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Prenatal sequencing tests are being introduced into clinical practice in many developed countries. In part due to its greater ability to detect genetic variation, offering prenatal sequencing can present ethical challenges. Here we review ethical issues arising following the implementation of prenatal sequencing in the English National Health Service (NHS). We analysed semi structured interviews conducted with 48 parents offered prenatal sequencing and 63 health professionals involved in delivering the service to identify the ethical issues raised. Two main themes were identified: (1) Equity of access (including issues around eligibility criteria, laboratory analytical processes, awareness and education of clinicians, fear of litigation, geography, parental travel costs, and access to private healthcare), and (2) Timeliness and its impact on parental decision-making in pregnancy (in the context of the law around termination of pregnancy, decision-making in the absence of prenatal sequencing results, and the "importance" of prenatal sequencing results). Recognising both the practical and systemic ethical issues that arise out of delivering a national prenatal sequencing service is crucial. Although specific to the English context, many of the issues we identified are applicable to prenatal sequencing services more broadly. Education of health professionals and parents will help to mitigate some of these ethical issues., (© 2024. The Author(s).)

Genome sequencing (GS) has the potential to reduce the "diagnostic odyssey" that many parents of children with rare undiagnosed conditions experience. While much research has considered the impact of receiving a diagnostic result, research has rarely focused solely on the impact of receiving a "no primary finding" (NPF) result. This study aimed to investigate the experience of parents of children with rare and undiagnosed conditions following an NPF result from GS. Nine parents whose child had an NPF result from GS were recruited through the social media platform of the charity SWAN (Syndromes Without A Name) UK. Semi-structured telephone interviews were conducted, transcribed verbatim, and analyzed using grounded theory. Analysis led to the emergence of two main themes. The first theme "Striving to Solve the Unsolved Puzzle" concerned the experience of striving to end the "diagnostic odyssey." The second theme "Navigating Hope, Lost then Found" plots the trajectory of hope raised by the promise of a new technology, dashed by the NPF, and the eventual return of small and distant hope for the future. Taken together, these themes allowed for a proposed theory: "The Disequilibrium of Hope," which highlights the dynamic and modifiable experience of hope participants experience in their GS journey. These results suggest GS can be an emotional rollercoaster for parents. While hope plays an important role in coping with the day-to-day life of living with a rare disease, careful management of expectations from GS is important during pre-test counseling, and continued follow-up and support are needed beyond result disclosure. An understanding of the disappointment and distress caused by an NPF result is valuable for healthcare professionals in this field to ensure counseling can be tailored. Further research should consider how to support parents after an NPF result., (© 2023 The Authors. Journal of Genetic Counseling published by Wiley Periodicals LLC on behalf of National Society of Genetic Counselors.)

Background: With the potential to identify a vast number of rare diseases soon after birth, genomic newborn screening (gNBS) could facilitate earlier interventions and improve health outcomes. Designing a gNBS programme will involve balancing stakeholders' opinions and addressing concerns. The views of medical students-future clinicians who would deliver gNBS-have not yet been explored., Methods: We conducted a nationwide online survey of UK medical students via the REDCap platform. Perceptions of gNBS, including scope of testing and potential benefits and drawbacks, were explored using a mix of multiple-choice questions, Likert scales, visual analogue scales and free-text questions., Results: In total, 116 medical students across 16 universities participated. Overall, 45% supported gNBS, with a positively skewed mean support score of 3.24 (SD 1.26, range: 1.0-5.0), and 55% felt it relevant to their future practice. Almost all agreed that infant-onset and childhood-onset diseases and conditions with effective treatments should be included. Most felt that earlier interventions and personalised care would be the most important benefit of gNBS. Other perceived benefits included earlier diagnoses, diagnosing more patients and enabling research for new treatments. However, several perceived challenges were highlighted: risk of genomic discrimination, incidental or uncertain findings, data security and breaching children's future autonomy. Students expressed conflicting opinions on the psychological impact on families, but most were concerned about a lack of support due to current resource limitations in health services. Students frequently reported having insufficient knowledge to form an opinion, which may reflect gaps in genomics education at medical school and the current lack of evidence base for gNBS., Conclusion: Although some support for gNBS was demonstrated, ethicolegal and social challenges were raised, emphasising a need for ongoing discussions about the implications of gNBS., Competing Interests: Competing interests: AP is an employee of Genomics England, a company wholly owned by the United Kingdom Department of Health and Social Care and funded to deliver the Generation Study., (© 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.)

Objectives: To measure the effect of routine vaccination on serum amyloid A (SAA) concentration in apparently healthy horses. We hypothesized that routine vaccination would increase SAA in healthy horses., Animals: 21 apparently healthy client-owned horses and 15 Kansas State University College of Veterinary Medicine-owned horses., Methods: In experiment 1 (n = 8 horses), a blinded, randomized, prospective, crossover study was performed. Horses were either vaccinated (rabies, tetanus, West Nile, Eastern and Western equine encephalomyelitis, equine herpesvirus-1/-4, influenza) or administered saline, and SAA was measured at 6, 12, and 24 hours and daily until day 10 with a commercial lateral-flow immunoassay. In experiment 2 (n = 28 horses), a prospective, observational study measured SAA after vaccination at 12 and 24 hours and daily until day 10. A linear mixed-effect model with repeated measures over time blocked by horse tested the effect of treatment on SAA. A repeated-measures correlation tested the correlation between SAA and temperature., Results: Over time, vaccinated horses had increased model-adjusted SAA compared to unvaccinated horses without clinical evidence of adverse reaction (P < .01). In experiment 1, the model-adjusted SAA after vaccination peaked on day 2 (median, 1,872 µg/mL; IQR, 1,220.8 to 2,402.5 µg/mL) and returned to normal (< 20 µg/mL) by day 9 (median, 6 µg/mL; IQR, 0.8 to 23.5 µg/mL) after vaccination. In experiment 2, vaccinated horses had increased SAA over time; temperature and SAA were not correlated (P = .78)., Clinical Relevance: Results of this study indicated that routine vaccination results in increased SAA concentration and provided evidence for a period of convalescence following vaccination. Measuring SAA for 10 days following vaccination cannot be used as an indicator of illness.

Introduction: In October 2020, rapid prenatal exome sequencing (pES) was introduced into routine National Health Service (NHS) care in England, requiring the coordination of care from specialist genetics, fetal medicine (FM) and laboratory services. This mixed methods study explored the experiences of professionals involved in delivering the pES service during the first 2 years of its delivery in the NHS., Methods: A survey ( n = 159) and semi-structured interviews ( n = 63) with healthcare professionals, including clinical geneticists, FM specialists, and clinical scientists (interviews only) were used to address: 1) Views on the pES service; 2) Capacity and resources involved in offering pES; 3) Awareness, knowledge, and educational needs; and 4) Ambitions and goals for the future., Results: Overall, professionals were positive about the pES service with 77% rating it as Good or Excellent. A number of benefits were reported, including the increased opportunity for receiving actionable results for parental decision-making, improving equity of access to genomic tests and fostering close relationships between FM and genetics departments. Nonetheless, there was evidence that the shift to offering pES in a clinical setting had brought some challenges, such as additional clinic time, administrative processes, perceived lack of autonomy in decision-making regarding pES eligibility and difficulty engaging with peripheral maternity units. Concerns were also raised about the lack of confidence and gaps in genomics knowledge amongst non-genetics professionals - especially midwives. However, the findings also highlighted value in both FM, obstetric and genetics professionals benefiting from further training with a focus on recognising and managing prenatally diagnosed genetic conditions., Conclusion: Healthcare professionals are enthusiastic about the benefits of pES, and through multi-collaborative working, have developed relationships that have contributed to effective communication across specialisms. Although limitations on resources and variation in knowledge about pES have impacted service delivery, professionals were hopeful that improvements to infrastructure and the upskilling of all professionals involved in the pathway would optimise the benefits of pES for both parents and professionals., 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 Peter, Mellis, McInnes-Dean, Daniel, Walton, Fisher, Leeson-Beevers, Allen, Baple, Beleza-Meireles, Bertoli, Campbell, Canham, Cilliers, Cobben, Eason, Harrison, Holder-Espinasse, Male, Mansour, McEwan, Park, Smith, Stewart, Tapon, Vasudevan, Williams, Wu, Chitty and Hill.)

Introduction: Severe osteogenesis imperfecta (OI) is a debilitating disease with no cure or sufficiently effective treatment. Mesenchymal stem cells (MSCs) have good safety profile, show promising effects and can form bone. The Boost Brittle Bones Before Birth (BOOSTB4) trial evaluates administration of allogeneic expanded human first trimester fetal liver MSCs (BOOST cells) for OI type 3 or severe type 4., Methods and Analysis: BOOSTB4 is an exploratory, open-label, multiple dose, phase I/II clinical trial evaluating safety and efficacy of postnatal (n=15) or prenatal and postnatal (n=3, originally n=15) administration of BOOST cells for the treatment of severe OI compared with a combination of historical (1-5/subject) and untreated prospective controls (≤30). Infants<18 months of age (originally<12 months) and singleton pregnant women whose fetus has severe OI with confirmed glycine substitution in COL1A1 or COL1A2 can be included in the trial.Each subject receives four intravenous doses of 3×10 6 /kg BOOST cells at 4 month intervals, with 48 (doses 1-2) or 24 (doses 3-4) hours in-patient follow-up, primary follow-up at 6 and 12 months after the last dose and long-term follow-up yearly until 10 years after the first dose. Prenatal subjects receive the first dose via ultrasound-guided injection into the umbilical vein within the fetal liver (16+0 to 35+6 weeks), and three doses postnatally.The primary outcome measures are safety and tolerability of repeated BOOST cell administration. The secondary outcome measures are number of fractures from baseline to primary and long-term follow-up, growth, change in bone mineral density, clinical OI status and biochemical bone turnover., Ethics and Dissemination: The trial is approved by Competent Authorities in Sweden, the UK and the Netherlands (postnatal only). Results from the trial will be disseminated via CTIS, ClinicalTrials.gov and in scientific open-access scientific journals., Trial Registration Numbers: EudraCT 2015-003699-60, EUCT: 2023-504593-38-00, NCT03706482., Competing Interests: Competing interests: ALD is a consultant for Esperare Foundation for a clinical trial unrelated to this work. CG, LW-J and MW are cofounders and coowners of BOOST Pharma ApS founded in 2020. OS is a scientific advisor for BOOST Pharma ApS., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Although there are numerous benefits to diagnostic prenatal testing, such as fetal exome sequencing, there are also consequences, including the possibility of receiving variants of uncertain significance or identifying secondary findings. In this study, we utilized a survey-based discrete choice experiment to elicit the preferences of pregnant people in Northern California for hypothetical prenatal genomic tests. Pregnant individuals were invited to complete the survey through advertisements on social media. Five test attributes were studied: likelihood of getting a result, time taken to receive results, who explains results, reporting of uncertain results, and reporting of secondary findings. The survey also gathered information about the participants' demographics, current and past pregnancies, and tolerance of uncertainty using the IUS-12 scale. Participants were eligible if they were female, currently 24 or more weeks pregnant, and able to read/write enough English or Spanish to complete an online survey. Overall, participants (n = 56) preferred the option of having a prenatal test over not having a prenatal test (p < 0.01) and had substantially higher preferences for tests with the highest likelihood of getting a result (p < 0.01). There were also positive preferences for tests that reported secondary findings (p = 0.01) and those where results were returned by a genetic specialist (vs. their prenatal provider) (p = 0.04). These findings can be used to guide conversations between pregnant individuals and genetics specialists, such as genetic counselors, as they weigh the pros and cons of diagnostic prenatal testing options., (© 2023 The Authors. Journal of Genetic Counseling published by Wiley Periodicals LLC on behalf of National Society of Genetic Counselors.)

Introduction: Low confidence in genomics knowledge among clinicians is a major barrier to the integration of genomics into mainstream medicine. Here, we assessed the genomics confidence of UK medical students approaching graduation., Methods: We conducted a web-based nationwide survey of UK medical students in the final 2 years of study where participants rated their confidence in genomics concepts., Results: In total, 145 medical students across 19 medical schools participated. The amount of genomics teaching students reported receiving was positively associated with genomics confidence, with the amount of basic science teaching having the strongest influence. While confidence was high in core genomics principles, such as the difference between DNA, genes and chromosomes (95%), confidence dropped in clinical applications of genomics - only 50% reported a good understanding of the genetic contribution to disease and 28% reported good knowledge of clinically used genomic tests. Overall, 59% reported a poor understanding of variant interpretation; however, over half who reported receiving 'lots' of genomic medicine teaching reported a good understanding of this topic., Conclusion: Gaps in genomics knowledge and drivers in confidence have been identified herein, highlighting the need for improvements in undergraduate genomics education to prepare future doctors to confidently practise in the genomics era., 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., (© 2024 The Author(s).)

Objectives: In October 2020, rapid prenatal exome sequencing (pES) was introduced into routine National Health Service (NHS) care in England. This study aimed to explore parent experiences and their information and support needs from the perspective of parents offered pES and of health professionals involved in its delivery., Methods: In this qualitative study, semi-structured interviews were conducted with 42 women and 6 male partners and 63 fetal medicine and genetic health professionals. Interviews were transcribed verbatim and analysed using thematic analysis., Results: Overall views about pES were positive and parents were grateful to be offered the test. Highlighted benefits of pES included the value of the additional information for pregnancy management and planning for future pregnancies. An anxious wait for results was common, often associated with the need to make decisions near to 24 weeks in pregnancy when there are legal restrictions for late termination. Descriptions of dealing with uncertainty were also common, even when results had been returned. Many parents described pES results as informing decision-making around whether or not to terminate pregnancy. Some professionals were concerned that a non-informative result could be overly reassuring and highlighted that careful counselling was needed to ensure parents have a good understanding of what the result means for their pregnancy. Emotional support from professionals was valued; however, some parents felt that post-test support was lacking., Conclusion: Parents and professionals welcomed the introduction of pES. Results inform parents' decision-making around the termination of pregnancy. When there are no diagnostic findings or uncertain findings from pES, personalised counselling that considers scans and other tests are crucial. Directing parents to reliable online sources of information and providing emotional support throughout could improve their experiences of care., (© 2024 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Currently, there are multiple breast dosimetry estimation methods for mammography and its variants in use throughout the world. This fact alone introduces uncertainty, since it is often impossible to distinguish which model is internally used by a specific imaging system. In addition, all current models are hampered by various limitations, in terms of overly simplified models of the breast and its composition, as well as simplistic models of the imaging system. Many of these simplifications were necessary, for the most part, due to the need to limit the computational cost of obtaining the required dose conversion coefficients decades ago, when these models were first implemented. With the advancements in computational power, and to address most of the known limitations of previous breast dosimetry methods, a new breast dosimetry method, based on new breast models, has been developed, implemented, and tested. This model, developed jointly by the American Association of Physicists in Medicine and the European Federation for Organizations of Medical Physics, is applicable to standard mammography, digital breast tomosynthesis, and their contrast-enhanced variants. In addition, it includes models of the breast in both the cranio-caudal and the medio-lateral oblique views. Special emphasis was placed on the breast and system models used being based on evidence, either by analysis of large sets of patient data or by performing measurements on imaging devices from a range of manufacturers. Due to the vast number of dose conversion coefficients resulting from the developed model, and the relative complexity of the calculations needed to apply it, a software program has been made available for download or online use, free of charge, to apply the developed breast dosimetry method. The program is available for download or it can be used directly online. A separate User's Guide is provided with the software., (© 2023 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Objective: The aim of the study is to estimate the association between arcuate uterus and pregnancy outcomes using controls selected from a similarly high-risk cohort., Study Design: This is a retrospective cohort study of women with an arcuate uterus cared for by a single maternal-fetal medicine practice from 2005 to 2020. We included all women with a singleton pregnancy ≥20 weeks and diagnosis of arcuate uterus and randomly selected (3:1) patients with a singleton pregnancy and no uterine anomaly from the same practice as controls. Baseline characteristics and pregnancy outcomes were compared between the two groups. Chi-square, Fisher's exact, and independent samples t -test were used for data analysis, as indicated., Results: A total of 37 women with an arcuate uterus (55 independent singleton pregnancies) and 165 controls were included. There were no differences in baseline characteristics. Women with an arcuate uterus had a significantly higher rate of spontaneous preterm birth less than 37 weeks (10.9 vs. 3.0%, p  = 0.031) and were more likely to require vaginal progesterone (5.5 vs. 0.6%, p  = 0.049) and administration of antenatal corticosteroids (16.4 vs. 5.5%, p  = 0.020). Arcuate uterus was also associated with lower birthweight (3,028.1 ± 528.0 vs. 3257.2 ± 579.9 g, p  = 0.010) and higher incidence of intrauterine fetal growth restriction (20.0 vs. 7.3%, p  = 0.008), despite similar starting body mass index (BMI) and weight gain throughout pregnancy. There were no differences in preeclampsia, malpresentation, cesarean delivery, blood transfusion, retained placenta, or morbidly adherent placenta., Conclusion: Arcuate uterus is associated with a significantly increased risk of spontaneous preterm birth (<37 weeks), need for vaginal progesterone for short cervix and antenatal corticosteroids, fetal growth restriction, and lower mean birthweight. These findings suggest that arcuate uterus is not just a normal variant of uterine anatomy but rather a risk factor for poor fetal growth, short cervix, and a higher risk pregnancy., Key Points: · Arcuate uterus is associated with increased risk of preterm birth and fetal growth restriction.. · Women with arcuate uteri had higher rates of vaginal progesterone use during pregnancy.. · Arcuate uterus should be treated as a true finding rather than a normal anatomical variant.., Competing Interests: None declared., (Thieme. All rights reserved.)

We used cross-sectional surveys to compare the knowledge, attitudes, and decision regret of participants who had consented for genome sequencing (GS) for rare disease diagnosis in the 100,000 Genomes Project (100kGP) across two timepoints (at the time of consenting for GS (T1) and 12-18 months later (T2)). At T1, participants (n = 504) completed a survey that included measures of general knowledge of GS ("Knowledge of Genome Sequencing" (KOGS)), specific knowledge of GS and attitudes towards GS ("General attitudes" and "Specific attitudes"). At T2, participants (n = 296) completed these same assessments (apart from the specific knowledge scale) together with an assessment of decision regret towards GS ("Decisional Regret Scale"). At 12-18 months after consenting for GS, participants' basic knowledge of GS had remained stable. General knowledge of GS varied across topics; concepts underlying more general information about genetics were better understood than the technical details of genomic testing. Attitudes towards GS at T2 were generally positive, and feelings towards GS (both positive and negative) remained unchanged. However, those who were more positive about the test at the outset had greater specific knowledge (as opposed to general knowledge) of GS. Finally, although the majority of participants indicated feeling little regret towards undergoing GS, those with low positive attitude and high negative attitude about GS at T1 reported greater decision regret at T2. Careful assessment of patient knowledge about and attitudes towards GS at the time of offering testing is crucial for supporting informed decision making and mitigating later regret., (© 2023. The Author(s).)

Background: Health-care organisations in England that are rated as inadequate for leadership and one other domain enter the Special Measures for Quality regime to receive support and oversight. A 'watch list' of challenged providers that are at risk of entering Special Measures for Quality also receive support. Knowledge is limited about whether or not the support interventions drive improvements in quality, the costs of the support interventions and whether or not the support interventions strike the right balance between support and scrutiny., Objective: To analyse the responses of trusts to the implementation of (1) interventions for Special Measures for Quality trusts and (2) interventions for challenged provider trusts to determine their impact on these organisations' capacity to achieve and sustain quality improvements., Design: This was rapid research comprising five interrelated workstreams: (1) a literature review using systematic methods; (2) an analysis of policy documents and interviews at the national level; (3) eight multisite, mixed-methods trust case studies; (4) an analysis of national performance and workforce indicators; and (5) an economic analysis., Results: The Special Measures for Quality/challenged provider regimes were intended to be 'support' programmes. Special Measures for Quality/challenged provider regimes had an emotional impact on staff. Perceptions of NHS Improvement interventions were mixed overall. Senior leadership teams were a key driver of change, with strong clinical input being vital. Local systems have a role in improvement. Trusts focus efforts to improve across multiple domains. Internal and external factors contribute to positive performance trajectories. Nationally, only 15.8% of Special Measures for Quality trusts exited the regime in 24 months. Entry into Special Measures for Quality/challenged provider regimes resulted in changes in quality indicators (such the number of patients waiting in emergency departments for more than 4 hours, mortality and the number of delayed transfers of care) that were more positive than national trends. The trends in staff sickness and absence improved after trusts left Special Measures for Quality/challenged provider regimes. There was some evidence that staff survey results improved. No association was found between Special Measures for Quality/challenged provider regimes and referral to treatment times or cancer treatment waiting times. NHS Improvement spending in case study trusts was mostly directed at interventions addressing 'training on cultural change' (33.6%), 'workforce quality and safety' (21.7%) and 'governance and assurance' (18.4%). The impact of Special Measures for Quality on financial stability was equivocal; most trusts exiting Special Measures for Quality experienced the same financial stability before and after exiting., Limitations: The rapid research design and 1-year time frame precludes longitudinal observations of trusts and local systems. The small number of indicators limited the quantitative analysis of impact. Measurement of workforce effects was limited by data availability., Conclusions: Empirical evidence of positive impacts of Special Measures for Quality/challenged provider regimes were identified; however, perceptions were mixed. Key lessons were that (1) time is needed to implement and embed changes; (2) ways to mitigate emotional costs and stigma are needed; (3) support strategies should be more trust specific; (4) poor organisational performance needs to be addressed within local systems; (5) senior leadership teams with stability, strong clinical input and previous Special Measures for Quality experience helped to enact change; (6) organisation-wide quality improvement strategies and capabilities are needed; (7) staff engagement and an open-listening culture promote continuous learning and a quality improvement 'mindset', which is critical for sustainable improvement; and (8) consideration of the level of sustainable funds required to improve patients' outcomes is needed., Future Work: Future work could include evaluating recent changes to the regimes, the role of local systems and longitudinal approaches., Study Registration: The review protocol is registered with PROSPERO (CRD42019131024)., Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme and will be published in full in Health and Social Care Delivery Research ; Vol. 11, No. 19. See the NIHR Journals Library website for further project information.

There are many cellular mechanisms implicated in the initiation and progression of neurodegenerative disorders. However, age and the accumulation of unwanted cellular products are a common theme underlying many neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and Niemann-Pick type C. Autophagy has been studied extensively in these diseases and various genetic risk factors have implicated disruption in autophagy homoeostasis as a major pathogenic mechanism. Autophagy is essential in the maintenance of neuronal homeostasis, as their postmitotic nature makes them particularly susceptible to the damage caused by accumulation of defective or misfolded proteins, disease-prone aggregates, and damaged organelles. Recently, autophagy of the endoplasmic reticulum (ER-phagy) has been identified as a novel cellular mechanism for regulating ER morphology and response to cellular stress. As neurodegenerative diseases are generally precipitated by cellular stressors such as protein accumulation and environmental toxin exposure the role of ER-phagy has begun to be investigated. In this review we discuss the current research in ER-phagy and its involvement in neurodegenerative diseases., (© 2023 The Authors. Journal of Neuroscience Research published by Wiley Periodicals LLC.)

Background: Difficult intravenous access is a frequent occurrence in critical care and emergency medicine. Prior intravenous access, chemotherapy use, and obesity are a few factors associated with difficult access. Alternatives to peripheral access are often contraindicated, not feasible, or not readily available., Objectives: To describe the feasibility and safety of peripheral insertion of peripherally inserted pediatric central venous catheters (PIPCVC) in a cohort of adult critical care patients with difficult intravenous access., Methods: Prospective observational study of adult patients with difficult intravenous access who underwent peripheral insertion of pediatric PIPCVCs at a large university hospital., Results: During a 1-year period, 46 patients were evaluated for PIPCVC; 40 catheters were placed successfully. The median age of the patients was 59 years (range 19-95 years) and 20 (50%) were female. The median body mass index was 27.2 (range 17.1-41.8). The basilic vein was accessed in 25/40 (63%) patients, the cephalic in 10/40 (25%), and the accessed vessel was missing in 5/40 (13%) cases. The PIPCVCs were in place for a median of 8 days (range 1-32). One superficial thrombosis and one deep occurred; pulmonary embolism did not occur., Conclusions: PIPCVC placement seems to be a feasible option in patients in whom peripheral intravenous access is difficult. The safety of this technique needs to be evaluated in prospective studies., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: There is limited knowledge about interventions used for the improvement of low-performing healthcare organisations and their unintended consequences. Our evaluation sought to understand how healthcare organisations in the National Health Service (NHS) in England responded to a national improvement initiative (the Special Measures for Quality [SMQ] and challenged provider [CP] regimes) and its perceived impact on achieving quality improvements (QIs)., Methods: Our evaluation included national-level interviews with key stakeholders involved in the delivery of SMQ (n=6); documentary analysis (n=20); and a qualitative study based on interviews (n=60), observations (n=8) and documentary analysis (n=291) in eight NHS case study sites. The analysis was informed by literature on failure, turnaround and QI in organisations in the public sector., Results: At the policy level, SMQ/CP regimes were intended to be "support" programmes, but perceptions of the interventions at hospital level were mixed. The SMQ/CP regimes tended to consider failure at an organisational level and turnaround was visualised as a linear process. There was a negative emotional impact reported by staff, especially in the short-term. Key drivers of change included: engaged senior leadership teams, strong clinical input and supportive external partnerships within local health systems. Trusts focused efforts to improve across multiple domains with particular investment in improving overall staff engagement, developing an open, listening organisational culture and better governance to ensure clinical safety and reporting., Conclusion: Organisational improvement in healthcare requires substantial time to embed and requires investment in staff to drive change and cultivate QI capabilities at different tiers. The time this takes may be underestimated by external 'turn-around' interventions and performance regimes designed to improve quality in the short-term and which come at an emotional cost for staff. Shifting an improvement focus to the health system or regional level may promote sustainable improvement across multiple organisations over the long-term., (© 2022 The Author(s); Published by Kerman University of Medical Sciences This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

Purpose: Parkinson's disease (PD) is the second most prevalent neurodegenerative disease. It is generally diagnosed clinically after the irreversible loss of dopaminergic neurons and no general biomarkers currently exist. To gain insight into the underlying cellular causes of PD we aimed to quantify the proteomic differences between healthy control and PD patient cells., Experimental Design: Sequential Window Acquisition of all THeoretical Mass Spectra was performed on primary cells from healthy controls and PD patients., Results: In total, 1948 proteins were quantified and 228 proteins were significantly differentially expressed in PD patient cells. In PD patient cells, we identified seven significantly increased proteins involved in the unfolded protein response (UPR) and focused on cells with high and low amounts of PDIA6 and HYOU1. We discovered that PD patients with high amounts of PDIA6 and HYOU1 proteins were more sensitive to endoplasmic reticulum stress, in particular to tunicamycin. Data is available via ProteomeXchange with identifier PXD030723., Conclusions and Clinical Relevance: This data from primary patient cells has uncovered a critical role of the UPR in patients with PD and may provide insight to the underlying cellular dysfunctions in these patients., (© 2022 The Authors. PROTEOMICS-Clinical Applications published by Wiley-VCH GmbH.)

The genetic study of multi-incident families is a powerful tool to investigate genetic contributions to the development of Parkinson's disease. In this study, we identified the rare PTPRA p.R223W variant as one of three putative genetic factors potentially contributing to disease in an Australian family with incomplete penetrance. Whole exome sequencing identified these mutations in three affected cousins. The rare PTPRA missense variant was predicted to be damaging and was absent from 3,842 alleles from PD cases. Overexpression of the wild-type RPTPα and R223W mutant in HEK293T cells identified that the R223W mutation did not impair RPTPα expression levels or alter its trafficking to the plasma membrane. The R223W mutation did alter proteolytic processing of RPTPα, resulting in the accumulation of a cleavage product. The mutation also resulted in decreased activation of Src family kinases. The functional consequences of this variant, either alone or in concert with the other identified genetic variants, highlights that even minor changes in normal cellular function may increase the risk of developing PD., Competing Interests: The authors have declared that no competing interests exist.

Background: Prenatal exome sequencing (ES) for the diagnosis of fetal anomalies was implemented nationally in England in October 2020 by the NHS Genomic Medicine Service (GMS). is the GMS is based around seven regional Genomic Laboratory Hubs (GLHs). Prenatal ES has the potential to significantly improve NHS prenatal diagnostic services by increasing genetic diagnoses and informing prenatal decision-making. Prenatal ES has not previously been offered routinely in a national healthcare system and there are gaps in knowledge and guidance., Methods: Our mixed-methods evaluation commenced in October 2020, aligning with the start date of the NHS prenatal ES service . Study design draws on a framework developed in previous studies of major system innovation. There are five interrelated workstreams. Workstream-1 will use interviews and surveys with professionals, non-participant observations and documentary analysis to produce in-depth case studies across all GLHs. Data collection at multiple time points will track changes over time. In Workstream-2 qualitative interviews with parents offered prenatal ES will explore experiences and establish information and support needs. Workstream-3 will analyse data from all prenatal ES tests for nine-months to establish service outcomes (e.g. diagnostic yield, referral rates, referral sources). Comparisons between GLHs will identify factors (individual or service-related) associated with any variation in outcomes. Workstream-4 will identify and analyse practical ethical problems. Requirements for an effective ethics framework for an optimal and equitable service will be determined. Workstream-5 will assess costs and cost-effectiveness of prenatal ES versus standard tests and evaluate costs of implementing an optimal prenatal ES care pathway. Integration of findings will determine key features of an optimal care pathway from a service delivery, parent and professional perspective., Discussion: The proposed formative and summative evaluation will inform the evolving prenatal ES service to ensure equity of access, high standards of care and benefits for parents across England., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 Hill M et al.)

Background: Prenatal exome sequencing (ES) for the diagnosis of fetal anomalies was implemented nationally in England in October 2020 by the NHS Genomic Medicine Service (GMS). The GMS is based around seven regional Genomic Laboratory Hubs (GLHs). Prenatal ES has the potential to significantly improve NHS prenatal diagnostic services by increasing genetic diagnoses and informing prenatal decision-making. Prenatal ES has not previously been offered routinely in a national healthcare system and there are gaps in knowledge and guidance., Methods: Our mixed-methods evaluation commenced in October 2020, aligning with the start date of the NHS prenatal ES service. Study design draws on a framework developed in previous studies of major system innovation. There are five interrelated workstreams. Workstream-1 will use interviews and surveys with professionals, non-participant observations and documentary analysis to produce indepth case studies across all GLHs. Data collection at multiple time points will track changes over time. In Workstream-2 qualitative interviews with parents offered prenatal ES will explore experiences and establish information and support needs. Workstream-3 will analyse data from all prenatal ES tests for nine-months to establish service outcomes (e.g. diagnostic yield, referral rates, referral sources). Comparisons between GLHs will identify factors (individual or service-related) associated with any variation in outcomes. Workstream-4 will identify and analyse practical ethical problems. Requirements for an effective ethics framework for an optimal and equitable service will be determined. Workstream-5 will assess costs and cost-effectiveness of prenatal ES versus standard tests and evaluate costs of implementing an optimal prenatal ES care pathway. Integration of findings will determine key features of an optimal care pathway from a service delivery, parent and professional perspective., Discussion: The proposed formative and summative evaluation will inform the evolving prenatal ES service to ensure equity of access, high standards of care and benefits for parents across England., Competing Interests: Competing interests: No competing interests were disclosed.

Objective: We conducted a survey-based discrete-choice experiment (DCE) to understand the test features that drive women's preferences for prenatal genomic testing, and explore variation across countries., Methods: Five test attributes were identified as being important for decision-making through a literature review, qualitative interviews and quantitative scoring exercise. Twelve scenarios were constructed in which respondents choose between two invasive tests or no test. Women from eight countries who delivered a baby in the previous 24 months completed a DCE presenting these scenarios. Choices were modeled using conditional logit regression analysis., Results: Surveys from 1239 women (Australia: n = 178; China: n = 179; Denmark: n = 88; Netherlands: n = 177; Singapore: n = 90; Sweden: n = 178; UK: n = 174; USA: n = 175) were analyzed. The key attribute affecting preferences was a test with the highest diagnostic yield (p < 0.01). Women preferred tests with short turnaround times (p < 0.01), and tests reporting variants of uncertain significance (VUS; p < 0.01) and secondary findings (SFs; p < 0.01). Several country-specific differences were identified, including time to get a result, who explains the result, and the return of VUS and SFs., Conclusion: Most women want maximum information from prenatal genomic tests, but our findings highlight country-based differences. Global consensus on how to return uncertain results is not necessarily realistic or desirable., (© 2022 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Background: Helicopter medical transportation (HMT) is a valuable resource that can expedite medical care by shortening transferring times. However, there is conflicting evidence regarding its cost and efficacy. No specific studies have addressed its use in patients transferred to the neuroscience intensive care unit (NSICU)., Methods: This was a retrospective study performed at a university hospital in the coastal southeastern USA. The flight logs for the air ambulance company were reviewed, and all patients undergoing HMT to the NSICU during a 1-year period were identified. Flight logs and medical records were reviewed to obtain basic demographics, diagnosis, mortality, transportation distance, and performance of time-sensitive interventions (TSIs) to include ventriculostomy placement, emergency craniotomy, emergency craniectomy, emergency aneurysm obliteration, emergency spine surgery, emergent endovascular procedures, subdural drain placement, emergent shunt revision, and continuous electroencephalography (EEG) performed within 4 h of admission. We analyzed the cost of HMT and correlated the clinical variables with the performance of TSIs., Results: A total of 101 patients underwent HMT during a 12-month period; 26 underwent 30 TSIs (4 underwent 2 TSIs) and an additional 4 were transported for EEG monitoring. The only clinical variable associated with a TSI was subarachnoid hemorrhage with ventriculostomy placement. Continuous EEG monitoring performed in four patients with suspected status epilepticus did not show status epilepticus in any of them (one was performed after 4 h). Transportation distance was less than 60 miles in four patients who underwent TSIs. The total cost of HMT was $3,360,573: $842,672 for those who underwent TSIs and $2,517,901 for those who did not. When compared with ground transportation, an excess cost of $3,129,415.25 was incurred by using HMT. There was no difference in the median cost of transportation between patients who underwent TSIs and those who did not ($30,210 vs. $30,211). The median cost transportation difference between HMT and ground transportation was significantly different (p < 0.001), with a median excess cost of $28,023 (range $15,553-76,155) per patient., Conclusions: The majority of patients who were transferred via HMT did not undergo TSIs, and among those who underwent TSIs, approximately one in six was transported from a hospital located less than 60 miles away from the NSICU; the distances of ground and air transportation are equivalent. Helicopter transfers may play a role in subarachnoid hemorrhage management. A significant expense was incurred by using HMT for the majority of patients (75%) who did not undergo TSIs., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Objectives: We conducted a systematic review and meta-analysis to determine the diagnostic yield of exome sequencing (ES) for prenatal diagnosis of fetal structural anomalies, where karyotype/chromosomal microarray (CMA) is normal., Methods: Following electronic searches of four databases, we included studies with ≥10 structurally abnormal fetuses undergoing ES or whole genome sequencing. The incremental diagnostic yield of ES over CMA/karyotype was calculated and pooled in a meta-analysis. Sub-group analyses investigated effects of case selection and fetal phenotype on diagnostic yield., Results: We identified 72 reports from 66 studies, representing 4350 fetuses. The pooled incremental yield of ES was 31% (95% confidence interval (CI) 26%-36%, p < 0.0001). Diagnostic yield was significantly higher for cases pre-selected for likelihood of monogenic aetiology compared to unselected cases (42% vs. 15%, p < 0.0001). Diagnostic yield differed significantly between phenotypic sub-groups, ranging from 53% (95% CI 42%-63%, p < 0.0001) for isolated skeletal abnormalities, to 2% (95% CI 0%-5%, p = 0.04) for isolated increased nuchal translucency., Conclusion: Prenatal ES provides a diagnosis in an additional 31% of structurally abnormal fetuses when CMA/karyotype is non-diagnostic. The expected diagnostic yield depends on the body system(s) affected and can be optimised by pre-selection of cases following multi-disciplinary review to determine that a monogenic cause is likely., (© 2022 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

In this mixed methods study, a survey and in-depth interviews were used to explore whether decision regret and the psychological impact of receiving genome sequencing (GS) results differed between parents and patients, and between those who received a genetic diagnosis and those who did not. Participants (n = 77) completed a survey that included the Decisional Regret Scale (DRS) and an adaptation of the Multidimensional Impact of Cancer Risk Assessment (MICRA) at least 12 months after consenting for GS for rare disease diagnosis in the 100,000 Genomes Project. Survey participants were invited to take part in an interview and 39 agreed; 12 with a diagnosis, 5 with variants of uncertain significance, and 19 with no pathogenic findings identified. Both survey and interview findings indicated that decision regret was low. DRS scores revealed no differences in levels of regret between parents and patients, or between those with a diagnosis and those without. Though MICRA scores indicated minimal evidence of negative psychological impacts of receiving GS results, subscale analysis revealed greater distress and uncertainty for parents compared to patients. Receiving a diagnosis was found not to influence MICRA scores, supporting interview findings of both positive and negative emotional and psychological impacts irrespective of a genetic diagnosis. Our findings have implications for policy and practice as GS is integrated into the UK and worldwide; notably, that expectation-setting is critical when offering GS, and that post-test counselling is important regardless of the GS result received, with parents perhaps needing additional emotional support., (© 2022. The Author(s).)

Objectives: Prenatal exome sequencing (pES) for the diagnosis of fetal abnormalities is being introduced more widely in clinical practice. Here we explore parents' and professionals' views and experiences of pES, to identify perceived benefits, concerns, and support needs., Methods: Semi-structured interviews were conducted with 11 parents and 20 health professionals (fetal medicine and clinical genetics) with experience of rapid pES prior to implementation in the English National Health Service. Interviews were transcribed verbatim and analysed thematically., Results: Parents and professionals were largely positive about pES, emphasising clinical and psychosocial benefits of a timely, definitive diagnosis in pregnancy. Concerns included parental anxiety related to the timing of pES results or uncertain findings, a need for guidelines for case selection and reporting, and ensuring sufficient capacity for counselling, phenotyping and variant interpretation. Professionals were concerned non-genetics professionals may not be equipped to counsel parents on the complexities of pES., Conclusion: These findings highlight important issues for clinical implementation of pES. Expert counselling is required to enable parents to make informed decisions during a stressful time. To achieve this, professionals need further education and training, and fetal medicine and genetics services must work closely together to ensure parental understanding and appropriate support., (© 2022 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Prenatal DNA tests, such as chromosomal microarray analysis or exome sequencing, increase the likelihood of receiving a diagnosis when fetal structural anomalies are identified. However, some parents will receive uncertain results such as variants of uncertain significance and secondary findings. We aimed to develop a set of attributes and associated levels for a discrete-choice experiment (DCE) that will examine parents' preferences for tests that may reveal uncertain test results. A two phase mixed-methods approach was used to develop attributes for the DCE. In Phase 1, a "long list" of candidate attributes were identified via two approaches: 1) a systematic review of the literature around parental experiences of uncertainty following prenatal testing; 2) 16 semi-structured interviews with parents who had experienced uncertainty during pregnancy and 25 health professionals who return uncertain prenatal results. In Phase 2, a quantitative scoring exercise with parents prioritised the candidate attributes. Clinically appropriate levels for each attribute were then developed. A final set of five attributes and levels were identified: likelihood of getting a result, reporting of variants of uncertain significance, reporting of secondary findings, time taken to receive results, and who tells you about your result. These attributes will be used in an international DCE study to investigate preferences and differences across countries. This research will inform best practice for professionals supporting parents to manage uncertainty in the prenatal setting., Competing Interests: The authors have read the journal’s policy and have the following competing interests: JB received travel support from Illumina to attend conferences. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Purpose: The purpose of this study was to assess decisions, attitudes, and understanding of participants (patients, parents, relatives) having genome sequencing for rare disease diagnosis., Methods: This study involved a cross-sectional observational survey with participants in the 100,000 Genomes Project., Results: Survey response rate was 51% (504/978). Most participants self-reported that they had decided to undergo genome sequencing (94%) and that this was an informed decision (84%) with low decisional conflict (95%). Most self-reported that they had chosen to receive additional findings (88%) and that this was an informed decision (89%) with low decisional conflict (95%). Participants were motivated more by the desire to help others via research than by the belief it would help them obtain a diagnosis (Z = 14.23, P = 5.75 × 10 -46 ), although both motivations were high. Concerns were relatively few but, where expressed, were more about the potential psychological impact of results than data sharing/access (Z = 9.61, P = 7.65 × 10 -22 ). Concerns were higher among male, Asian or Asian British, and more religious participants. General and context-specific understanding of genome sequencing were both moderately high (means 5.2/9.0 and 22.5/28.0, respectively)., Conclusion: These findings are useful to inform consent guidelines and clinical implementation of genome sequencing., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Osteogenesis imperfecta (OI) is a rare genetic condition characterised by increased bone fragility. Recurrent fractures, pain and fatigue have a considerable impact on many aspects of the life of a person affected with OI and their families., Objective: To improve our understanding of the impact of OI on the daily lives of individuals and families and consider how the condition is managed so that support needs can be better addressed., Methods: Semi-structured qualitative interviews (n = 56) were conducted with adults affected with OI, with (n = 9) and without children (n = 8), parents of children affected with OI (n = 8), health professionals (n = 29) and patient advocates (n = 2). Interviews were digitally recorded, transcribed verbatim and analysed using thematic analysis., Results: Three overarching themes are described: OI is not just a physical condition, parenting and family functioning and managing the condition. Fractures, chronic pain and tiredness impact on daily life and emotional well-being. For parents with OI, pain, tiredness and mobility issues can limit interactions and activities with their children. Specialist paediatric health services for OI were highly valued. The need for more emotional support and improved coordination of adult health services was highlighted., Conclusions: Our findings allow a better understanding of the day-to-day experiences of individuals and families affected with OI. Supporting emotional well-being needs greater attention from policy makers and researchers. Improvements to the coordination of health services for adults with OI are needed and an in-depth exploration of young people's support needs is warranted with research focused on support through the teenage years., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To identify what online patient information (presented in English) is available to parents about prenatal microarray (CMA) and exome sequencing (ES), and evaluate its content, quality, and readability., Method: Systematic searches (Google and Bing) were conducted, and websites were categorised according to their purpose. Websites categorised as patient information were included if they were: in English, directed at patients, or were a text, video, or online version of an information leaflet. Author-developed content checklists, the DISCERN Genetics tool, and readability tests (the Flesch Reading Ease Score, the Gunning Fog Index, and the Simple Measure of Gobbledygook Index) were then used to assess those sources of patient information., Results: Of the 665 websites screened, 18 met the criteria. A further 8 sources were found through a targeted search of professional organisations, resulting in 26 sources available for further evaluation. In general, this was found to be low in quality, omitted details recommended by national or international guidance, and was written at a level too advanced for average readers., Conclusion: Improvements should be made to the content, quality, and readability of online information so that it both reinforces and complements the discussions between parents and clinicians about testing options during pregnancy., (© 2021 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Purpose: Contrast-Enhanced Mammography (CEM) produces a dual-energy subtracted (DES) image that demonstrates iodine uptake (neovascularity) in breast tissue. We aim to review a range of artifacts on DES images produced using equipment from two different vendors and compare their incidence and subjective severity., Methods: We retrospectively reviewed CEM studies performed between September 2013 and March 2017 using GE Senographe Essential (n = 100) and Hologic Selenia Dimensions (n = 100) equipment. Artifacts were categorized and graded in severity by a subspecialist breast radiologist and one of two medical imaging technologists in consensus. The incidence of artifacts between vendors was compared by calculating the relative risk, and the severity gradings were compared using a Wilcoxon rank-sum test., Results: Elephant rind, corrugations and the black line on chest wall artifact were seen exclusively in Hologic images. Artifacts such as cloudy fat, negative rim around lesion and white line on pectoral muscle were seen in significantly more Hologic images (p < 0.05) whilst halo, ripple, skin line enhancement, black line on pectoral muscle, bright pectorals, chest wall high-lighting and air gap were seen in significantly more GE images (p < 0.05). The severity gradings for cloudy fat had a significantly higher mean rank in Hologic images (p < 0.001) whilst halo and ripple artifacts had a significantly higher mean rank in GE images (p < 0.001 and p = 0.028 respectively)., Conclusion: The type, incidence and subjective severity of CEM-specific artifacts differ between vendors. Further research is needed, but differences in algorithms used to produce the DE image are postulated to be a significant contributor., (Copyright © 2021. Published by Elsevier Inc.)

Exome sequencing (ES) enhanced the diagnostic yield of genetic testing, but has also increased the possibility of uncertain findings. Prenatal ES is increasingly being offered after a fetal abnormality is detected through ultrasound. It is important to know how to handle uncertainty in this particularly stressful period. This systematic review aimed to provide a comprehensive overview of guidelines available for addressing uncertainty related to prenatal chromosomal microarray (CMA) and ES. Ten uncertainty types associated with prenatal ES and CMA were identified and defined by an international multidisciplinary team. Medline (all) and Embase were systematically searched. Laboratory scientists, clinical geneticists, psychologists, and a fetal medicine specialist screened the papers and performed the data extraction. Nineteen papers were included. Recommendations generally emphasized the importance of trio analysis, clinical information, data sharing, validation and re-analysis, protocols, multidisciplinary teams, genetic counselling, whether to limit the possible scope of results, and when to report particular findings. This systematic review helps provide a vocabulary for uncertainties, and a compass to navigate uncertainties. Prenatal CMA and ES guidelines provide a strong starting point for determining how to handle uncertainty. Gaps in guidelines and recommendations were identified and discussed to provide direction for future research and policy making., (© 2021 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Background: A new nationally commissioned NHS England Genomic Medicine Service (GMS) was recently established to deliver genomic testing with equity of access for patients affected by rare diseases and cancer. The overarching aim of this research is to evaluate the implementation of the GMS during its early years, identify barriers and enablers to successful implementation, and provide recommendations for practice. The focus will be on the use of genomic testing for paediatric rare diseases., Methods: This will be a four-year mixed-methods research programme using clinic observations, interviews and surveys. Study 1 consists of qualitative interviews with designers/implementers of the GMS in Year 1 of the research programme, along with documentary analysis to understand the intended outcomes for the Service. These will be revisited in Year 4 to compare intended outcomes with what happened in practice, and to identify barriers and facilitators that were encountered along the way. Study 2 consists of clinic observations (pre-test counselling and results disclosure) to examine the interaction between health professionals and parents, along with follow-up interviews with both after each observation. Study 3 consists of a longitudinal survey with parents at two timepoints (time of testing and 12 months post-results) along with follow-up interviews, to examine parent-reported experiences and outcomes. Study 4 consists of qualitative interviews and a cross-sectional survey with medical specialists to identify preparedness, facilitators and challenges to mainstreaming genomic testing. The use of theory-based and prespecified constructs will help generalise the findings and enable integration across the various sub-studies., Dissemination: We will disseminate our results to policymakers as findings emerge, so any suggested changes to service provision can be considered in a timely manner. A workshop with key stakeholders will be held in Year 4 to develop and agree a set of recommendations for practice., Competing Interests: Competing interests: Jillian Hastings Ward is the independent Chair of the Participant Panel at Genomic England and also sits on the National Genomics Board and the NHS GMS People and Communities Forum. Christine Patch has been on a secondment with Genomics England as Clinical Lead for Genetic Counselling since October 2016. Alexandra Pickard is Deputy Director of Genomics at NHS England. Saskia Sanderson is Chief Behavioural Scientist at Our Future Health. Sarah Lewell is a representative on the Genomics Clinical Reference Group and sits on the NHS GMS People and Communities Forum. No other competing interests were disclosed.

Background: A new nationally commissioned NHS England Genomic Medicine Service (GMS) was recently established to deliver genomic testing with equity of access for patients affected by rare diseases and cancer. The overarching aim of this research is to evaluate the implementation of the GMS during its early years, identify barriers and enablers to successful implementation, and provide recommendations for practice. The focus will be on the use of genomic testing for paediatric rare diseases., Methods: This will be a four-year mixed-methods research programme using clinic observations, interviews and surveys. Study 1 consists of qualitative interviews with designers/implementers of the GMS in Year 1 of the research programme, along with documentary analysis to understand the intended outcomes for the Service. These will be revisited in Year 4 to compare intended outcomes with what happened in practice, and to identify barriers and facilitators that were encountered along the way. Study 2 consists of clinic observations (pre-test counselling and results disclosure) to examine the interaction between health professionals and parents, along with follow-up interviews with both after each observation. Study 3 consists of a longitudinal survey with parents at two timepoints (time of testing and 12 months post-results) along with follow-up interviews, to examine parent-reported experiences and outcomes. Study 4 consists of qualitative interviews and a cross-sectional survey with medical specialists to identify preparedness, facilitators and challenges to mainstreaming genomic testing. The use of theory-based and pre-specified constructs will help generalise the findings and enable integration across the various sub-studies., Dissemination: We will disseminate our results to policymakers as findings emerge, so any suggested changes to service provision can be considered in a timely manner. A workshop with key stakeholders will be held in Year 4 to develop and agree a set of recommendations for practice., Competing Interests: Competing interests: Jillian Hastings Ward is the independent Chair of the Participant Panel at Genomic England and also sits on the National Genomics Board and the NHS GMS People and Communities Forum. Christine Patch has been on a secondment with Genomics England as Clinical Lead for Genetic Counselling since October 2016. Alexandra Pickard is Deputy Director of Genomics at NHS England. Saskia Sanderson is Chief Behavioural Scientist at Our Future Health. Sarah Lewell is a representative on the Genomics Clinical Reference Group and sits on the NHS GMS People and Communities Forum. No other competing interests were disclosed., (Copyright: © 2021 Lewis C et al.)

Objective: To compare the effectiveness of an animation against two leaflets with and without images, in educating young people about genome sequencing (GS)., Methods: An experimental survey with three assessment points (pre- intervention [T1], post - intervention [T2], 6-week follow-up [T3]). Participants (N = 606) were randomly assigned to receive one of three educational interventions; animation (n = 212); leaflet with images (n = 197); or leaflet with text only (n = 197). Measures of objective and subjective knowledge were completed at T1 (N = 606), T2 (N = 606) and T3 (N = 459). Measures of attitudes, intentions and beliefs towards GS and satisfaction with intervention were completed at T2 only., Results: The type of educational intervention young people received had no significant impact on their objective or subjective knowledge at both T2 and T3 (all p > .05), nor did the educational intervention type affect their attitudes, intentions and beliefs towards GS at T2 (p > .05). However, participant satisfaction was significantly higher in the animation group than the leaflet groups (p < .001)., Conclusion: Animations and leaflets are both effective ways to deliver genomic education to young people, but the animations lead to higher satisfaction., Practice Implications: Different individuals may find different modes of educational resources more accessible than others. Therefore a range of resources should ideally be made available to patients., Competing Interests: Declaration of Competing Interest CP has been on a secondment with Genomics England as Clinical Lead for Genetic Counselling since October 2017. The other authors declare no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Discovery and validation of pragmatic biomarkers represent significant advancements in the field of pain management. Evaluating relationships between objective biomarkers and patient-reported outcomes (PROs) is an effective way to gain mechanistic insight into the potential role of biochemistry in chronic pain. The aim of this study was to validate the Foundation Pain Index (FPI) by evaluating associations between deranged biochemical function and PROMIS-29 domains in individuals living with chronic pain., Patients and Methods: PROMIS-29 scores and FPI test results were obtained from 298 patients with chronic pain in this retrospective, observational study. Statistical analysis was performed using clinical test data to evaluate relationships between deranged biochemical function and quality of life measures across 8 universal domains., Results: FPI scores significantly associated with multiple PROMIS-29 domains including physical function, impact score, fatigue, pain interference, and depression (P < 0.05). Moreover, specific analytes that comprise the FPI significantly correlated with PROMIS-29 domains, including 5-hydroxyindolacetic acid (pain interference, physical function, and pain impact scores), hydroxymethylglutarate (physical function), homocysteine (pain impact scores), kynurenic acid (pain interference and physical function), and quinolinic acid (physical function) (P < 0.05)., Conclusion: Cross-validation of the FPI with PROMIS-29 domains further supports the role of deranged biochemical function in the etiology of chronic pain. Objective identification of atypical biochemical function and subsequent correction holds tremendous promise for the non-opioid management of pain. Continued research efforts will aim to determine the impact of biochemical optimization in pre-surgical periods and post-surgical outcomes in patients with chronic pain., Competing Interests: Dr Jason E Pope is a consultant for Ethos Labs, Flowonix, Saluda Medical, PainTEQ, Aurora Spine, SpineThera, Abbott, Medtronic, Vertos, SPARK, SPR Therapeutics, WISE, Tersera, Boston Scientific, and AIS, and owns equity in Celeri Health, AGR, and NIS, outside the submitted work. Dr Michael A Fishman is a consultant for Abbott, Aurora Pain Care, Biotronik, Braeburn, Foundation Fusion Solutions, Institute for Musculoskeletal Health, Medtronic, Nevro, Boston Scientific, Cornerloc, Lumbrera, Nalu Medical, Saluda Medical, and StimGenics, and owns equity in Celeri Health, SGX International, and Thermaquil, outside the submitted work. Dr Joshua A Gunn has a patent pending for Methods of Diagnosing and Treating Particular Causal Components of Chronic Pain in a Patient and is Chief Scientific Officer and part-owner of Ethos Research & Development. Dr Timothy R Deer is a consultant for Abbott, Flowonix, Mainstay, Ethos Labs, Stimgenics, SI Bone, Nevro, Medtronic, and PainTeq, and owns equity in Vertos Medical, Axonics, SpineThera, Saluda Medical, Nalu, Vertiflex, Cornerloc, SPR Therapeutics, and Boston Scientific, outside the submitted work. In addition, Dr Timothy Deer is the DRG Surgical Leads and has a patent pending to Abbott. The authors report no other conflicts of interest in this work., (© 2021 Pope et al.)

Contrast-enhanced mammography (CEM) demonstrates a potential role in personalized screening models, in particular for women at increased risk and women with dense breasts. In this study, volumetric breast density (VBD) measured in CEM images was compared with VBD obtained from digital mammography (DM) or tomosynthesis (DBT) images. A total of 150 women who underwent CEM between March 2019 and December 2020, having at least a DM/DBT study performed before/after CEM, were included. Low-energy CEM (LE-CEM) and DM/DBT images were processed with automatic software to obtain the VBD. VBDs from the paired datasets were compared by Wilcoxon tests. A multivariate regression model was applied to analyze the relationship between VBD differences and multiple independent variables certainly or potentially affecting VBD. Median VBD was comparable for LE-CEM and DM/DBT (12.73% vs. 12.39%), not evidencing any statistically significant difference ( p = 0.5855). VBD differences between LE-CEM and DM were associated with significant differences of glandular volume, breast thickness, compression force and pressure, contact area, and nipple-to-posterior-edge distance, i.e., variables reflecting differences in breast positioning (coefficient of determination 0.6023; multiple correlation coefficient 0.7761). Volumetric breast density was obtained from low-energy contrast-enhanced spectral mammography and was not significantly different from volumetric breast density measured from standard mammograms.

Objectives: To conduct qualitative interviews with healthcare providers working in different countries to understand their experiences of dealing with uncertain results from prenatal chromosome microarray analysis (CMA) and exome sequencing (ES)., Methods: Semi-structured interviews with 31 healthcare providers who report or return prenatal CMA and/or ES results (clinicians, genetic counsellors and clinical scientists) in six countries with differing healthcare systems; Australia (4), Denmark (5), Netherlands (6), Singapore (4), Sweden (6) and United Kingdom (6). The topic guide explored the main sources of uncertainty and their management., Results: There was variation in reporting practices both between and across countries for variants of uncertain significance, however, there was broad agreement on reporting practices for incidental findings. There was also variation in who decides what results are reported (clinical scientists or clinicians). Technical limitations and lack of knowledge (to classify variants and of prenatal phenotypes) were significant challenges, as were turnaround times and lack of guidelines., Conclusion: Health professionals around the globe are dealing with similar sources of uncertainty, but managing them in different ways, Continued dialogue with international colleagues on ways of managing uncertain results is important to compare and contrast the benefits and limitations of the different approaches., (© 2021 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

In this essay, a medical student details how she struggled to let go of a patient with whom she connected throughout the patient's pregnancy during her second year of medical school. Although she learned in her preclinical "doctoring" courses how to build quick connections with patients, such training did not delve into how to manage meaningful, emotionally complex connections that may form with patients during longitudinal rotations or, as in this case, extracurricular activities. While primary care physicians may have decades of practice managing evolving longitudinal relationships, medical students who form strong connections with patients are just learning what it means to navigate those relationships, some of which come to an end. Reflecting on the end of this particular relationship helped the author appreciate the power of the longitudinal physician-patient relationship and taught her that taking care of patients also requires taking care of one's self., (© 2021 Annals of Family Medicine, Inc.)

For a number of prospective parents, uncertainty during pregnancy starts when an anomaly is found during a routine fetal anomaly scan. This may be followed by numerous tests to determine the etiology and nature of the anomaly. In this study, we aimed to understand how prospective parents perceive and manage uncertainty after being confronted with a structural anomaly during their routine ultrasound. Han's taxonomy of uncertainty was used as a framework to identify and understand the different types of uncertainty experienced. Interviews were held in the UK (n = 8 women and n = 1 male partner) and in the Netherlands (n = 7 women) with participants who had experienced uncertainty in their pregnancy after a fetal scan. Data were analyzed using thematic analysis, and the uncertainties experienced by parents were mapped against the dimensions of the Han taxonomy (sources, issues, and locus). Participants' experience of uncertainty was relevant to all dimensions and subcategories of the Han taxonomy, showing its applicability in the prenatal setting. Sources of uncertainty included receiving probabilistic or ambiguous information about the anomaly, or information that was complex and challenging to understand. Issues of uncertainty included were those that were scientific-such as a probable diagnosis with no further information, personal-such as the emotional impact of uncertainty, and practical-such as limited information about medical procedures and practical aspects of care. Additionally, participants described what helped them to manage uncertainty. This included active coping strategies such as searching for information on the Internet, external coping resources such as seeking social support, and internal coping resources such as using positivity and hope. Several recommendations for the healthcare professional to minimize uncertainty and help the patient deal with uncertainty have been proposed based on these findings., (© 2020 The Authors. Journal of Genetic Counseling published by Wiley Periodicals LLC on behalf of National Society of Genetic Counselors.)

Objective: We sought to determine if women with twin pregnancies and blood pressure (BP) above the 95th percentile but within normal ranges (i.e. less than 140 systolic and 90 diastolic) are at increased risk of hypertensive disorders of pregnancy. Methods: Retrospective cohort study of all women with twin pregnancies being cared for by a single Maternal Fetal Medicine practice between 2012 and 2018. We identified all women who had a systolic blood pressure (SBP) or diastolic blood pressure (DBP) above the 95th percentile but less than 140 systolic and 90 diastolic at any point during pregnancy. Based on prior publications, the 95th percentile was defined as: a SBP 121-139 mmHg up to 30 weeks or 131-139 mmHg after 30 weeks, a DBP 81-89 mmHg up to 34 weeks or 85-89 mmHg after 34 weeks. We excluded women diagnosed with chronic hypertension either before or during pregnancy. The primary outcome was the development of preeclampsia. Chi-square and logistic regression were used. Results: A total of 457 patients met the inclusion criteria, of whom 109 (23.9%) had either a systolic or diastolic BP above the 95th percentile (but normal) at any time during pregnancy. These women were significantly more likely to develop preeclampsia (30.3 versus 12.6%, p  < .001, aOR 2.32 (1.31, 4.09)) and gestational hypertension without preeclampsia (16.5 versus 4.6%, p  < .001, aOR 4.27 (2.01, 9.07)). Conclusions: In women with twin pregnancies, a high-normal systolic or diastolic BP (above 120 systolic or 80 diastolic prior to 30 weeks, or above 130 systolic or 84 diastolic after 30 weeks) is associated with a significantly increased risk of gestational hypertension and preeclampsia.

Introduction: Chronic pain assessment and post-treatment evaluation continues to be challenging due to a lack of validated, objective tools to measure patient outcomes. Validation of mechanistic pain biomarkers would allow clinicians to objectively identify abnormal biochemistry contributing to painful symptoms., Methods: We describe the clinical validation of a multi-biomarker assay with algorithmic analysis known as the Foundation Pain Index (FPI) in diverse cohorts of chronic pain patients in a prospective, cross-sectional, observational validation study. Levels of 11 urinary pain biomarkers were measured and tabulated using a proprietary algorithm to generate FPI scores for chronic pain subjects (N = 153) and age- and sex-matched pain-free controls (N = 334)., Results: FPI scores were significantly correlated with the 36-Item Short Form Health Survey (SF-36) scores among chronic pain subjects (P value < 0.015) and specific components of SF-36, including emotional well-being, limitations due to emotional problems, and general health (P value < 0.05). Area under ROC analysis (AUROC) revealed FPI to accurately distinguish biomarker profiles between pain-free and chronic pain cohorts (AUROC: 0.7490, P value < 0.0001) as well as the SF-36 scores between chronic pain subjects with low vs. high FPI scores (AUROC: 0.7715, P value < 0.01)., Conclusions: Our findings establish the validity and discriminatory power of a novel multi-biomarker test that evaluates the role of biochemistry in chronic pain and correlates with clinical assessments of patients. This test provides novel, reproducible, objective data which may pave the way for non-opioid therapeutic strategies to treat chronic pain.

Genome sequencing (GS) will have a profound impact on the diagnosis of rare and inherited diseases in children and young people. We conducted 27 semi-structured interviews with young people aged 11-19 having GS through the UK 100, 000 Genomes Project. Participants demonstrated an understanding of the role and function of genes and DNA, however the terms 'genome' and 'genome sequencing' were less well understood. Participants were primarily motivated to take part to get a diagnosis or identify the gene causing their condition. The majority of participants understood they might not receive a diagnostic result. Most were unconcerned about data security or access, however anxieties existed around what the results might show and the potential for disappointment if the result was negative. Signing an assent form empowered young people, formalised the process and instilled a sense of responsibility for their choice to participate. Most young people (≥16 years) had consented to receive secondary findings and had come to that decision without parental influence. Our research suggests that at least some young people are capable of making informed decisions about taking part in GS, and that involving them in discussions about testing can empower them to take responsibility over healthcare decisions that affect them., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Rapid genomic sequencing (RGS) is increasingly being used in the care of critically ill children. Here we describe a qualitative study exploring parent and professional perspectives around the usefulness of this test, the potential for unintended harms and the challenges for delivering a wider clinical service. The Rapid Paediatric Sequencing (RaPS) study offered trio RGS for diagnosis of critically ill children with a likely monogenic disorder. Main and actionable secondary findings were reported. Semi-structured interviews were conducted with parents of children offered RGS (n = 11) and professionals (genetic clinicians, non-genetic clinicians, scientists and consenters) (n = 19) by telephone (parents n = 10/professionals n = 1) or face-to-face (parents n = 1/professionals n = 18). We found that participants held largely positive views about RGS, describing clinical and emotional benefits from the opportunity to obtain a rapid diagnosis. Parental stress surrounding their child's illness complicates decision making. Parental concerns are heightened when offered RGS and while waiting for results. The importance of multidisciplinary team working to enable efficient delivery of a rapid service was emphasised. Our findings give insight into the perceived value of RGS for critically ill children. Careful pre-test counselling is needed to support informed parental decision making. Many parents would benefit from additional support while waiting for results. Education of mainstream clinicians is required to facilitate clinical implementation.

Every year, thousands of medical students in the United States and internationally take the USMLE Step 1 exam, just as their mentors did before them. Numerous commentators - physicians and students - have argued that there are problems with the USMLE Step 1 exam, including that it devalues clinically relevant educational content not tested on Step 1, it has negative consequences for student mental health, it perpetuates the misuse of race in clinical diagnosis, and dependence on Step 1 scores may hinder efforts to diversify residency cohorts. Less prominent is any conversation regarding the nuanced benefits beyond consolidation of knowledge that one may reap from preparing for the USMLE exams. In this article, the author reflects on how preparation for Step 1 helped her and her classmates develop crucial skills of compassion and empathy in a way that will be of enormous benefit to their practice as future clinicians.

Background: Tests in pregnancy such as chromosomal microarray analysis and exome sequencing are increasing diagnostic yield for fetal structural anomalies, but have greater potential to result in uncertain findings. This systematic review investigated the experiences of prospective parents about receiving uncertain results from these tests., Methods: A systematic search of three electronic databases was conducted. Data extraction was performed for studies that met the eligibility and quality criteria. Results were synthesised following the principles of thematic analysis., Results: Fourteen studies (10 qualitative, 4 quantitative) were included. Findings were grouped into three overarching themes. Sources of uncertainty included the testing procedure, the diagnosis and prognosis, and health professionals' own uncertainty. The clinical impact of the uncertainty included parents struggling to make clinical decisions with the information available, the emotional impact included decisional-regret, shock, worry and feeling overwhelmed. To manage the uncertainty, parents sought support from healthcare professionals, friends, family, the internet and other parents as well as remaining hopeful., Conclusions: Prospective parents experience a myriad of uncertainties in the prenatal setting, which must be handled sensitively. Future research should explore optimal ways of managing uncertainty to minimise harm. Recommendations are made for discussing uncertainty during pre- and post-test counseling., (© 2020 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Children and young people with rare and inherited diseases will be significant beneficiaries of genome sequencing. However, most educational resources are developed for adults. To address this gap in informational resources, we have co-designed, developed and evaluated an educational resource about genome sequencing for young people. The first animation explains what a genome is, genomic variation and genome sequencing ("My Genome Sequence": http://bit.ly/mygenomesequence), the second focuses on the limitations and uncertainties of genome sequencing ("My Genome Sequence part 2": http://bit.ly/mygenomesequence2). In total, 554 school pupils (11-15 years) took part in the quantitative evaluation. Mean objective knowledge increased from before to after watching one or both animations (4.24 vs 7.60 respectively; t = 32.16, p < 0.001). Self-rated awareness and understanding of the words 'genome' and 'genome sequencing' increased significantly after watching the animation. Most pupils felt they understood the benefits of sequencing after watching one (75.4%) or both animations (76.6%). Only 17.3% felt they understood the limitations and uncertainties after watching the first, however this was higher among those watching both (58.5%, p < 0.001). Twelve young people, 14 parents and 3 health professionals consenting in the 100,000 Genomes Project reported that the animation was clear and engaging, eased concerns about the process and empowered young people to take an active role in decision-making. To increase accessibility, subtitles in other languages could be added, and the script could be made available in a leaflet format for those that do not have internet access. Future research could focus on formally evaluating the animations in a clinical setting.

Purpose: Stigma is a common barrier to mental health professionals (MHPs) seeking help for occupational stress and burnout, although there is a lack of psychometrically sound tools to measure this construct. The current study aimed to develop and validate a scale (the Mental Health Professional Stigma Scale; MHPSS) for this purpose., Methods: The MHPSS and related measures were completed by 221 Australian MHPs via online survey, with a subsample completing the MHPSS again 2 weeks after initial completion., Results: Exploratory factor analysis revealed a four-factor solution, comprising of 13 items and accounting for 50.16% of variance. Factors were Perceived Other Stigma, Perceived Structural Stigma, Personal Stigma, and Self stigma. The internal consistency, test-retest reliability, and validity of the scale were supported., Conclusions: The MHPSS has utility to capture stigmatising attitudes and beliefs related to occupational stress and burnout among MHPs. It may be used to assist in the development and evaluation of initiatives to reduce stigma and increase help-seeking among MHPs.

The 100,000 Genomes Project is a hybrid clinical and research project in which patients and parents are offered genome sequencing for cancer and rare and inherited disease diagnosis; all participants receive their main findings and contribute their data for research, and are offered optional secondary findings. Our aim was to explore participating parents' attitudes towards and understanding of genome sequencing in this hybrid context. We conducted in-depth telephone interviews with 20 parents of children with rare diseases participating in the 100,000 Genomes Project. Parents were positive about contributing to research, although some had needed reassurance about data protections. Although most felt positive about secondary findings, some could not recall or misunderstood key aspects. Some were also concerned about potential emotional impact of results and a few raised concerns about life insurance implications, and the impact of future legal changes. Participants were generally positive about consent appointments, but several raised concerns about 'information overload' because of deciding about secondary findings at the same time as about the main diagnostic genome sequencing and data contribution. Additional information resources, particularly online tools, were highlighted as potentially useful ways of supporting the consent process. We conclude that parents offered genome sequencing as part of a national hybrid clinical and research project report many positive attitudes and experiences, but also concerns and misunderstandings. Further research is needed on how best to support informed consent, particularly about secondary findings. Additional resources such as online tools might usefully support future genome sequencing consent processes.