Case report: The management of advanced oral cancer in a Jehovah's Witness using the Ultracision Harmonic Scalpel

We present the first case of a head and neck oncological procedure accomplished in a Jehovah's Witness using the Ultracision Harmonic Scalpel (Ethicon, Cincinnati, OH). Jehovah's Witnesses present a serious challenge to the head and neck cancer surgeon due to their refusal to accept transfusion of any blood products. However, our experience reinforces the view that surgical management of head and neck cancer is possible in these patients. We show the Harmonic Scalpel, an ultrasonic tissue dissector, to be a useful surgical tool in obviating the need for blood transfusion. Preoperative optimisation, intra-operative surgical and anaesthetic techniques are also fully discussed

Targeted genetic analysis in a large cohort of familial and sporadic cases of aneurysm or dissection of the thoracic aorta

PURPOSE: Thoracic aortic aneurysm/aortic dissection (TAAD) is a disorder with highly variable age of onset and phenotype. We sought to determine the prevalence of pathogenic variants in TAAD-associated genes in a mixed cohort of sporadic and familial TAAD patients and identify relevant genotype–phenotype relationships. METHODS: We used a targeted polymerase chain reaction and next-generation sequencing–based panel for genetic analysis of 15 TAAD-associated genes in 1,025 unrelated TAAD cases. RESULTS: We identified 49 pathogenic or likely pathogenic (P/LP) variants in 47 cases (4.9% of those successfully sequenced). Almost half of the variants were in nonsyndromic cases with no known family history of aortic disease. Twenty-five variants were within FBN1 and two patients were found to harbor two P/LP variants. Presence of a related syndrome, younger age at presentation, family history of aortic disease, and involvement of the ascending aorta increased the risk of carrying a P/LP variant. CONCLUSION: Given the poor prognosis of TAAD that is undiagnosed prior to acute rupture or dissection, genetic analysis of both familial and sporadic cases of TAAD will lead to new diagnoses, more informed management, and possibly reduced mortality through earlier, preclinical diagnosis in genetically determined cases and their family members

Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement

Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal-dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, joint hypermobility, and mild skin findings. A locus was mapped to an approximately 5.8 Mb region at 12p13.1 but no candidate gene was identified. In an international consortium we recruited 19 independent families comprising 107 individuals with pEDS to identify the locus, characterize the clinical details in those with defined genetic causes, and try to understand the physiological basis of the condition. In 17 of these families, we identified heterozygous missense or in-frame insertion/deletion mutations in C1R (15 families) or C1S (2 families), contiguous genes in the mapped locus that encode subunits C1r and C1s of the first component of the classical complement pathway. These two proteins form a heterotetramer that then combines with six C1q subunits. Pathogenic variants involve the subunit interfaces or inter-domain hinges of C1r and C1s and are associated with intracellular retention and mild endoplasmic reticulum enlargement. Clinical features of affected individuals in these families include rapidly progressing periodontitis with onset in the teens or childhood, a previously unrecognized lack of attached gingiva, pretibial hyperpigmentation, skin and vascular fragility, easy bruising, and variable musculoskeletal symptoms. Our findings open a connection between the inflammatory classical complement pathway and connective tissue homeostasis

Practices Driving the Adoption of Agile Project Management Methodologies in the Design Stage of Building Construction Projects

The aim of this study is to identify practices that would enable building construction companies to adopt agile project management methodologies during the design stage of projects that use building information modelling (BIM) solutions in the designing process. Due to the benefits of agile project management methodologies, a considerable amount of research has been conducted regarding the adoption of this methodology for building construction projects. However, waterfall project management is still more widely used in the building construction industry than agile project management is. Several recent studies claim that firms could focus on adopting agile methodologies during the design stage of a building construction project because due to the advent of BIM software solutions, the design stage can be carried out in a manner such as a software development project. Since software development industry is experiencing a widespread adoption of agile methods, if the design stage of a building construction project can be carried out such as a software development project, then there is a possibility to drive agile adoption in the design stage. Based on this information, researchers found an architectural consultancy firm that has been using a BIM solution to adopt agile project management methodologies in the design stage. The authors carried out a systematic literature review and identified 10 possible practices that might drive the adoption of agile practices. Those practices were presented to the architectural consultancy firm to identify practices that they are using to successfully adopt agile methods. The findings suggest that maintaining a backlog, running sprints, engaging a cross-functional team, continuous integration, and iterative/incremental development of the design are practices that have enabled the firm to adopt agile methods. Practical and theoretical implications were derived from the findings, and suggestions for future research and limitations of the study are discussed in the discussion. Concluding remarks are provided in final section of the paper

Utility of high resolution MR imaging to assess carotid plaque morphology:A comparison of acute symptomatic, recently symptomatic and asymptomatic patients with carotid artery disease

Objectives: Compare carotid plaque morphology of acute symptomatic, recently symptomatic and asymptomatic patients (groups 1, 2 and 3 respectively) with carotid artery disease using high resolution magnetic resonance imaging (MRI), to identify high-risk plaque characteristics best associated with risk of recurrent thrombo-embolic events. Methods: 60 patients underwent multi-contrast imaging of their internal carotid arteries. Different plaque components were manually delineated on acquired axial images to assess the difference in prevalence of plaque hemorrhage, fibrous cap (FC) rupture and FC thickness among the three groups. Results: 55% acute symptomatic patients had plaque hemorrhage vs. 35% for recently symptomatic group and 5% for asymptomatic group (p-value: group 1 vs. 3: 0.001, group 2 vs. 3: 0.04). Type 1 hemorrhage was more common in acute symptomatic patients than recently symptomatic patients (40% vs. 5%, p = 0.01). Type 2 hemorrhage was more common in recently symptomatic vs. acute symptomatic patients (15% vs. 30%). FC rupture was observed in 50% of patients in group 1 vs. 35% of group 2 patients (p = 0.02) but none in group 3. The mean minimum FC thickness was same in acute and recently symptomatic groups (600 ± 200 μm), compared to 800 ± 200 μm for asymptomatic patients (p-value: 0.03 and 0.007 respectively). Good correlation was present among the three MR readers (intra-class correlation coefficient = 0.71). Conclusion: High resolution MRI can differentiate plaque components associated with increased risk of thrombo-embolic events.</p

Genetic complexity of diagnostically unresolved Ehlers-Danlos syndrome

Peer reviewed: TrueAcknowledgements: The study was supported by the National Institute for Health Research England (NIHR) for the NIHR BioResource project (grant number RG65966). We thank NIHR BioResource volunteers for their participation, and gratefully acknowledge NIHR BioResource Centres, NHS Trusts and staff for their contribution. We thank the National Institute for Health and Care Research, NHS Blood and Transplant, and Health Data Research UK as part of the Digital Innovation Hub Programme. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. We acknowledge Julie Leary and Cherida Watkins (NWLH) for their assistance with recruitment and administrative support. This study also makes use of data generated by the UK10K Consortium, derived from samples from ALSPAC; a full list of the investigators who contributed to the generation of this data is available from www.UK10K.org. Funding for the UK10K was provided by the Wellcome Trust under award WT091310.BackgroundThe Ehlers-Danlos syndromes (EDS) are heritable disorders of connective tissue (HDCT), reclassified in the 2017 nosology into 13 subtypes. The genetic basis for hypermobile Ehlers-Danlos syndrome (hEDS) remains unknown.MethodsWhole exome sequencing (WES) was undertaken on 174 EDS patients recruited from a national diagnostic service for complex EDS and a specialist clinic for hEDS. Patients had already undergone expert phenotyping, laboratory investigation and gene sequencing, but were without a genetic diagnosis. Filtered WES data were reviewed for genes underlying Mendelian disorders and loci reported in EDS linkage, transcriptome and genome-wide association studies (GWAS). A genetic burden analysis (Minor Allele Frequency (MAF) &lt;0.05) incorporating 248 Avon Longitudinal Study of Parents and Children (ALSPAC) controls sequenced as part of the UK10K study was undertaken using TASER methodology.ResultsHeterozygous pathogenic (P) or likely pathogenic (LP) variants were identified in known EDS and Loeys-Dietz (LDS) genes. Multiple variants of uncertain significance where segregation and functional analysis may enable reclassification were found in genes associated with EDS, LDS, heritable thoracic aortic disease (HTAD), Mendelian disorders with EDS symptomatology and syndromes with EDS-like features. Genetic burden analysis revealed a number of novel loci, although none reached the threshold for genome-wide significance. Variants with biological plausibility were found in genes and pathways not currently associated with EDS or HTAD.ConclusionsWe demonstrate the clinical utility of large panel-based sequencing and WES for patients with complex EDS in distinguishing rare EDS subtypes, LDS and related syndromes. Although many of the P and LP variants reported in this cohort would be identified with current panel testing, they were not at the time of this study, highlighting the use of extended panels and WES as a clinical tool for complex EDS. Our results are consistent with the complex genetic architecture of EDS and suggest a number of novel hEDS and HTAD candidate genes and pathways.</jats:sec