Physical and statistical shape modelling in craniomaxillofacial surgery: a personalised approach for outcome prediction

Orthognathic surgery involves repositioning of the jaw bones to restore face function and shape for patients who require an operation as a result of a syndrome, due to growth disturbances in childhood or after trauma. As part of the preoperative assessment, three-dimensional medical imaging and computer-assisted surgical planning help to improve outcomes, and save time and cost. Computer-assisted surgical planning involves visualisation and manipulation of the patient anatomy and can be used to aid objective diagnosis, patient communication, outcome evaluation, and surgical simulation. Despite the benefits, the adoption of three-dimensional tools has remained limited beyond specialised hospitals and traditional two-dimensional cephalometric analysis is still the gold standard. This thesis presents a multidisciplinary approach to innovative surgical simulation involving clinical patient data, medical image analysis, engineering principles, and state-of-the-art machine learning and computer vision algorithms. Two novel three-dimensional computational models were developed to overcome the limitations of current computer-assisted surgical planning tools. First, a physical modelling approach – based on a probabilistic finite element model – provided patient-specific simulations and, through training and validation, population-specific parameters. The probabilistic model was equally accurate compared to two commercial programs whilst giving additional information regarding uncertainties relating to the material properties and the mismatch in bone position between planning and surgery. Second, a statistical modelling approach was developed that presents a paradigm shift in its modelling formulation and use. Specifically, a 3D morphable model was constructed from 5,000 non-patient and orthognathic patient faces for fully-automated diagnosis and surgical planning. Contrary to traditional physical models that are limited to a finite number of tests, the statistical model employs machine learning algorithms to provide the surgeon with a goal-driven patient-specific surgical plan. The findings in this thesis provide markers for future translational research and may accelerate the adoption of the next generation surgical planning tools to further supplement the clinical decision-making process and ultimately to improve patients’ quality of life

The Transformation of Enterovirus Replication Structures: a Three-Dimensional Study of Single- and Double-Membrane Compartments

All positive-strand RNA viruses induce membrane structures in their host cells which are thought to serve as suitable microenvironments for viral RNA synthesis. The structures induced by enteroviruses, which are members of the family Picornaviridae, have so far been described as either single- or double-membrane vesicles (DMVs). Aside from the number of delimiting membranes, their exact architecture has also remained elusive due to the limitations of conventional electron microscopy. In this study, we used electron tomography (ET) to solve the three-dimensional (3-D) ultrastructure of these compartments. At different time points postinfection, coxsackievirus B3-infected cells were high-pressure frozen and freeze-substituted for ET analysis. The tomograms showed that during the exponential phase of viral RNA synthesis, closed smooth single-membrane tubules constituted the predominant virus-induced membrane structure, with a minor proportion of DMVs that were either closed or connected to the cytosol in a vase-like configuration. As infection progressed, the DMV number steadily increased, while the tubular single-membrane structures gradually disappeared. Late in infection, complex multilamellar structures, previously unreported, became apparent in the cytoplasm. Serial tomography disclosed that their basic unit is a DMV, which is enwrapped by one or multiple cisternae. ET also revealed striking intermediate structures that strongly support the conversion of single-membrane tubules into double-membrane and multilamellar structures by a process of membrane apposition, enwrapping, and fusion. Collectively, our work unravels the sequential appearance of distinct enterovirus-induced replication structures, elucidates their detailed 3-D architecture, and provides the basis for a model for their transformation during the course of infection

A novel soft tissue prediction methodology for orthognathic surgery based on probabilistic finite element modelling

Repositioning of the maxilla in orthognathic surgery is carried out for functional and aesthetic purposes. Pre-surgical planning tools can predict 3D facial appearance by computing the response of the soft tissue to the changes to the underlying skeleton. The clinical use of commercial prediction software remains controversial, likely due to the deterministic nature of these computational predictions. A novel probabilistic finite element model (FEM) for the prediction of postoperative facial soft tissues is proposed in this paper. A probabilistic FEM was developed and validated on a cohort of eight patients who underwent maxillary repositioning and had pre- and postoperative cone beam computed tomography (CBCT) scans taken. Firstly, a variables correlation assessed various modelling parameters. Secondly, a design of experiments (DOE) provided a range of potential outcomes based on uniformly distributed input parameters, followed by an optimisation. Lastly, the second DOE iteration provided optimised predictions with a probability range. A range of 3D predictions was obtained using the probabilistic FEM and validated using reconstructed soft tissue surfaces from the postoperative CBCT data. The predictions in the nose and upper lip areas accurately include the true postoperative position, whereas the prediction under-estimates the position of the cheeks and lower lip. A probabilistic FEM has been developed and validated for the prediction of the facial appearance following orthognathic surgery. This method shows how inaccuracies in the modelling and uncertainties in executing surgical planning influence the soft tissue prediction and it provides a range of predictions including a minimum and maximum, which may be helpful for patients in understanding the impact of surgery on the face

Quantifying the effect of corrective surgery for trigonocephaly: A non-invasive, non-ionizing method using three-dimensional handheld scanning and statistical shape modelling

Trigonocephaly in patients with metopic synostosis is corrected by fronto-orbital remodelling (FOR). The aim of this study was to quantitatively assess aesthetic outcomes of FOR by capturing 3D forehead scans of metopic patients pre- and post-operatively and comparing them with controls. Ten single-suture metopic patients undergoing FOR and 15 age-matched non-craniosynostotic controls were recruited at Great Ormond Street Hospital for Children (UK). Scans were acquired with a three-dimensional (3D) handheld camera and post-processed combining 3D imaging software. 3D scans were first used for cephalometric measurements. Statistical shape modelling was then used to compute the 3D mean head shapes of the three groups (FOR pre-op, post-op and controls). Head shape variations were described via principal component analysis (PCA). Cephalometric measurements showed that FOR significantly increased the forehead volume and improved trigonocephaly. This improvement was supported visually by pre- and post-operative computed mean 3D shapes and numerically by PCA (p < 0.001). Compared with controls, post-operative scans showed flatter foreheads (p < 0.001). In conclusion, 3D scanning followed by 3D statistical shape modelling enabled the 3D comparison of forehead shapes of metopic patients and non-craniosynostotic controls, and demonstrated that the adopted FOR technique was successful in correcting bitemporal narrowing but overcorrected the rounding of the forehead

Extensive coronavirus-induced membrane rearrangements are not a determinant of pathogenicity

Positive-strand RNA (+RNA) viruses rearrange cellular membranes during replication, possibly in order to concentrate and arrange viral replication machinery for efficient viral RNA synthesis. Our previous work showed that in addition to the conserved coronavirus double membrane vesicles (DMVs), Beau-R, an apathogenic strain of avian Gammacoronavirus infectious bronchitis virus (IBV), induces regions of ER that are zippered together and tethered open-necked double membrane spherules that resemble replication organelles induced by other +RNA viruses. Here we compared structures induced by Beau-R with the pathogenic lab strain M41 to determine whether membrane rearrangements are strain dependent. Interestingly, M41 was found to have a low spherule phenotype. We then compared a panel of pathogenic, mild and attenuated IBV strains in ex vivo tracheal organ culture (TOC). Although the low spherule phenotype of M41 was conserved in TOCs, each of the other tested IBV strains produced DMVs, zippered ER and spherules. Furthermore, there was a significant correlation for the presence of DMVs with spherules, suggesting that these structures are spatially and temporally linked. Our data indicate that virus induced membrane rearrangements are fundamentally linked to the viral replicative machinery. However, coronavirus replicative apparatus clearly has the plasticity to function in different structural contexts

Reevaluation of the role of Pex1 and dynamin-related proteins in peroxisome membrane biogenesis

A recent model for peroxisome biogenesis postulates that peroxisomes form de novo continuously in wild-type cells by heterotypic fusion of endoplasmic reticulum–derived vesicles containing distinct sets of peroxisomal membrane proteins. This model proposes a role in vesicle fusion for the Pex1/Pex6 complex, which has an established role in matrix protein import. The growth and division model proposes that peroxisomes derive from existing peroxisomes. We tested these models by reexamining the role of Pex1/Pex6 and dynamin-related proteins in peroxisome biogenesis. We found that induced depletion of Pex1 blocks the import of matrix proteins but does not affect membrane protein delivery to peroxisomes; markers for the previously reported distinct vesicles colocalize in pex1 and pex6 cells; peroxisomes undergo continued growth if ission is blocked. Our data are compatible with the established primary role of the Pex1/Pex6 complex in matrix protein import and show that peroxisomes in Saccharomyces cerevisiae multiply mainly by growth and division

Healthy Lifestyle and Leukocyte Telomere Length in U.S. Women

Context: Whether a healthy lifestyle may be associated with longer telomere length is largely unknown. Objectives: To examine healthy lifestyle practices, which are primary prevention measures against major age-related chronic diseases, in relation to leukocyte telomere length. Design and Setting: Cross-sectional analysis in the Nurses' Health Study (NHS). Participants: The population consisted of 5,862 women who participated in multiple prospective case-control studies within the NHS cohort. Z scores of leukocyte telomere length were derived within each case-control study. Based on prior work, we defined low-risk or healthy categories for five major modifiable factors assessed in 1988 or 1990: non-current smoking, maintaining a healthy body weight (body mass index in 18.5-24.9 kg/m(2)), engaging in regular moderate or vigorous physical activities (>= 150 minutes/week), drinking alcohol in moderation (1 drink/week to,2 drinks/day), and eating a healthy diet (Alternate Healthy Eating Index score in top 50%). We calculated difference (%) of the z scores contrasting low-risk groups with reference groups to evaluate the association of interest. Results: Although none of the individual low-risk factors was significantly associated with larger leukocyte telomere length z scores, we observed a significant, positive relationship between the number of low-risk factors and the z scores. In comparison with women who had zero low-risk factors (1.9% of the total population) and were, therefore, considered the least healthy group, the leukocyte telomere length z scores were 16.4%, 22.1%, 28.7%, 22.6%, and 31.2% (P for trend = 0.015) higher for women who had 1 to 5 low-risk factors, respectively. Conclusions: Adherence to a healthy lifestyle, defined by major modifiable risk factors, was associated with longer telomere length in leukocytes

A reappraisal of the impact of dairy foods and milk fat on cardiovascular disease risk

Background This review provides a reappraisal of the potential effects of dairy foods, including dairy fats, on cardiovascular disease (CVD)/coronary heart disease (CHD) risk. Commodities and foods containing saturated fats are of particular focus as current public dietary recommendations are directed toward reducing the intake of saturated fats as a means to improve the overall health of the population. A conference of scientists from different perspectives of dietary fat and health was convened in order to consider the scientific basis for these recommendations. Aims This review and summary of the conference focus on four key areas related to the biology of dairy foods and fats and their potential impact on human health: (a) the effect of dairy foods on CVD in prospective cohort studies; (b) the impact of dairy fat on plasma lipid risk factors for CVD; (c) the effects of dairy fat on non-lipid risk factors for CVD; and (d) the role of dairy products as essential contributors of micronutrients in reference food patterns for the elderly. Conclusions Despite the contribution of dairy products to the saturated fatty acid composition of the diet, and given the diversity of dairy foods of widely differing composition, there is no clear evidence that dairy food consumption is consistently associated with a higher risk of CVD. Thus, recommendations to reduce dairy food consumption irrespective of the nature of the dairy product should be made with cautionJ. Bruce German, Robert A. Gibson, Ronald M. Krauss, Paul Nestel, Benoît Lamarche, Wija A. van Staveren, Jan M. Steijns, Lisette C. P. G. M. de Groot, Adam L. Lock and Frédéric Destaillat

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

The Impact of Health Behaviours on Incident Cardiovascular Disease in Europeans and South Asians - A Prospective Analysis in the UK SABRE Study

Background: There is consistent evidence on the impact of health behaviours on risk of cardiovascular disease (CVD) in European populations. As South Asians in the UK have an excess risk of CVD and coronary heart disease (CHD) compared to Europeans, we investigated whether a similar association between combined health behaviours and risk of CVD and CHD among this high-risk group exists, and estimated the population impact. Methods and Findings: In a prospective cohort of 1090 Europeans and 1006 South Asians (40–69 y) without prevalent CVD at baseline (1988–1990), followed up for 21 years to 2011, there were 601 incident CVD events [Europeans n = 255; South Asians n = 346] of which 520 were CHD events [n = 207 and 313 respectively]. Participants scored between 0 to 4 points for a composite score including four baseline healthy behaviours (non-smoker, moderate alcohol intake, physically active, frequent fruit/vegetable intake). Adjusted hazard ratios (95% confidence intervals) for incident CHD in Europeans who had three, two, one, and zero compared to four health behaviours were 1.33 (0.78–2.29), 1.96 (1.15–3.33), 1.36 (0.74–2.48) and 2.45 (1.18–5.10), respectively, p-trend = 0.025. In South Asians, corresponding HRs were 2.88 (1.33–6.24), 2.28 (1.06–4.91), 3.36 (1.53–7.39) and 3.48 (1.38–8.81), p-trend = 0.022. The results were similar for incident CVD; Europeans HR 2.12 (1.14–3.94), p–trend = 0.014; South Asians HR 2.73 (1.20–6.21), p-trend = 0.018. The population attributable fraction in Europeans was 43% for CHD and 28% for CVD. In South Asians it was 63% and 51% respectively. Conclusions: Lack of adherence to four combined health behaviours was associated with 2 to 3-fold increased risk of incident CVD in Europeans and South Asians. A substantial population impact in the South Asian group indicates important potential for disease prevention in this high-risk group by adherence to healthy behaviours