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Competing Interests: Competing interests: None declared.

Background: There is increasing policy interest in the consideration of frailty measures (rather than chronological age alone) to inform more equitable allocation of health and social care resources. In this study the Clinical Frailty Scale (CFS) classification tree was applied to data from The Irish Longitudinal Study on Ageing (TILDA) and correlated with health and social care utilisation. CFS transitions over time were also explored. Methods: Applying the CFS classification tree algorithm, secondary analyses of TILDA data were performed to examine distributions of health and social care by CFS categories using descriptive statistics weighted to the population of Ireland aged ≥65 years at Wave 5 (n=3,441; mean age 74.5 (SD ±7.0) years, 54.7% female). CFS transitions over 8 years and (Waves 1-5) were investigated using multi-state Markov models and alluvial charts. Results : The prevalence of CFS categories at Wave 5 were: 6% 'very fit', 36% 'fit', 31% 'managing well', 16% 'vulnerable', 6% 'mildly frail', 4% 'moderately frail' and 1% 'severely frail'. No participants were 'very severely frail' or 'terminally ill'. Increasing CFS categories were associated with increasing hospital and community health services use and increasing hours of formal and informal social care provision. The transitions analyses suggested CFS transitions are dynamic, with 2-year probability of transitioning from 'fit' (CFS1-3) to 'vulnerable' (CFS4), and 'fit' to 'frail' (CFS5+) at 34% and 6%, respectively. 'Vulnerable' and 'frail' had a 22% and 17% probability of reversal to 'fit' and 'vulnerable', respectively. Conclusions: Our results suggest that the CFS classification tree stratified the TILDA population aged ≥65 years into subgroups with increasing health and social care needs. The CFS could be used to aid the allocation of health and social care resources in older people in Ireland. We recommend that CFS status in individuals is reviewed at least every 2 years., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 O'Halloran AM et al.)

Previous research cross-sectionally characterised eight morphological systolic blood pressure (SBP) active stand (AS) patterns using a clinical clustering approach at Wave 1 (W1) of the Irish Longitudinal Study on Ageing. We explored the longitudinal stability and clinical associations of these groupings at Wave 3 (W3), four years later. Eight AS groups had their clinical characteristics and AS patterns at W3 compared to W1. We explored longitudinal associations (new cognitive decline, falls, syncope, disability, and mortality) using multivariate logistic regression models. In total, 2938 participants (60% of Wave 1 sample) had adequate AS data from both W1 and 3 for analysis. We found no longitudinal stability of the eight AS groups or their morphological patterns between the waves. A pattern of impaired stabilisation and late deficit seemed more preserved and was seen in association with new cognitive decline (OR 1.63, 95% CI: 1.12-2.36, p = 0.011). An increase in antihypertensive usage seemed associated with reduced immediate SBP drops, improved AS patterns, and reduced orthostatic intolerance (OI). In pure longitudinal groups, AS patterns were not preserved after 4 years. AS patterns are longitudinally dynamic, and improvements after 4 years are possible even in the presence of higher antihypertensive burden.

Background: Orthostatic hypotension (OH) can be assessed with non-invasive continuous beat-to-beat haemodynamic monitoring during active stand (AS) testing; this yields large volumes of data outside the scope of the traditional OH definition. We explored clinical associations of different AS patterns in participants from Wave 1 of the Irish Longitudinal Study on Ageing., Methods: AS patterns were generated based on three sequential binary systolic blood pressure features: drop ≥40 mmHg within 10 sec post-stand ("immediate deficit"), failure to return to within 20 mmHg of supine level at 40 sec after standing ("stabilisation deficit") and drop ≥20 mmHg between >40 and 120 sec post-stand ("late deficit"). Eight AS groups resulted from combining the presence/absence of these three features. The groups were cross-sectionally characterised, and their ability to independently predict orthostatic intolerance (OI) during AS, and falls or syncope in the past year, was evaluated using multivariate logistic regression models., Results: A total of 4,899 participants were included (mean age 61), of which 3,312 (68%) had no deficits. Older age was associated with stabilisation deficit and late deficits were seen in groups with higher proportions of beta blockers and psychotropic medications. Regression models identified independent associations between OI and three immediate-deficit groups; associations seemed stronger as more deficits were present. There was a significant association between falls history and the three-deficit group (odds ratio 1.54, 95% confidence interval: 1.15-2.07, P = 0.004)., Conclusions: More deficits seemed associated with the higher risk of OI and falls history. Observations are not causal but the recognition of these patterns may help clinicians focus on careful prescribing., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The long-term clinical and physiological consequences of COVID-19 infection remain unclear. While fatigue has emerged as a common symptom following infection, little is known about its links with autonomic dysfunction. SARS-CoV-2 is known to infect endothelial cells in acute infection, resulting in autonomic dysfunction. Here we set out to test the hypothesis that this results in persistent autonomic dysfunction and is associated with post-COVID fatigue in convalescent patients., Methods: We recruited 20 fatigued and 20 non-fatigued post-COVID patients (median age 44.5 years, 36/40 (90%) female, median time to follow up 166.5 days). Fatigue was assessed using the Chalder Fatigue Scale. These underwent the Ewing's autonomic function test battery, including deep breathing, active standing, Valsalva manoeuvre and cold-pressor testing, with continuous electrocardiogram and blood pressure monitoring, as well as near-infrared spectroscopy-based cerebral oxygenation. 24-hour ambulatory blood pressure monitoring was also conducted, and patients completed the generalised anxiety disorder-7 questionnaire. We assessed between-group differences in autonomic function test results and used unadjusted and adjusted linear regression to investigate the relationship between fatigue, anxiety, and autonomic test results., Results: We found no pathological differences between fatigued and non-fatigued patients on autonomic testing or on 24-hour blood pressure monitoring. Symptoms of orthostatic intolerance were reported by 70% of the fatigued cohort at the time of active standing, with no associated physiological abnormality detected. Fatigue was strongly associated with increased anxiety (p <0.001), with no patients having a pre-existing diagnosis of anxiety., Conclusions: These results demonstrate the significant burden of fatigue, symptoms of autonomic dysfunction and anxiety in the aftermath of COVID-19 infection, but reassuringly do not demonstrate pathological findings on autonomic testing., Competing Interests: The authors have declared that no competing interests exist.

In this paper, we study deep learning approaches for monocular visual odometry (VO). Deep learning solutions have shown to be effective in VO applications, replacing the need for highly engineered steps, such as feature extraction and outlier rejection in a traditional pipeline. We propose a new architecture combining ego-motion estimation and sequence-based learning using deep neural networks. We estimate camera motion from optical flow using Convolutional Neural Networks (CNNs) and model the motion dynamics using Recurrent Neural Networks (RNNs). The network outputs the relative 6-DOF camera poses for a sequence, and implicitly learns the absolute scale without the need for camera intrinsics. The entire trajectory is then integrated without any post-calibration. We evaluate the proposed method on the KITTI dataset and compare it with traditional and other deep learning approaches in the literature.

The required precision for attitude determination in spacecraft is increasing, providing a need for more accurate attitude determination sensors. The star sensor or star tracker provides unmatched arc-second precision and with the rise of micro satellites these sensors are becoming smaller, faster and more efficient. The most critical component in the star sensor system is the lost-in-space star identification algorithm which identifies stars in a scene without a priori attitude information. In this paper, we present an efficient lost-in-space star identification algorithm using a neural network and a robust and novel feature extraction method. Since a neural network implicitly stores the patterns associated with a guide star, a database lookup is eliminated from the matching process. The search time is therefore not influenced by the number of patterns stored in the network, making it constant (O(1)). This search time is unrivalled by other star identification algorithms. The presented algorithm provides excellent performance in a simple and lightweight design, making neural networks the preferred choice for star identification algorithms.

A 38-year-old woman presented with a history of recurrent episodes of transient loss of consciousness (TLOC) with seizure-like activity and post-TLOC left sided paresis. Electroencephalogram and MRI of the brain were normal, and events were not controlled by anti-convulsant therapy. Tilt testing produced reflex mixed pattern vasovagal syncope, with exact symptom reproduction, including bilateral upper and lower limb myoclonic movements and post-TLOC left hemiparesis that persisted for 27 min. A witness for the tilt event confirmed reproduction of patients 'typical' TLOC event. Syncope is the most frequent cause of TLOC. Myoclonic movements during syncope are not uncommon and can be misdiagnosed as epilepsy. It is rare to experience paresis after syncope, which in this case, lead to misdiagnosis and unnecessary anti-convulsant treatment., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

The lost-in-space star identification algorithm is able to identify stars without a priori attitude information and is arguably the most critical component of a star sensor system. In this paper, the 2009 survey by Spratling and Mortari is extended and recent lost-in-space star identification algorithms are surveyed. The covered literature is a qualitative representation of the current research in the field. A taxonomy of these algorithms based on their feature extraction method is defined. Furthermore, we show that in current literature the comparison of these algorithms can produce inconsistent conclusions. In order to mitigate these inconsistencies, this paper lists the considerations related to the relative performance evaluation of these algorithms using simulation.

Purpose: Circulating tumor cells (CTCs) have clinical relevance, but their study has been limited by their low frequency. Experimental Design: We evaluated liquid biopsies by apheresis to increase CTC yield from patients suffering from metastatic prostate cancer, allow precise gene copy-number calls, and study disease heterogeneity. Results: Apheresis was well tolerated and allowed the separation of large numbers of CTCs; the average CTC yield from 7.5 mL of peripheral blood was 167 CTCs, whereas the average CTC yield per apheresis (mean volume: 59.5 mL) was 12,546 CTCs. Purified single CTCs could be isolated from apheresis product by FACS sorting; copy-number aberration (CNA) profiles of 185 single CTCs from 14 patients revealed the genomic landscape of lethal prostate cancer and identified complex intrapatient, intercell, genomic heterogeneity missed on bulk biopsy analyses. Conclusions: Apheresis facilitated the capture of large numbers of CTCs noninvasively with minimal morbidity and allowed the deconvolution of intrapatient heterogeneity and clonal evolution. Clin Cancer Res; 24(22); 5635-44. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Purpose: CHD1 deletions and SPOP mutations frequently cooccur in prostate cancer with lower frequencies reported in castration-resistant prostate cancer (CRPC). We monitored CHD1 expression during disease progression and assessed the molecular and clinical characteristics of CHD1 -deleted/ SPOP -mutated metastatic CRPC (mCRPC). Experimental Design: We identified 89 patients with mCRPC who had hormone-naive and castration-resistant tumor samples available: These were analyzed for CHD1, PTEN, and ERG expression by IHC. SPOP status was determined by targeted next-generation sequencing (NGS). We studied the correlations between these biomarkers and (i) overall survival from diagnosis; (ii) overall survival from CRPC; (iii) duration of abiraterone treatment; and (iv) response to abiraterone. Relationship with outcome was analyzed using Cox regression and log-rank analyses. Results: CHD1 protein loss was detected in 11 (15%) and 13 (17%) of hormone-sensitive prostate cancer (HSPC) and CRPC biopsies, respectively. Comparison of CHD1 expression was feasible in 56 matched, same patient HSPC and CRPC biopsies. CHD1 protein status in HSPC and CRPC correlated in 55 of 56 cases (98%). We identified 22 patients with somatic SPOP mutations, with six of these mutations not reported previously in prostate cancer. SPOP mutations and/or CHD1 loss was associated with a higher response rate to abiraterone (SPOP: OR, 14.50 P = 0.001; CHD1: OR, 7.30, P = 0.08) and a longer time on abiraterone (SPOP: HR, 0.37, P = 0.002, CHD1: HR, 0.50, P = 0.06). Conclusions: SPOP -mutated mCRPCs are strongly enriched for CHD1 loss. These tumors appear highly sensitive to abiraterone treatment. Clin Cancer Res; 24(22); 5585-93. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Embedded systems control and monitor a great deal of our reality. While some "classic" features are intrinsically necessary, such as low power consumption, rugged operating ranges, fast response and low cost, these systems have evolved in the last few years to emphasize connectivity functions, thus contributing to the Internet of Things paradigm. A myriad of sensing/computing devices are being attached to everyday objects, each able to send and receive data and to act as a unique node in the Internet. Apart from the obvious necessity to process at least some data at the edge (to increase security and reduce power consumption and latency), a major breakthrough will arguably come when such devices are endowed with some level of autonomous "intelligence". Intelligent computing aims to solve problems for which no efficient exact algorithm can exist or for which we cannot conceive an exact algorithm. Central to such intelligence is Computer Vision (CV), i.e., extracting meaning from images and video. While not everything needs CV, visual information is the richest source of information about the real world: people, places and things. The possibilities of embedded CV are endless if we consider new applications and technologies, such as deep learning, drones, home robotics, intelligent surveillance, intelligent toys, wearable cameras, etc. This paper describes the Eyes of Things (EoT) platform, a versatile computer vision platform tackling those challenges and opportunities., Competing Interests: The authors declare no conflict of interest.

Fringe modulates Notch signaling resulting in the establishment of compartmental boundaries in developing organisms. Fringe is a beta 3N-acetylglucosaminyltransferase (beta 3GlcNAcT) that transfers GlcNAc to O-fucose in epidermal growth factor-like repeats of Notch. Here we use five different Chinese hamster ovary cell glycosylation mutants to identify a key aspect of the mechanism of fringe action. Although the beta 3GlcNAcT activity of manic or lunatic fringe is shown to be necessary for inhibition of Jagged1-induced Notch signaling in a coculture assay, it is not sufficient. Fringe fails to inhibit Notch signaling if the disaccharide generated by fringe action, GlcNAc beta 3Fuc, is not elongated. The trisaccharide, Gal beta 4GlcNAc beta 3Fuc, is the minimal O-fucose glycan to support fringe modulation of Notch signaling. Of six beta 4galactosyltransferases (beta 4GalT) in Chinese hamster ovary cells, only beta 4GalT-1 is required to add Gal to GlcNAc beta 3Fuc, identifying beta 4GalT-1 as a new modulator of Notch signaling.

The use of sentinel node biopsy in the staging of malignant melanoma has led to the identification of lymph nodes outside the described regional basins, so-called aberrant nodes. We present a case in which such an aberrant sentinel node was found to be positive for metastatic disease, and discuss our surgical management., (Copyright 2001 The British Association of Plastic Surgeons.)

Lentigo maligna has the potential for malignant change, and is managed in many cases by wide local excision. However, there are clinical situations in which aggressive surgical management is inappropriate or unsuccessful. We present three such cases, in which a more conservative surgical approach was adopted and maintained over several decades., (Copyright 2001 The British Association of Plastic Surgeons.)

Aryliminopropadienethiones 9 have been generated by flash vacuum thermolysis of isoxazolones of the type 5 and characterized by mass spectrometry and matrix isolation IR spectroscopy in conjunction with DFT calculations and chemical trapping.

Patients who are critically ill and have large areas of skin loss or breakdown present a difficult management problem. They require the combination of intensive therapy facilities to support failing organs and specialized skin care, sometimes including extensive debridement and reconstruction. The expertise required for both aspects of treatment are found uniquely on a burns unit. We present five patients with large areas of cutaneous loss or damage secondary to a variety of non-burn aetiologies who were managed on a burns unit. We suggest that a burns unit may be the most appropriate place for such patients to be treated during both the acute phase of their illness and the later stages of surgical reconstruction and physical rehabilitation.

Notch receptors function in highly conserved intercellular signalling pathways that direct cell-fate decisions, proliferation and apoptosis in metazoans. Fringe proteins can positively and negatively modulate the ability of Notch ligands to activate the Notch receptor. Here we establish the biochemical mechanism of Fringe action. Drosophila and mammalian Fringe proteins possess a fucose-specific beta1,3 N-acetylglucosaminyltransferase activity that initiates elongation of O-linked fucose residues attached to epidermal growth factor-like sequence repeats of Notch. We obtained biological evidence that Fringe-dependent elongation of O-linked fucose on Notch modulates Notch signalling by using co-culture assays in mammalian cells and by expression of an enzymatically inactive Fringe mutant in Drosophila. The post-translational modification of Notch by Fringe represents a striking example of modulation of a signalling event by differential receptor glycosylation and identifies a mechanism that is likely to be relevant to other signalling pathways.

Mutations in the coding region of the TWIST gene (encoding a basic helix-loop-helix transcription factor) have been identified in some cases of Saethre-Chotzen syndrome. Haploinsufficiency appears to be the pathogenic mechanism involved. To investigate the possibility that complete deletions of the TWIST gene also contribute to this disorder, we have developed a comprehensive strategy to screen for coding-region mutations and for complete gene deletions. Heterozygous TWIST mutations were identified in 8 of 10 patients with Saethre-Chotzen syndrome and in 2 of 43 craniosynostosis patients with no clear diagnosis. In addition to six coding-region mutations, our strategy revealed four complete TWIST deletions, only one of which associated with a translocation was suspected on the basis of conventional cytogenetic analysis. This case and two interstitial deletions were detectable by analysis of polymorphic microsatellite loci, including a novel (CA)n locus 7.9 kb away from TWIST, combined with FISH; these deletions ranged in size from 3.5 Mb to >11.6 Mb. The remaining, much smaller deletion was detected by Southern blot analysis and removed 2,924 bp, with a 2-bp orphan sequence at the breakpoint. Significant learning difficulties were present in the three patients with megabase-sized deletions, which suggests that haploinsufficiency of genes neighboring TWIST contributes to developmental delay. Our results identify a new microdeletion disorder that maps to chromosome band 7p21.1 and that causes a significant proportion of Saethre-Chotzen syndrome.

The underlying basis of many forms of syndromic craniosynostosis has been defined on a molecular level. However, many patients with familial or sporadic craniosynostosis do not have the classical findings of those craniosynostosis syndromes. Here we present 61 individuals from 20 unrelated families where coronal synostosis is due to an amino acid substitution (Pro250Arg) that results from a single point mutation in the fibroblast growth factor receptor 3 gene on chromosome 4p. In this instance, a new clinical syndrome is being defined on the basis of the molecular finding. In addition to the skull findings, some patients had abnormalities on radiographs of hands and feet, including thimble-like middle phalanges, coned epiphyses, and carpal and tarsal fusions. Brachydactyly was seen in some cases; none had clinically significant syndactyly or deviation of the great toe. Sensorineural hearing loss was present in some, and developmental delay was seen in a minority. While the radiological findings of hands and feet can be very helpful in diagnosing this syndrome, it is not in all cases clearly distinguishable on a clinical basis from other craniosynostosis syndromes. Therefore, this mutation should be tested for in patients with coronal synostosis.

Dominantly acting, allelic mutations of the fibroblast growth factor receptor 2 (FGFR2) gene have been described in five craniosynostosis syndromes. In Apert syndrome, characterised by syndactyly of the hands and feet, recurrent mutations of a serine-proline dipeptide (either Ser252Trp or Pro253Arg) in the linker between the IgII and IgIII extracellular immunoglobulin-like domains, have been documented in more than 160 unrelated individuals. We have identified three novel mutations of this dipeptide, associated with distinct phenotypes. A C-->T mutation that predicts a Ser252Leu substitution, ascertained in a boy with mild Crouzon syndrome (craniosynostosis with normal limbs) is also present in three clinically normal members of his family. A CG-->TT mutation that predicts a Ser252Phe substitution results in a phenotype consistent with Apert syndrome. Finally, a CGC-->TCT mutation that predicts a double amino acid substitution (Ser252Phe and Pro253Ser) causes a Pfeiffer syndrome variant with mild craniosynostosis, broad thumbs and big toes, fixed extension of several digits, and only minimal cutaneous syndactyly. The observation that the Ser252Phe mutation causes Apert syndrome, whereas the other single or double substitutions are associated with milder or normal phenotypes, highlights the exquisitely specific molecular pathogenesis of the limb and craniofacial abnormalities associated with Apert syndrome. Ser252Phe is the first noncanonical mutation to be identified in this disorder, its rarity being explained by the requirement for two residues of the serine codon to be mutated. The description of independent, complex nucleotide substitutions involving identical nucleotides is unprecedented, and we speculate that this may result from functional selection of FGFR mutations in sperm.