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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is familial in 10% of cases. We have identified a missense mutation in the gene encoding fused in sarcoma (FUS) in a British kindred, linked to ALS6. In a survey of 197 familial ALS index cases, we identified two further missense mutations in eight families. Postmortem analysis of three cases with FUS mutations showed FUS-immunoreactive cytoplasmic inclusions and predominantly lower motor neuron degeneration. Cellular expression studies revealed aberrant localization of mutant FUS protein. FUS is involved in the regulation of transcription and RNA splicing and transport, and it has functional homology to another ALS gene, TARDBP, which suggests that a common mechanism may underlie motor neuron degeneration.

Haemangioblastomas are rare, highly vascularised tumours that typically occur in the cerebellum, brain stem and spinal cord. Up to a third of individuals with a haemangioblastoma will have von Hippel–Lindau (VHL) disease. Individuals with haemangioblastoma and underlying VHL disease present, on average, at a younger age and frequently have a personal or family history of VHL disease-related tumours (e.g., retinal or central nervous system (CNS) haemangioblastomas, renal cell carcinoma, phaeochromocytoma). However, a subset present an apparently sporadic haemangioblastoma without other features of VHL disease. To detect such individuals, it has been recommended that genetic testing and clinical/radiological assessment for VHL disease should be offered to patients with a haemangioblastoma. To assess “real-world” clinical practice, we undertook a national survey of clinical genetics centres. All participating centres responded that they would offer genetic testing and a comprehensive assessment (ophthalmological examination and CNS and abdominal imaging) to a patient presenting with a CNS haemangioblastoma. However, for individuals who tested negative, there was variability in practice with regard to the need for continued follow-up. We then reviewed the results of follow-up surveillance in 91 such individuals seen at four centres. The risk of developing a potential VHL-related tumour (haemangioblastoma or RCC) was estimated at 10.8% at 10 years follow-up. The risks of developing a recurrent haemangioblastoma were higher in those who presented <40 years of age. In the light of these and previous findings, we propose an age-stratified protocol for surveillance of VHL-related tumours in individuals with apparently isolated haemangioblastoma.

BackgroundVon Hippel-Lindau (VHL) disease is an inherited tumour predisposition syndrome and a paradigm for the importance of early diagnosis and surveillance. However, there is limited information on the “real world” management of VHL disease.MethodsA national audit of VHL disease in the United Kingdom.ResultsVHL disease was managed mostly via specialist clinics coordinated through regional clinical genetics services (but frequently involving additional specialties). Over the study period, 19 genetic centres saw 842 individuals (393 males, 449 females) with a clinical and/or molecular diagnosis of VHL disease and 74 individuals (35 male, 39 female) with a prior risk of 50% (affected parent). All centres offered retinal, central nervous system and abdominal surveillance to affected individuals and at-risk relatives though surveillance details differed between centres (but complied with international recommendations). Renal lesions detected on the first surveillance scan were, on average, larger than those detected during subsequent scans and the larger the diameter at detection the greater the likelihood of early intervention.ConclusionsIn a state-funded health care system individuals with a rare inherited cancer predisposition syndrome are generally able to access appropriate surveillance and patient management is improved compared to historical data. The “real world” data from this study will inform the future development of VHL management protocols.

Purpose and scopeThe aim of this position statement is to provide recommendations regarding the delivery of genomic testing to patients with rare disease in the UK and Ireland. The statement has been developed to facilitate timely and equitable access to genomic testing with reporting of results within commissioned turnaround times.Methods of statement developmentA 1-day workshop was convened by the UK Association for Clinical Genomic Science and attended by key stakeholders within the NHS Genomic Medicine Service, including clinical scientists, clinical geneticists and patient support group representatives. The aim was to identify best practice and innovations for streamlined, geographically consistent services delivering timely results. Attendees and senior responsible officers for genomic testing services in the UK nations and Ireland were invited to contribute.Results and conclusionsWe identified eight fundamental requirements and describe these together with key enablers in the form of specific recommendations. These relate to laboratory practice (proportionate variant analysis, bioinformatics pipelines, multidisciplinary team working model and test request monitoring), compliance with national guidance (variant classification, incidental findings, reporting and reanalysis), service development and improvement (multimodal testing and innovation through research, informed by patient experience), service demand, capacity management, workforce (recruitment, retention and development), and education and training for service users. This position statement was developed to provide best practice guidance for the specialist genomics workforce within the UK and Ireland but is relevant to any publicly funded healthcare system seeking to deliver timely rare disease genomic testing in the context of high demand and limited resources.

Vocation is most often linked with a specific calling for those in professional ministry. Doing More with Life explores the way higher education can expand this limited understanding of vocation. Specifically, this volume shows that higher education can clarify how God calls all people, allow mentoring across specific vocations, and inspire future generations to think of their lives as vocations.

Humility has become an unpopular, even forgotten, virtue in contemporary Western culture. Central throughout most of Christian history, its value today has changed dramatically. Within Christian circles, the world-affirming and liberating dimensions of the gospel have led to questions about whether humility frustrates human flourishing and fosters a passive acceptance of injustice. Several feminist scholars have argued that humility can exacerbate women's struggle for self-identity and empowerment. At this time, St. Augustine's work is worth exploring because he both places humility at the center of Christian life and provides a Christological hermeneutic for distinguishing between true and false humility. According to Augustine, all Christian virtues are rooted in this foundational Christian attribute revealed in Jesus Christ. The first and last chapters respectively introduce contemporary criticism of humility and then evaluate it in light of Augustine's thought. Chapters two and three explore Augustine's claim that humility is at the heart of who Christ is and what his disciples are to become (Matthew 11:29). The way that God saves us is inseparable from salvation itself: “our very salvation in Christ consists in the humility of Christ.” ( Serm. 285.4). In other words, humility is more than simply moral; it is soteriological, for it describes the very logic of our reconciliation with God in Jesus Christ. Through humility, Christ confronts our pride, mediates between humanity and divinity, and empties himself in love for our sake. Chapter four examines how Johann Baptist Metz offers resources for a contemporary renewal of humility through his historically and politically conscious account of “poverty of spirit,” relating it to modern forms of alienation and exploitation. In a mutually corrective reading of Augustine and Metz, humility emerges as the source of both a Christian anthropology and a more radical, active love that calls us out of ourselves into solidarity and communion. The twofold shape of Christ-like humility, as true self-knowledge and self-emptying (Philippians 2), reveals the expansive and liberating nature of this virtue too often aligned with a privatized and somber Christianity.

\"Thirty Days on Retreat with the Exercises of Saint Ignatius\" by Paul Mariani is reviewed.

Ruddy shares her response to the sexual-abuse scandal involving priests. She opines that despite her anger about the church's failure to protect the innocent and to own up its terrible truths, she is not led to despair or to seek another church.

Lung infections with Mycobacterium abscessus, a species of multidrug-resistant nontuberculous mycobacteria, are emerging as an important global threat to individuals with cystic fibrosis (CF), in whom M. abscessus accelerates inflammatory lung damage, leading to increased morbidity and mortality. Previously, M. abscessus was thought to be independently acquired by susceptible individuals from the environment. However, using whole-genome analysis of a global collection of clinical isolates, we show that the majority of M. abscessus infections are acquired through transmission, potentially via fomites and aerosols, of recently emerged dominant circulating clones that have spread globally. We demonstrate that these clones are associated with worse clinical outcomes, show increased virulence in cell-based and mouse infection models, and thus represent an urgent international infection challenge.

BackgroundAlthough not guideline recommended, studies suggest 50% of locoregional breast cancer patients undergo systemic imaging during follow-up, prompting its inclusion as a Choosing Wisely measure of potential overuse. Most studies rely on administrative data that cannot delineate scan intent (prompted by signs/symptoms vs. asymptomatic surveillance). This is a critical gap as intent is the only way to distinguish overuse from appropriate care.ObjectiveOur aim was to assess surveillance systemic imaging post-breast cancer treatment in a national sample accounting for scan intent.MethodsA stage-stratified random sample of 10 women with stage II–III breast cancer in 2006–2007 was selected from each of 1217 Commission on Cancer-accredited facilities, for a total of 10,838 patients. Registrars abstracted scan type (computed tomography [CT], non-breast magnetic resonance imaging, bone scan, positron emission tomography/CT) and intent (cancer-related vs. not, asymptomatic surveillance vs. not) from medical records for 5 years post-diagnosis. Data were merged with each patient’s corresponding National Cancer Database record, containing sociodemographic and tumor/treatment information.ResultsOf 10,838 women, 30% had one or more, and 12% had two or more, systemic surveillance scans during a 4-year follow-up period. Patients were more likely to receive surveillance imaging in the first follow-up year (lower proportions during subsequent years) and if they had estrogen receptor/progesterone receptor-negative tumors.ConclusionsLocoregional breast cancer patients undergo asymptomatic systemic imaging during follow-up despite guidelines recommending against it, but at lower rates than previously reported. Providers appear to use factors that confer increased recurrence risk to tailor decisions about systemic surveillance imaging, perhaps reflecting limitations of data on which current guidelines are based.ClinicalTrials.gov Identifier: NCT02171078.