Serum amyloid A increases following routine vaccination of healthy adult horses.

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.

Delivery of a national prenatal exome sequencing service in England: a mixed methods study exploring healthcare professionals' views and experiences.

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.

An exploratory open-label multicentre phase I/II trial evaluating the safety and efficacy of postnatal or prenatal and postnatal administration of allogeneic expanded fetal mesenchymal stem cells for the treatment of severe osteogenesis imperfecta in infants and fetuses: the BOOSTB4 trial protocol.

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 3×106/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.

Preparing tomorrow's doctors for the genomics era: A nationwide survey of UK medical students.

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.

'Something that helped the whole picture': Experiences of parents offered rapid prenatal exome sequencing in routine clinical care in the English National Health Service.

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.

Joint AAPM Task Group 282/EFOMP Working Group Report: Breast dosimetry for standard and contrast-enhanced mammography and breast tomosynthesis.

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.

The disequilibrium of hope: A grounded theory analysis of parents' experiences of receiving a "no primary finding" result from genome sequencing.

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.

Rapid evaluation of the Special Measures for Quality and challenged provider regimes: a mixed-methods study.

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.

When health-care trusts in England have serious failings in the quality of care that they provide, they can be placed in 'Special Measures for Quality' and receive additional support from the NHS. There is also a list of 'challenged providers' at risk of entering Special Measures for Quality that receive support. In January 2019, of the 234 trusts in England, one-quarter had at some point been a challenged provider and/or entered Special Measures for Quality. We studied how trusts responded to entering the Special Measures for Quality or challenged provider regimes. We wanted to understand if the support that the trusts receive can help the trust to improve the quality of care provided to patients. We did this by reviewing the relevant literature; speaking to a range of staff in eight trusts and nearby health organisations; analysing costs; and observing meetings in four of these trusts. We also compared national performance information between Special Measures for Quality/challenged provider trusts and non-Special Measures for Quality/challenged provider trusts. We found that when a trust enters the Special Measures for Quality regime there is often an emotional impact on staff, who may experience low morale. Some staff thought that their trust received the right type of support, but others saw Special Measures for Quality as heavy-handed scrutiny or punishment. With hindsight, Special Measures for Quality was sometimes viewed more positively, as a pathway to make changes that were needed. Looking at all trusts in England, we found that when trusts entered Special Measures for Quality or became challenged providers they started to get better at seeing emergency department patients within 4 hours and reduced avoidable deaths. We also found that some parts of the staff survey results improved. We found that staff need time and space to make changes. Looking after staff and having a leadership and culture that supports continuous learning are important for making improvements. Regional health-care systems and local organisations have an important role to play in supporting trusts to make improvements.

Knowledge, attitudes and decision regret: a longitudinal survey study of participants offered genome sequencing in the 100,000 Genomes Project.

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.

Exploring prenatal testing preferences among US pregnant individuals: A discrete choice experiment.

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.

ER-phagy in neurodegeneration.

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.

Peripheral Insertion of Pediatric Central Venous Catheters in Adults with Difficult I.V. Access.

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.

Does a rare mutation in PTPRA contribute to the development of Parkinson's disease in an Australian multi-incident family?

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.

Proteomic profiling of idiopathic Parkinson's disease primary patient cells by SWATH-MS.

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.

The Special Measures for Quality and Challenged Provider Regimes in the English NHS: A Rapid Evaluation of a National Improvement Initiative for Failing Healthcare Organisations.

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.

Factors that impact on women's decision-making around prenatal genomic tests: An international discrete choice survey.

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.

Implementing a rapid fetal exome sequencing service: What do parents and health professionals think?

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.

Participant experiences of genome sequencing for rare diseases in the 100,000 Genomes Project: a mixed methods study.

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.

Diagnostic yield of exome sequencing for prenatal diagnosis of fetal structural anomalies: A systematic review and meta-analysis.

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.