What is the power of a genomic multidisciplinary team approach? A systematic review of implementation and sustainability.

Due to the increasing complexity of genomic data interpretation, and need for close collaboration with clinical, laboratory, and research expertise, genomics often requires a multidisciplinary team (MDT) approach. This systematic review aims to establish the evidence for effectiveness of the genomic multidisciplinary team, and the implementation components of this model that can inform precision care. MEDLINE, Embase and PsycINFO databases were searched in 2022 and 2023. We included qualitative and quantitative studies of the genomic MDT, including observational and cohort studies, for diagnosis and management, and implementation outcomes of effectiveness, adoption, efficiency, safety, and acceptability. A narrative synthesis was mapped against the Genomic Medicine Integrative Research framework. 1530 studies were screened, and 17 papers met selection criteria. All studies pointed towards the effectiveness of the genomic MDT approach, with 10-78% diagnostic yield depending on clinical context, and an increased yield of 6-25% attributed to the MDT. The genomic MDT was found to be highly efficient in interpretation of variants of uncertain significance, timeliness for a rapid result, made a significant impact on management, and was acceptable for adoption by a wide variety of subspecialists. Only one study utilized an implementation science based approach. The genomic MDT approach appears to be highly effective and efficient, facilitating higher diagnostic rates and improved patient management. However, key gaps remain in health systems readiness for this collaborative model, and there is a lack of implementation science based research especially addressing the cost, sustainability, scale up, and equity of access.

Early life sleep disruption has long lasting, sex specific effects on later development of sleep in prairie voles.

In mammals, sleep duration is highest in the early postnatal period of life and is critical for shaping neural circuits that control the development of complex behaviors. The prairie vole is a wild, highly social rodent that serves as a unique model for the study of complex, species-typical social behaviors. Previous work in our laboratory has found that early life sleep disruption (ELSD) in prairie voles during a sensitive window of postnatal development leads to long lasting changes in social and cognitive behaviors as well as structural changes in excitatory and inhibitory neural circuits in the brain. However, it is currently unknown how later sleep is impacted by ELSD, both shortly after ELSD and over the long term. Therefore, the aim of this study was to describe the effects of ELSD on later life sleep, compared to sleep in normally developing prairie voles. First, we conducted tethered electroencephalogram/electromyogram (EEG/EMG) recordings in juvenile prairie voles undergoing ELSD, compared to Control conditions. Second, we conducted 24 h of home cage tethered EEG/EMG recordings in either adolescent or adult male and female prairie voles that had previously undergone ELSD or Control conditions as juveniles. We found that, as adults, male ELSD prairie voles showed persistently lower REM sleep duration and female ELSD prairie voles showed persistently higher NREM sleep duration compared to Controls, but no other sleep parameters differed. We concluded that 1) persistent effects of ELSD on sleep into adulthood may contribute to the social and cognitive deficits observed in adult voles, and 2) sleep disruption early in life can influence later sleep patterns in adulthood.

Characterization of health concerns in people with neurofibromatosis type 1.

BACKGROUND: Neurofibromatosis 1 (NF1) is a common cancer predisposition syndrome. Affected individuals require lifelong surveillance and often suffer progressive disfigurement due to cutaneous neurofibromas. The aim of this research was to characterize health concerns and quality of life (QOL) in a population cohort. METHODS: An online survey was completed by 68 adults and 32 parents of children with NF1, and 60 controls. The survey included the Skindex-29 QOL scale, 5D-itch scale, and additional health questions. RESULTS: Frequency of itch was high in children (50%) and adults (69%), with most expressing interest in treatment for itch. The presence of itch and increased visibility of NF1 were predictors of poorer QoL. Many adults (53%) and parents (44%) desired access to treatment to improve cosmetic appearance. Muscle weakness/tiredness was also prevalent amongst (60-70%) adults and children with NF1. Two-thirds of adults with NF1 reported limited awareness of NF1 services and poor knowledge of surveillance, particularly breast screening in young women. CONCLUSION: This study highlights the impact of NF1-related itch and visibility in adults and children with a need for cosmetic and itch treatment. The findings emphasize a need for strategies to promote awareness, and access to management and treatment of NF1 in adults.

Exploring the Genetic Architecture of Spontaneous Coronary Artery Dissection Using Whole-Genome Sequencing.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) is a cause of acute coronary syndrome that predominantly affects women. Its pathophysiology remains unclear but connective tissue disorders (CTD) and other vasculopathies have been observed in many SCAD patients. A genetic component for SCAD is increasingly appreciated, although few genes have been robustly implicated. We sought to clarify the genetic cause of SCAD using targeted and genome-wide methods in a cohort of sporadic cases to identify both common and rare disease-associated variants. METHODS: A cohort of 91 unrelated sporadic SCAD cases was investigated for rare, deleterious variants in genes associated with either SCAD or CTD, while new candidate genes were sought using rare variant collapsing analysis and identification of novel loss-of-function variants in genes intolerant to such variation. Finally, 2 SCAD polygenic risk scores were applied to assess the contribution of common variants. RESULTS: We identified 10 cases with at least one rare, likely disease-causing variant in CTD-associated genes, although only one had a CTD phenotype. No genes were significantly associated with SCAD from genome-wide collapsing analysis, however, enrichment for TGF (transforming growth factor)-ß signaling pathway genes was found with analysis of 24 genes harboring novel loss-of-function variants. Both polygenic risk scores demonstrated that sporadic SCAD cases have a significantly elevated genetic SCAD risk compared with controls. CONCLUSIONS: SCAD shares some genetic overlap with CTD, even in the absence of any major CTD phenotype. Consistent with a complex genetic architecture, SCAD patients also have a higher burden of common variants than controls.

Efficient stimulation of retinal regeneration from Müller glia in adult mice using combinations of proneural bHLH transcription factors.

Regenerative neuroscience aims to stimulate endogenous repair in the nervous system to replace neurons lost from degenerative diseases. Recently, we reported that overexpressing the transcription factor Ascl1 in Müller glia (MG) is sufficient to stimulate MG to regenerate functional neurons in the adult mouse retina. However, this process is inefficient, and only a third of the Ascl1-expressing MG generate new neurons. Here, we test whether proneural transcription factors of the Atoh1/7 class can further promote the regenerative capacity of MG. We find that the combination of Ascl1:Atoh1 is remarkably efficient at stimulating neurogenesis, even in the absence of retinal injury. Using electrophysiology and single-cell RNA sequencing (scRNA-seq), we demonstrate that Ascl1:Atoh1 generates a diversity of retinal neuron types, with the majority expressing characteristics of retinal ganglion cells. Our results provide a proof of principle that combinations of developmental transcription factors can substantially improve glial reprogramming to neurons and expand the repertoire of regenerated cell fates.

Measuring the Effect of Cutaneous Neurofibromas on Quality of Life in Neurofibromatosis Type 1.

OBJECTIVE: In order to explore the use of Skindex scoring in patients with neurofibromatosis type 1 (NF1) across multiple clinical sites and inform design of additional quality of life measures, we analyzed correlations between Skindex, site, and clinical measures for 79 patients with NF1 from specialized clinics in Sydney, Australia (Royal North Shore Hospital [RNS]) and Minneapolis, Minnesota (University of Minnesota [UMN]). METHODS: The relationship between clinical factors and Skindex scores were explored by clinic site and overall. RESULTS: A total of 40 participants were recruited from RNS and 39 from UMN. Female sex, total number of cutaneous neurofibroma (cNF), and whether cNF were present on the face correlated highly with Skindex and not Riccardi scores. The UMN site had lower average scores, but these differences were almost entirely removed after adjusting for age, sex, facial cNF, and total cNF number. CONCLUSIONS: The development of cNF in adolescence and adulthood in NF1 often leads to progressive disfigurement and discomfort and is among one of the most common reasons for patients to seek medical treatment. Skindex has been used to assess skin-related quality of life in NF1 previously but is not specific to NF1. These findings highlight the need for a low threshold for referral to dermatologists for all patients with NF1 regardless of the severity of disease. The finding that facial cNF and higher total number of cNF correlates with poorer skin-related quality of life may benefit design of more specific NF1 skin-related quality of life measures.

Microglia Suppress Ascl1-Induced Retinal Regeneration in Mice.

The innate immune system plays key roles in tissue regeneration. For example, microglia promote neurogenesis in Müller glia in birds and fish after injury. Although mammalian retina does not normally regenerate, neurogenesis can be induced in mouse Müller glia by Ascl1, a proneural transcription factor. We show that in mice, microglia inhibit the Ascl1-mediated retinal regeneration, suggesting that the innate immune system limits the regenerative response to injury.

Generation of VCCRIi001-A, a human induced pluripotent stem cell line, from a patient with spontaneous coronary artery dissection.

Spontaneous coronary artery dissection (SCAD) is a non-atherosclerotic form of coronary artery disease of unknown cause that predominantly affects women (>90%; mean age 44-55 years) and can be fatal. The finding of familial clustering, including the concordant involvement of monozygotic twins, and its association with the PHACTR1/EDN1 genetic locus, indicate a genetic predisposition to its pathophysiology. A human induced pluripotent stem cell line (hiPSC) was generated from a patient who had survived an episode of SCAD. This disease-specific hiPSC line will be useful for the study of SCAD after differentiation into blood vessel-forming cells.

Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene. OBJECTIVES: This study sought to test the association between the rs9349379 genotype and SCAD. METHODS: Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD. RESULTS: The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence. CONCLUSIONS: The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.

Idiopathic sclerochoroidal calcification.

PURPOSE: Sclerochoroidal calcification is a rare ocular condition characterized by multifocal, yellow-white elevated fundus lesions typically located in the superotemporal quadrant along the superior arcades. The pathology of calcification can be classified as dystrophic, metastatic, or idiopathic. Vision-threatening complications may arise, such as choroidal neovascular membrane and serous retinal detachment. The pathogenesis of sclerochoroidal calcification remains unclear. CASE REPORT: A 72-year-old Caucasian male patient presented to the clinic for routine examination. Fundus evaluation revealed bilateral, multifocal, pale yellow elevated lesions in the superotemporal fundus. Ultrasonography showed a focal area of hyper-reflectivity located in the posterior retina of both eyes, and optical coherence tomography showed an intact retina overlying the elevated lesions in the choroid. Systemic evaluation for dystrophic and metastatic calcification was negative, and the patient was diagnosed with idiopathic sclerochoroidal calcification. CONCLUSIONS: It is important to distinguish sclerochoroidal calcification from other conditions to prevent unnecessary intervention. Calcification of body tissues warrants a systemic evaluation, including screening for calcium and phosphorous levels, to rule out underlying systemic disease. If a biochemical abnormality is discovered, it can be appropriately treated with supplements. If calcification is deemed idiopathic, then annual dilated examinations are recommended to monitor the fundus lesions. Visual prognosis for sclerochoroidal classification is good, as the lesions are typically located away from the macula and foveal encroachment is rare.

Health advice for older people travelling overseas.

Old age should not prevent people from venturing to foreign climes for their holidays, but some of the hazards associated with travel are of more concern for older tourists. Nurses caring for older people in community, acute and residential settings should know where to direct them for pre- and post-travel health advice. Risk assessment and management are important parts of travel health consultations. This article provides a summary of the dangers of overseas travel and the general principles of health advice applicable to the specific needs of the older traveller.

Travel risk assessment and risk management.

Risk assessment and risk management are fundamental to travel health consultations. Undertaking a comprehensive risk assessment involves gathering information on the traveller and their proposed journey. This information, as well as identifying specific travel-related hazards, should ensure risk-management advice and strategies are appropriate for individuals. This article outlines the principles of risk assessment and risk management in the context of travel health consultations.

Advising travellers who have special risks.

The aim of an effective travel health consultation is to provide advice that is tailored to the individual traveller; this is particularly the case when advising travellers with special health needs. This article discusses the general principles of identifying travellers with special risks and tailoring travel health advice accordingly. This is the second in a three-part series looking at the principles of travel health.

Preventing malaria in travellers: an overview.

Malaria is a common, potentially fatal infection found in more than 100 countries. Nurses play an important role in advising travellers about the risk of malaria, methods of prevention and in recognising the disease in returning travellers. This article provides an overview and outlines key areas of knowledge that are essential for nurses involved in giving pre- and post-travel malaria advice.

Evaluation of travel medicine practice by yellow fever vaccination centers in England, Wales, and Northern Ireland.

BACKGROUND: The National Travel Health Network and Centre (NaTHNaC) introduced a program of registration, training, standards, and audit for yellow fever vaccination centers (YFVCs) in England, Wales, and Northern Ireland (EWNI) in 2005. Prior to rolling out the program, NaTHNaC surveyed YFVCs in England. OBJECTIVES: To reassess the practice of YFVCs in 2009, 4 years after the institution of the NaTHNaC program, to identify areas for ongoing support, and to assess the impact of the program. METHODS: In 2009, all YFVCs in EWNI were asked to complete a questionnaire on type of practice, administration of travel vaccines, staff training, vaccine storage and patient record keeping, use of travel health information, evaluation of NaTHNaC yellow fever (YF) training, and resource and training needs. Data were analyzed using Microsoft Excel® and STATA 9®. RESULTS: The questionnaire was completed by 1,438 YFVCs (41.5% of 3,465 YFVCs). Most YFVCs were based in General Practice (87.4%). In nearly all YFVCs (97.0%), nurses advised travelers and administered YF vaccine. An annual median of 50 doses of YF vaccine was given by each YFVC. A total of 96.7% of nurses had received training in travel medicine, often through study days run by vaccine manufacturers. The internet was frequently used for information during travel consultations (84.8%) and NaTHNaC's on-line and telephone advice resources were highly rated. Following YF training, 95.8% of attendees expressed improved confidence regarding YF vaccination issues. There was excellent adherence to vaccination standards: ≥ 94% correctly stored vaccines, recorded refrigerator temperatures, and maintained YF vaccination records. CONCLUSIONS: In the 4 years since institution of the NaTHNaC program for YFVCs, there has been improved adherence to basic standards of immunization practice and increased confidence of health professionals in YF vaccination. The NaTHNaC program could be a model for other national public health bodies, as they establish a program for YF centers.

Travel health: routine, recommended and required vaccines.

Vaccines are an important public health measure and may be the prompt for travellers to attend for pre-travel health advice. Nurses involved in the provision of travel health advice require a sound knowledge of available vaccines together with the diseases they prevent and other risk management strategies. Travel vaccines should always be administered following a travel health consultation and risk assessment, taking into account the informed choice of the traveller. This paper discusses vaccine preventable disease in the context of travel health, and the appropriate use of routine, recommended and required pre-travel vaccines, which can be considered following individual risk assessment.

Travel health. Part 2: advising travellers visiting friends and relatives abroad.

International travel has become more accessible and affordable, and travel, particularly to tropical and malaria regions, has increased by up to 8% annually. This change in travel has surprisingly not resulted in an increase in imported diseases. Surveillance reports of hepatitis A and enteric fever have not increased and a significant and sustained fall in malaria over the decade has been described. Nurses in primary care are the predominant providers of pre-travel health services and they have an important and influential role in preventing travel-associated illness. This is the second article in a 3-part series on the spectrum of health issues associated with travel. Part one discussed pre-travel health advice, including risk assessment and educating travellers. This article explores the highest risk group of traveller, those visiting friends and relatives (VFRs). The article highlights the specific disease risks for VFRs and how these may be influenced by their health beliefs. The article explores ways in which nurses can optimize the travel health consultation to ensure that the specific needs ofVFRs are met and that they receive accurate and achievable advice.