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Background: Providing care and support for a person with intellectual disabilities can be challenging and may negatively impact on family carers' health and wellbeing. A online support programme was co-designed with charitable organisations and family carers, to help meet the mental health and wellbeing needs of family carers. Objective: To test the acceptability of a newly developed online support programme for carers of people with profound and multiple intellectual disabilities. Methods: A sequential mixed-methods explanatory design was utilised. An adapted version of the Acceptability of Health Apps among Adolescents Scale was distributed to family carers across the United Kingdom and Ireland who had viewed the Carers-ID.com intervention. Participants were then invited to take part in an online interview. Qualitative and quantitative data were analysed separately and then brought together through the triangulation protocol. Results: Seventy family carers (47 female, 23 male) responded to the acceptability survey, with 10 (7 female, 3 male) taking part in interviews. Carers expressed high levels of programme acceptability (mean = 75.43 out of 88). Six themes were generated from interviews with family carers; i) time is precious, ii) the breadth and depth of module content, iii) it was somebody's experience; it was meaningful, iv) won't work for everyone, v) representation: people I could identify with, and vi) module specific suggestions for future changes. Based on our triangulation, four areas of convergence were identified: programme usability and ease, attitudes towards the programme, perceptions of effectiveness, and programme relatability. Conclusions: To be acceptable, online interventions for carers of people with intellectual disability need to be accessible, understandable and easy to use, as carers' free time can be limited. It would be important to investigate the effectiveness of online interventions for family carers, specifically considering which carers the intervention works for, and for whom it may not. [ABSTRACT FROM AUTHOR]

To demonstrate the blockage of uterine arteries on uterus for laparoscopic myomectomy. Video presentation. Patient consent was obtained. A tertiary referral center and teaching hospital. A 31 years old female, G 0 P 0 , with complaining of AUB-L. She has PSH of umbilical hernia repair. Thorough preoperative counselling was conducted and the patient desired minimally invasive surgical intervention. The patient understood that power morcellation is not allowed in our practice. Laparoscopic myomectomy was performed. The total operative time was about 200 min. The EBL was 100 cc and the specimen weighted 830 grams. The patient was discharged at POD#1. Blockage of uterine arteries from anterior cul-de-sac is accessible and effective to minimize bleeding during myomectomy. [ABSTRACT FROM AUTHOR]

To demonstrate the results and surgical techniques of laparoscopic hysterectomy for extreme large uterus. Video presentation. Patient consent was obtained. A tertiary referral center and teaching hospital. A 46 years old female with complaining of AUB-L and bulk symptoms. She has no PMH or PSH. BMI was 45 and uterus was about 35 weeks size on examination. Thorough preoperative counseling was conducted and the patient desired minimally invasive surgical intervention. The patient understood the minimal possibility of occult uterine sarcoma and agreed to specimen extraction without containment. The patient understood that power morcellation is not allowed in our practice. Laparoscopic hysterectomy was performed. The total operative time was about 5 hours. The EBL was 50 cc and the specimen weighted 3064 grams. The patient was discharged at POD#1. Laparoscopic hysterectomy on extreme large uterus is feasible, safe and beneficial to patients. [ABSTRACT FROM AUTHOR]

Three behaviour types – suicide, trespass and risky behaviours, which can result in entry to railway tracks – present an ongoing challenge to the rail industry for fatality prevention. Many preventative interventions exist, operating at different stages in the timeline of a person's decision to access the tracks to the point that they have entered and remain in the track area. However, there is little understanding of the impacts of interventions on the behaviours in question. This paper outlines the generation of the functional requirements for the use of lighting as safety interventions, which can contribute towards the development and evaluation of such interventions. The study includes the analysis of literature on how lighting has been used to date in the prevention of suicide, trespass and other risky behaviour on railway property. Interviews were carried out with 13 key stakeholders who have expertise in the behaviours in question and awareness of the range of safety interventions used in practice in railway settings. The analysis explores how lighting can be used to influence these different behaviour types. Functionalities that are both theoretically and empirically promising are identified. These functionalities include the need for reactive environmental changes, novelty, ability to influence decision-making and ability to support a human response, for example, through highlighting to staff when someone has entered the tracks. These functionalities offer developers a framework for developing (and subsequently evaluating) a range of novel intervention technologies, which could highlight specific lighting properties that could influence behaviour. [ABSTRACT FROM AUTHOR]

Features of lighting that can influence people's behaviours have been identified in an earlier study, along with six scenarios where these could be applied to solve problems with movements through railway stations. The current paper describes the development and testing of novel lighting interventions for three of these scenarios, with two new products controlled by the Internet of Things technology integrated with operational railway systems. The first uses projected light to indicate preferred platform waiting locations. The second uses chasing light-emitting diode lighting along a staircase to encourage bi-directional movements. The field study has been carried out in real-world operational railway settings. An evaluation has been based on a theory-based approach to consider whether the lighting functions as intended and whether people react in anticipated ways. The study found that the lighting interventions have been successfully implemented, and there are indications of favourable responses from passengers, though these have been small effects. The approach to evaluation also assists with diagnosis of weaknesses in the initial concepts and determination of the situational factors that can compete with the behaviour influencing effect of the lighting. This enables refinement and further product development. Practical challenges in implementing trials in this type of operational setting have been identified. [ABSTRACT FROM AUTHOR]

This paper investigates the air dense medium fluidized bed (ADMFB) as a suitable dry beneficiation technique to upgrade +5.6 mm-13.2 mm South African coal. The separation efficiency of the ADMFB was assessed by determining the effect, if any, of particle size range, medium to coal feed ratios, and the addition of vibration on the separation ability of the bed. The coal was upgraded to varying degrees, depending on the parameters of the applied methods. For example, when considering the bottom bed layer (one quarter of the total bed height) as discard, the cumulative ash yield of the clean coal fraction ranged between 13.0% and 17.6% with a corresponding yield of 82.21%–83.93%, respectively. A variation in feed coal PSD did not significantly influence the response of the bed pertaining to its ability to beneficiate the coal. This was quantified by the similarity in percentage ash yield for the feed, top and bottom layers. In addition, it was established that by feeding a coal and magnetite (+300 µm) mixture, in various mass ratios, did not significantly influence the separation efficiency of the bed, nor did the application of external vibration to the bed aid in the beneficiation of the coal. Although these factors did not influence the performance of the ADMFB, it was found that the minimum fluidization velocity and bed stability were largely improved by the introduction of these variables. [ABSTRACT FROM AUTHOR]

Introduction: Adolescents and young adults (AYA) are a unique subgroup of patients who experience cancer at the interface between pediatric and adult oncology services. Central nervous system (CNS) tumors are the leading cause of cancer-related morbidity and mortality in this group. Socioeconomic status and ethnicity are known to impact CNS tumor survival in patients of all ages. Studies reporting AYA CNS survival outcomes by ethnicity and area-based deprivation, however, are lacking in the United Kingdom (UK). Methods: Using cancer registration data for 351 patients (12-29 years) who received systemic chemotherapy for a high-grade malignant CNS tumor in England between April 2014 and December 2018, we quantified differences in survival at 1, 2, and 3 years post-diagnosis by ethnicity and area-based socioeconomic status. Results: Lower survival estimates were seen for non-White ethnicity and lower socioeconomic groups. Three-year survival was 64.4% (95% CI 58.3-69.9) for White patients but 46.6% (95% CI 29.9-61.7) for non-Whites and 64.0% (95% confidence interval [CI] 49.0-75.7) and 62.9% (95% CI 50.7-72.8) in those from the two least deprived fifths compared to 50.2% (95% CI 36.1-62.7) and 56.1% (95% CI 42.4-67.7) in the two most deprived groups. Conclusion: Our study is the first to show the existence of health disparities in AYA treated with chemotherapy for a primary CNS tumor in England, where patients from ethnic minorities and deprived areas had worse survival rates than their White and socioeconomically advantaged counterparts. These findings call for further research into the underlying reasons behind survival differences between sociodemographic groups to improve survivorship outcomes.

Background: Women with polycystic ovary syndrome (PCOS) experience higher rates of depression and anxiety. There is limited research relating to perinatal mental health in women with PCOS. Studies suggest PCOS is associated with a higher prevalence of perinatal mental health disorders. Perinatal guidelines currently do not recognise PCOS as a risk factor for perinatal mental health disorders. We aimed to prospectively assess the prevalence of mental health disorders in pregnant women with PCOS., Methods: Consenting pregnant women, with and without PCOS, were invited to participate. Standardised validated questionnaires were carried out including Generalised Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9) and Edinburgh Postnatal Depression Scale (EPDS)., Results: Fifty-one with PCOS and 49 without PCOS responded. Pregnant women with PCOS had a higher mean (SD) anxiety score (GAD-7) than those without PCOS (8.2 [6.7] vs. 5.89 [4.7], p = 0.04). Pregnant women with PCOS had higher mean (SD) depression scores than those without PCOS on EPDS (9.1 [6.4] vs. 6.4 [4.5], p = 0.02) but not PHQ-9 score (median (IQR) 4 (3-9) vs. 4 (2-7.5), p = 0.25). Women with PCOS were more likely to experience moderate/severe anxiety (PCOS 34%, control 20%) and moderate/severe depression (PCOS 34%, control 20%) symptoms than women without PCOS. Twenty-nine percent of pregnant women with PCOS had an EPDS score >13 showing significantly higher rates of severe depression (PCOS 29%, control 12%, p = 0.03)., Conclusion: Our findings suggest a higher prevalence of perinatal depression and anxiety in women with PCOS. Our findings may suggest increased need for screening for mental health disorders in women with PCOS.

Competing Interests: No funding has been received to write this article. DS is funded by Strong-AYA, an academic research grant from Horizon Europe. DS has also received travel and accommodation reimbursement from the European Society of Medical Oncology Educational committee in 2022 and 2024 and has unpaid roles as the Chair for the European Network for Teenagers and Young Adults with Cancer, and is Chair for the Teenage and Young Adult Cancer research committee for teenage and young adult cancer and germ cell tumours. NH holds a National Institute for Health and Care Research academic clinical lectureship. RF declares no competing interests.

Background: Less than 50% of stroke survivors regain their pre-stroke level of upper limb function, compounded with a lack of long-term rehabilitation options available. The Graded Repetitive Arm Supplementary Programme (GRASP) is an evidence-based upper limb programme delivered as a standalone programme to stroke survivors. To improve access to such a programme, there is the potential to combine it with a high-utility community-based exercise programme, such as the post-rehabilitation enablement programme (PREP). We aimed to establish if this was feasible to deliver alongside the experience of stroke survivors and therapists, identify any refinements the intervention and the acceptability of the intervention and trial procedures., Methods: A cluster feasibility-controlled trial was conducted using both quantitative and qualitative outcome measures with stroke survivors who were discharged from NHS care. Participants completed PREP for 6 weeks (control), with the intervention group also completing GRASP. The GRASP intervention was refined in between five iterative testing cycles. Focus groups with participants explored the acceptability and feasibility. Individual interviews with intervention therapists explored how feasible it was to embed the intervention into practice, and determine the feasibility of a future larger, mixed methods, randomised controlled trial. Clinical endpoints for upper limb and overall function were explored through the Rating of Everyday Arm use in the Community and Home, 10-metre walk test (10MWT) and quality of life via the Shortened Edinburgh Warwick questionnaire. No further suggestions for intervention design were noted after cycle 4., Results: Recruitment (n=72) and retention levels (84.7%) were high with 61 participants (mean age of 66 years and 49 weeks post-stroke) completing the study. Participants and therapists reported positive acceptability of the intervention with goal setting and family support noted as beneficial. The home exercise programme was noted as challenging. Participants within both groups demonstrated improvements in clinical measures, with the intervention group demonstrating a greater improvement within the Rating of Everyday Arm-use in the Community and Home and the 10MWT., Conclusion: This study successfully recruited and retained stroke survivors into an upper limb community-based programme. It poses a feasible delivery mechanism to combine evidence-based upper limb approaches with established physical activity programmes in a future large scale and fully powered study., Trial Registration Number: NCT05090163., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This systematic literature review examines the evidence base on the effectiveness of online programmes on the mental health and well-being of family carers of people with intellectual disabilities. Databases (ERIC, Medline, PsycINFO and CINAHL) were searched for intervention studies that considered online interventions for family carers of people with intellectual disabilities. Data were extracted using standardised data extraction tools. Bias was assessed using the Cochrane risk of bias tool for randomised trials (RoB 2). Screening, extraction and assessment of bias were completed independently by two members of the research team. Given the low number of included studies and different outcomes assessed within them, it was not possible to conduct a meta-analysis; therefore, data are presented narratively. Two studies met the criteria to be included in the review. Both studies utilised a feasibility randomised controlled trial methodology. One study found a significant decrease in parental stress, while the other found a significant increase in psychological well-being. Caution must be taken in drawing firm conclusions, given the small sample sizes and low retention rates in both studies. Online programmes seem to offer potential benefits to family carers of people with intellectual disabilities. However, further investigation is needed to examine these programmes, adopting a collaborative approach with family carers.

Background and Objective: When the uterus is or more than 18 to 20 weeks in size, laparotomy but not minimally invasive surgery (MIS) is commonly performed for hysterectomy. It is, however, acknowledged that MIS carries numerous benefits to patients compared to laparotomy. The uterine size should therefore not be an excluding factor for MIS. This study aims to demonstrate the feasibility and benefits of MIS for hysterectomy for large uterus and explain specific techniques employed., Methods: Data from 73 laparoscopic and robotic hysterectomy cases were collected. Cases were divided in two groups based on uterine weight (≥500 g vs <500 g). Estimated blood loss (EBL), operative time, length of hospital stays, and perioperative complications were compared between the groups., Results: The average specimen weight in two groups was 244 ± 102.75 g vs 903 ± 438.18 g ( P  < .01). There was no statistically significant difference in length of hospital stay between the two groups. Only 3 patients were hospitalized for more than one day. There were no instances of conversion to laparotomy, intraoperative or postoperative blood transfusion. There was a statistically significant difference in the EBL (78.19 ± 43.8 ml vs 127.88 ± 69.76 ml, P  < .01) and operative time (180.68 ± 48.36 vs 228.85 ± 53.04 minutes, P  < .01) between the two groups. There were two cases of bladder laceration in the group with uterine weight exceeding 500 g., Conclusion: With advanced surgical skills and the adoption of specific techniques, hysterectomy for large uterus can be performed safely and efficiently by MIS., Competing Interests: Conflicts of interest: The authors report no conflict of interest., (© 2024 by SLS, Society of Laparoscopic & Robotic Surgeons.)

Weaning patients from ventilation in intensive care units (ICU) is a complex task. There is a growing desire to build decision-support tools to help clinicians during this process, especially those employing Artificial Intelligence (AI). However, tools built for this purpose should fit within and ideally improve the current work environment, to ensure they can successfully integrate into clinical practice. To do so, it is important to identify areas where decision-support tools may aid clinicians, and associated design requirements for such tools. This study analysed the work context surrounding the weaning process from mechanical ventilation in ICU environments, via cognitive task and work domain analyses. In doing so, both what cognitive processes clinicians perform during weaning, and the constraints and affordances of the work environment itself, were described. This study found a number of weaning process tasks where decision-support tools may prove beneficial, and from these a set of contextual design requirements were created. This work benefits researchers interested in creating human-centred decision-support tools for mechanical ventilation that are sensitive to the wider work system., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Dissociation is a multifaceted phenomenon that occurs in various mental disorders, including borderline personality disorder (BPD), but also in non-clinical populations. Severity of childhood trauma (abuse, neglect) plays an important role in the development of dissociation and BPD. However, the complex interplay of different dissociative symptoms, BPD features, and self-reported childhood trauma experiences is not yet fully understood. Graph-theoretical network analysis can help to better understand such multivariate interrelations. Objective: This study aimed to investigate associations between self-reported dissociation, BPD features, and childhood trauma experiences using a graph-theoretical approach. Data was collected online via international mental health platforms and research sites. N  = 921 individuals (77.4% female) were included; 40% reported pathological levels of dissociation. Variables were assessed with established psychometric scales (Dissociative Experiences Scale; Personality Assessment Inventory Borderline Features Scale; Childhood Trauma Questionnaire) and analyzed within a partial correlation network. Positive bivariate correlations between all variables were found. When accounting for their mutual influence on each other, dissociation was predominantly connected to BPD features with effect sizes between rp  = .028 and rp  = .126, while still showing a slight unique relationship with physical neglect ( rp  = .044). Findings suggest close associations between dissociative experiences and BPD features. While childhood trauma plays an important role in the development of dissociation and BPD, its recall may not fully explain their current co-occurrence. Prospective studies are needed to shed more light on causal pathways to better understand which factors contribute to dissociation and its link to BPD (features).

Biomedical data are generated and collected from various sources, including medical imaging, laboratory tests and genome sequencing. Sharing these data for research can help address unmet health needs, contribute to scientific breakthroughs, accelerate the development of more effective treatments and inform public health policy. Due to the potential sensitivity of such data, however, privacy concerns have led to policies that restrict data sharing. In addition, sharing sensitive data requires a secure and robust infrastructure with appropriate storage solutions. Here, we examine and compare the centralized and federated data sharing models through the prism of five large-scale and real-world use cases of strategic significance within the European data sharing landscape: the French Health Data Hub, the BBMRI-ERIC Colorectal Cancer Cohort, the federated European Genome-phenome Archive, the Observational Medical Outcomes Partnership/OHDSI network and the EBRAINS Medical Informatics Platform. Our analysis indicates that centralized models facilitate data linkage, harmonization and interoperability, while federated models facilitate scaling up and legal compliance, as the data typically reside on the data generator's premises, allowing for better control of how data are shared. This comparative study thus offers guidance on the selection of the most appropriate sharing strategy for sensitive datasets and provides key insights for informed decision-making in data sharing efforts., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Conservative management is an option for prostate cancer (PCa) patients either with the objective of delaying or even avoiding curative therapy, or to wait until palliative treatment is needed. PIONEER, funded by the European Commission Innovative Medicines Initiative, aims at improving PCa care across Europe through the application of big data analytics., Objective: To describe the clinical characteristics and long-term outcomes of PCa patients on conservative management by using an international large network of real-world data., Design, Setting, and Participants: From an initial cohort of >100 000 000 adult individuals included in eight databases evaluated during a virtual study-a-thon hosted by PIONEER, we identified newly diagnosed PCa cases (n = 527 311). Among those, we selected patients who did not receive curative or palliative treatment within 6 mo from diagnosis (n = 123 146)., Outcome Measurements and Statistical Analysis: Patient and disease characteristics were reported. The number of patients who experienced the main study outcomes was quantified for each stratum and the overall cohort. Kaplan-Meier analyses were used to estimate the distribution of time to event data., Results and Limitations: The most common comorbidities were hypertension (35-73%), obesity (9.2-54%), and type 2 diabetes (11-28%). The rate of PCa-related symptomatic progression ranged between 2.6% and 6.2%. Hospitalization (12-25%) and emergency department visits (10-14%) were common events during the 1st year of follow-up. The probability of being free from both palliative and curative treatments decreased during follow-up. Limitations include a lack of information on patients and disease characteristics and on treatment intent., Conclusions: Our results allow us to better understand the current landscape of patients with PCa managed with conservative treatment. PIONEER offers a unique opportunity to characterize the baseline features and outcomes of PCa patients managed conservatively using real-world data., Patient Summary: Up to 25% of men with prostate cancer (PCa) managed conservatively experienced hospitalization and emergency department visits within the 1st year after diagnosis; 6% experienced PCa-related symptoms. The probability of receiving therapies for PCa decreased according to time elapsed after the diagnosis., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Recent advancements in contact map-based protein three-dimensional (3D) structure prediction have been driven by the evolution of deep learning algorithms. However, the gap in accessible software tools for novices in this domain remains a significant challenge. This study introduces GoFold, a novel, standalone graphical user interface (GUI) designed for beginners to perform contact map overlap (CMO) problems for better template selection. Unlike existing tools that cater more to research needs or assume foundational knowledge, GoFold offers an intuitive, user-friendly platform with comprehensive tutorials. It stands out in its ability to visually represent the CMO problem, allowing users to input proteins in various formats and explore the CMO problem. The educational value of GoFold is demonstrated through benchmarking against the state-of-the-art contact map overlap method, map&#95;align, using two datasets: PSICOV and CAMEO. GoFold exhibits superior performance in terms of TM-score and Z-score metrics across diverse qualities of contact maps and target difficulties. Notably, GoFold runs efficiently on personal computers without any third-party dependencies, thereby making it accessible to the general public for promoting citizen science. The tool is freely available for download for macOS, Linux, and Windows., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Baker, Hughes and Bhattacharya.)

Competing Interests: TL has received an honorarium for a lecture on this topic from Al Sultan United Medical Co and is head of clinical artificial intelligence at Bradford Teaching Hospitals NHS Foundation Trust, and a potential liability sink All other authors report no conflicts of interest

Background: Family carers play a crucial role in supporting the health and well-being of people with intellectual disabilities. Given their role and responsibilities, many family carers experience significant and ongoing stress and mental health difficulties. Programmes and interventions which provide training and support to family carers have been shown to have a positive impact on levels of stress and quality of life. However, these are often face to face which can create barriers to full participation. Online interventions have been shown to offer flexibility in delivery compared with traditional face-to-face approaches. The primary objective of this study is to determine the feasibility of delivering the Carers-ID online intervention, while the secondary outcome is improved mental health in family carers of people with intellectual disabilities., Methods: Family carers (n = 120) will be randomised to receive the intervention (n = 60) or assigned to a wait-list control (n = 60) group. The intervention ( www.Carers-ID.com ) consists of 14 modules which cover topics including the following: promoting resilience, providing peer support, reducing anxiety, managing stress, accessing local supports and managing family conflict and information for siblings who are carers. The intervention has been co-produced with voluntary sector organisations and family carers and tested for acceptability. Primary outcomes for this study include acceptability and feasibility of the outcome measures, recruitment, participation and retention rates and effect sizes. Secondary outcomes will be completed at three time points (baseline, following intervention completion and 3 months after completion). These include the following: the Depression, Anxiety and Stress Scale, the Warwick-Edinburgh Mental Well-being Scale, the Resilience Scale and the Social Connectedness Scale Revised. Participants (n = 12) who have taken part in the intervention arm of the research will be invited to participate in semi-structured interviews as part of the process evaluation., Discussion: The Carers-ID intervention provides an online resource for family carers to support their mental health and well-being and promote their resilience. It represents an affordable and accessible means of delivering such support. Testing the feasibility of the intervention and related trial procedures is required to determine whether a full-scale randomised controlled trial to evaluate the intervention's effectiveness is warranted., Trial Registration: ClinicalTrials.gov : NCT05737823., (© 2024. The Author(s).)

The 17 th Workshop on Recent Issues in Bioanalysis (17 th WRIB) took place in Orlando, FL, USA on June 19-23, 2023. Over 1000 professionals representing pharma/biotech companies, CROs, and multiple regulatory agencies convened to actively discuss the most current topics of interest in bioanalysis. The 17 th WRIB included 3 Main Workshops and 7 Specialized Workshops that together spanned 1 week to allow an exhaustive and thorough coverage of all major issues in bioanalysis of biomarkers, immunogenicity, gene therapy, cell therapy and vaccines.Moreover, in-depth workshops on "EU IVDR 2017/746 Implementation and impact for the Global Biomarker Community: How to Comply with this NEW Regulation" and on "US FDA/OSIS Remote Regulatory Assessments (RRAs)" were the special features of the 17 th edition.As in previous years, WRIB continued to gather a wide diversity of international, industry opinion leaders and regulatory authority experts working on both small and large molecules as well as gene, cell therapies and vaccines to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance, and achieving scientific excellence on bioanalytical issues.This 2023 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2023 edition of this comprehensive White Paper has been divided into three parts for editorial reasons.This publication covers the recommendations on Mass Spectrometry Assays, Regulated Bioanalysis/BMV (Part 1A) and Regulatory Inputs (Part 1B). Part 2 (Biomarkers, IVD/CDx, LBA and Cell-Based Assays) and Part 3 (Gene Therapy, Cell therapy, Vaccines and Biotherapeutics Immunogenicity) are published in volume 16 of Bioanalysis, issues 7 and 8 (2024), respectively.

While current MR-Linac (MRL) treatment workflows utilize a large table overlay during CT simulation to convert indexing between the two machines, we developed a look-up-table (LUT) as an alternative approach. After populating the LUT, index conversion factors were verified at three separate table locations. The resultant root-mean-square isocenter shifts on the MRL were 0.04/0.08 cm, 0.08/0.07 cm, and 0.09/0.08 cm with/without using the table overlay during simulation in the lateral, longitudinal, and vertical directions, respectively, which is within registration tolerance. Clinical implementation of the LUT has resulted in a more efficient MRL treatment workflow while maintaining accurate patient setup., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

The immune response is an energy-demanding process that must be coordinated with systemic metabolic changes redirecting nutrients from stores to the immune system. Although this interplay is fundamental for the function of the immune system, the underlying mechanisms remain elusive. Our data show that the pro-inflammatory polarization of Drosophila macrophages is coupled to the production of the insulin antagonist ImpL2 through the activity of the transcription factor HIF1α. ImpL2 production, reflecting nutritional demands of activated macrophages, subsequently impairs insulin signaling in the fat body, thereby triggering FOXO-driven mobilization of lipoproteins. This metabolic adaptation is fundamental for the function of the immune system and an individual's resistance to infection. We demonstrated that analogically to Drosophila, mammalian immune-activated macrophages produce ImpL2 homolog IGFBP7 in a HIF1α-dependent manner and that enhanced IGFBP7 production by these cells induces mobilization of lipoproteins from hepatocytes. Hence, the production of ImpL2/IGFBP7 by macrophages represents an evolutionarily conserved mechanism by which macrophages alleviate insulin signaling in the central metabolic organ to secure nutrients necessary for their function upon bacterial infection., (© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)

Introduction: Murray Valley encephalitis virus (MVEV) is a mosquito-borne flavivirus known to cause infrequent yet substantial human outbreaks around the Murray Valley region of south-eastern Australia, resulting in significant mortality., Methods: The public health response to MVEV in Victoria in 2022-2023 included a climate informed pre-season risk assessment, and vector surveillance with mosquito trapping and laboratory testing for MVEV. Human cases were investigated to collect enhanced surveillance data, and human clinical samples were subject to serological and molecular testing algorithms to assess for co-circulating flaviviruses. Equine surveillance was carried out via enhanced investigation of cases of encephalitic illness. Integrated mosquito management and active health promotion were implemented throughout the season and in response to surveillance signals., Findings: Mosquito surveillance included a total of 3,186 individual trapping events between 1 July 2022 and 20 June 2023. MVEV was detected in mosquitoes on 48 occasions. From 2 January 2023 to 23 April 2023, 580 samples (sera and CSF) were tested for flaviviruses. Human surveillance detected 6 confirmed cases of MVEV infection and 2 cases of "flavivirus-unspecified." From 1 September 2022 to 30 May 2023, 88 horses with clinical signs consistent with flavivirus infection were tested, finding one probable and no confirmed cases of MVE., Discussion: The expanded, climate-informed vector surveillance system in Victoria detected MVEV in mosquitoes in advance of human cases, acting as an effective early warning system. This informed a one-health oriented public health response including enhanced human, vector and animal surveillance, integrated mosquito management, and health promotion., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Braddick, O’Brien, Lim, Feldman, Bunter, Neville, Bailie, Butel-Simoes, Jung, Yuen, Hughes and Friedman.)

Objective: To examine criminal justice system (CJS) interactions and pathways through the justice system for young adults with ADHD compared to young adults without ADHD., Method: Nationwide 3-year birth cohort study using linked health and CJS data. Cox proportional hazards models were employed to examine associations between ADHD and police proceedings, court charges, court convictions, and incarcerations., Results: Young adults with ADHD were significantly more likely to interact with the CJS including police proceedings (hazard ratio [HR], 2.1 95% CI [2.0, 2.2]) court charges (HR, 2.2 95% CI [2.1, 2.3]), court convictions (HR, 2.3 95% CI [2.2, 2.4]), and incarceration (HR, 4.8 95% CI [4.3, 5.4])., Conclusions: Young adults with ADHD are overrepresented at all stages of the CJS. Results highlight the importance of early identification and responsivity to ADHD within the CJS and suggest that the NZ justice system may require changes to both areas to ensure that young individuals with ADHD receive equitable access to, and treatment within, the CJS.

Efficient data sharing is hampered by an array of organizational, ethical, behavioral, and technical challenges, slowing research progress and reducing the utility of data generated by clinical research studies on neurodegenerative diseases. There is a particular need to address differences between public and private sector environments for research and data sharing, which have varying standards, expectations, motivations, and interests. The Neuronet data sharing Working Group was set up to understand the existing barriers to data sharing in public-private partnership projects, and to provide guidance to overcome these barriers, by convening data sharing experts from diverse projects in the IMI neurodegeneration portfolio. In this policy and practice review, we outline the challenges and learnings of the WG, providing the neurodegeneration community with examples of good practices and recommendations on how to overcome obstacles to data sharing. These obstacles span organizational issues linked to the unique structure of cross-sectoral, collaborative research initiatives, to technical issues that affect the storage, structure and annotations of individual datasets. We also identify sociotechnical hurdles, such as academic recognition and reward systems that disincentivise data sharing, and legal challenges linked to heightened perceptions of data privacy risk, compounded by a lack of clear guidance on GDPR compliance mechanisms for public-private research. Focusing on real-world, neuroimaging and digital biomarker data, we highlight particular challenges and learnings for data sharing, such as data management planning, development of ethical codes of conduct, and harmonization of protocols and curation processes. Cross-cutting solutions and enablers include the principles of transparency, standardization and co-design - from open, accessible metadata catalogs that enhance findability of data, to measures that increase visibility and trust in data reuse., Competing Interests: NH is an employee of Janssen Pharmaceutica NV and owns stock in Johnson & Johnson, but no product-related aspects. LS is an employee of Janssen Pharmaceutica NV. RB was employed by Aridhia Informatics Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bradshaw, Hughes, Vallez-Garcia, Chokoshvili, Owens, Hansen, Emmert, Maetzler, Killin, Barnes, Brookes, Visser, Hofmann-Apitius, Diaz and Steukers.)

Nearly 14% of disease-causing germline variants result from the disruption of mRNA splicing. Most (67%) DNA variants predicted in silico to disrupt splicing are classified as variants of uncertain significance. An analytic workflow-splice effect event resolver (SPEER)-was developed and validated to use mRNA sequencing to reveal significant deviations in splicing, pinpoint the DNA variants potentially involved, and measure the deleterious effects of the altered splicing on mRNA transcripts, providing evidence for assessing the pathogenicity of the variant. SPEER was used to analyze leukocyte RNA encoding 63 hereditary cancer syndrome-related genes in 20,317 patients. Among 3563 patients (17.5%) with at least one DNA variant predicted to affect splicing, 971 (4.8%) had altered splicing with a deleterious effect on the transcript, and 40 had altered splicing due to a DNA variant located outside of the reportable range of the test. Integrating SPEER results into the interpretation of variants allowed variants of uncertain significance to be reclassified as pathogenic or likely pathogenic in 0.4%, and as benign or likely benign in 5.9%, of the 20,317 patients. SPEER-based evidence was associated with a significantly greater effect on classifications of pathogenic or likely pathogenic and benign or likely benign in nonwhite versus non-Hispanic white patients, illustrating that evidence derived from mRNA splicing analysis may help to reduce ethnic/ancestral disparities in genetic testing., (Copyright © 2023 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Introduction: Poor recovery of the upper limb following a stroke has been recognised as a significant problem in the UK. Although there is good evidence that early, intense rehabilitation can lead to upper limb recovery, often this is not maintained, with less than 50% of people regaining the ability to use their upper limb for independent function at 6 months. Upper limb recovery potential is reported for many years poststroke, yet current long-term provision is insufficient., Methods and Analysis: 60 participants will be recruited into this feasibility study, with 30 allocated to a Post Rehabilitation Enablement Programme (PREP) alone and 30 allocated to a combined programme, PREP Plus, consisting of PREP and the Graded Repetitive Arm Supplementary Programme (GRASP). We will aim to complete four iterative waves. Within each wave, the intervention design will be refined, based on participant feedback. Within each wave, there will be one cluster unit (one intervention group ;PREP Plus) and one control group ;PREP alone)). A total of five PREP sites within Northern Ireland Health and Social Care Trusts will be used for this study. PREP Plus will have a home exercise component along with exercises logs and a behaviour contract. Qualitative and quantitative measures will evaluate the acceptability and feasibility to determine how feasible it is to embed the intervention into practice, as well as to determine the feasibility of a larger, mixed-methods, randomised controlled trial to assess intervention efficacy. Clinical endpoints will also be explored., Ethics and Dissemination: This study has been approved by the Health and Social Care Research Ethics Committee A, IRAS project ID (278620). Participants will provide informed consent prior to participating in the study. Information outlining the purpose of the study, what data will be collected and how the data will be managed will be provided. Results will be published in peer-reviewed journals and any published data will be available on the university data repository. The project management group will advise on different avenues for dissemination to ensure it reaches appropriate audiences., Trial Registration Number: NCT05090163., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Since 2000, some thirteen quinolones and fluoroquinolones have been developed and have come to market. The quinolones, one of the most successful classes of antibacterial drugs, stabilize DNA cleavage complexes with DNA gyrase and topoisomerase IV (topo IV), the two bacterial type IIA topoisomerases. The dual targeting of gyrase and topo IV helps decrease the likelihood of resistance developing. Here, we report on a 2.8 Å X-ray crystal structure, which shows that zoliflodacin, a spiropyrimidinetrione antibiotic, binds in the same DNA cleavage site(s) as quinolones, sterically blocking DNA religation. The structure shows that zoliflodacin interacts with highly conserved residues on GyrB (and does not use the quinolone water-metal ion bridge to GyrA), suggesting it may be more difficult for bacteria to develop target mediated resistance. We show that zoliflodacin has an MIC of 4 µg/mL against Acinetobacter baumannii ( A. baumannii ), an improvement of four-fold over its progenitor QPT-1. The current phase III clinical trial of zoliflodacin for gonorrhea is due to be read out in 2023. Zoliflodacin, together with the unrelated novel bacterial topoisomerase inhibitor gepotidacin, is likely to become the first entirely novel chemical entities approved against Gram-negative bacteria in the 21st century. Zoliflodacin may also become the progenitor of a new safer class of antibacterial drugs against other problematic Gram-negative bacteria.

Background: Childhood traumatic brain injury (TBI) can result in impairments in learning, cognition, and behaviour; all of which can adversely influence educational outcomes. Schools can play a crucial role in rehabilitation, therefore it is important that evidence-based supports are available in these settings., Objective: The aim of this systematic review was to evaluate the effectiveness of school-based supports and interventions available following childhood TBI., Methods: A comprehensive search strategy involved eight research databases, grey literature, and backward reference searching., Results: The search identified 19 studies, reporting on sixteen distinct interventions, which used a variety of person-centred and systemic approaches, and typically contained multiple components, including: psychoeducation, behavioural scripts, and attention training. While offering some indication for future directions in intervention, the evidence base for individual interventions was typically limited, and does not take account of cost or issues in sustainability., Conclusion: While there appears to be great potential to support students who may otherwise not gain access to services, there is insufficient evidence to guide widespread policy or practice change without further research. Greater collaboration between researchers, clinical practitioners, and educators is necessary to ensure that all interventions developed are robustly evaluated and disseminated.

Objective: The purpose of this study was to quantify three-dimensional (3D) stifle kinematics during walking in dogs with complete cranial cruciate ligament insufficiency (CCL-I) treated with a CORA-based leveling osteotomy (CBLO)., Study Design: Four client-owned dogs with unilateral complete CCL-I were prospectively enrolled. Custom digital 3D models of the femora and tibiae were created from pre-and postoperative computed tomographic scans for each dog. Lateral view fluoroscopic images were collected during treadmill walking preoperatively and 6 months after CBLO. Results were generated using a 3D-to-2D image registration process. Pre-and postoperative stifle kinematics (craniocaudal translation, extension angle) were compared to that of the unaffected contralateral (control) stifle. Force plate gait analysis was performed, and symmetry indices (SI) were calculated for peak vertical force (PVF) and vertical impulse (VI)., Results: After CBLO, craniocaudal femorotibial motion was reduced by a median (range) of 43.0 (17.0-52.6) % over the complete gait cycle. Median (range) PVF SI was 0.49 (0.26-0.56) preoperatively and 0.92 (0.86-1.00) postoperatively, and VI SI was 0.44 (0.20-0.48) preoperatively and 0.92 (0.82-0.99) postoperatively., Conclusion: CBLO mitigated but did not fully resolve abnormal craniocaudal translation; lameness was substantially improved at 6 months., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tinga, Hughes, Jones, Park, Palm, Desaraju, Banks, MacArthur and Lewis.)

Competing Interests: Author NH was employed by Janssen Pharmaceutica NV. Authors CD and LK were employed by Synapse Research Management Partners SL.

Lay Abstract: Sensationalist headlines and highly publicised criminal cases lead many in the public to believe that people with autism are more likely to engage in criminal behaviour. However, recent studies present an unresolved debate, and indicate this may not necessarily be the case. The aims of this study were to examine the prevalence of criminal justice system interactions among young adults with and without autism, and determine whether offence types differ between these groups. We tracked a national birth cohort until their 25th birthday, detecting criminal justice system interactions from age 17 onwards. Linked health and criminal justice system data were used to identify those with autism and detect interactions with the criminal justice system. We found that young people with autism interacted with the criminal justice system at lower rates compared to those without autism. However, there were considerable differences in the types of offences these young people were charged with. For example, among those charged with an offence, people with autism were more likely to be charged with a serious offence, punishable by 2 or more years in prison. We conclude that although young people with autism are not over-represented in the criminal justice system, disparities in offence types and incarceration rates among those charged with an offence suggest the importance of identification and appropriate response to autism within the criminal justice system.

The May 2022 proposal from the European commission for a 'European health data space' envisages advantages for health from exploiting the growing mass of health data in Europe. However, key stakeholders have identified aspects that demand clarification to ensure success. Data will need to be freed from traditional silos to flow more easily and to cross artificial borders. Wide engagement will be necessary among healthcare professionals, researchers, and the patients and citizens that stand to gain the most but whose trust must be won if they are to allow use or transfer of their data. This paper aims to alert the wider scientific community to the impact the ongoing discussions among lawmakers will have. Based on the literature and the consensus findings of an expert multistakeholder panel organised by the European Alliance for Personalised Medicine (EAPM) in June 2022, it highlights the key issues at the intersection of science and policy, and the potential implications for health research for years, perhaps decades, to come.

Purpose: Magnetic resonance imaging-guided linear accelerator systems (MR-linacs) can facilitate the daily adaptation of radiation therapy plans. Here, we report our early clinical experience using a MR-linac for adaptive radiation therapy of gynecologic malignancies., Methods and Materials: Treatments were planned with an Elekta Monaco v5.4.01 and delivered by a 1.5 Tesla Elekta Unity MR-linac. The system offers a choice of daily adaptation based on either position (ATP) or shape (ATS) of the tumor and surrounding normal structures. The ATS approach has the option of manually editing the contours of tumors and surrounding normal structures before the plan is adapted. Here, we documented the duration of each treatment fraction; set-up variability (assessed by isocenter shifts in each plan) between fractions; and, for quality assurance, calculated the percentage of plans meeting the γ-criterion of 3%/3-mm distance to agreement. Deformable accumulated dose calculations were used to compare accumulated versus planned dose for patient treated with exclusively ATP fractions., Results: Of the 10 patients treated with 90 fractions on the MR-linac, most received boost doses to recurrence in nodes or isolated tumors. Each treatment fraction lasted a median 32 minutes; fractions were shorter with ATP than with ATS (30 min vs 42 min, P < .0001). The γ criterion for all fraction plans exceeded >90% (median, 99.9%; range, 92.4%-100%; ie, all plans passed quality assurance testing). The average extent of isocenter shift was <0.5 cm in each axis. The accumulated dose to the gross tumor volume was within 5% of the reference plan for all ATP cases. Accumulated doses for lesions in the pelvic periphery were within <1% of the reference plan as opposed to -1.6% to -4.4% for central pelvic tumors., Conclusions: The MR-linac is a reliable and clinically feasible tool for treating patients with gynecologic cancer., (Copyright © 2022 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)