Neuroprotection is improved by watertightness of fetal spina bifida repair in the sheep model.

OBJECTIVES: A contributing factor to unsuccessful prenatal spina bifida aperta (SBA) repair via an open approach may be incomplete neurosurgical repair causing persistent in-utero leakage of cerebrospinal fluid (CSF) and exposure of the fetal spinal cord to amniotic fluid. We aimed to investigate the neurostructural and neurofunctional efficacy of watertight prenatal SBA repair in a validated SBA fetal lamb model. METHODS: A well-powered superiority study was conducted in the validated SBA fetal lamb model (n = 7 per group). The outcomes of lambs which underwent watertight or non-watertight multilayer repair through an open approach were compared to those of unrepaired SBA lambs (historical controls) at delivery (term = 145 days). At ∼75 days, fetal lambs underwent standardized induction of lumbar SBA. At ∼100 days, they were assigned to an either watertight or non-watertight layered repair group based on an intraoperative watertightness test using subcutaneous fluorescein injection. At 1-2 days postnatally, as primary outcome, we assessed reversal of hindbrain herniation using magnetic resonance imaging (MRI). Secondary proxies of neuroprotection were: absence of CSF leakage at the repair site; hindlimb motor function based on joint-movement score, locomotor grade and Motor Evoked Potential (MEP); four-score neuroprotection scale, encompassing live birth, complete hindbrain herniation reversal, absence of CSF leakage and joint-movement score ≥ 9/15; and brain and spinal cord histology and immunohistochemistry. As the watertightness test cannot be used clinically due to its invasiveness, we developed a potential surrogate intraoperative three-score skin-repair-quality scale based on visual assessment of the quality of the skin repair (suture inter-run distance ≤ 3 mm, absence of tear and absence of ischemia), with high quality defined by a score ≥ 2/3 and low quality by a score < 2/3, and assessed its relationship with improved outcome. RESULTS: Compared with unrepaired lambs, lambs with watertight repair achieved a high level of neuroprotection (neuroprotection score of 4/4 in 5/7 vs 0/7 lambs) as evidenced by: a significant 100% (vs 14%) reversal of hindbrain herniation on MRI; low CSF leakage (14% vs 100%); better hindlimb motor function, with higher joint-movement score, locomotor grade and MEP area under the curve and peak-to-peak amplitude; higher neuronal density in the hippocampus and corpus callosum; and higher reactive astrogliosis at the SBA lesion epicenter. Conversely, lambs with non-watertight SBA repair did not achieve the same level of neuroprotection (score of 4/4 in 1/7 lambs) compared with unrepaired lambs, with: a non-significant 86% (vs 14%) reversal of hindbrain herniation; high CSF leakage (43% vs 100%); no improvement in motor function; low brain neuron count in both the hippocampus and corpus callosum; and small spinal astroglial cell area at the epicenter. Both watertight layered repair and high (≥ 2/3) intraoperative skin-repair-quality score were associated with improved outcome, but the watertightness test and skin-repair-quality scale could not be used interchangeably due to result discrepancies. CONCLUSIONS: Watertight layered fetal SBA repair is neuroprotective since it improves brain and spinal-cord structure and function in the fetal lamb model. This translational research has important clinical implications. A neurosurgical technique that achieves watertightness should be adopted in all fetal centers to improve neuroprotection. Future clinical studies could assess whether a high skin-repair-quality score (≥ 2/3) correlates with neuroprotection. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Diagnostic value of cutaneous manifestation of SARS-CoV-2 infection.

BACKGROUND: One of the challenging aspects of SARS-CoV-2 infection is its diverse multisystemic disease presentation. OBJECTIVES: To evaluate the diagnostic value of cutaneous manifestations of SARS-CoV-2 infection and investigate their duration and timing in relation to other COVID-19 symptoms. METHODS: We used data from 336 847 UK users of the COVID Symptom Study app to assess the diagnostic value of body rash or an acral rash in SARS-CoV-2 infection, and data from an independent online survey of 11 544 respondents to investigate skin-specific symptoms and collect their photographs. RESULTS: Using data from the app, we show significant association between skin rashes and a positive swab test result (odds ratio 1·67, 95% confidence interval 1·42-1·97). Strikingly, among the respondents of the independent online survey, we found that 17% of SARS-CoV-2-positive cases reported skin rashes as the first presentation, and 21% as the only clinical sign of COVID-19. Together with the British Association of Dermatologists, we have compiled a catalogue of images of the most common skin manifestations of COVID-19 from 400 individuals (https://covidskinsigns.com), which we have made publicly available to assist clinicians in recognition of this early clinical feature of COVID-19. CONCLUSIONS: Skin rashes cluster with other COVID-19 symptoms, are predictive of a positive swab test, and occur in a significant number of cases, either alone or before other classical symptoms. Recognizing rashes is important in identifying new and earlier cases of COVID-19.

Cranial findings detected by second-trimester ultrasound in fetuses with myelomeningocele: a systematic review.

BACKGROUND: Abnormal intracranial findings are often detected at mid-trimester ultrasound (US) in fetuses with myelomeningocele (MMC). It is unclear whether these findings constitute a spectrum of the disease or are an independent finding, which should contraindicate fetal surgery. OBJECTIVE: To ascertain the spectrum and frequency of US-detected cranial findings in fetuses with MMC. SEARCH STRATEGY: MEDLINE, Embase, Web of Science and CENTRAL were searched from January 2000 to June 2020. SELECTION CRITERIA: Study reporting incidence of cranial US findings in consecutive cases of second-trimester fetuses with MMC. DATA COLLECTION AND ANALYSIS: Publication quality was assessed by Newcastle-Ottawa Scale (NOS) and modified NOS. Meta-analysis could not be performed as a result of high clinical diversity and study heterogeneity. MAIN RESULTS: Fourteen cranial US findings were reported in 15 studies. Findings in classic Chiari II malformation (CIIM) spectrum included posterior fossa funnelling (96%), small transcerebellar diameter (82-96%), 'banana' sign (50-100%), beaked tectum (65%) and 'lemon' sign (53-100%). Additional cranial findings were small biparietal diameter (BPD) and head circumference (HC) (<5th centile; 53 and 71%, respectively), ventriculomegaly (45-89%), abnormal pointed shape of the occipital horn (77-78%), thinning of the posterior cerebrum, perinodular heterotopia (11%), abnormal gyration (3%), corpus callosum disorders (60%) and midline interhemispheric cyst (42%). CONCLUSIONS: We identified 14 cranial findings by second-trimester US in fetuses with MMC. The relatively high incidence of these findings and their unclear prognostic significance might not contraindicate fetal surgery in the case of normal fetal genetic testing. Some cranial findings may independently affect postnatal outcome, however. Long-term detailed follow-up is required to investigate this. TWEETABLE ABSTRACT: A high rate of cranial abnormalities found on second-trimester ultrasound in fetuses with myelomeningocele.

Magnetic resonance imaging measurement of placental perfusion and oxygen saturation in early-onset fetal growth restriction.

OBJECTIVE: We hypothesised that a multi-compartment magnetic resonance imaging (MRI) technique that is sensitive to fetal blood oxygenation would identify changes in placental blood volume and fetal blood oxygenation in pregnancies complicated by early-onset fetal growth restriction (FGR). DESIGN: Case-control study. SETTING: London, UK. POPULATION: Women with uncomplicated pregnancies (estimated fetal weight [EFW] >10th centile for gestational age [GA] and normal maternal and fetal Doppler ultrasound, n = 12) or early-onset FGR (EFW <3rd centile with or without abnormal Doppler ultrasound <32 weeks GA, n = 12) were studied. METHODS: All women underwent MRI examination. Using a multi-compartment MRI technique, we quantified fetal and maternal blood volume and feto-placental blood oxygenation. MAIN OUTCOME MEASURES: Disease severity was stratified according to Doppler pulsatility index and the relationship to the MRI parameters was investigated, including the influence of GA at scan. RESULTS: The FGR group (mean GA 27+5  weeks, range 24+2 to 33+6  weeks) had a significantly lower EFW compared with the control group (mean GA 29+1  weeks; -705 g, 95% CI -353 to -1057 g). MRI-derived feto-placental oxygen saturation was higher in controls compared with FGR (75 ± 9.6% versus 56 ± 16.2%, P = 0.02, 95% CI 7.8-30.3%). Feto-placental oxygen saturation estimation correlated strongly with GA at scan in controls (r = -0.83). CONCLUSION: Using a novel multimodal MRI protocol we demonstrated reduced feto-placental blood oxygen saturation in pregnancies complicated by early-onset FGR. The degree of abnormality correlated with disease severity defined by ultrasound Doppler findings. Gestational age-dependent changes in oxygen saturation were also present in normal pregnancies. TWEETABLE ABSTRACT: MRI reveals differences in feto-placental oxygen saturation between normal and FGR pregnancy that is associated with disease severity.

Comparison of manual and semi-automatic registration in augmented reality image-guided liver surgery: a clinical feasibility study.

BACKGROUND: The laparoscopic approach to liver resection may reduce morbidity and hospital stay. However, uptake has been slow due to concerns about patient safety and oncological radicality. Image guidance systems may improve patient safety by enabling 3D visualisation of critical intra- and extrahepatic structures. Current systems suffer from non-intuitive visualisation and a complicated setup process. A novel image guidance system (SmartLiver), offering augmented reality visualisation and semi-automatic registration has been developed to address these issues. A clinical feasibility study evaluated the performance and usability of SmartLiver with either manual or semi-automatic registration. METHODS: Intraoperative image guidance data were recorded and analysed in patients undergoing laparoscopic liver resection or cancer staging. Stereoscopic surface reconstruction and iterative closest point matching facilitated semi-automatic registration. The primary endpoint was defined as successful registration as determined by the operating surgeon. Secondary endpoints were system usability as assessed by a surgeon questionnaire and comparison of manual vs. semi-automatic registration accuracy. Since SmartLiver is still in development no attempt was made to evaluate its impact on perioperative outcomes. RESULTS: The primary endpoint was achieved in 16 out of 18 patients. Initially semi-automatic registration failed because the IGS could not distinguish the liver surface from surrounding structures. Implementation of a deep learning algorithm enabled the IGS to overcome this issue and facilitate semi-automatic registration. Mean registration accuracy was 10.9 ± 4.2 mm (manual) vs. 13.9 ± 4.4 mm (semi-automatic) (Mean difference - 3 mm; p = 0.158). Surgeon feedback was positive about IGS handling and improved intraoperative orientation but also highlighted the need for a simpler setup process and better integration with laparoscopic ultrasound. CONCLUSION: The technical feasibility of using SmartLiver intraoperatively has been demonstrated. With further improvements semi-automatic registration may enhance user friendliness and workflow of SmartLiver. Manual and semi-automatic registration accuracy were comparable but evaluation on a larger patient cohort is required to confirm these findings.

Somatosensory function and pain in extremely preterm young adults from the UK EPICure cohort: sex-dependent differences and impact of neonatal surgery.

BACKGROUND: Surgery or multiple procedural interventions in extremely preterm neonates influence neurodevelopmental outcome and may be associated with long-term changes in somatosensory function or pain response. METHODS: This observational study recruited extremely preterm (EP, <26 weeks' gestation; n=102, 60% female) and term-born controls (TC; n=48) aged 18-20 yr from the UK EPICure cohort. Thirty EP but no TC participants had neonatal surgery. Evaluation included: quantitative sensory testing (thenar eminence, chest wall); clinical pain history; questionnaires (intelligence quotient; pain catastrophising; anxiety); and structural brain imaging. RESULTS: Reduced thermal threshold sensitivity in EP vs TC participants persisted at age 18-20 yr. Sex-dependent effects varied with stimulus intensity and were enhanced by neonatal surgery, with reduced threshold sensitivity in EP surgery males but increased sensitivity to prolonged noxious cold in EP surgery females (P<0.01). Sex-dependent differences in thermal sensitivity correlated with smaller amygdala volume (P<0.05) but not current intelligence quotient. While generalised decreased sensitivity encompassed mechanical and thermal modalities in EP surgery males, a mixed pattern of sensory loss and sensory gain persisted adjacent to neonatal scars in males and females. More EP participants reported moderate-severe recurrent pain (22/101 vs 4/48; χ2=0.04) and increased pain intensity correlated with higher anxiety and pain catastrophising. CONCLUSIONS: After preterm birth and neonatal surgery, different patterns of generalised and local scar-related alterations in somatosensory function persist into early adulthood. Sex-dependent changes in generalised sensitivity may reflect central modulation by affective circuits. Early life experience and sex/gender should be considered when evaluating somatosensory function, pain experience, or future chronic pain risk.

Bullseye's representation of cerebral white matter hyperintensities.

BACKGROUND AND PURPOSE: Visual rating scales have limited capacities to depict the regional distribution of cerebral white matter hyperintensities (WMH). We present a regional-zonal volumetric analysis alongside a visualization tool to compare and deconstruct visual rating scales. MATERIALS AND METHODS: 3D T1-weighted, T2-weighted spin-echo and FLAIR images were acquired on a 3T system, from 82 elderly participants in a population-based study. Images were automatically segmented for WMH. Lobar boundaries and distance to ventricular surface were used to define white matter regions. Regional-zonal WMH loads were displayed using bullseye plots. Four raters assessed all images applying three scales. Correlations between visual scales and regional WMH as well as inter and intra-rater variability were assessed. A multinomial ordinal regression model was used to predict scores based on regional volumes and global WMH burdens. RESULTS: On average, the bullseye plot depicted a right-left symmetry in the distribution and concentration of damage in the periventricular zone, especially in frontal regions. WMH loads correlated well with the average visual rating scores (e.g. Kendall's tau [Volume, Scheltens]=0.59 CI=[0.53 0.62]). Local correlations allowed comparison of loading patterns between scales and between raters. Regional measurements had more predictive power than global WMH burden (e.g. frontal caps prediction with local features: ICC=0.67 CI=[0.53 0.77], global volume=0.50 CI=[0.32 0.65], intra-rater=0.44 CI=[0.23 0.60]). CONCLUSION: Regional-zonal representation of WMH burden highlights similarities and differences between visual rating scales and raters. The bullseye infographic tool provides a simple visual representation of regional lesion load that can be used for rater calibration and training.

Music-of-light stethoscope: a demonstration of the photoacoustic effect.

In this paper we present a system aimed at demonstrating the photoacoustic (PA) effect for educational purposes. PA imaging is a hybrid imaging modality that requires no contrast agent and has a great potential for spine and brain lesion characterisation, breast cancer and blood flow monitoring notably in the context of fetal surgery. It relies on combining light excitation with ultrasound reception. Our brief was to present and explain PA imaging in a public-friendly way suitable for a variety of ages and backgrounds. We developed a simple, accessible demonstration unit using readily available materials. We used a modulated light emitting diode (LED) torch and an electronic stethoscope. The output of a music player was used for light modulation and the chest piece of the stethoscope covered by a black tape was used as an absorbing target and an enclosed chamber. This demonstration unit was presented to the public at the Bloomsbury Festival On Light in October 2015. Our stall was visited by over 100 people of varying ages. Twenty families returned in-depth evaluation questionnaires, which show that our explanations of the photoacoustic effect were well understood. Their interest in biomedical engineering was increased.

Estimating anatomical trajectories with Bayesian mixed-effects modeling.

We introduce a mass-univariate framework for the analysis of whole-brain structural trajectories using longitudinal Voxel-Based Morphometry data and Bayesian inference. Our approach to developmental and aging longitudinal studies characterizes heterogeneous structural growth/decline between and within groups. In particular, we propose a probabilistic generative model that parameterizes individual and ensemble average changes in brain structure using linear mixed-effects models of age and subject-specific covariates. Model inversion uses Expectation Maximization (EM), while voxelwise (empirical) priors on the size of individual differences are estimated from the data. Bayesian inference on individual and group trajectories is realized using Posterior Probability Maps (PPM). In addition to parameter inference, the framework affords comparisons of models with varying combinations of model order for fixed and random effects using model evidence. We validate the model in simulations and real MRI data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) project. We further demonstrate how subject specific characteristics contribute to individual differences in longitudinal volume changes in healthy subjects, Mild Cognitive Impairment (MCI), and Alzheimer's Disease (AD).

In vivo imaging of tau pathology using multi-parametric quantitative MRI.

As the number of people diagnosed with Alzheimer's disease (AD) reaches epidemic proportions, there is an urgent need to develop effective treatment strategies to tackle the social and economic costs of this fatal condition. Dozens of candidate therapeutics are currently being tested in clinical trials, and compounds targeting the aberrant accumulation of tau proteins into neurofibrillary tangles (NFTs) are the focus of substantial current interest. Reliable, translatable biomarkers sensitive to both tau pathology and its modulation by treatment along with animal models that faithfully reflect aspects of the human disease are urgently required. Magnetic resonance imaging (MRI) is well established as a valuable tool for monitoring the structural brain changes that accompany AD progression. However the descent into dementia is not defined by macroscopic brain matter loss alone: non-invasive imaging measurements sensitive to protein accumulation, white matter integrity and cerebral haemodynamics probe distinct aspects of AD pathophysiology and may serve as superior biomarkers for assessing drug efficacy. Here we employ a multi-parametric array of five translatable MRI techniques to characterise the in vivo pathophysiological phenotype of the rTg4510 mouse model of tauopathy (structural imaging, diffusion tensor imaging (DTI), arterial spin labelling (ASL), chemical exchange saturation transfer (CEST) and glucose CEST). Tau-induced pathological changes included grey matter atrophy, increased radial diffusivity in the white matter, decreased amide proton transfer and hyperperfusion. We demonstrate that the above markers unambiguously discriminate between the transgenic group and age-matched controls and provide a comprehensive profile of the multifaceted neuropathological processes underlying the rTg4510 model. Furthermore, we show that ASL and DTI techniques offer heightened sensitivity to processes believed to precede detectable structural changes and, as such, provides a platform for the study of disease mechanisms and therapeutic intervention.

Application of Automatic Segmentation on Super-Resolution Reconstruction MR Images of the Abnormal Fetal Brain.

BACKGROUND AND PURPOSE: Fetal brain MR imaging is clinically used to characterize fetal brain abnormalities. Recently, algorithms have been proposed to reconstruct high-resolution 3D fetal brain volumes from 2D slices. By means of these reconstructions, convolutional neural networks have been developed for automatic image segmentation to avoid labor-intensive manual annotations, usually trained on data of normal fetal brains. Herein, we tested the performance of an algorithm specifically developed for segmentation of abnormal fetal brains. MATERIALS AND METHODS: This was a single-center retrospective study on MR images of 16 fetuses with severe CNS anomalies (gestation, 21-39 weeks). T2-weighted 2D slices were converted to 3D volumes using a super-resolution reconstruction algorithm. The acquired volumetric data were then processed by a novel convolutional neural network to perform segmentations of white matter and the ventricular system and cerebellum. These were compared with manual segmentation using the Dice coefficient, Hausdorff distance (95th percentile), and volume difference. Using interquartile ranges, we identified outliers of these metrics and further analyzed them in detail. RESULTS: The mean Dice coefficient was 96.2%, 93.7%, and 94.7% for white matter and the ventricular system and cerebellum, respectively. The Hausdorff distance was 1.1, 2.3, and 1.6 mm, respectively. The volume difference was 1.6, 1.4, and 0.3 mL, respectively. Of the 126 measurements, there were 16 outliers among 5 fetuses, discussed on a case-by-case basis. CONCLUSIONS: Our novel segmentation algorithm obtained excellent results on MR images of fetuses with severe brain abnormalities. Analysis of the outliers shows the need to include pathologies underrepresented in the current data set. Quality control to prevent occasional errors is still needed.

Placental differences between uncomplicated and complicated monochorionic diamniotic pregnancies on diffusion and multicompartment Magnetic Resonance Imaging.

INTRODUCTION: Twin-twin transfusion syndrome (TTTS) and selective fetal growth restriction (sFGR) are common complications in monochorionic diamniotic (MCDA) pregnancies. The Diffusion-rElaxation Combined Imaging for Detailed Placental Evaluation (DECIDE) model, a placental-specific model, separates the T2 values of the fetal and maternal blood from the background tissue and estimates the fetal blood oxygen saturation. This study investigates diffusion and relaxation differences in uncomplicated MCDA pregnancies and MCDA pregnancies complicated by TTTS and sFGR in mid-pregnancy. METHODS: This prospective monocentric cohort study included uncomplicated MCDA pregnancies and pregnancies complicated by TTTS and sFGR. We performed MRI with conventional diffusion-weighted imaging (DWI) and combined relaxometry - DWI-intravoxel incoherent motion. DECIDE analysis was used to quantify different parameters within the placenta related to the fetal, placental, and maternal compartments. RESULTS: We included 99 pregnancies, of which 46 were uncomplicated, 12 were complicated by sFGR and 41 by TTTS. Conventional DWI did not find differences between or within cohorts. On DECIDE imaging, fetoplacental oxygen saturation was significantly lower in the smaller member of sFGR (p = 0.07) and in both members of TTTS (p = 0.01 and p = 0.004) compared to the uncomplicated pairs. Additionally, average T2 relaxation time was significantly lower in the smaller twin of the sFGR (p = 0.004) compared to the uncomplicated twins (p = 0.03). CONCLUSION: Multicompartment functional MRI showed significant differences in several MRI parameters between the placenta of uncomplicated MCDA pregnancies and those complicated by sFGR and TTTS in mid-pregnancy.

Distinct neuropsychological profiles correspond to distribution of cortical thinning in inherited prion disease caused by insertional mutation.

BACKGROUND: The human prion diseases are a group of universally fatal neurodegenerative disorders associated with the auto-catalytic misfolding of the normal cell surface prion protein (PrP). Mutations causative of inherited human prion disease (IPD) include an insertion of six additional octapeptide repeats (6-OPRI) and a missense mutation (P102L) with large families segregating for each mutation residing in southern England. Here we report for the first time the neuropsychological and clinical assessments in these two groups. METHOD: The cognitive profiles addressing all major domains were obtained for 26 patients (18 6-OPRI, 8 P102L) and the cortical thickness determined using 1.5T MRI in a subset of 10 (six 6-OPRI, four P102L). RESULTS: The cognitive profiles were different in patients with the two mutations in the symptomatic phase of the disease. The 6-OPRI group had lower premorbid optimal levels of functioning (assessed on the NART) than the P102L group. In the symptomatic phase of the disease the 6-OPRI patients had significantly more executive dysfunction than the P102L group and were more impaired on tests of perception and nominal functions. There was anecdotal evidence of low premorbid social performance in the 6-OPRI but not P102L patients. Cortical thinning distribution correlated with the neuropsychological profile in the 6-OPRI group principally involving the parietal, occipital and posterior frontal regions. The small number of patients in the P102L group precluded statistical comparison between the groups. CONCLUSIONS: The 6-OPRI patients had more widespread and severe cognitive dysfunction than the P102L group and this correlated with cortical thinning distribution.

Advanced quantitative evaluation of PET systems using the ACR phantom and NiftyPET software.

PURPOSE: A novel phantom-imaging platform, a set of software tools, for automated and high-precision imaging of the American College of Radiology (ACR) positron emission tomography (PET) phantom for PET/magnetic resonance (PET/MR) and PET/computed tomography (PET/CT) systems is proposed. METHODS: The key feature of this platform is the vector graphics design that facilitates the automated measurement of the knife-edge response function and hence image resolution, using composite volume of interest templates in a 0.5 mm resolution grid applied to all inserts of the phantom. Furthermore, the proposed platform enables the generation of an accurate µ $\mu$ -map for PET/MR systems with a robust alignment based on two-stage image registration using specifically designed PET templates. The proposed platform is based on the open-source NiftyPET software package used to generate multiple list-mode data bootstrap realizations and image reconstructions to determine the precision of the two-stage registration and any image-derived statistics. For all the analyses, iterative image reconstruction was employed with and without modeled shift-invariant point spread function and with varying iterations of the ordered subsets expectation maximization (OSEM) algorithm. The impact of the activity outside the field of view (FOV) was assessed using two acquisitions of 30 min each, with and without the activity outside the FOV. RESULTS: The utility of the platform has been demonstrated by providing a standard and an advanced phantom analysis including the estimation of spatial resolution using all cylindrical inserts. In the imaging planes close to the edge of the axial FOV, we observed deterioration in the quantitative accuracy, reduced resolution (FWHM increased by 1-2 mm), reduced contrast, and background uniformity due to the activity outside the FOV. Although it slows convergence, the PSF reconstruction had a positive impact on resolution and contrast recovery, but the degree of improvement depended on the regions. The uncertainty analysis based on bootstrap resampling of raw PET data indicated high precision of the two-stage registration. CONCLUSIONS: We demonstrated that phantom imaging using the proposed methodology with the metric of spatial resolution and multiple bootstrap realizations may be helpful in more accurate evaluation of PET systems as well as in facilitating fine tuning for optimal imaging parameters in PET/MR and PET/CT clinical research studies.

Optimal symptom combinations to aid COVID-19 case identification: Analysis from a community-based, prospective, observational cohort.

OBJECTIVES: Diagnostic work-up following any COVID-19 associated symptom will lead to extensive testing, potentially overwhelming laboratory capacity whilst primarily yielding negative results. We aimed to identify optimal symptom combinations to capture most cases using fewer tests with implications for COVID-19 vaccine developers across different resource settings and public health. METHODS: UK and US users of the COVID-19 Symptom Study app who reported new-onset symptoms and an RT-PCR test within seven days of symptom onset were included. Sensitivity, specificity, and number of RT-PCR tests needed to identify one case (test per case [TPC]) were calculated for different symptom combinations. A multi-objective evolutionary algorithm was applied to generate combinations with optimal trade-offs between sensitivity and specificity. FINDINGS: UK and US cohorts included 122,305 (1,202 positives) and 3,162 (79 positive) individuals. Within three days of symptom onset, the COVID-19 specific symptom combination (cough, dyspnoea, fever, anosmia/ageusia) identified 69% of cases requiring 47 TPC. The combination with highest sensitivity (fatigue, anosmia/ageusia, cough, diarrhoea, headache, sore throat) identified 96% cases requiring 96 TPC. INTERPRETATION: We confirmed the significance of COVID-19 specific symptoms for triggering RT-PCR and identified additional symptom combinations with optimal trade-offs between sensitivity and specificity that maximize case capture given different resource settings.

Optimal symptom combinations to aid COVID-19 case identification: analysis from a community-based, prospective, observational cohort.

OBJECTIVES: Diagnostic work-up following any COVID-19 associated symptom will lead to extensive testing, potentially overwhelming laboratory capacity whilst primarily yielding negative results. We aimed to identify optimal symptom combinations to capture most cases using fewer tests with implications for COVID-19 vaccine developers across different resource settings and public health. METHODS: UK and US users of the COVID-19 Symptom Study app who reported new-onset symptoms and an RT-PCR test within seven days of symptom onset were included. Sensitivity, specificity, and number of RT-PCR tests needed to identify one case (test per case [TPC]) were calculated for different symptom combinations. A multi-objective evolutionary algorithm was applied to generate combinations with optimal trade-offs between sensitivity and specificity. FINDINGS: UK and US cohorts included 122,305 (1,202 positives) and 3,162 (79 positive) individuals. Within three days of symptom onset, the COVID-19 specific symptom combination (cough, dyspnoea, fever, anosmia/ageusia) identified 69% of cases requiring 47 TPC. The combination with highest sensitivity (fatigue, anosmia/ageusia, cough, diarrhoea, headache, sore throat) identified 96% cases requiring 96 TPC. INTERPRETATION: We confirmed the significance of COVID-19 specific symptoms for triggering RT-PCR and identified additional symptom combinations with optimal trade-offs between sensitivity and specificity that maximize case capture given different resource settings.

Memory complaints and increased rates of brain atrophy: risk factors for mild cognitive impairment and Alzheimer's disease.

AIM: To determine rates of cerebral atrophy in individuals with symptoms of memory loss but no objective cognitive impairment (SNCI) and their association with future cognitive decline. METHODS: Thirty-two SNCI subjects, 16 with mild cognitive impairment (MCI) and 27 control subjects had clinical assessment and magnetic resonance imaging at baseline and 1 year later. Rates of whole brain atrophy (WBA), hippocampal atrophy (HA) and ventricular enlargement (VE) were measured. Our outcome was clinical diagnosis at 2 years after entry into the study. RESULTS: The MCI group had greater rates of WBA, HA and VE than both controls and SNCI subjects. As a group SNCI subjects did not have significantly greater rates of atrophy than the controls. However, SNCI subjects who progressed to MCI or dementia had increased rates of atrophy compared with those who remained stable. DISCUSSION: Individuals with memory complaints but no objective memory deficits, who progress to MCI or dementia, have increased rates of cerebral atrophy.

Micro-CT and histological investigation of the spatial pattern of feto-placental vascular density.

INTRODUCTION: There are considerable variations in villous morphology within a normal placenta. However, whether there is a reproducible spatial pattern of variation in villous vascular density is not known. Micro-CT provides three-dimensional volume imaging with spatial resolution down to the micrometre scale. In this study, we applied Micro-CT and histological analysis to investigate the degree of heterogeneity of vascularisation within the placenta. METHOD: Ten term placentas were collected at elective caesarean section, perfused with contrast agent and imaged whole with Micro-CT. Eight full depth tissue blocks were then taken from each placenta and imaged. Sections were taken for histological analysis. Data was analysed to investigate vascular fill, and vascular density in relation to location from cord insertion to placental edge at each scale. RESULTS: Whole placental imaging revealed no spatially consistent difference in villous vessel density within the main placental tissue, although there was a great degree of heterogeneity. Both block imaging and histological analysis found a large degree of heterogeneity of vascular density within placentas, but no strong correlation between villous vascular density and block location (rs = 0.066, p = 0.7 block imaging, rs = 0.06, p = 0.6 histological analysis). DISCUSSION: This work presents a novel method for imaging the human placenta vascular tree using multiscale Micro-CT imaging. It demonstrates that there is a large degree of variation in vascular density throughout normal term human placentas. The three-dimensional data created by this technique could be used, with more advanced computer analysis, to further investigate the structure of the vascular tree.

Interactive virtual 3D models of renal cancer patient anatomies alter partial nephrectomy surgical planning decisions and increase surgeon confidence compared to volume-rendered images.

PURPOSE: To determine whether the interactive visualisation of patient-specific virtual 3D models of the renal anatomy influences the pre-operative decision-making process of urological surgeons for complex renal cancer operations. METHODS: Five historic renal cancer patient pre-operative computed tomography (CT) datasets were retrospectively selected based on RENAL nephrectomy score and variety of anatomy. Interactive virtual 3D models were generated for each dataset using image segmentation software and were made available for online visualisation and manipulation. Consultant urologists were invited to participate in the survey which consisted of CT and volume-rendered images (VRI) for the control arm, and CT with segmentation overlay and the virtual 3D model for the intervention arm. A questionnaire regarding anatomical structures, surgical approach, and confidence was administered. RESULTS: Twenty-five participants were recruited (54% response rate), with 19/25 having > 5 years of renal surgery experience. The median anatomical clarity score increased from 3 for the control to 5 for the intervention arm. A change in planned surgical approach was reported in 19% of cases. Virtual 3D models increased surgeon confidence in the surgical decisions in 4/5 patient datasets. There was a statistically significant improvement in surgeon opinion of the potential utility for decision-making purposes of virtual 3D models as compared to VRI at the multidisciplinary team meeting, theatre planning, and intra-operative stages. CONCLUSION: The use of pre-operative interactive virtual 3D models for surgery planning influences surgical decision-making. Further studies are needed to investigate if the use of these models changes renal cancer surgery outcomes.

Artificial intelligence for the real-time classification of intrapapillary capillary loop patterns in the endoscopic diagnosis of early oesophageal squamous cell carcinoma: A proof-of-concept study.

Background: Intrapapillary capillary loops (IPCLs) represent an endoscopically visible feature of early squamous cell neoplasia (ESCN) which correlate with invasion depth - an important factor in the success of curative endoscopic therapy. IPCLs visualised on magnification endoscopy with Narrow Band Imaging (ME-NBI) can be used to train convolutional neural networks (CNNs) to detect the presence and classify staging of ESCN lesions. Methods: A total of 7046 sequential high-definition ME-NBI images from 17 patients (10 ESCN, 7 normal) were used to train a CNN. IPCL patterns were classified by three expert endoscopists according to the Japanese Endoscopic Society classification. Normal IPCLs were defined as type A, abnormal as B1-3. Matched histology was obtained for all imaged areas. Results: This CNN differentiates abnormal from normal IPCL patterns with 93.7% accuracy (86.2% to 98.3%) and sensitivity and specificity for classifying abnormal IPCL patterns of 89.3% (78.1% to 100%) and 98% (92% to 99.7%), respectively. Our CNN operates in real time with diagnostic prediction times between 26.17 ms and 37.48 ms. Conclusion: Our novel and proof-of-concept application of computer-aided endoscopic diagnosis shows that a CNN can accurately classify IPCL patterns as normal or abnormal. This system could be used as an in vivo, real-time clinical decision support tool for endoscopists assessing and directing local therapy of ESCN.