The complexity of multidisciplinary respiratory care in amyotrophic lateral sclerosis.

Motor neurone disease/amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with no known cure, where death is usually secondary to progressive respiratory failure. Assisting people with ALS through their disease journey is complex and supported by clinics that provide comprehensive multidisciplinary care (MDC). This review aims to apply both a respiratory and a complexity lens to the key roles and areas of practice within the MDC model in ALS. Models of noninvasive ventilation care, and considerations in the provision of palliative therapy, respiratory support, and speech and language therapy are discussed. The impact on people living with ALS of both inequitable funding models and the complexity of clinical care decisions are illustrated using case vignettes. Considerations of the impact of emerging antisense and gene modifying therapies on MDC challenges are also highlighted. The review seeks to illustrate how MDC members contribute to collective decision-making in ALS, how the sum of the parts is greater than any individual care component or health professional, and that the MDC per se adds value to the person living with ALS. Through this approach we hope to support clinicians to navigate the space between what are minimum, guideline-driven, standards of care and what excellent, person-centred ALS care that fully embraces complexity could be. Educational aims: To highlight the complexities surrounding respiratory care in ALS.To alert clinicians to the risk that complexity of ALS care may modify the effectiveness of any specific, evidence-based therapy for ALS.To describe the importance of person-centred care and shared decision-making in optimising care in ALS.

Incorporating Genetic Testing Into the Care of Patients With Amyotrophic Lateral Sclerosis/Frontotemporal Degeneration Spectrum Disorders.

Purpose of Review: Amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) spectrum disorders have a strong genetic component. Genetic counselors are a limited resource, and therefore, other providers must be prepared to integrate genetic testing into their practice. Recent Findings: Recent ALS/FTD studies have demonstrated that lack of family history does not preclude a genetic etiology. The benefits of a genetic diagnosis have expanded to include the potential to treat; thus, genetic testing is increasingly recommended to be offered to all persons with ALS/FTD. Summary: Offering genetic testing to persons with ALS/FTD spectrum disorders should be part of routine clinical neurologic care. All genetic testing should include discussion about the medical and psychosocial implications of testing for the patient and family members. Neurologists should be prepared to facilitate this process and recognize when referral to a genetic counselor is indicated.

A mainstreaming oncogenomics model: improving the identification of Lynch syndrome.

Introduction: "Mainstreaming" is a proposed strategy to integrate genomic testing into oncology. The aim of this paper is to develop a mainstreaming oncogenomics model by identifying health system interventions and implementation strategies for mainstreaming Lynch syndrome genomic testing. Methods: A rigorous theoretical approach inclusive of conducting a systematic review and qualitative and quantitative studies was undertaken using the Consolidated Framework for Implementation Research. Theory-informed implementation data were mapped to the Genomic Medicine Integrative Research framework to generate potential strategies. Results: The systematic review identified a lack of theory-guided health system interventions and evaluation for Lynch syndrome and other mainstreaming programs. The qualitative study phase included 22 participants from 12 health organizations. The quantitative Lynch syndrome survey included 198 responses: 26% and 66% from genetic and oncology health professionals, respectively. Studies identified the relative advantage and clinical utility of mainstreaming to improve genetic test access and to streamline care, and adaptation of current processes was recognized for results delivery and follow-up. Barriers identified included funding, infrastructure and resources, and the need for process and role delineation. The interventions to overcome barriers were as follows: embedded mainstream genetic counselors, electronic medical record genetic test ordering, results tracking, and mainstreaming education resources. Implementation evidence was connected through the Genomic Medicine Integrative Research framework resulting in a mainstreaming oncogenomics model. Discussion: The proposed mainstreaming oncogenomics model acts as a complex intervention. It features an adaptable suite of implementation strategies to inform Lynch syndrome and other hereditary cancer service delivery. Implementation and evaluation of the model are required in future research.

Clinical and imaging modality factors impacting radiological interpretation of breast screening in young women with neurofibromatosis type 1.

Young women with Neurofibromatosis type 1 (NF1) have a high risk of developing breast cancer and poorer survival following breast cancer diagnosis. International guidelines recommend commencing breast screening between 30 and 35 years; however, the optimal screening modality is unestablished, and previous reports suggest that breast imaging may be complicated by the presence of intramammary and cutaneous neurofibromas (cNFs). The aim of this study was to explore potential barriers to implementation of breast screening for young women with NF1.Twenty-seven women (30-47 years) with NF1 completed breast screening with breast MRI, mammogram and breast ultrasound. Nineteen probably benign/suspicious lesions were detected across 14 women. Despite the presence of breast cNFs, initial biopsy rate for participants with NF1 (37%), were comparable to a BRCA pathogenic variant (PV) cohort (25%) (P = 0.311). No cancers or intramammary neurofibromas were identified. Most participants (89%) returned for second round screening.The presence of cNF did not affect clinician confidence in 3D mammogram interpretation, although increasing breast density, frequently seen in young women, impeded confidence for 2D and 3D mammogram. Moderate or marked background parenchymal enhancement on MRI was higher in the NF1 cohort (70.4%) than BRCA PV carriers (47.3%), which is an independent risk factor for breast cancer.Breast MRI was the preferred mode of screening over mammogram, as the majority (85%) with NF1 demonstrated breast density (BI-RADS 3C/4D), which hinders mammogram interpretation. For those with high breast density and high cNF breast coverage, 3D rather than 2D mammogram is preferred, if MRI is unavailable.

Outcomes of Importance to Patients in Reproductive Genetic Carrier Screening: A Qualitative Study to Inform a Core Outcome Set.

There is significant heterogeneity in the outcomes assessed across studies of reproductive genetic carrier screening (RGCS). Only a small number of studies have measured patient-reported outcomes or included patients in the selection of outcomes that are meaningful to them. This study was a cross-sectional, qualitative study of 15 patient participants conducted to inform a core outcome set. A core outcome set is an approach to facilitate standardisation in outcome reporting, allowing direct comparison of outcomes across studies to enhance understanding of impacts and potential harms. The aim of this study was to incorporate the patient perspective in the development of a core outcome set by eliciting a detailed understanding of outcomes of importance to patients. Data were collected via online, semi-structured interviews using a novel method informed by co-design and the nominal group technique. Data were analysed using reflexive thematic analysis. Outcomes elicited from patient stakeholder interviews highlighted several under-explored areas for future research. This includes the role of grief and loss in increased risk couples, the role of empowerment in conceptualising the utility of RGCS, the impact of societal context and barriers that contribute to negative experiences, and the role of genetic counselling in ensuring that information needs are met and informed choice facilitated as RGCS becomes increasingly routine. Future research should focus on incorporating outcomes that accurately reflect patient needs and experience.

Genetic counseling and diagnostic genetic testing for familial amyotrophic lateral sclerosis and/or frontotemporal dementia: A qualitative study of client experiences.

Genetic counseling and diagnostic genetic testing is part of the multidisciplinary care of people with amyotrophic lateral sclerosis (ALS, commonly called motor neurone disease, MND) and frontotemporal dementia (FTD). We explored client experiences of genetic counseling and diagnostic testing to inform the care of future families. Semi-structured interviews with individuals with ALS/MND/FTD or their relatives were conducted. The study was designed to include a wide variety of participants with varying disease status and abilities. Genetic counseling and diagnostic testing experiences were explored using interpretive description methodology. Bioecological theory was used as the framework for the reflexive thematic analysis. Eighteen individuals with ALS/MND/FTD or their relatives from 13 Australian families participated. Three themes were identified: sharing knowledge, (un)supportive care, and 'circumstance is everything'. Consistent with bioecological theory, one's genetic counseling experience was informed by individual circumstances, time, and proximal factors. These informed the level of information and support required in the genetic counseling process. Although some client circumstances cannot be changed, efforts could be made to enhance genetic counseling experiences by improving interactions between the client and their care team. Some clients may benefit from further discussions regarding the familial implications of genetic testing, and greater support with family communication. Clients' needs were derived from the data and will contribute to genetic counseling consensus guidelines.

Toward genetic counseling practice standards for diagnostic testing in amyotrophic lateral sclerosis and frontotemporal dementia.

Objective: Genetic counseling and diagnostic genetic testing are considered part of the multidisciplinary care of individuals with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We aimed to investigate the ideal components of genetic counseling for ALS/FTD diagnostic testing amongst various stakeholders using an online, modified Delphi survey. Methods: Experts in genetic counseling and testing for ALS/FTD were purposively then snowball recruited and included genetic health professionals, health professionals outside of genetics and consumer experts (patients, relatives, and staff representatives from ALS/FTD support organizations). First-round items were informed by two systematic literature reviews and qualitative interviews with patients and families who had experienced diagnostic testing. Analysis of each round informed the development of the subsequent round and the final results. Results: Forty-six experts participated in the study, 95.65% completed both rounds. After round one, items were updated based on participant responses and were presented again for consensus in round two. After round two, a high level of consensus (≥80% agreement) was achieved on 16 items covering various topics related to genetic counseling service delivery, before and after diagnostic testing is facilitated. Conclusions: Genetic counseling for individuals with ALS/FTD and their families should include the provision of client-centered counseling, education and support throughout. The items developed are adaptable to varied healthcare settings and may inform a standard of genetic counseling practice for health professionals who facilitate testing and counseling discussions. This area of work is timely, given demand for testing is likely to increase as more genotype-driven clinical trials become available.

Incorporating patient perspectives in the development of a core outcome set for reproductive genetic carrier screening: a sequential systematic review.

There is currently no consensus on the key outcomes of reproductive genetic carrier screening (RGCS). This has led to a large amount of variability in approaches to research, limiting direct comparison and synthesis of findings. In a recently published systematic review of quantitative studies on RGCS, we found that few studies incorporated patient-reported outcomes. In response to this gap, we conducted a sequential systematic review of qualitative studies to identify outcomes exploring the patient experience of RGCS. In conjunction with the review of quantitative studies, these outcomes will be used to inform the development of a core outcome set. Text excerpts relevant to outcomes, including quotes and themes, were extracted verbatim and deductively coded as outcomes. We conducted a narrative synthesis to group outcomes within domains previously defined in our review of quantitative studies, and identify any new domains that were unique to qualitative studies. Seventy-eight outcomes were derived from qualitative studies and grouped into 19 outcome domains. Three new outcome domains were identified; 'goals of pre- and post-test genetic counselling', 'acceptability of further testing and alternative reproductive options', and 'perceived utility of RGCS'. The identification of outcome domains that were not identified in quantitative studies indicates that outcomes reflecting the patient perspective may be under-represented in the quantitative literature on this topic. Further work should focus on ensuring that outcomes reflect the real world needs and concerns of patients in order to maximise translation of research findings into clinical practice.

Surveillance Improves Outcomes for Carriers of SDHB Pathogenic Variants: A Multicenter Study.

CONTEXT: Carriers of succinate dehydrogenase type B (SDHB) pathogenic variants (PVs) are at risk of pheochromocytoma and paraganglioma (PPGL) from a young age. It is widely recommended carriers enter a surveillance program to detect tumors, but there are limited studies addressing outcomes of surveillance protocols for SDHB PV carriers. OBJECTIVE: The purpose of this study was to describe surveillance-detected (s-d) tumors in SDHB PV carriers enrolled in a surveillance program and to compare their outcomes to probands. METHODS: This was a multicenter study of SDHB PV carriers with at least 1 surveillance episode (clinical, biochemical, imaging) in Australian genetics clinics. Data were collected by both retrospective and ongoing prospective follow-up. Median duration of follow-up was 6.0 years. RESULTS: 181 SDHB PV carriers (33 probands and 148 nonprobands) were assessed. Tumors were detected in 20% of nonprobands undergoing surveillance (age range 9-76 years). Estimated 10-year metastasis-free survival was 66% for probands and 84% for nonprobands with s-d tumors (P = .027). S-d tumors were smaller than those in probands (median 27 mm vs 45 mm respectively, P = .001). Tumor size ≥40 mm was associated with progression to metastatic disease (OR 16.9, 95% CI 2.3-187.9, P = .001). Patients with s-d tumors had lower mortality compared to probands: 10-year overall survival was 79% for probands and 100% for nonprobands (P = .029). CONCLUSION: SDHB carriers with s-d tumors had smaller tumors, reduced risk of metastatic disease, and lower mortality than probands. Our results suggest that SDHB PV carriers should undertake surveillance to improve clinical outcomes.

Systematic review of outcomes in studies of reproductive genetic carrier screening: Towards development of a core outcome set.

PURPOSE: Current practice recommendations support the widespread implementation of reproductive genetic carrier screening (RGCS). These consensus-based recommendations highlight a research gap, with findings from current studies being insufficient to meet the standard required for more rigorous evidence-based recommendations. This systematic review assessed methodological aspects of studies on RGCS to inform the need for a core outcome set. METHODS: We conducted a systematic search to identify peer-reviewed published studies offering population-based RGCS. Study designs, outcomes, and measurement methods were extracted. A narrative synthesis was conducting using an existing outcome taxonomy and criteria used in the evaluation of genetic screening programs as frameworks. RESULTS: Sixty-five publications were included. We extracted 120 outcomes representing 24 outcome domains. Heterogeneity in outcome selection, measurement methods and time points of assessment was extensive. Quality appraisal raised concerns for bias. We found that reported outcomes had limited applicability to criteria used to evaluate genetic screening programs. CONCLUSION: Despite a large body of literature, diverse approaches to research have limited the conclusions that can be cumulatively drawn from this body of evidence. Consensus regarding meaningful outcomes for evaluation of RGCS would be a valuable first step in working towards evidence-based practice recommendations, supporting the development of a core outcome set.

Genetic counseling and testing practices for late-onset neurodegenerative disease: a systematic review.

OBJECTIVE: To understand contemporary genetic counseling and testing practices for late-onset neurodegenerative diseases (LONDs), and identify whether practices address the internationally accepted goals of genetic counseling: interpretation, counseling, education, and support. METHODS: Four databases were systematically searched for articles published from 2009 to 2020. Peer-reviewed research articles in English that reported research and clinical genetic counseling and testing practices for LONDs were included. A narrative synthesis was conducted to describe different practices and map genetic counseling activities to the goals. Risk of bias was assessed using the Qualsyst tool. The protocol was registered with PROSPERO (CRD42019121421). RESULTS: Sixty-one studies from 68 papers were included. Most papers focused on predictive testing (58/68) and Huntington's disease (41/68). There was variation between papers in study design, study population, outcomes, interventions, and settings. Although there were commonalities, novel and inconsistent genetic counseling practices were identified. Eighteen papers addressed all four goals of genetic counseling. CONCLUSION: Contemporary genetic counseling and testing practices for LONDs are varied and informed by regional differences and the presence of different health providers. A flexible, multidisciplinary, client- and family-centered care continues to emerge. As genetic testing becomes a routine part of care for patients (and their relatives), health providers must balance their limited time and resources with ensuring clients are safely and effectively counseled, and all four genetic counseling goals are addressed. Areas of further research include diagnostic and reproductive genetic counseling/testing practices, evaluations of novel approaches to care, and the role and use of different health providers in practice.

The psychological impact and experience of breast cancer screening in young women with an increased risk of breast cancer due to neurofibromatosis type 1.

Women with neurofibromatosis type 1 (NF1) have an increased risk of developing early breast cancer with a poorer prognosis compared to the general population. Therefore, international management guidelines recommend regular screening in women with NF1 starting from 30 to 35 years. As the psychological impacts of breast cancer screening in other high-risk populations cannot be extended to women with NF1, due to increased incidence of cognitive and mental health issues, the psychological harms of breast screening in women with NF1 are unknown. Consequently, the aim of this study was to assess the psychological impact of breast cancer screening in women with NF1 attending an established risk management clinic. Twenty-eight women with NF1 (30-50 years) completed psychological well-being and patient experience questionnaires, administered across five time points, before and after their initial and second round annual breast screening visits. Preliminary findings demonstrated the screening regimen was well-tolerated, with most participants reporting high satisfaction with the screening process. Overall, no significant increase in psychological distress related to the breast screening process was identified, with mean cancer worry and anxiety scores decreasing over time. However, some women did experience negative aspects of screening and barriers to re-attendance at annual breast screening appointments. As some women with NF1 exhibited clinical levels of psychological distress prior to screening, efforts to identify those at risk and additional support to address concerns and expectations throughout the breast screening process may be beneficial.

Patient and Relative Experiences and Decision-making About Genetic Testing and Counseling for Familial ALS and FTD: A Systematic Scoping Review.

Genetic testing and counseling is an emerging part of care for patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and their families. This scoping review aimed to map patients' and relatives' experiences of genetic testing and counseling for familial ALS and FTD and the factors influencing their decision to proceed with testing or counseling. Informed by the Joanna Briggs Institute methodology, 5 databases were systematically searched. Thirty studies from 39 references were included. A descriptive numerical summary analysis and narrative synthesis was conducted. Mostly positive diagnostic testing experiences were reported, but issues arose due to progressive disease and discordant results. Predictive testing impacted at-risk relatives, regardless of the result received, and psychosocial sequelae ranged from relief to guilt, worry or contemplating suicide. Four reproductive testing experiences were reported. Personal, familial and practical factors, and the lived experience of disease, informed decision-making. Greater uncertainty and complexity may be faced in familial ALS/FTD than in other late-onset neurodegenerative diseases due to clinical and genetic heterogeneity, and testing limitations. Genetic counseling models of care should consider this difference to ensure that individuals with, or at risk of, ALS/FTD are effectively managed. Implications for research and practice are discussed.

Health system interventions to integrate genetic testing in routine oncology services: A systematic review.

BACKGROUND: Integration of genetic testing into routine oncology care could improve access to testing. This systematic review investigated interventions and the tailored implementation strategies aimed at increasing access to genetic counselling and testing and identifying hereditary cancer in oncology. METHODS: The search strategy results were reported using the PRISMA statement and four electronic databases were searched. Eligible studies included routine genetic testing for breast and ovarian cancer or uptake after universal tumour screening for colorectal or endometrial cancer. The titles and abstracts were reviewed and the full text articles screened for eligibility. Data extraction was preformed using a designed template and study appraisal was assessed using an adapted Newcastle Ottawa Scale. Extracted data were mapped to Proctor's et al outcomes and the Consolidated Framework for Implementation Research and qualitatively synthesised. RESULTS: Twenty-seven studies, published up to May 2020, met the inclusion criteria. Twenty-five studies ranged from poor (72%), fair to good (28%) quality. Most interventions identified were complex (multiple components) such as; patient or health professional education, interdisciplinary practice and a documentation or system change. Forty-eight percent of studies with complex interventions demonstrated on average a 35% increase in access to genetic counselling and a 15% increase in testing completion. Mapping of study outcomes showed that 70% and 32% of the studies aligned with either the service and client or the implementation level outcome and 96% to the process or inner setting domains of the Consolidated Framework for Implementation Research. CONCLUSION: Existing evidence suggests that complex interventions have a potentially positive effect towards genetic counselling and testing completion rates in oncology services. Studies of sound methodological quality that explore a greater breadth of pre and post implementation outcomes and informed by theory are needed. Such research could inform future service delivery models for the integration of genetics into oncology services.

Helping young children understand inherited cancer predisposition syndromes using bibliotherapy.

Communication with children about hereditary conditions in the family can be difficult for parents. Yet, good communication strategies are leading determinants of adaptation and resilience. With inherited cancer predisposition syndromes that can affect young children such as Li-Fraumeni syndrome (LFS) and hereditary pheochromocytoma and paraganglioma syndrome (HPPS), genetic testing and subsequent surveillance in at-risk children is the optimal intervention. Given testing often commences early, providing children and their parents with appropriate genetic counseling and communication strategies is important for informed decision making. To inform such communication strategies, we used a bibliotherapeutic framework, where stories are delivered prescriptively (i.e., 'bibliotherapy'), to develop a psycho-educational resource for children aged 5-10 years old at risk of either LFS or HPPS. Illustrated storybooks for children were created based on models of developmental comprehension. To ascertain their experience, parents were invited to read a storybook to their child/ren and participate in semi-structured qualitative interviews. Transcripts were analyzed thematically using a general inductive approach. The bibliotherapeutic resource reportedly supported parents with communication about these issues without raising emotional distress in either themselves or their children. The key stages of a bibliotherapeutic interaction were facilitated by the use of this resource, and all parents reported that it would have been useful when their children were first tested and/or diagnosed. This study lays the foundation for the application of bibliotherapy as a psycho-educational intervention in genetic counseling and demonstrates that bibliotherapy may improve the process of communication between parents and children regarding pediatric-inherited cancer syndromes.

Implementing gene curation for hereditary cancer susceptibility in Australia: achieving consensus on genes with clinical utility.

BACKGROUND: The strength of evidence supporting the validity of gene-disease relationships is variable. Hereditary cancer has the additional complexity of low or moderate penetrance for some confirmed disease-associated alleles. METHODS: To promote national consistency in interpretation of hereditary cancer/tumour gene test results, we requested opinions of representatives from Australian Family Cancer Clinics regarding the clinical utility of 157 genes initially collated for a national research project. Viewpoints were sought by initial survey, face-to-face workshop and follow-up survey. Subsequent review was undertaken by the eviQ Cancer Genetics Reference Committee, a national resource providing evidence-based and consensus-driven cancer treatment protocols. RESULTS: Genes were categorised by clinical actionability as: relevant for testing on presentation of common cancer/tumour types (n=45); relevant for testing in the context of specific rare phenotypes (n=74); insufficient clinical utility (n=34) or contentious clinical utility (n=3). Opinions for several genes altered during the study time frame, due to new information. CONCLUSION: Through an iterative process, consensus was achieved on genes with clinical utility for hereditary cancer/tumour conditions in the Australian setting. This study highlighted need for regular review of gene-disease lists, a role assumed in Australia for hereditary cancer/tumour predisposition genes by the eviQ Cancer Genetics Reference Committee.

BAM1/2 receptor kinase signaling drives CLE peptide-mediated formative cell divisions in Arabidopsis roots.

Cell division is often regulated by extracellular signaling networks to ensure correct patterning during development. In Arabidopsis, the SHORT-ROOT (SHR)/SCARECROW (SCR) transcription factor dimer activates CYCLIND6;1 (CYCD6;1) to drive formative divisions during root ground tissue development. Here, we show plasma-membrane-localized BARELY ANY MERISTEM1/2 (BAM1/2) family receptor kinases are required for SHR-dependent formative divisions and CYCD6;1 expression, but not SHR-dependent ground tissue specification. Root-enriched CLE ligands bind the BAM1 extracellular domain and are necessary and sufficient to activate SHR-mediated divisions and CYCD6;1 expression. Correspondingly, BAM-CLE signaling contributes to the restriction of formative divisions to the distal root region. Additionally, genetic analysis reveals that BAM-CLE and SHR converge to regulate additional cell divisions outside of the ground tissues. Our work identifies an extracellular signaling pathway regulating formative root divisions and provides a framework to explore this pathway in patterning and evolution.