, Angelman syndrome, and Silver–Russell syndrome. We propose a Generalized Additive Model to perform age and sex adjusted outlier analysis of around 700,000 CpG sites throughout the human genome. Utilizing z-scores among the cohort for each site, we deployed an ensemble based machine learning pipeline and achieved a combined prediction accuracy of 0.96 (Binomial 95% Confidence Interval 0.868 $$-$$ - 0.995). Conclusion We demonstrate a method for age and sex adjusted outlier detection of differentially methylated loci based on a large cohort of healthy individuals. We present a custom machine learning pipeline utilizing this outlier analysis to classify samples for potential methylation associated congenital disorders. These methods are able to achieve high accuracy when used with machine learning methods to classify abnormal methylation patterns.

Abstract Background Before COVID-19, people with rare diseases (RD) experienced numerous disparities in quality of life and healthcare access and quality, yet little is known about the experiences of this underserved group during the pandemic. Results During the first wave of the COVID-19 pandemic in the United States, spring and summer of 2020, 759 participants representing 231 unique RDs responded to open-ended questions about the impact of the pandemic on life with a RD, healthcare access, and coping. Qualitative conventional content analysis was used to analyze responses. Identified themes represented positive and negative dimensions of change, including a shock to the (health) system, coping with uncertainty, and the value of social support while isolated. Conclusions Limitations in healthcare access and quality were the most frequently described as impacts of COVID-19. Other major negative impacts included exacerbation of symptoms, psychological distress, and a lack of usual social support and reliable information. However, participants also noted silver linings, especially in healthcare. For some, expanded telehealth enhanced their ability to access medical and mental health providers and RD specialists. Finally, many participants hoped that, by highlighting social and health inequities faced by people with RDs and other minorities, the pandemic would prompt greater understanding and policies that could improve the quality of life of the RD community.

Abstract Background Neurally adjusted ventilatory assist (NAVA) is a mode of mechanical ventilation that delivers oxygen pressures in proportion to electrical signals of the diaphragm. The proportional assistance can be adjusted by the clinician to reduce the patient’s work of breathing. Several case series of infants with congenital diaphragmatic hernias (CDH) have shown that NAVA may reduce oxygenation index and mean airway pressures. To date, no clinical trial has compared NAVA to standard methods of mechanical ventilation for babies with CDH. Methods The aim of this dual-centre randomised cross-over trial is to compare post-operative NAVA with assist control ventilation (ACV) for infants with CDH. If eligible, infants will be enrolled for a ventilatory support tolerance trial (VSTT) to assess their suitability for randomisation. If clinically stable during the VSTT, infants will be randomised to receive either NAVA or ACV first in a 1:1 ratio for a 4-h period. The oxygenation index, respiratory severity score and cumulative sedative medication use will be measured. Discussion Retrospective studies comparing NAVA to ACV in neonates with congenital diaphragmatic hernia have shown the ventilatory mode may improve respiratory parameters and benefit neonates. To our knowledge, this is the first prospective cross-over trial comparing NAVA to ACV. Trial registration NAN-C was prospectively registered on ClinicalTrials.gov NCT05839340 Registered on May 2023