Secondary (additional) findings from the 100,000 Genomes Project: Disease manifestation, health care outcomes, and costs of disclosure.

PURPOSE: The UK 100,000 Genomes Project offered participants screening for additional findings (AFs) in genes associated with familial hypercholesterolemia (FH) or hereditary cancer syndromes including breast/ovarian cancer (HBOC), Lynch, familial adenomatous polyposis, MYH-associated polyposis, multiple endocrine neoplasia (MEN), and von Hippel-Lindau. Here, we report disclosure processes, manifestation of AF-related disease, outcomes, and costs. METHODS: An observational study in an area representing one-fifth of England. RESULTS: Data were collected from 89 adult AF recipients. At disclosure, among 57 recipients of a cancer-predisposition-associated AF and 32 recipients of an FH-associated AF, 35% and 88%, respectively, had personal and/or family history evidence of AF-related disease. During post-disclosure investigations, 4 cancer-AF recipients had evidence of disease, including 1 medullary thyroid cancer. Six women with an HBOC AF, 3 women with a Lynch syndrome AF, and 2 individuals with a MEN AF elected for risk-reducing surgery. New hyperlipidemia diagnoses were made in 6 FH-AF recipients and treatment (re-)initiated for 7 with prior hyperlipidemia. Generating and disclosing AFs in this region cost £1.4m; £8680 per clinically significant AF. CONCLUSION: Generation and disclosure of AFs identifies individuals with and without personal or familial evidence of disease and prompts appropriate clinical interventions. Results can inform policy toward secondary findings.

Home-based fecal calprotectin utilization in a general pediatric gastroenterology clinic.

OBJECTIVE: Remote investigation and monitoring have gained importance in ambulatory practice. A home-based fecal calprotectin (FC) test has been developed where the sample is processed and analyzed at home through a smartphone application. We aimed to assess the use of standard ELISA (sFC) versus home-based (hFC) FC testing in a general pediatric gastroenterology clinic. METHODS: Ambulatory pediatric patients with hFC or sFC performed between August 2019 and November 2020 were included. Data regarding demographics, clinical characteristics, medication use, investigations, and final diagnosis, categorized as inflammatory bowel disease (IBD), functional gastrointestinal (GI) disorders, organic non-IBD (ONI) GI disorders, non-GI disorders, and undetermined after 6 months of investigation, were recorded. RESULTS: A total of 453 FC tests from 453 unique patients were included. Of those, 249 (55%) were hFC. FC levels (median) were higher in children with IBD compared to non-IBD diagnosis (sFC 795 vs. 57 µg/g, hFC 595 vs. 47 µg/g, p < 0.001), and in ONI compared to functional GI disorders (sFC 85 vs. 54 µg/g, p = 0.003, hFC 57 vs. 40 µg/g, p < 0.001). No significant difference was observed between different ONI GI disorders or subtypes of functional disorders. Age did not significantly influence levels. CONCLUSIONS: Overall, hFC and sFC provide similar results in the general pediatric GI ambulatory setting. FC is a sensitive but not disease-specific marker to identify patients with IBD. Values appear to be higher in ONI GI disorders over functional disorders, although cut-off values have yet to be determined.

Exploring the training needs of inherited cardiac conditions (ICC) nurses: Elucidating role boundaries and competencies for practice in the genomics era.

Nurses represent the largest professional group within the National Health Service (NHS) and are therefore central to the successful integration of mainstreaming genomics into routine healthcare. Inherited cardiac conditions (ICC) nurse roles have been developed in recent years to streamline the care for patients and families affected by an ICC. Like many nurse specialists, ICC nurses' prior exposure to genomics and the wider implications surrounding inherited conditions is limited. The aim of the study was to explore the education needs and support required for ICC nurses to fulfill their role within the genomic medicine era. A convenience sampling approach was adopted to invite ICC nurses working within various NHS Trusts across the United Kingdom to take part. Semi-structured interviews were conducted with ICC nurses (n = 8), which were recorded, transcribed, coded, and analyzed using an inductive thematic analysis approach. Analysis of interview data highlighted four core themes, which were transferrable core competencies; managing genomic information; mixed-modality learning; defining multidisciplinary team boundaries. The study highlights areas for further training and demonstrates the importance of defining competencies and role boundaries within ICC services. The ICC nurses identified the limits of their practice and the complementary role of genetic counselors, indicating the need for both professions within the ICC service and proposing implications for practice.

Paediatric obesity and Crohn's disease: a descriptive review of disease phenotype and clinical course.

Objectives: In an era of increasing paediatric obesity and inflammatory bowel disease (IBD), this study evaluates the disease phenotype and clinical course of Crohn's disease (CD) in paediatric patients who are obese or overweight. Methods: This is a retrospective, single-center, descriptive observational study from January 2010 to May 2020. Participants were included if they were: aged 2 to 18 years at the time of diagnosis, had a confirmed diagnosis of CD, and met WHO criteria for overweight or obesity at the time of diagnosis or within one year before diagnosis. Results: A total of 345 patient charts with CD were screened during the study period, with 16 patients meeting inclusion criteria. Median age of patients was 15.5 years (IQR = 13.6, 16.1). Of the 15 patients over 10 years of age, median anthropometrics at diagnosis included body mass index (BMI) of 27.2 (IQR = 24.9, 29.4) and BMI for age z-score of 1.82 (IQR = 1.58, 2.19). Presenting symptoms included abdominal pain (80.0%), diarrhea (66.7%), hematochezia (66.7%), and weight loss (26.7%). Five patients (33.3%) had obesity-related complications. Median time from symptom onset to diagnosis was 146 days (IQR = 31, 367), and median time from diagnosis to remission was 229 days (IQR = 101.8, 496.3). Conclusions: Patients with elevated BMI and CD present with typical symptoms of IBD, although weight loss was a less common presenting symptom. Time to disease remission is delayed, and obesity-related complications are common. Primary care providers must have a high degree of clinical suspicion in patients to prevent delays to gastroenterology referral and to improve time to disease remission.

The impact of a "Psychiatric Genetics for Genetic Counselors" workshop on genetic counselor attendees: An exploratory study.

Genetic counseling is the process of supporting patients' and families' adaptation to genetic information. Psychiatric genetic counseling has been proven to be effective in improving empowerment, self-efficacy, and knowledge even in the absence of genetic testing. Despite this, only one specialist psychiatric genetic counseling clinic currently exists. In order to engage genetic counselors in providing psychiatric genetic counseling, a 2-day workshop: "Psychiatric Genetic Counseling for Genetic Counselors", was developed and implemented aimed at empowering genetic counselors to feel confident and competent in this practice domain. The aim of the study was to qualitatively explore the impact of the workshop. Semistructured interviews were carried out with 12 genetic counselors who attended the workshop between 2015 and 2018. Thematic analysis revealed that the workshop empowered all participants to feel comfortable and confident offering psychiatric genetic counseling to patients. Participants also reflected how the workshop highlighted the stigma associated with mental illnesses and offered support in normalizing these conditions. Overall, this study presents that the "Psychiatric Genetic Counseling for Genetic Counselors" workshop fulfilled its proposed aims and outcomes.

Psychiatric genetic counseling: A mapping exercise.

Psychiatric genetic counseling (PGC) is gradually developing globally, with countries in various stages of development. In some, PGC is established as a service or as part of research projects while in others, it is just emerging as a concept. In this article, we describe the current global landscape of this genetic counseling specialty and this field's professional development. Drawing on information provided by expert representatives from 16 countries, we highlight the following: (a) current understanding of PGC; (b) availability of services for patients; (c) availability of training; (d) healthcare system disparities and cultural differences impacting practice; and (e) anticipated challenges going forward.

Cost effectiveness of cascade testing for familial hypercholesterolaemia, based on data from familial hypercholesterolaemia services in the UK.

AIMS: Familial hypercholesterolaemia (FH) is a vastly under-diagnosed genetic disorder, associated with early development of coronary heart disease and premature mortality which can be substantially reduced by effective treatment. Patents have recently expired on high-intensity statins, reducing FH treatment costs. We build a model using UK data to estimate the cost effectiveness of DNA testing of relatives of those with monogenic FH. METHODS AND RESULTS: A Markov model was used to estimate the cost effectiveness of cascade testing, using data from UK cascade services. The estimated incremental cost effectiveness ratio (ICER) was £5806 and the net marginal lifetime cost per relative tested was £2781. More than 80% of lifetime costs were diagnosis-related and incurred in the 1st year. In UK services, 23% of 6396 index cases were mutation-positive. For each mutation-positive index case, 1.33 relatives were tested, resulting overall in a rate of 0.31 tested relatives per tested index case. If the number of relatives tested per tested index case rose to 3.2 (projected by National Institute for Health and Care Excellence in 2008) the ICER would reduce to £2280 and lifetime costs to £1092. CONCLUSION: Cascade testing of relatives of those with suspected FH is highly cost effective. The current Europe-wide high levels of undiagnosed FH, and associated morbidity and mortality, mean adoption of cascade services should yield substantial quality of life and survival gains.

CHAMBER: A Regional Performance Improvement CME Initiative for Breast Cancer Health Care Providers.

CHAMBER was a regional educational initiative for providers of care to patients with HER2+ breast cancer. The study goals were to (1) enhance testing for HER2/neu overexpression in patients with invasive breast cancer; (2) increase the appropriate use of targeted therapy for patients with HER2+ breast cancer; and (3) enhance patients' coping ability. This Performance Improvement Continuing Medical Education (PI-CME) initiative included clinical practice assessment, educational activities, and reassessment. Chart review revealed a high rate of HER2 testing (98%) before and after education. Targeted therapy for patients with HER2+ breast cancer declined after the program (from 96% to 61%), perhaps attributable to an increase in awareness of medical reasons to avoid use of targeted therapy. Assessment for patients' emotional coping ability increased after education (from 55% to 76%; P=.01). Rates of testing for HER2 amplification and assessment of emotional well-being after education were consistent with ASCO Quality Oncology Practice Initiative benchmark values. Documentation of actions to address emotional problems remained an area for improvement.

Challenges and opportunities for identifying people with Familial hypercholesterolaemia in the UK: Evidence from the National FH PASS database.

BACKGROUND: Familial Hypercholesterolaemia (FH) is a monogenic disorder that causes high levels of low-density lipoprotein (LDL) cholesterol. Cascade testing, where relatives of known individuals with FH ('index') are genetically tested, is effective and cost-effective, but implementation in the UK varies. OBJECTIVE: This study aims to provide evidence on current UK FH cascade yields and to identify common obstacles cascade services face and individual- and service-level predictors of success. METHODS: Electronic health records from 875 index families and 5,958 linked relatives in the UK's Welsh and Wessex FH services (2019) were used to explore causes for non-testing and to estimate testing rates, detection yields, and how relative characteristics and contact methods relate to the probability of relatives being tested (using logistic regression). RESULTS: In Wales (Wessex), families included 7.35 (7.01) members on average, with 2.41 (1.66) relatives tested and 1.35 (0.96) diagnosed with FH per index. Cascade testing is limited by individualised circumstances (too young, not at-risk, etc.) and FH services' reach, with approximately one in four relatives out-of-area. In Wales, first-degree relatives (odds ratio (OR):1.55 [95 % confidence interval (CI):1.28,1.88]) and directly contacted relatives (OR:2.11 [CI:1.66,2.69]) were more likely to be tested. In Wales and Wessex, women were more likely to be tested than men (ORs:1.53 [CI:1.28,1.85] and 1.74 [CI:1.32,2.27]). CONCLUSION: In Wales and Wessex less than a third of relatives of an index are tested for FH. Improvements are likely possible by integrating geographically dispersed families into cascade testing, services directly contacting relatives where possible, and finding new ways to encourage participation, particularly amongst men.

A framework for more equitable, diverse, and inclusive Patient and Public Involvement for palliative care research.

BACKGROUND: There are marked inequalities in palliative care provision. Research is needed to understand how such inequalities can be addressed, so that everyone living with advanced illness can receive the care they need, when they need it. Research into inequalities in palliative care should be guided by Patient and Public Involvement (PPI) that includes people from diverse backgrounds, who are less likely to receive specialist services. Multi-disciplinary research partnerships, bringing together primary care (the main providers of palliative care to diverse communities) and specialist palliative care, have the potential to work together in new ways to do research to address inequalities and improve palliative care in practice. This report describes a research partnership between primary care and palliative care that aimed to: (1) create opportunities for more inclusive PPI in palliative care research, (2) co-design new resources to support more equitable, diverse and inclusive PPI for palliative care, (3) propose a new framework for inclusive PPI in palliative care research. METHODS: PPI members were recruited via primary care and palliative care research networks from three diverse areas of the UK. A pragmatic, collaborative approach was taken to achieve the partnership aims. Online workshops were carried out to understand barriers to inclusive PPI in palliative care and to co-design resources. Evaluation included a "you said, we did" impact log and a short survey. The approach was informed by good practice principles from previous PPI, and existing theory relating to equity, equality, diversity, and inclusion. RESULTS: In total, 16 PPI members were recruited. Most were White British (n = 10), other ethnicities were Asian (n = 4), Black African (n = 1) and British mixed race (n = 1). The research team co-ordinated communication and activities, leading to honest conversations about barriers to inclusive PPI. Resources were co-designed, including a role description for an Equity, Equality, Diversity and Inclusion Champion, a "jargon buster", an animation and an online recipe book ( http://www.re-equipp.co.uk/ ) to inform future PPI. Learning from the partnership has been collated into a new framework to inform more inclusive PPI for future palliative care research. CONCLUSION: Collaboration and reciprocal learning across a multi-disciplinary primary care and palliative care research partnership led to the development of new approaches and resources. Research team commitment, shared vision, adequate resource, careful planning, relationship building and evaluation should underpin approaches to increase equality, diversity and inclusivity in future PPI for palliative care research.

Research is needed to understand how inequalities in palliative care can be addressed, so that everyone living with advanced illness can receive the care they need. Research into inequalities in palliative care should be guided by Patient and Public Involvement (PPI) that includes people from diverse backgrounds, who are less likely to receive specialist palliative care. Primary care services are grounded in the community they serve and can be the main providers of palliative care, but this is rarely the focus of research. Primary care and palliative care researchers can work together in new ways to do research to address inequalities and improve palliative care in practice. This paper describes the work of the RE-EQUIPP (REducing inEQUalities through Integration of Primary and Palliative Care) Care Partnership. The partnership involved researchers from primary care and palliative care working with people with lived experience of serious illness as patient or carer from three diverse areas of the United Kingdom: (1) London, (2) inner-city Sheffield and (3) Worthing in Sussex, a rural, coastal setting. The project provided opportunity to develop new ways of working and resources for more inclusive and equitable PPI for future palliative care research. Sixteen PPI members from diverse backgrounds and with a range of experience joined the partnership. Workshops were held to understand the barriers to inclusive PPI. New roles and resources were developed, including an Equity, Equality, Diversity and Inclusion Champion role, a "jargon buster", an animation, and an online recipe book to inform future PPI. Learning from the partnership was used to develop a new framework, which is presented to inform inclusive PPI for palliative care research in the future. This outlines the need for research team commitment and shared vision, adequate resource, careful planning, relationship building and evaluation.

Project GIVE: using a virtual genetics service platform to reduce health inequities and improve access to genomic care in an underserved region of Texas.

BACKGROUND: The utilization of genomic information to improve health outcomes is progressively becoming more common in clinical practice. Nonetheless, disparities persist in accessing genetic services among ethnic minorities, individuals with low socioeconomic status, and other vulnerable populations. The Rio Grande Valley (RGV) at the Texas-Mexico border is predominantly Hispanic/Latino with a high poverty rate and very limited access to genetic services. Funded by the National Center for Advancing Translational Sciences, Project GIVE (Genetic Inclusion by Virtual Evaluation) was launched in 2022 to reduce the time to diagnosis and increase provider knowledge of genomics in this region, with the goal of improving pediatric health outcomes. We describe our experience of establishing a virtual pediatric genomic service in this region to expeditiously identify, recruit, and evaluate pediatric patients with undiagnosed diseases. METHODS: We have utilized an innovative electronic health record (EHR) agnostic virtual telehealth and educational platform called Consultagene to receive referrals from healthcare providers in the RGV. Using this portal, genetic services, including virtual evaluation and genome sequencing (GS), are being delivered to children with rare diseases. The study has also integrated effective methods to involve and educate community providers through in-person meetings and Continuing Professional Education (CPE) events. RESULTS: The recruitment efforts have proven highly successful with the utilization of Consultagene in this medically underserved region. The project's ongoing engagement efforts with local healthcare providers have resulted in progressively more referrals to the study over time, thus improving inclusion and access to genomic care in the RGV. Additionally, the curated CPE content has been well received by healthcare providers in the region. CONCLUSIONS: Project GIVE study has allowed advanced genetic evaluation and delivery of GS through the virtual Consultagene portal, effectively circumventing the recognized socioeconomic and logistical barriers to accessing genetic services within this border community.

Predictors of sexually transmitted infection in Australian women: evidence from the Australian Longitudinal Study on Women's Health.

This longitudinal study examined characteristics of women diagnosed with sexually transmitted infections (STI) for the first time in their later 20s and early 30s. Participants were 6,840 women (born 1973-1978) from the Australian Longitudinal Study on Women's Health. Women aged 18-23 years were surveyed in 1996 (S1), 2000 (S2), 2003 (S3), and 2006 (S4). There were 269 women reporting an STI for the first time at S3 or S4. Using two multivariable logistic regression analyses (examining 18 predictor variables), these 269 women were compared (1) with 306 women who reported an STI at S2 and (2) with 5,214 women who never reported an STI across the four surveys. Women who reported an STI for the first time at S3 or S4 were less likely to have been pregnant or had a recent Pap smear compared to women reporting an STI at S2. Women reporting a first STI at S3 or S4 were less likely to have been pregnant or had a recent Pap smear compared to women reporting an STI at S2. Women were more likely to report an STI for the first time at S3 or S4 compared to women not reporting an STI at any survey if they were younger, unpartnered, had a higher number of sexual partners, had never been pregnant, were recently divorced or separated, and reported poorer access to Women's Health or Family Planning Centres at S2. These findings demonstrate the value of longitudinal studies of sexual health over the life course beyond adolescence.

A novel dynamic layer-by-layer assembled nano-scale biointerface: functionality tests with platelet adhesion and aggregate morphology influenced by adenosine diphosphate.

An improved biointerface was developed, dynamic layer-by-layer self-assembly surface (d-LbL), and utilized as a biologically-active substrate for platelet adhesion and aggregation. Possible clinical applications for this research include improved anti-coagulation surfaces. This work demonstrated the functionality of d-LbL biointerfaces in the presence of platelet-rich-plasma (PRP) with the addition of 20 µM adenosine diphosphate (ADP), a thrombus activator. The surface morphology of the experimental control, plain PRP, was compared to PRP containing additional ADP (PRP + ADP) and resulted in an expected increase of platelet adhesions along the fibrinogen d-LbL substrate. The d-LbL process was used to coat glass slides with fibrinogen, Poly (sodium 4-styrene-sulfonate), and Poly (diallydimethlyammonium chloride). Slides were exposed to PRP under flow and static conditions with and without 20 µM of ADP. Fluorescence microscopy (FM), phase contrast microscopy (PCM), atomic force microscopy (AFM), and field emission-scanning electron microscopy (FE-SEM) were used to evaluate platelet adhesions under the influence of varied shear conditions. PCM images illustrated differences between the standard LbL and d-LbL substrates. FM images provided percent surface coverage values. For high-shear conditions, percent surface coverage values increased when using ADP whereas plain PRP exposure displayed no significant increase. AFM scans also displayed higher mean peak height values and unique surface characteristics for PRP + ADP as opposed to plain PRP. FE-SEM images revealed platelet adhesions along the biointerface and unique characteristics of the d-LbL surface. In conclusion, PRP + ADP was more effective at increasing platelet aggregation, especially under high shear conditions, providing further validation of the improved biointerface.

Pre-pregnancy BMI: costs associated with maternal underweight and obesity in Queensland.

BACKGROUND: The economic costs of maternal obesity and underweight have not been described. We aim to assess the effect of maternal underweight and obesity on hospital utilisation and hospital costs. METHODS: Data from the Queensland Perinatal Data Collection and Queensland Hospital Admitted Patient Data Collection were analysed for 2008. The sample included 37,912 Queensland resident mothers with a singleton pregnancy who gave birth in a public facility. Outcome measures were hospital length of stay (LOS) and hospital costs accrued during the birth admission and during pre- and postnatal admissions within 90 days of the birth admission. RESULTS: There were 1,581 (4.2%) underweight, 17,175 (45.3%) normal weight, 10,155 (26.8%) overweight and 9,001 (23.7%) obese women. Maternal obesity was associated with significantly longer stays although effect sizes were modest (≤0.5 days) and specific to women who delivered vaginally. LOS was significantly higher among babies born to underweight mothers when compared to those born to normal weight women. Maternal obesity was associated with a total increase of $5 million in mothers' hospital costs when compared to those amongst normal weight women; the corresponding figure for underweight mothers was $385,734. The total hospital costs for babies born to underweight women were $1.6 million higher than those born to mothers in the normal weight category. Maternal obesity was not associated with an increase in babies' hospital costs. CONCLUSIONS: Maternal obesity contributed to an increase in mothers' hospital LOS and hospitalisation costs. Maternal underweight contributed to an increase in babies' hospital costs.

Competencies of the UK nursing and midwifery workforce to mainstream genomics in the National Health Service: the ongoing gap between perceived importance and confidence in genomics.

The United Kingdom is recognised worldwide as a leader in genomics. The use of genomic technologies in the National Health Service (NHS) is expected to deliver faster and more accurate diagnoses, supporting personalized treatments to improve patient outcomes. The ambition of embedding genomic medicine in the diagnostic pathway requires involvement of the front-line clinical workforce, known as 'mainstreaming'. Nurses and midwives are the largest professionally qualified workforce in the National Health Service thus, it is anticipated that they will play key roles in mainstreaming. This study investigated the level of competence/confidence of practicing nurses and midwives to support mainstreaming and their perception of the importance of genomics in delivery of patient care. A literature review of genetics/genomics competency frameworks, semi structured interviews of lead nurses and stakeholders were conducted to identify relevant competencies needed for mainstreaming. These were then used to survey four cohorts of nurses (n = 153) across England in four consecutive years (2019-22). The confidence level of these professionals in all aspects of genomics was 2.07 ± 0.47 measured on a 5-point Likert scale (1"Low confidence"; 5 "High confidence"). Intriguingly, these professionals all appreciated the importance of genomics for their patient care (4.01 ± 0.06). Whilst the importance scores increased, the confidence scores declined at the time when major genomic transformation took place in the NHS (e.g.: launch of the Genomic Medicine Service, the National Genomic Test Directory). To bridge this gap, relevant genomic education can play key roles. However, nurses and midwives were found to be grossly underrepresented in formal genomic education courses offered by Health Education England Genomics Education Programme since 2014. This may result from the lack of direct applicability of the currently offered courses for their practice and role. Thematic analysis revealed that nurses and midwives wish to support their patients by providing more information on their condition, inheritance, and treatment options in combination with the use of relevant genetic counselling skills. This study identified easy to follow competencies for embedding genomics into routine clinical care. We propose a training programme that addresses the gap that nurses and midwives currently have, to enable them to harness genomic opportunities for patients and services.

Alternative cascade-testing protocols for identifying and managing patients with familial hypercholesterolaemia: systematic reviews, qualitative study and cost-effectiveness analysis.

Background: Cascade testing the relatives of people with familial hypercholesterolaemia is an efficient approach to identifying familial hypercholesterolaemia. The cascade-testing protocol starts with identifying an index patient with familial hypercholesterolaemia, followed by one of three approaches to contact other relatives: indirect approach, whereby index patients contact their relatives; direct approach, whereby the specialist contacts the relatives; or a combination of both direct and indirect approaches. However, it is unclear which protocol may be most effective. Objectives: The objectives were to determine the yield of cases from different cascade-testing protocols, treatment patterns, and short- and long-term outcomes for people with familial hypercholesterolaemia; to evaluate the cost-effectiveness of alternative protocols for familial hypercholesterolaemia cascade testing; and to qualitatively assess the acceptability of different cascade-testing protocols to individuals and families with familial hypercholesterolaemia, and to health-care providers. Design and methods: This study comprised systematic reviews and analysis of three data sets: PASS (PASS Software, Rijswijk, the Netherlands) hospital familial hypercholesterolaemia databases, the Clinical Practice Research Datalink (CPRD)-Hospital Episode Statistics (HES) linked primary-secondary care data set, and a specialist familial hypercholesterolaemia register. Cost-effectiveness modelling, incorporating preceding analyses, was undertaken. Acceptability was examined in interviews with patients, relatives and health-care professionals. Result: Systematic review of protocols: based on data from 4 of the 24 studies, the combined approach led to a slightly higher yield of relatives tested [40%, 95% confidence interval (CI) 37% to 42%] than the direct (33%, 95% CI 28% to 39%) or indirect approaches alone (34%, 95% CI 30% to 37%). The PASS databases identified that those contacted directly were more likely to complete cascade testing (p < 0.01); the CPRD-HES data set indicated that 70% did not achieve target treatment levels, and demonstrated increased cardiovascular disease risk among these individuals, compared with controls (hazard ratio 9.14, 95% CI 8.55 to 9.76). The specialist familial hypercholesterolaemia register confirmed excessive cardiovascular morbidity (standardised morbidity ratio 7.17, 95% CI 6.79 to 7.56). Cost-effectiveness modelling found a net health gain from diagnosis of -0.27 to 2.51 quality-adjusted life-years at the willingness-to-pay threshold of £15,000 per quality-adjusted life-year gained. The cost-effective protocols cascaded from genetically confirmed index cases by contacting first- and second-degree relatives simultaneously and directly. Interviews found a service-led direct-contact approach was more reliable, but combining direct and indirect approaches, guided by index patients and family relationships, may be more acceptable. Limitations: Systematic reviews were not used in the economic analysis, as relevant studies were lacking or of poor quality. As only a proportion of those with primary care-coded familial hypercholesterolaemia are likely to actually have familial hypercholesterolaemia, CPRD analyses are likely to underestimate the true effect. The cost-effectiveness analysis required assumptions related to the long-term cardiovascular disease risk, the effect of treatment on cholesterol and the generalisability of estimates from the data sets. Interview recruitment was limited to white English-speaking participants. Conclusions: Based on limited evidence, most cost-effective cascade-testing protocols, diagnosing most relatives, select index cases by genetic testing, with services directly contacting relatives, and contacting second-degree relatives even if first-degree relatives have not been tested. Combined approaches to contact relatives may be more suitable for some families. Future work: Establish a long-term familial hypercholesterolaemia cohort, measuring cholesterol levels, treatment and cardiovascular outcomes. Conduct a randomised study comparing different approaches to contact relatives. Study registration: This study is registered as PROSPERO CRD42018117445 and CRD42019125775. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 16. See the NIHR Journals Library website for further project information.

Familial hypercholesterolaemia is an inherited condition that causes raised cholesterol levels from birth and increases risk of heart disease if left untreated. After someone in a family is found to have familial hypercholesterolaemia (called an index case), their close relatives need to be contacted and checked to see if they have familial hypercholesterolaemia, using genetic or cholesterol testing. This is called 'cascade testing'. We planned to find the most cost-effective and acceptable way to do this. The relatives could be contacted for testing by the index case (indirect approach), by a health-care professional (direct approach) or by a combination of both approaches. We found, based on looking at hospital records, that more relatives were tested if health-care professionals directly contacted relatives. In previous studies, slightly more relatives were tested for familial hypercholesterolaemia with a combination approach. Interviews with patients also suggested that the direct approach was the most effective, but the most acceptable and successful approach depends on family relationships: using one approach for some families and using both for other families. Furthermore, by looking at the health-care records of large numbers of patients, we confirmed that people with a recorded diagnosis of familial hypercholesterolaemia in general practice records have a much higher risk of heart disease than the general population, and this was especially so for those with previous heart disease and/or raised cholesterols levels when diagnosed. However, one-quarter of new patients with familial hypercholesterolaemia recorded in their records were not treated within 2 years, with less than one-third reaching recommended cholesterol levels. We used what we had learned to help us estimate the most cost-effective way to do cascade testing. This showed that if the health service directly contact all relatives simultaneously for further assessment, rather than the current approach whereby close (first-degree) relatives are contacted first, this was cost-effective and good value for money.

Reducing Time to Diagnosis of Rare Genetic Diseases in a Medically Underserved Hispanic Population- Lessons Learned for Meaningful Engagement.

Background: The utilization of genomic information to improve health outcomes is progressively becoming more common in clinical practice. Nonetheless, disparities persist in accessing genetic services among ethnic minorities, individuals with low socioeconomic status, and other vulnerable populations. The Rio Grande Valley at the Texas-Mexico border is predominantly Hispanic with a high poverty rate and an increased prevalence of birth defects, with very limited access to genetics services. The cost of a diagnosis is often times out of reach for these underserved families. Funded by the National Center for Advancing Translational Sciences (NCATS), Project GIVE (Genetic Inclusion by Virtual Evaluation) was launched in 2022 to shorten the time to diagnosis and alleviate healthcare inequities in this region, with the goal of improving pediatric health outcomes. Methods: Utilizing Consultagene, an innovative electronic health record (EHR) agnostic virtual telehealth and educational platform, we designed the study to recruit 100 children with rare diseases over a period of two years from this region, through peer-to-peer consultation and referral. Conclusions: Project GIVE study has allowed advanced genetic evaluation and delivery of genome sequencing through the virtual portal, effectively circumventing the recognized socioeconomic and other barriers within this population. This paper explores the successful community engagement process and implementation of an alternate genomics evaluation platform and testing approach, aiming to reduce the diagnostic journey for individuals with rare diseases residing in a medically underserved region.

Interleukin-1alpha and HMGB1 mediate hippocampal dysfunction in SIGIRR-deficient mice.

Single-Ig-interleukin-1 related receptor (SIGIRR) is a member of the interleukin (IL)-1/Toll-like receptor (TLR) family. It negatively regulates inflammation, rendering SIGIRR(-/-) mice more susceptible to inflammatory challenge. This susceptibility extends to the brain, where increased responsiveness to lipopolysaccharide has been observed in SIGIRR-deficient mice. While this is likely due to enhanced TLR4-mediated signaling, the functional consequences of these changes have not yet been described. In the current study, we have investigated the impact of SIGIRR deficiency on hippocampal function, and show that novel object recognition, spatial reference memory, and long-term potentiation (LTP) were impaired in SIGIRR(-/-) mice. These changes were accompanied by increased expression of IL-1RI and TLR4, and upregulation of their downstream signaling events, namely IRAK1 (IL-1R-associated kinase 1), c-Jun N-terminal protein kinase (JNK), and nuclear factor κB (NF-κB). The deficit in LTP was attenuated by the endogenous IL-1 receptor antagonist (IL-1ra) and an anti-TLR4 antibody, and also by inhibition of JNK and NF-κB. We propose that IL-1RI is activated by IL-1α and TLR4 is activated by the endogenous agonist, high mobility group box 1 (HMGB1), as we identified enhanced expression of both cytokines in the hippocampus of SIGIRR(-/-) mice. Additionally, application of HMGB1 increased the activation of JNK and NF-κB and was found to be detrimental to LTP in a TLR4-dependent manner. These findings highlight the functional role of SIGIRR in regulating inflammatory-mediated synaptic and cognitive decline, and describe evidence of the key role of HMGB1 in this process.

The serum hepcidin:ferritin ratio is a potential biomarker for cirrhosis.

BACKGROUND: Serum hepcidin concentration is potentially affected by inflammation and iron stores in chronic liver disease (CLD), but little is known about the relationship between hepcidin and the degree of hepatic fibrosis. We investigated the potential role of serum hepcidin as a biomarker of advanced liver disease. METHODS: Serum hepcidin was measured in 332 adults with CLD of varying aetiologies, 45 healthy and 50 non-liver disease patient controls. Liver biopsy data were available for 228 CLD subjects. RESULTS: Hepcidin was decreased in CLD patients compared with non-liver disease patient controls (P < 0.0001) but not healthy controls, and was lowest in those with cirrhosis (P < 0.0001). Serum hepcidin correlated with hepatic hepcidin mRNA expression in 91 biopsy samples available for genetic analysis (r = 0.68, P < 0.0001). Hepcidin also correlated positively with serum ferritin concentration, transferrin saturation, ALT, serum albumin and haemoglobin, but negatively with serum bilirubin. The hepcidin:ferritin ratio was significantly lower in CLD subjects compared with healthy and disease controls, and decreased with each increase in the stage of fibrosis and siderosis. The hepcidin:ferritin ratio was associated with progressive fibrosis on linear regression, and a value of less than 0.1 was independently associated with cirrhosis on logistic regression analyses (OR 5.54, P < 0.001). Receiver operating characteristic analysis showed the hepcidin:ferritin ratio was able to distinguish between F0 and F4 stages of fibrosis (area under receiver operating characteristic curve = 0.86). CONCLUSIONS: The hepcidin:ferritin ratio is reduced in relation to increasing fibrosis in CLD and the use of this ratio may have potential future diagnostic implications as a marker of cirrhosis.

Patients' Access to Telephone and E-mail Services Provided by IBD Nurses in Canada.

Background: Inflammatory bowel disease (IBD) can impact the quality of life and increase health care resource utilization. Nurses play an integral role in ensuring ease of access to care between scheduled office visits. Aims: This study aimed to capture the utilization of Canadian IBD nursing telephone and e-mail services. Methods: A descriptive cross-sectional study with an eight-item online survey was completed by nurses to assess the use of nurse-led telephone and e-mail services for IBD patients. Results: Twenty-one IBD nurses participated, and 572 patients nurse encounters were reported. Patients with ulcerative (UC) contacted with disease flare when compared to Crohn's disease (CD) (40% versus 24%, P < 0.001). Nursing services were primarily utilized for queries regarding medication (39.3%), disease exacerbations (29.6%), investigations (26%), and scheduling appointments (17.6%). Patients with CD had more telephone conversations (62.7%) and required more follow-up telephone calls (72.2%) compared to patients with UC (33%) and 25%, respectively. Nurse-managed interventions were provided independently for 61.4% of encounters, while 19% required a scheduled appointment in the IBD clinic. In the absence of telephone or e-mail assistance, older patients were more likely to call their family doctor (r = 0.18, P < 0.001), visit the emergency room (r = 0.18, P < 0.001), visit an urgent access clinic (r = 0.22, P < 0.001), or visit a walk-in clinic (r = 0.29, P < 0.001) than younger patients. Conclusions: Nurse-managed IBD advice lines are proactive services that can address most patient disease-related concerns.