Genetic complexity of diagnostically unresolved Ehlers-Danlos syndrome.

BACKGROUND: The 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. METHODS: Whole 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) <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. RESULTS: Heterozygous 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. CONCLUSIONS: We 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.

A Retrospective Cohort Study of Cerebrovascular Fibromuscular Dysplasia.

BACKGROUND: Fibromuscular dysplasia (FMD) is a rare vasculopathy for which limited data are available particularly from Europe. Our aim was to study the clinical characteristics of a regional cohort of carotid fibromuscular dysplasia patients to assess their clinical outcomes and the rate of vascular complications. METHODS: A retrospective cohort study of all cases of carotid/cerebrovascular FMD presenting to our regional vascular service (catchment population approximately 2 million), between 1998 and 2020. Imaging reports and patient case notes were screened using the keywords "FMD", "Fibromuscular Dysplasia", and "carotid". From case-note and imaging review, all relevant clinical data were extracted and the anatomical extent of vascular disease recorded. RESULTS: Eighty six patients with a diagnosis of cerebrovascular fibromuscular dysplasia were identified on imaging (31 computed tomography angiography, 46 magnetic resonance angiography, and 9 digital subtraction angiography) by a neurovascular radiologist. The mean age was 64 years, 78 (90%) patients were female, and 45/59 (75%) were Caucasian. Presenting clinical syndromes were Stroke/transient ischemic attack in 54 (63%) patients, symptomatic intracranial aneurysm in 6 (10%), and other neurological symptoms (headache/migraine, tinnitus) in 14 (16%), with 11 (13%) presenting incidentally. Six patients (7%) had a positive family history of FMD (2 patients) or other cerebrovascular event (4 patients: carotid dissection, intracerebral bleed, or stroke). Eight patients (9%) had a known or suspected hereditary connective tissue disorder (2 Ehlers-Danlos syndrome). Involved vessels were as follows: Carotid (mainly extracranial) in 79 (92%), vertebral 19 (22%), and a combination of these in 15 (17%) patients. Fifty eight (67%) patients had bilateral disease. Cerebrovascular complications were observed in 35 (41%) patients as follows: carotid dissection 11 (23%), carotid stenosis or occlusion 8 (9%), carotid aneurysm 8 (9%), cerebral aneurysm 9 (11%), vertebral aneurysm/dissection 2 (2%), and carotid-cavernous fistula 2 (2%). Of the 22 patients who had extracranial imaging, 14 (60%) had FMD affecting other beds-renal artery in 8 (36%) patients, other visceral arteries in 4 (18%), and aorta in 2 (9%). In addition, 4 (18%) patients had aneurysm or dissection affecting renal, splenic, and lower limb arteries. Overall, 67 (80%) patients had FMD affecting more than 1 vessel and 50 (58%) had multisite FMD (>/ = 2 vascular beds involved). Fifty nine (68%) patients were managed conservatively on close surveillance. Nineteen (21%) patients required carotid/cerebrovascular intervention and 9 (10%) required vascular intervention at other sites. Recurrent cerebrovascular events (stroke/transient ischemic attack, symptomatic Berry aneurysm) were seen in 20 (23%) patients. Overall mortality was 7% over a median follow-up period of 47 months. CONCLUSIONS: Carotid FMD patients have a high rate of multisite involvement, extracerebral vascular complications, and evidence of hereditary vasculopathy, requiring careful screening and surveillance.

The clinical application of electrical impedance technology in the detection of malignant neoplasms: a systematic review.

BACKGROUND: Electrical impedance technology has been well established for the last 20 years. Recently research has begun to emerge into its potential uses in the detection and diagnosis of pre-malignant and malignant conditions. The aim of this study was to systematically review the clinical application of electrical impedance technology in the detection of malignant neoplasms. METHODS: A search of Embase Classic, Embase and Medline databases was conducted from 1980 to 22/02/2018 to identify studies reporting on the use of bioimpedance technology in the detection of pre-malignant and malignant conditions. The ability to distinguish between tissue types was defined as the primary endpoint, and other points of interest were also reported. RESULTS: 731 articles were identified, of which 51 reported sufficient data for analysis. These studies covered 16 different cancer subtypes in a total of 7035 patients. As the studies took various formats, a qualitative analysis of each cancer subtype's data was undertaken. All the studies were able to show differences in electrical impedance and/or related metrics between malignant and normal tissue. CONCLUSIONS: Electrical impedance technology provides a novel method for the detection of malignant tissue, with large studies of cervical, prostate, skin and breast cancers showing encouraging results. Whilst these studies provide promising insights into the potential of this technology as an adjunct in screening, diagnosis and intra-operative margin assessment, customised development as well as multi-centre clinical trials need to be conducted before it can be reliably employed in the clinical detection of malignant tissue.

Targeted next-generation sequencing makes new molecular diagnoses and expands genotype-phenotype relationship in Ehlers-Danlos syndrome.

PURPOSE: Ehlers-Danlos syndrome (EDS) comprises a group of overlapping hereditary disorders of connective tissue with significant morbidity and mortality, including major vascular complications. We sought to identify the diagnostic utility of a next-generation sequencing (NGS) panel in a mixed EDS cohort. METHODS: We developed and applied PCR-based NGS assays for targeted, unbiased sequencing of 12 collagen and aortopathy genes to a cohort of 177 unrelated EDS patients. Variants were scored blind to previous genetic testing and then compared with results of previous Sanger sequencing. RESULTS: Twenty-eight pathogenic variants in COL5A1/2, COL3A1, FBN1, and COL1A1 and four likely pathogenic variants in COL1A1, TGFBR1/2, and SMAD3 were identified by the NGS assays. These included all previously detected single-nucleotide and other short pathogenic variants in these genes, and seven newly detected pathogenic or likely pathogenic variants leading to clinically significant diagnostic revisions. Twenty-two variants of uncertain significance were identified, seven of which were in aortopathy genes and required clinical follow-up. CONCLUSION: Unbiased NGS-based sequencing made new molecular diagnoses outside the expected EDS genotype-phenotype relationship and identified previously undetected clinically actionable variants in aortopathy susceptibility genes. These data may be of value in guiding future clinical pathways for genetic diagnosis in EDS.Genet Med 18 11, 1119-1127.

Surgical technology and operating-room safety failures: a systematic review of quantitative studies.

BACKGROUND: Surgical technology has led to significant improvements in patient outcomes. However, failures in equipment and technology are implicated in surgical errors and adverse events. We aim to determine the proportion and characteristics of equipment-related error in the operating room (OR) to further improve quality of care. METHODS: A systematic review of the published literature yielded 19 362 search results relating to errors and adverse events occurring in the OR, from which 124 quantitative error studies were selected for full-text review and 28 were finally selected. RESULTS: Median total errors per procedure in independently-observed prospective studies were 15.5, interquartile range (IQR) 2.0-17.8. Failures of equipment/technology accounted for a median 23.5% (IQR 15.0%-34.1%) of total error. The median number of equipment problems per procedure was 0.9 (IQR 0.3-3.6). From eight studies, subdivision of equipment failures was possible into: equipment availability (37.3%), configuration and settings (43.4%) and direct malfunctioning (33.5%). Observed error rates varied widely with study design and with type of operation: those with a greater burden of technology/equipment tended to show higher equipment-related error rates. Checklists (or similar interventions) reduced equipment error by mean 48.6% (and 60.7% in three studies using specific equipment checklists). CONCLUSIONS: Equipment-related failures form a substantial proportion of all error occurring in the OR. Those procedures that rely more heavily on technology may bear a higher proportion of equipment-related error. There is clear benefit in the use of preoperative checklist-based systems. We propose the adoption of an equipment check, which may be incorporated into the current WHO checklist.

Slow vasogenic fluctuations of intracranial pressure and cerebral near infrared spectroscopy--an observational study.

BACKGROUND/PURPOSE: Increased slow-wave activity in intracranial pressure (ICP) signifies an exhausted cerebrospinal compensatory reserve across a range of conditions. In this study, we attempted to describe synchronisation between slow waves of ICP and of near-infrared spectroscopy (NIRS) variables during controlled elevation of ICP. METHOD: Nineteen patients presenting with symptomatic hydrocephalus underwent a Computerised Infusion Test. NIRS-derived indices, ICP and arterial blood pressure (ABP) were recorded simultaneously. FINDINGS: ICP increased from 9.3 (6.0) mmHg to a 17.1 (8.9) mmHg during infusion. Slow waves in ICP were accompanied by concurrent waves in each NIRS variable (including deoxygenated haemoglobin (Hb) and oxygenated haemoglobin (HbO2)) with a mean coherence of >0.7 and no significant phase shift. In the same bandwidth (0.3-1.8 min(-1)), ABP fluctuations occurred with a coherence of 0.77 and phase lead of 40° with respect to ICP. The power of ICP slow waves increased significantly during infusion plateau with a corresponding increase in power of Hb waves. CONCLUSIONS: Slow fluctuations in cerebral oximetry as detected by NIRS coincide with and are implicated in the origin of ICP slow waves and increases during periods of exhausted cerebrospinal compensatory reserve. NIRS may be used as a non-invasive marker of increased ICP slow waves (and therefore reduced CSF compensatory reserve).

Carotid artery stenosis-an evidence-based review of surgical and non-surgical treatments.

Carotid artery disease underlies a significant proportion of ischaemic strokes. Whilst secondary prevention by drug treatment is the first step in managing patients with known carotid stenoses, evidence from a number of large randomised controlled trials have clearly demonstrated a benefit for surgical treatment in symptomatic patients with moderate-to-severe stenosis. In asymptomatic patients with severe stenosis a benefit is conferred by surgery in selected patients. Carotid endarterectomy has formed the mainstay of surgical treatment. Endovascular angioplasty (with/without stenting) for carotid stenoses has been proposed as a viable or even superior alternative to carotid endarterectomy. The results from four large randomised controlled trials comparing the two modalities, considered together suggest a marginally better outcome for carotid endarterectomy compared with angioplasty in terms of perioperative mortality and stroke, though the results of further studies are awaited. For carotid surgery, a multi-centre randomised controlled trial evaluating the use of local anaesthesia versus general anaesthesia demonstrated no significant difference in outcome. Refinements in surgical technique such as patch angioplasty and intraluminal shunting provide equivocal benefit, with wide variation in their usage and in the results of studies evaluating them. More robust evidence supporting or refuting a benefit for these techniques is required.

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+/-200microm), compared to 800+/-200microm 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.