An integrated analysis and comparison of serum, saliva and sebum for COVID-19 metabolomics.

The majority of metabolomics studies to date have utilised blood serum or plasma, biofluids that do not necessarily address the full range of patient pathologies. Here, correlations between serum metabolites, salivary metabolites and sebum lipids are studied for the first time. 83 COVID-19 positive and negative hospitalised participants provided blood serum alongside saliva and sebum samples for analysis by liquid chromatography mass spectrometry. Widespread alterations to serum-sebum lipid relationships were observed in COVID-19 positive participants versus negative controls. There was also a marked correlation between sebum lipids and the immunostimulatory hormone dehydroepiandrosterone sulphate in the COVID-19 positive cohort. The biofluids analysed herein were also compared in terms of their ability to differentiate COVID-19 positive participants from controls; serum performed best by multivariate analysis (sensitivity and specificity of 0.97), with the dominant changes in triglyceride and bile acid levels, concordant with other studies identifying dyslipidemia as a hallmark of COVID-19 infection. Sebum performed well (sensitivity 0.92; specificity 0.84), with saliva performing worst (sensitivity 0.78; specificity 0.83). These findings show that alterations to skin lipid profiles coincide with dyslipidaemia in serum. The work also signposts the potential for integrated biofluid analyses to provide insight into the whole-body atlas of pathophysiological conditions

Early Mechanical Alterations in Phospholamban Mutation Carriers: Identifying Subclinical Disease Before Onset of Symptoms

OBJECTIVES: This study aimed to explore echocardiographic characteristics of phospholamban (PLN) p.Arg14del mutation carriers to investigate whether structural and/or functional abnormalities could be identified before onset of symptoms. BACKGROUND: Carriers of the genetic PLN p.Arg14del mutation may develop arrhythmogenic and/or dilated cardiomyopathy. Overt disease is preceded by a pre-symptomatic phase of variable length in which disease expression seems to be absent. METHODS: PLN p.Arg14del mutation carriers with an available echocardiogram were included. Mutation carriers were classified as pre-symptomatic if they had no history of ventricular arrhythmias (VAs), a premature ventricular complex count of <500/24 h, and a left ventricular (LV) ejection fraction of ≥45%. In addition, we included 70 control subjects with similar age and sex distribution as the pre-symptomatic mutation carriers. Comprehensive echocardiographic analysis (including deformation imaging) was performed. RESULTS: The final study population consisted of 281 PLN p.Arg14del mutation carriers, 139 of whom were classified as pre-symptomatic. In comparison to control subjects, pre-symptomatic mutation carriers had lower global longitudinal strain and higher LV mechanical dispersion (both p < 0.001). In addition, post-systolic shortening (PSS) in the LV apex was observed in 43 pre-symptomatic mutation carriers (31%) and in none of the control subjects. During a median follow-up of 3.2 years (interquartile range: 2.1 to 5.6 years) in 104 pre-symptomatic mutation carriers, nonsustained VA occurred in 13 (13%). Presence of apical PSS was the strongest echocardiographic predictor of VA (multivariable hazards ratio: 5.11; 95% confidence interval [CI]: 1.37 to 19.08; p = 0.015), which resulted in a negative predictive value of 96% (95% CI: 89% to 98%) and a positive predictive value of 29% (95% CI: 21% to 40%). CONCLUSIONS: Global and regional LV mechanical alterations in PLN p.Arg14del mutation carriers precede arrhythmic symptoms and overt structural disease. Pre-symptomatic mutation carriers with normal deformation patterns in the apex are at low risk of developing VA within 3 years, whereas mutation carriers with apical PSS appear to be at higher risk

Radiopaque drug-eluting embolisation beads as fiducial markers for stereotactic liver radiotherapy

OBJECTIVE: To determine the feasibility of using radiopaque (RO) beads as direct tumour surrogates for image-guided radiotherapy (IGRT) in patients with liver tumours after transarterial chemoembolisation (TACE). METHODS: A novel vandetanib-eluting RO bead was delivered via TACE as part of a first-in-human clinical trial in patients with either hepatocellular carcinoma or liver metastases from colorectal cancer. Following TACE, patients underwent simulated radiotherapy imaging with 4-dimensional computed tomography (4D-CT) and cone-beam CT (CBCT) imaging. RO beads were contoured using automated thresholding, and feasibility of matching between the simulated radiotherapy planning dataset (AVE-IP image from 4D data) and CBCT scans assessed. Additional kV, MV, helical CT and CBCT images of RO beads were obtained using an in-house phantom. Stability of RO bead position was assessed by comparing 4D-CT imaging to CT scans taken 6-20 days following TACE. RESULTS: Eight patients were treated and 4D-CT and CBCT images acquired. RO beads were visible on 4D-CT and CBCT images in all cases and matching successfully performed. Differences in centre of mass of RO beads between CBCT and simulated radiotherapy planning scans (AVE-IP dataset) were: 2.0 mm mediolaterally, 1.7 mm anteroposteriorally, 3.5 mm craniocaudally. RO beads in the phantom were visible on all imaging modalities assessed. RO bead position remained stable up to 29 days post-TACE. CONCLUSION: RO beads are visible on IGRT imaging modalities, showing minimal artefact. They can be used for on-set matching with CBCT and remain stable over time. ADVANCES IN KNOWLEDGE: The role of RO beads as fiducial markers for stereotactic liver radiotherapy is feasible and warrants further exploration as a combination therapy approach

Recurrent and Founder Mutations in the Netherlands: the Long-QT Syndrome

Background and objective The long-QT syndrome (LQTS) is associated with premature sudden cardiac deaths affecting whole families and is caused by mutations in genes encoding for cardiac proteins. When the same mutation is found in different families (recurrent mutations), this may imply either a common ancestor (founder) or multiple de novo mutations. We aimed to review recurrent mutations in patients with LQTS. Methods By use of our databases, we investigated the number of mutations that were found recurrently (at least three times) in LQT type 1-3 patients in the Netherlands. We studied familial links in the apparently unrelated probands, and we visualised the geographical distribution of these probands. Our results were compared with published literature of founder effects in LQTS outside the Netherlands. Results We counted 14 recurrent LQT mutations in the Netherlands. There are 326 identified carriers of one of these mutations. For three of these mutations, familial links were found between apparently unrelated probands. Conclusion Whereas true LQT founder mutations are described elsewhere in the world, we cannot yet demonstrate a real founder effect of these recurrent mutations in the Netherlands. Further studies on the prevalence of these mutations are indicated, and haplotype-sharing of the mutation carriers is pertinent to provide more evidence for founder mutation-based LQTS pathology in our countr

Deep neural network-based clustering of deformation curves reveals novel disease features in PLN pathogenic variant carriers

Echocardiographic deformation curves provide detailed information on myocardial function. Deep neural networks (DNNs) may enable automated detection of disease features in deformation curves, and improve the clinical assessment of these curves. We aimed to investigate whether an explainable DNN-based pipeline can be used to detect and visualize disease features in echocardiographic deformation curves of phospholamban (PLN) p.Arg14del variant carriers. A DNN was trained to discriminate PLN variant carriers (n = 278) from control subjects (n = 621) using raw deformation curves obtained by 2D-speckle tracking in the longitudinal axis. A visualization technique was used to identify the parts of these curves that were used by the DNN for classification. The PLN variant carriers were clustered according to the output of the visualization technique. The DNN showed excellent discriminatory performance (C-statistic 0.93 [95% CI 0.87–0.97]). We identified four clusters with PLN-associated disease features in the deformation curves. Two clusters showed previously described features: apical post-systolic shortening and reduced systolic strain. The two other clusters revealed novel features, both reflecting delayed relaxation. Additionally, a fifth cluster was identified containing variant carriers without disease features in the deformation curves, who were classified as controls by the DNN. This latter cluster had a very benign disease course regarding development of ventricular arrhythmias. Applying an explainable DNN-based pipeline to myocardial deformation curves enables automated detection and visualization of disease features. In PLN variant carriers, we discovered novel disease features which may improve individual risk stratification. Applying this approach to other diseases will further expand our knowledge on disease-specific deformation patterns. Graphical abstract: [Figure not available: see fulltext.] Overview of the deep neural network-based pipeline for feature detection in myocardial deformation curves. Firstly, phospholamban (PLN) p.Arg14del variant carriers and controls were selected and a deep neural network (DNN) was trained to detect the PLN variant carriers. Subsequently, a clustering-based approach was performed on the attention maps of the DNN, which revealed 4 distinct phenotypes of PLN variant carriers with different prognoses. Moreover, a cluster without features and a benign prognosis was detected

Cadaveric and three-dimensional computed tomography study of the morphology of the scapula with reference to reversed shoulder prosthesis

<p>Abstract</p> <p>Purpose</p> <p>The purpose of this study is to analyze the morphology of the scapula with reference to the glenoid component implantation in reversed shoulder prosthesis, in order to improve primary fixation of the component.</p> <p>Methods</p> <p>Seventy-three 3-dimensional computed tomography of the scapula and 108 scapular dry specimens were analyzed to determine the anterior and posterior length of the glenoid neck, the angle between the glenoid surface and the upper posterior column of the scapula and the angle between the major craneo-caudal glenoid axis and the base of the coracoid process and the upper posterior column.</p> <p>Results</p> <p>The anterior and posterior length of glenoid neck was classified into two groups named "short-neck" and "long-neck" with significant differences between them. The angle between the glenoid surface and the upper posterior column of the scapula was also classified into two different types: type I (mean 50°–52°) and type II (mean 62,50°–64°), with significant differences between them (p < 0,001). The angle between the major craneo-caudal glenoid axis and the base of the coracoid process averaged 18,25° while the angle with the upper posterior column of the scapula averaged 8°.</p> <p>Conclusion</p> <p>Scapular morphological variability advices for individual adjustments of glenoid component implantation in reversed total shoulder prosthesis. Three-dimensional computed tomography of the scapula constitutes an important tool when planning reversed prostheses implantation.</p

The Production of Antibody by Invading B Cells Is Required for the Clearance of Rabies Virus from the Central Nervous System

Every year over 50,000 people die from rabies worldwide, primarily due to the poor availability of rabies vaccine in developing countries. However, even when vaccines are available, human deaths from rabies occur if exposure to the causative virus is not recognized and vaccination is not sought in time. This is because rabies virus immunity induced by the natural infection or current vaccines is generally not effective at removing disease-causing rabies virus from brain tissues. Our studies provide insight into why this is the case and how vaccination can be changed so that the immune response can clear the virus from brain tissues. We show that the type of immune response induced by a live-attenuated rabies virus vaccine may be the key. In animal models, live-attenuated rabies virus vaccines are effective at delivering the immune cells capable of clearing the virus into CNS tissues and promote recovery from a rabies virus infection that has spread to the brain while conventional vaccines based on killed rabies virus do not. The production of rabies-specific antibody by B cells that invade the CNS tissues is important for complete elimination of the virus. We hypothesize that similar mechanisms may promote rabies virus clearance from individuals who are diagnosed after the virus has reached, but not extensively spread, through the CNS

Bilateral femoral neck fractures due to transient osteoporosis of pregnancy: a case report

We describe a case of bilateral femoral neck fractures secondary to transient osteoporosis of pregnancy, which were diagnosed after delivery due to the desire to avoid ionising radiation. These fractures were presumed to be secondary to transient osteoporosis of pregnancy and were treated successfully with internal fixation despite delayed presentation. We discuss the role of MRI in the evaluation of hip pain in pregnancy