Mixed-reality visualization environments to facilitate ultrasound-guided vascular access

Ultrasound-guided needle insertions at the site of the internal jugular vein (IJV) are routinely performed to access the central venous system. Ultrasound-guided insertions maintain high rates of carotid artery puncture, as clinicians rely on 2D information to perform a 3D procedure. The limitations of 2D ultrasound-guidance motivated the research question: “Do 3D ultrasound-based environments improve IJV needle insertion accuracy”. We addressed this by developing advanced surgical navigation systems based on tracked surgical tools and ultrasound with various visualizations. The point-to-line ultrasound calibration enables the use of tracked ultrasound. We automated the fiducial localization required for this calibration method such that fiducials can be automatically localized within 0.25 mm of the manual equivalent. The point-to-line calibration obtained with both manual and automatic localizations produced average normalized distance errors less than 1.5 mm from point targets. Another calibration method was developed that registers an optical tracking system and the VIVE Pro head-mounted display (HMD) tracking system with sub-millimetre and sub-degree accuracy compared to ground truth values. This co-calibration enabled the development of an HMD needle navigation system, in which the calibrated ultrasound image and tracked models of the needle, needle trajectory, and probe were visualized in the HMD. In a phantom experiment, 31 clinicians had a 96 % success rate using the HMD system compared to 70 % for the ultrasound-only approach (p= 0.018). We developed a machine-learning-based vascular reconstruction pipeline that automatically returns accurate 3D reconstructions of the carotid artery and IJV given sequential tracked ultrasound images. This reconstruction pipeline was used to develop a surgical navigation system, where tracked models of the needle, needle trajectory, and the 3D z-buffered vasculature from a phantom were visualized in a common coordinate system on a screen. This system improved the insertion accuracy and resulted in 100 % success rates compared to 70 % under ultrasound-guidance (p=0.041) across 20 clinicians during the phantom experiment. Overall, accurate calibrations and machine learning algorithms enable the development of advanced 3D ultrasound systems for needle navigation, both in an immersive first-person perspective and on a screen, illustrating that 3D US environments outperformed 2D ultrasound-guidance used clinically

Towards a First-Person Perspective Mixed Reality Guidance System for Needle Interventions

While ultrasound (US) guidance has been used during central venous catheterization to reduce complications, including the puncturing of arteries, the rate of such problems remains non-negligible. To further reduce complication rates, mixed-reality systems have been proposed as part of the user interface for such procedures. We demonstrate the use of a surgical navigation system that renders a calibrated US image, and the needle and its trajectory, in a common frame of reference. We compare the effectiveness of this system, whereby images are rendered on a planar monitor and within a head-mounted display (HMD), to the standard-of-care US-only approach, via a phantom-based user study that recruited 31 expert clinicians and 20 medical students. These users performed needle-insertions into a phantom under the three modes of visualization. The success rates were significantly improved under HMD-guidance as compared to US-guidance, for both expert clinicians (94% vs. 70%) and medical students (70% vs. 25%). Users more consistently positioned their needle closer to the center of the vessel’s lumen under HMD-guidance compared to US-guidance. The performance of the clinicians when interacting with this monitor system was comparable to using US-only guidance, with no significant difference being observed across any metrics. The results suggest that the use of an HMD to align the clinician’s visual and motor fields promotes successful needle guidance, highlighting the importance of continued HMD-guidance research

Towards fluoro-free interventions: Using radial intracardiac ultrasound for vascular navigation

Transcatheter cardio-vascular interventions have the advantage of patient safety,reduced surgery time, and minimal trauma to the patient\u27s body. Transcathetherinterventions, which are performed percutaneously, suffer from the lack of direct line-of-sight with the surgical tools and the patient anatomy. Therefore, such interventionalprocedures rely heavily on image guidance for navigating towards and deliveringtherapy at the target site. Vascular navigation via the inferior vena cava (IVC), from thegroin to the heart, is an imperative part of most transcatheter cardiovascularinterventions such as valve repair surgeries and ablation therapy. Traditionally, the IVCis navigated using fluoroscopic techniques such as angiography or CT venography.These X-ray based techniques can have detrimental effects on the patient as well asthe surgical team, causing increased radiation exposure, increased risk of cancer, fetaldefects, eye cataracts. The use of heavy lead apron has also been reported to causeback pain and spine issues thus leading to interventionalist’s disc disease. We proposethe use of a catheter-based ultrasound augmented with electromagnetic (EM) trackingtechnology to generate a vascular roadmap in real-time and perform navigation withoutharmful radiation. In this pilot study, we use intracardiac echocardiography (ICE) and tracking technology to reconstruct a vessel from a phantom in a 3D virtual space. Thispaper presents a pilot phantom study on ICE-based vessel reconstruction anddemonstrates how the proposed ultrasound-based navigation will appear in a virtualspace, by navigating a tracked guidewire within the vessels in the phantom without anyradiation-based imaging. The geometric accuracy is assessed using a CT scan of thephantom, with a Dice coefficient of 0.79. The average distance between the surface ofthe two models comes out to be 1.7 ± 1.12mm

Metallicity and Far-Infrared Luminosity of High Redshift Quasars

We present the results of an exploratory study of broad line region (BLR) metallicity in 34 2.2 < z < 4.6 quasars with far-infrared (FIR) luminosities (L_FIR) from 10^13.4 to 10^12.1 L_\odot . Quasar samples sorted by L_FIR might represent an evolutionary sequence if the star formation rates (SFRs) in quasar hosts generally diminish across quasar lifetimes. We use rest-frame ultraviolet spectra from the Sloan Digital Sky Survey to construct three composite spectra sorted by L_FIR, corresponding to average SFRs of 4980, 2130 and 340 M_\odot yr^-1 after correcting for a nominal quasar FIR contribution. The measured N V {\lambda} 1240/C IV {\lambda} 1550 and Si IV {\lambda} 1397+O IV] {\lambda} 1402/C IV {\lambda} 1550 emission line ratios indicate super-solar BLR metallicities in all three composites, with no evidence for a trend with the star formation rate. The formal derived metallicities, Z ~ 5-9 Z_\odot , are similar to those derived for the BLRs of other quasars at similar redshifts and luminosities. These results suggest that the ongoing star formation in the host is not responsible for the metal enrichment of the BLR gas. Instead, the BLR gas must have been enriched before the visible quasar phase. These results for high quasar metallicities, regardless of L_FIR, are consistent with evolution scenarios wherein visibly bright quasars appear after the main episode(s) of star formation and metal enrichment in the host galaxies. Finally, young quasars, those more closely associated with a recent merger or a blowout of gas and dust, may exhibit tracers of these events, such as redder continuum slopes and higher incidence of narrow absorption lines. With the caveat of small sample sizes, we find no relation between L_FIR and the reddening or the incidence of absorption lines.Comment: 10 pages, 3 figures. Accepted to MNRAS, May 201

Working memory and inhibitory control deficits in children with ADHD: an experimental evaluation of competing model predictions

IntroductionChildren with ADHD demonstrate difficulties on many different neuropsychological tests. However, it remains unclear whether this pattern reflects a large number of distinct deficits or a small number of deficit(s) that broadly impact test performance. The current study is among the first experiments to systematically manipulate demands on both working memory and inhibition, with implications for competing conceptual models of ADHD pathogenesis. MethodA clinically evaluated, carefully phenotyped sample of 110 children with ADHD, anxiety disorders, or co-occurring ADHD+anxiety (Mage=10.35, 44 girls; 69% White Not Hispanic/Latino) completed a counterbalanced, double dissociation experiment, with two tasks each per inhibition (low vs. high) x working memory (low vs. high) condition. ResultsBayesian and frequentist models converged in indicating that both manipulations successfully increased demands on their target executive function (BF10&gt;5.33x108, p&lt;.001). Importantly, occupying children’s limited capacity working memory system produced slower response times and reduced accuracy on inhibition tasks (BF10&gt;317.42, p&lt;.001, d=0.67-1.53). It also appeared to differentially reduce inhibition (and non-inhibition) accuracy for children with ADHD relative to children with anxiety (BF10=2.03, p=.02, d=0.50). In contrast, there was strong evidence against models that view working memory deficits as secondary outcomes of underlying inhibition deficits in ADHD (BF01=18.52, p=.85).DiscussionThis pattern indicates that working memory broadly affects children’s ability to inhibit prepotent tendencies and maintain fast/accurate performance, and may explain the errors that children with ADHD make on inhibition tests. These findings are broadly consistent with models describing working memory as a causal mechanism that gives rise to secondary impairments. In contrast, these findings provide evidence against models that view disinhibition as a cause of working memory difficulties or view working memory as a non-causal correlate or epiphenomenon in ADHD

Isolation of a Structural Mechanism for Uncoupling T Cell Receptor Signaling from Peptide-MHC Binding

TCR-signaling strength generally correlates with peptide-MHC binding affinity; however, exceptions exist. We find high-affinity, yet non-stimulatory, interactions occur with high frequency in the human T cell repertoire. Here, we studied human TCRs that are refractory to activation by pMHC ligands despite robust binding. Analysis of 3D affinity, 2D dwell time, and crystal structures of stimulatory versus non-stimulatory TCR-pMHC interactions failed to account for their different signaling outcomes. Using yeast pMHC display, we identified peptide agonists of a formerly non-responsive TCR. Single-molecule force measurements demonstrated the emergence of catch bonds in the activating TCR-pMHC interactions, correlating with exclusion of CD45 from the TCR-APC contact site. Molecular dynamics simulations of TCR-pMHC disengagement distinguished agonist from non-agonist ligands based on the acquisition of catch bonds within the TCR-pMHC interface. The isolation of catch bonds as a parameter mediating the coupling of TCR binding and signaling has important implications for TCR and antigen engineering for immunotherapy

Isolation of a Structural Mechanism for Uncoupling T Cell Receptor Signaling from Peptide-MHC Binding

TCR-signaling strength generally correlates with peptide-MHC binding affinity; however, exceptions exist. We find high-affinity, yet non-stimulatory, interactions occur with high frequency in the human T cell repertoire. Here, we studied human TCRs that are refractory to activation by pMHC ligands despite robust binding. Analysis of 3D affinity, 2D dwell time, and crystal structures of stimulatory versus non-stimulatory TCR-pMHC interactions failed to account for their different signaling outcomes. Using yeast pMHC display, we identified peptide agonists of a formerly non-responsive TCR. Single-molecule force measurements demonstrated the emergence of catch bonds in the activating TCR-pMHC interactions, correlating with exclusion of CD45 from the TCR-APC contact site. Molecular dynamics simulations of TCR-pMHC disengagement distinguished agonist from non-agonist ligands based on the acquisition of catch bonds within the TCR-pMHC interface. The isolation of catch bonds as a parameter mediating the coupling of TCR binding and signaling has important implications for TCR and antigen engineering for immunotherapy

Hospital admission and emergency care attendance risk for SARS-CoV-2 delta (B.1.617.2) compared with alpha (B.1.1.7) variants of concern: a cohort study

Background: The SARS-CoV-2 delta (B.1.617.2) variant was first detected in England in March, 2021. It has since rapidly become the predominant lineage, owing to high transmissibility. It is suspected that the delta variant is associated with more severe disease than the previously dominant alpha (B.1.1.7) variant. We aimed to characterise the severity of the delta variant compared with the alpha variant by determining the relative risk of hospital attendance outcomes. Methods: This cohort study was done among all patients with COVID-19 in England between March 29 and May 23, 2021, who were identified as being infected with either the alpha or delta SARS-CoV-2 variant through whole-genome sequencing. Individual-level data on these patients were linked to routine health-care datasets on vaccination, emergency care attendance, hospital admission, and mortality (data from Public Health England's Second Generation Surveillance System and COVID-19-associated deaths dataset; the National Immunisation Management System; and NHS Digital Secondary Uses Services and Emergency Care Data Set). The risk for hospital admission and emergency care attendance were compared between patients with sequencing-confirmed delta and alpha variants for the whole cohort and by vaccination status subgroups. Stratified Cox regression was used to adjust for age, sex, ethnicity, deprivation, recent international travel, area of residence, calendar week, and vaccination status. Findings: Individual-level data on 43 338 COVID-19-positive patients (8682 with the delta variant, 34 656 with the alpha variant; median age 31 years [IQR 17–43]) were included in our analysis. 196 (2·3%) patients with the delta variant versus 764 (2·2%) patients with the alpha variant were admitted to hospital within 14 days after the specimen was taken (adjusted hazard ratio [HR] 2·26 [95% CI 1·32–3·89]). 498 (5·7%) patients with the delta variant versus 1448 (4·2%) patients with the alpha variant were admitted to hospital or attended emergency care within 14 days (adjusted HR 1·45 [1·08–1·95]). Most patients were unvaccinated (32 078 [74·0%] across both groups). The HRs for vaccinated patients with the delta variant versus the alpha variant (adjusted HR for hospital admission 1·94 [95% CI 0·47–8·05] and for hospital admission or emergency care attendance 1·58 [0·69–3·61]) were similar to the HRs for unvaccinated patients (2·32 [1·29–4·16] and 1·43 [1·04–1·97]; p=0·82 for both) but the precision for the vaccinated subgroup was low. Interpretation: This large national study found a higher hospital admission or emergency care attendance risk for patients with COVID-19 infected with the delta variant compared with the alpha variant. Results suggest that outbreaks of the delta variant in unvaccinated populations might lead to a greater burden on health-care services than the alpha variant. Funding: Medical Research Council; UK Research and Innovation; Department of Health and Social Care; and National Institute for Health Research

Changes in symptomatology, reinfection, and transmissibility associated with the SARS-CoV-2 variant B.1.1.7: an ecological study

Background The SARS-CoV-2 variant B.1.1.7 was first identified in December, 2020, in England. We aimed to investigate whether increases in the proportion of infections with this variant are associated with differences in symptoms or disease course, reinfection rates, or transmissibility. Methods We did an ecological study to examine the association between the regional proportion of infections with the SARS-CoV-2 B.1.1.7 variant and reported symptoms, disease course, rates of reinfection, and transmissibility. Data on types and duration of symptoms were obtained from longitudinal reports from users of the COVID Symptom Study app who reported a positive test for COVID-19 between Sept 28 and Dec 27, 2020 (during which the prevalence of B.1.1.7 increased most notably in parts of the UK). From this dataset, we also estimated the frequency of possible reinfection, defined as the presence of two reported positive tests separated by more than 90 days with a period of reporting no symptoms for more than 7 days before the second positive test. The proportion of SARS-CoV-2 infections with the B.1.1.7 variant across the UK was estimated with use of genomic data from the COVID-19 Genomics UK Consortium and data from Public Health England on spike-gene target failure (a non-specific indicator of the B.1.1.7 variant) in community cases in England. We used linear regression to examine the association between reported symptoms and proportion of B.1.1.7. We assessed the Spearman correlation between the proportion of B.1.1.7 cases and number of reinfections over time, and between the number of positive tests and reinfections. We estimated incidence for B.1.1.7 and previous variants, and compared the effective reproduction number, Rt, for the two incidence estimates. Findings From Sept 28 to Dec 27, 2020, positive COVID-19 tests were reported by 36 920 COVID Symptom Study app users whose region was known and who reported as healthy on app sign-up. We found no changes in reported symptoms or disease duration associated with B.1.1.7. For the same period, possible reinfections were identified in 249 (0·7% [95% CI 0·6–0·8]) of 36 509 app users who reported a positive swab test before Oct 1, 2020, but there was no evidence that the frequency of reinfections was higher for the B.1.1.7 variant than for pre-existing variants. Reinfection occurrences were more positively correlated with the overall regional rise in cases (Spearman correlation 0·56–0·69 for South East, London, and East of England) than with the regional increase in the proportion of infections with the B.1.1.7 variant (Spearman correlation 0·38–0·56 in the same regions), suggesting B.1.1.7 does not substantially alter the risk of reinfection. We found a multiplicative increase in the Rt of B.1.1.7 by a factor of 1·35 (95% CI 1·02–1·69) relative to pre-existing variants. However, Rt fell below 1 during regional and national lockdowns, even in regions with high proportions of infections with the B.1.1.7 variant. Interpretation The lack of change in symptoms identified in this study indicates that existing testing and surveillance infrastructure do not need to change specifically for the B.1.1.7 variant. In addition, given that there was no apparent increase in the reinfection rate, vaccines are likely to remain effective against the B.1.1.7 variant. Funding Zoe Global, Department of Health (UK), Wellcome Trust, Engineering and Physical Sciences Research Council (UK), National Institute for Health Research (UK), Medical Research Council (UK), Alzheimer's Society

Genomic assessment of quarantine measures to prevent SARS-CoV-2 importation and transmission

Mitigation of SARS-CoV-2 transmission from international travel is a priority. We evaluated the effectiveness of travellers being required to quarantine for 14-days on return to England in Summer 2020. We identified 4,207 travel-related SARS-CoV-2 cases and their contacts, and identified 827 associated SARS-CoV-2 genomes. Overall, quarantine was associated with a lower rate of contacts, and the impact of quarantine was greatest in the 16–20 age-group. 186 SARS-CoV-2 genomes were sufficiently unique to identify travel-related clusters. Fewer genomically-linked cases were observed for index cases who returned from countries with quarantine requirement compared to countries with no quarantine requirement. This difference was explained by fewer importation events per identified genome for these cases, as opposed to fewer onward contacts per case. Overall, our study demonstrates that a 14-day quarantine period reduces, but does not completely eliminate, the onward transmission of imported cases, mainly by dissuading travel to countries with a quarantine requirement