Cerebral organoids with chromosome 21 trisomy secrete Alzheimer's disease-related soluble aggregates detectable by single-molecule-fluorescence and super-resolution microscopy.

Understanding the role of small, soluble aggregates of beta-amyloid (Aß) and tau in Alzheimer's disease (AD) is of great importance for the rational design of preventative therapies. Here we report a set of methods for the detection, quantification, and characterisation of soluble aggregates in conditioned media of cerebral organoids derived from human iPSCs with trisomy 21, thus containing an extra copy of the amyloid precursor protein (APP) gene. We detected soluble beta-amyloid (Aß) and tau aggregates secreted by cerebral organoids from both control and the isogenic trisomy 21 (T21) genotype. We developed a novel method to normalise measurements to the number of live neurons within organoid-conditioned media based on glucose consumption. Thus normalised, T21 organoids produced 2.5-fold more Aß aggregates with a higher proportion of larger (300-2000 nm2) and more fibrillary-shaped aggregates than controls, along with 1.3-fold more soluble phosphorylated tau (pTau) aggregates, increased inflammasome ASC-specks, and a higher level of oxidative stress inducing thioredoxin-interacting protein (TXNIP). Importantly, all this was detectable prior to the appearance of histological amyloid plaques or intraneuronal tau-pathology in organoid slices, demonstrating the feasibility to model the initial pathogenic mechanisms for AD in-vitro using cells from live genetically pre-disposed donors before the onset of clinical disease. Then, using different iPSC clones generated from the same donor at different times in two independent experiments, we tested the reproducibility of findings in organoids. While there were differences in rates of disease progression between the experiments, the disease mechanisms were conserved. Overall, our results show that it is possible to non-invasively follow the development of pathology in organoid models of AD over time, by monitoring changes in the aggregates and proteins in the conditioned media, and open possibilities to study the time-course of the key pathogenic processes taking place.

Informed or misinformed consent and use of modified texture diets in dysphagia.

BACKGROUND: Use of modified texture diets-thickening of liquids and modifying the texture of foods-in the hope of preventing aspiration, pneumonia and choking, has become central to the current management of dysphagia. The effectiveness of this intervention has been questioned. We examine requirements for a valid informed consent process for this approach and whether the need for informed consent for this treatment is always understood or applied by practitioners. MAIN TEXT: Valid informed consent requires provision of accurate and balanced information, and that agreement is given freely by someone who knows they have a choice. Current evidence, including surveys of practitioners and patients in different settings, suggests that practice in this area is often inadequate. This may be due to patients' communication difficulties but also poor communication-and no real attempt to obtain consent-by practitioners before people are 'put on' modified texture diets. Even where discussion occurs, recommendations may be influenced by professional misconceptions about the efficacy of this treatment, which in turn may poison the well for the informed consent process. Patients cannot make appropriate decisions for themselves if the information provided is flawed and unbalanced. The voluntariness of patients' decisions is also questionable if they are told 'you must', when 'you might consider' is more appropriate. Where the decision-making capacity of patients is in question, inappropriate judgements and recommendations may be made by substitute decision makers and courts unless based on accurate information. CONCLUSION: Research is required to examine the informed consent processes in different settings, but there is ample reason to suggest that current practice in this area is suboptimal. Staff need to reflect on their current practice regarding use of modified texture diets with an awareness of the current evidence and through the 'lens' of informed consent. Education is required for staff to clarify the importance of, and requirements for, valid informed consent and for decision making that reflects people's preferences and values.

Clare Island Digital Health Project - using technology to enable health for all.

INTRODUCTION: Island communities have a different experience of health services compared with urban dwellers. Islanders face challenges of accessing equitable health services with varied availability of local services and the added difficulty of sea and weather conditions on top of the physical distance to reach specialised services. In a 2017 review of primary care island services in Ireland, it was proposed that telemedicine solutions could potentially improve delivery of health services. However, these solutions must meet the unique needs of the island population. AIMS AND METHODS: This collaborative project brings together healthcare professionals, academic researchers, technology partners, business partners and the Clare Island community, to improve the health of the island population via novel technological interventions. The Clare Island project aims to identify specific healthcare needs of the island through community engagement, develop innovative solutions, and assess the impact of the interventions via a mixed-methods approach. RESULTS: Preliminary engagement with the Clare Island community via facilitated round table discussions has identified Islanders' overarching enthusiasm for digital solutions and added benefit of provision of 'health at home' for Island communities, particularly, the potential to better support the older person at home via technology. Key challenges including basic infrastructure, useability and sustainability of digital health initiatives were common themes identified. We also will discuss in detail the needs-led process of innovation of telemedicine solutions deployed on Clare Island. Finally, we will present the anticipated impact of the project and the challenges and opportunities of telehealth for island health services. DISCUSSION: Technology has the potential to narrow the gap of inequity of health services for island communities. This project is an example of how through cross-disciplinary collaboration, and needs-led, specifically 'island-led', innovation of digital health solutions, the unique challenges for island communities can be addressed.

Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain.

A population of more than six million people worldwide at high risk of Alzheimer's disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of ß-amyloid-(Aß)-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar Aß deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss. Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome 21 gene BACE2, but prevented by combined chemical ß and γ-secretase inhibition. We found that T21 organoids secrete increased proportions of Aß-preventing (Aß1-19) and Aß-degradation products (Aß1-20 and Aß1-34). We show these profiles mirror in cerebrospinal fluid of people with DS. We demonstrate that this protective mechanism is mediated by BACE2-trisomy and cross-inhibited by clinically trialled BACE1 inhibitors. Combined, our data prove the physiological role of BACE2 as a dose-sensitive AD-suppressor gene, potentially explaining the dementia delay in ~30% of people with DS. We also show that DS cerebral organoids could be explored as pre-morbid AD-risk population detector and a system for hypothesis-free drug screens as well as identification of natural suppressor genes for neurodegenerative diseases.

MRI safety management in patients with cardiac implantable electronic devices: Utilizing failure mode and effects analysis for risk optimization.

INTRODUCTION: Cardiac implantable electronic devices (CIEDs) are increasing in prevalence. Exposing patients with CIEDs to magnetic resonance imaging (MRI) can lead to adverse outcomes. This has led certain radiology departments to not accept MRI referrals related to patients with CIEDs. Patients with MR-conditional CIEDs can be safely scanned under specific conditions. Our institution has accepted such referrals since 2014. The aim of this study was to systematically identify and reduce risk in our CIED-MRI protocol using failure mode and effects analysis (FMEA). METHODS: A multidisciplinary FMEA team was assembled and included senior stakeholders from the CIED-MRI protocol. A process map was constructed followed by risk analysis and scoring. Targeted interventions were formulated and implemented; high-risk failure modes were prioritized. A new process map and protocol were drafted and repeat risk analysis was performed. Monitoring and re-evaluation of the CIED-MRI pathway were instigated at departmental quality assurance (QA) meetings. RESULTS: Interventions included direct CIED characterization using wireless technology pre-MRI, CIED programming and reprogramming in the MRI suite before and immediately after MRI reducing device downtime and continuous patient monitoring during MRI by a cardiac physiologist. The cumulative risk priority number (RPN) decreased from 1190 pre-FMEA to 492 post-FMEA. DISCUSSION: Despite the risk of exposing CIEDs to the MR environment, patients with MR-conditional CIEDs can be safely scanned with an appropriate multidisciplinary support. We found FMEA an indispensable tool in identifying and minimizing risk with no adverse events recorded since FMEA recommendations were implemented.

The perils of 'risk feeding'.

'Risk feeding' policies, for when people continue to eat and drink despite a perceived risk of choking or aspiration have become common in recent years. We argue that 'feeding' is demeaning language if referring to a person who is eating and drinking rather than to a healthcare technique and that 'risk-anything' is not how decisions are reached. It is true that patients with dysphagia are often unnecessarily designated nil-by-mouth (NBM), especially after a decision has been made that tube feeding is not indicated or is unwanted. However, risk-feeding policies may perpetuate common misperceptions that there is a straightforward relationship between aspiration and pneumonia and that interventions like NBM or tube feeding will reduce the risk of pneumonia. Such policies may reduce the potential for individualised and flexible decision making: many people's swallowing abilities and preferences fluctuate, sometimes from hour to hour, and staff need to have, and be encouraged to use, common sense, flexibility and judgement in these circumstances. There is also the potential for delays in providing food, fluid and medications if meetings must be held and risk-feeding paperwork completed and signed by someone with the necessary seniority and confidence. Further debate and discussion is required before risk-feeding policies become an established standard of care.

Role of Musculoskeletal Radiology in Modern Sports Medicine.

Musculoskeletal radiology's role in the recent and continued evolution of sports medicine is an exciting and expanding one. In this article we explore a variety of the ways that musculoskeletal radiology contributes to current practices in modern sports medicine, discussing advances across a variety of imaging modalities in the care of both elite athletes and so-called weekend warriors. We describe the technical and ethical factors pertaining to image-guided therapeutic intervention in athletes and speculate on the potential for future developments in the role of imaging in deciding when an athlete may return to participation. We also explore the recent shift to the delivery of imaging facilities at sporting events and in stadiums.

Brief report: isogenic induced pluripotent stem cell lines from an adult with mosaic down syndrome model accelerated neuronal ageing and neurodegeneration.

Trisomy 21 (T21), Down Syndrome (DS) is the most common genetic cause of dementia and intellectual disability. Modeling DS is beginning to yield pharmaceutical therapeutic interventions for amelioration of intellectual disability, which are currently being tested in clinical trials. DS is also a unique genetic system for investigation of pathological and protective mechanisms for accelerated ageing, neurodegeneration, dementia, cancer, and other important common diseases. New drugs could be identified and disease mechanisms better understood by establishment of well-controlled cell model systems. We have developed a first nonintegration-reprogrammed isogenic human induced pluripotent stem cell (iPSC) model of DS by reprogramming the skin fibroblasts from an adult individual with constitutional mosaicism for DS and separately cloning multiple isogenic T21 and euploid (D21) iPSC lines. Our model shows a very low number of reprogramming rearrangements as assessed by a high-resolution whole genome CGH-array hybridization, and it reproduces several cellular pathologies seen in primary human DS cells, as assessed by automated high-content microscopic analysis. Early differentiation shows an imbalance of the lineage-specific stem/progenitor cell compartments: T21 causes slower proliferation of neural and faster expansion of hematopoietic lineage. T21 iPSC-derived neurons show increased production of amyloid peptide-containing material, a decrease in mitochondrial membrane potential, and an increased number and abnormal appearance of mitochondria. Finally, T21-derived neurons show significantly higher number of DNA double-strand breaks than isogenic D21 controls. Our fully isogenic system therefore opens possibilities for modeling mechanisms of developmental, accelerated ageing, and neurodegenerative pathologies caused by T21.

Empowering international nursing students to become effective library users.

This article summarises the research conducted for a dissertation which addressed the needs of students and academic staff of the Bachelor of Nursing International programme at St. Angela's College, Ireland. Aoife Murray completed an MSc Econ Information and Library Studies in 2015 from Aberystwyth University via distance learning. She gained a distinction for her work and has co-written the article with Hugh Preston, her dissertation supervisor. Aoife highlights the recommendations she made as a result of her research and the programme put in place to deliver those recommendations. She also reports on some early evaluations of the new programme. AM.

Mixed Reality Platforms in Telehealth Delivery: Scoping Review.

BACKGROUND: The distinctive features of the digital reality platforms, namely augmented reality (AR), virtual reality (VR), and mixed reality (MR) have extended to medical education, training, simulation, and patient care. Furthermore, this digital reality technology seamlessly merges with information and communication technology creating an enriched telehealth ecosystem. This review provides a composite overview of the prospects of telehealth delivered using the MR platform in clinical settings. OBJECTIVE: This review identifies various clinical applications of high-fidelity digital display technology, namely AR, VR, and MR, delivered using telehealth capabilities. Next, the review focuses on the technical characteristics, hardware, and software technologies used in the composition of AR, VR, and MR in telehealth. METHODS: We conducted a scoping review using the methodological framework and reporting design using the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) guidelines. Full-length articles in English were obtained from the Embase, PubMed, and Web of Science databases. The search protocol was based on the following keywords and Medical Subject Headings to obtain relevant results: "augmented reality," "virtual reality," "mixed-reality," "telemedicine," "telehealth," and "digital health." A predefined inclusion-exclusion criterion was developed in filtering the obtained results and the final selection of the articles, followed by data extraction and construction of the review. RESULTS: We identified 4407 articles, of which 320 were eligible for full-text screening. A total of 134 full-text articles were included in the review. Telerehabilitation, telementoring, teleconsultation, telemonitoring, telepsychiatry, telesurgery, and telediagnosis were the segments of the telehealth division that explored the use of AR, VR, and MR platforms. Telerehabilitation using VR was the most commonly recurring segment in the included studies. AR and MR has been mainly used for telementoring and teleconsultation. The most important technical features of digital reality technology to emerge with telehealth were virtual environment, exergaming, 3D avatars, telepresence, anchoring annotations, and first-person viewpoint. Different arrangements of technology-3D modeling and viewing tools, communication and streaming platforms, file transfer and sharing platforms, sensors, high-fidelity displays, and controllers-formed the basis of most systems. CONCLUSIONS: This review constitutes a recent overview of the evolving digital AR and VR in various clinical applications using the telehealth setup. This combination of telehealth with AR, VR, and MR allows for remote facilitation of clinical expertise and further development of home-based treatment. This review explores the rapidly growing suite of technologies available to users within the digital health sector and examines the opportunities and challenges they present.

Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levels.

BACKGROUND: People with Down syndrome (DS) show clinical signs of accelerated ageing. Causative mechanisms remain unknown and hypotheses range from the (essentially untreatable) amplified-chromosomal-instability explanation, to potential actions of individual supernumerary chromosome-21 genes. The latter explanation could open a route to therapeutic amelioration if the specific over-acting genes could be identified and their action toned-down. METHODS: Biological age was estimated through patterns of sugar molecules attached to plasma immunoglobulin-G (IgG-glycans, an established "biological-ageing-clock") in n = 246 individuals with DS from three European populations, clinically characterised for the presence of co-morbidities, and compared to n = 256 age-, sex- and demography-matched healthy controls. Isogenic human induced pluripotent stem cell (hiPSCs) models of full and partial trisomy-21 with CRISPR-Cas9 gene editing and two kinase inhibitors were studied prior and after differentiation to cerebral organoids. FINDINGS: Biological age in adults with DS is (on average) 18.4-19.1 years older than in chronological-age-matched controls independent of co-morbidities, and this shift remains constant throughout lifespan. Changes are detectable from early childhood, and do not require a supernumerary chromosome, but are seen in segmental duplication of only 31 genes, along with increased DNA damage and decreased levels of LaminB1 in nucleated blood cells. We demonstrate that these cell-autonomous phenotypes can be gene-dose-modelled and pharmacologically corrected in hiPSCs and derived cerebral organoids. Using isogenic hiPSC models we show that chromosome-21 gene DYRK1A overdose is sufficient and necessary to cause excess unrepaired DNA damage. INTERPRETATION: Explanation of hitherto observed accelerated ageing in DS as a developmental progeroid syndrome driven by DYRK1A overdose provides a target for early pharmacological preventative intervention strategies. FUNDING: Main funding came from the "Research Cooperability" Program of the Croatian Science Foundation funded by the European Union from the European Social Fund under the Operational Programme Efficient Human Resources 2014-2020, Project PZS-2019-02-4277, and the Wellcome Trust Grants 098330/Z/12/Z and 217199/Z/19/Z (UK). All other funding is described in details in the "Acknowledgements".

Is it feasible to use a humanoid robot to promote hand hygiene adherence in a hospital setting?

Healthcare associated infections (HCAI) are a prevalent preventable cause of morbidity and mortality. Improving hand hygiene adherence is important for HCAI prevention. In this feasibility study, the objective was to determine if a humanoid robot could act as a novel single reminder intervention to improve hand hygiene adherence in a hospital setting. DAVE, a social humanoid robot, improved hand hygiene adherence at the entrance to a tertiary hospital and outpatient department, which was low at baseline, by 29%. DAVE shows promise as a novel intervention to improve hand hygiene adherence.

Key requirements of a video-call system in a critical care department as discovered during the rapid development of a solution to address COVID-19 visitor restrictions.

The COVID-19 pandemic necessitated stringent visitor restrictions in critical care departments worldwide, creating challenges in keeping family members connected to patients and clinical staff. Previous studies have examined how hospitals addressed this challenge by repurposing existing tele-ICU systems or by using personal smartphones as a workaround and have analyzed clinical and family feedback. This case report addresses the experience of rapidly implementing a video-call system in the critical care department of a tertiary referral hospital that had no prior video-call system in place, detailing the key requirements in that setting. The 24 requirements were identified via interviews and surveys to both clinical and technical professionals. The top requirements identified were sound and video quality, usability for clinical staff, call control by staff, and patient privacy. From tailoring a video-call solution for this setting, we learned that video-endpoint selection is a key design decision. The initial proposal was to use wireless tablets, but the selection of a large wired video-endpoint allowed us to better address the requirements in the critical care setting. This was based on several characteristics of the large wired video-endpoint, including: high-fidelity video and sound, with directional noise-cancelling; large touch-screen setup for minimal-click navigation; wired as well as wireless connectivity.

Localized delivery of CRISPR/dCas9 via layer-by-layer self-assembling peptide coating on nanofibers for neural tissue engineering.

The clustered regularly interspaced short palindromic repeat (CRISPR) systems have a wide variety of applications besides precise genome editing. In particular, the CRISPR/dCas9 system can be used to control specific gene expression by CRISPR activation (CRISPRa) or interference (CRISPRi). However, the safety concerns associated with viral vectors and the possible off-target issues of systemic administration remain huge concerns to be safe delivery methods for CRISPR/Cas9 systems. In this study, a layer-by-layer (LbL) self-assembling peptide (SAP) coating on nanofibers is developed to mediate localized delivery of CRISPR/dCas9 systems. Specifically, an amphiphilic negatively charged SAP- is first coated onto PCL nanofibers through strong hydrophobic interactions, and the pDNA complexes and positively charged SAP+-RGD are then absorbed via electrostatic interactions. The SAPcoated scaffolds facilitate efficient loading and sustained release of the pDNA complexes, while enhancing cell adhesion and proliferation. As a proof of concept, the scaffolds are used to activate GDNF expression in mammalian cells, and the secreted GDNF subsequently promotes neurite outgrowth of rat neurons. These promising results suggest that the LbL self-assembling peptide coated nanofibers can be a new route to establish a bioactive interface, which provides a simple and efficient platform for the delivery of CRISPR/dCas9 systems for regenerative medicine.

Modeling Down syndrome in cells: From stem cells to organoids.

Down Syndrome (DS) is a complex chromosomal disorder, with neurological issues, featuring among the symptoms. Primary neuronal cells and tissues are extremely useful, but limited both in supply and experimental manipulability. To better understand the cellular, molecular and pathological mechanisms involved in DS neurodevelopment and neurodegeneration, a range of different cellular models have been developed over the years including human: mouse hybrid cells, transchromosomic mouse embryonic stem cells (ESCs) and human ESC and induced pluripotent stem cells derived from different sources. All of these model systems have provided useful information in the study of DS. Furthermore, different technologies to genetically modify or correct trisomy of either single genes or the whole chromosome have been developed using these cellular models. New techniques and protocols to allow better modeling of cellular mechanisms and disease processes are being developed and the use of cerebral organoids offers great promise for future research into the neural phenotypes seen in DS.

Correction: Scaffold mediated gene knockdown for neuronal differentiation of human neural progenitor cells.

Correction for 'Scaffold mediated gene knockdown for neuronal differentiation of human neural progenitor cells' by Wai Hon Chooi et al., Biomater. Sci., 2018, 6, 3019-3029.

Provision of MR imaging for patients with cardiac implantable electronic devices (CIEDs): a single-center experience and national survey.

BACKGROUND: Patients with cardiac implantable electronic devices (CIEDs) were traditionally denied access to MR imaging due to safety concerns. AIMS: The aim of this study was to review a single-center experience of MR imaging at 1.5T of patients with CIEDs and survey national availability of this service. METHODS: Three hundred thirty-four patients with CIEDs were included in the review. Two hundred nine patients did not progress to MRI due to non MR-conditional CIEDs, retained pacing leads, recent implant insertion, and other patient factors. A record was made of CIED type, number of body parts imaged, numbers of repeat studies and complications. All devices were scanned with cardiology involvement. RESULTS: One hundred twenty-five patients, 90 males, 35 females, aged 20-91 years progressed to MR imaging. Eighty-six patients had pacemakers, 15 had implantable cardioverter devices (ICDs), and 24 had implantable loop recorders (ILRs). Twenty-one patients had more than one body part scanned. Regions scanned included spine n = 82, joints n = 42, head n = 40, heart n = 8, and abdomen/pelvis n = 13. Twenty-six patients had multiple separate MR studies (range 2-6). Three complications included diaphragmatic stimulation when the device was switched to MR-conditional mode resulting in scan abandonment, device failure post-MRI requiring manufacturer reprogramming, and patient dizziness post reprogramming requiring cardiology review. One cardiac study was non-diagnostic due to artifact from a low left-sided ICD. Imaging of patients with pacemakers is available in 14 of 42 (38%) hospitals with MR units nationally. CONCLUSION: MR-conditional CIEDs can be safely scanned with diagnostic quality at 1.5T using a protocol involving radiology and cardiology.

Scaffold mediated gene knockdown for neuronal differentiation of human neural progenitor cells.

The use of human induced pluripotent stem cell-derived neural progenitor cells (hiPSC-NPCs) is an attractive therapeutic option for damaged nerve tissues. To direct neuronal differentiation of stem cells, we have previously developed an electrospun polycaprolactone nanofiber scaffold that was functionalized with siRNA targeting Re-1 silencing transcription factor (REST), by mussel-inspired bioadhesive coating. However, the efficacy of nanofiber-mediated RNA interference on hiPSC-NPCs differentiation remains unknown. Furthermore, interaction between such cell-seeded scaffolds with injured tissues has not been tested. In this study, scaffolds were optimized for REST knockdown in hiPSC-NPCs to enhance neuronal differentiation. Specifically, the effects of two different mussel-inspired bioadhesives and transfection reagents were analyzed. Scaffolds functionalized with RNAiMAX Lipofectamine-siREST complexes enhanced the differentiation of hiPSC-NPCs into TUJ1+ cells (60% as compared to 22% in controls with scrambled siNEG after 9 days) without inducing high cytotoxicity. When cell-seeded scaffolds were transplanted to transected spinal cord organotypic slices, similar efficiency in neuronal differentiation was observed. The scaffolds also supported the migration of cells and neurite outgrowth from the spinal cord slices. Taken together, the results suggest that this scaffold can be effective in enhancing hiPSC-NPC neuronal commitment by gene-silencing for the treatment of injured spinal cords.

Viable pregnancies beyond 28 weeks gestation in women with a history of unexplained recurrent miscarriage have reduced platelet function.

OBJECTIVE: The aim of this study was to characterize platelet function in pregnant patients with a history of unexplained recurrent miscarriage (RM) in the third trimester of a subsequent viable pregnancy, a time at which platelet dysfunction may be associated with an increased obstetric risk. STUDY DESIGN: A prospective study was performed comparing 30 viable pregnancies that had reached at least 28 weeks' gestation amongst patients who had a background history of unexplained RM, with 30 healthy pregnant controls at a similar gestational age. Platelet function was determined by means of platelet aggregation in response to 5 different agonists at multiple concentrations. RESULTS: Amongst the 30 RM patients with ongoing viable pregnancies, we demonstrated significantly reduced platelet aggregation compared to the pregnant controls in the third trimester. For three out of five agonists, we demonstrated statistically significantly decreased platelet aggregation and for all five agonists we demonstrated significantly decreased platelet aggregation in the postnatal period. There were no obvious differences in obstetric outcomes. CONCLUSION: This study shows that women with a history of unexplained RM have reduced platelet function after 28 weeks' gestation in their subsequent pregnancies compared to healthy pregnant controls, but without this difference leading to any obvious increase in adverse obstetric risk.