A sequential Monte Carlo algorithm to incorporate model uncertainty in Bayesian sequential design

Here we present a sequential Monte Carlo (SMC) algorithm that can be used for any one-at-a-time Bayesian sequential design problem in the presence of model uncertainty where discrete data are encountered. Our focus is on adaptive design for model discrimination but the methodology is applicable if one has a different design objective such as parameter estimation or prediction. An SMC algorithm is run in parallel for each model and the algorithm relies on a convenient estimator of the evidence of each model which is essentially a function of importance sampling weights. Other methods for this task such as quadrature, often used in design, suffer from the curse of dimensionality. Approximating posterior model probabilities in this way allows us to use model discrimination utility functions derived from information theory that were previously difficult to compute except for conjugate models. A major benefit of the algorithm is that it requires very little problem specific tuning. We demonstrate the methodology on three applications, including discriminating between models for decline in motor neuron numbers in patients suffering from neurological diseases such as Motor Neuron disease.

Change Point Estimation in Monitoring Survival Time

Precise identification of the time when a change in a hospital outcome has occurred enables clinical experts to search for a potential special cause more effectively. In this paper, we develop change point estimation methods for survival time of a clinical procedure in the presence of patient mix in a Bayesian framework. We apply Bayesian hierarchical models to formulate the change point where there exists a step change in the mean survival time of patients who underwent cardiac surgery. The data are right censored since the monitoring is conducted over a limited follow-up period. We capture the effect of risk factors prior to the surgery using a Weibull accelerated failure time regression model. Markov Chain Monte Carlo is used to obtain posterior distributions of the change point parameters including location and magnitude of changes and also corresponding probabilistic intervals and inferences. The performance of the Bayesian estimator is investigated through simulations and the result shows that precise estimates can be obtained when they are used in conjunction with the risk-adjusted survival time CUSUM control charts for different magnitude scenarios. The proposed estimator shows a better performance where a longer follow-up period, censoring time, is applied. In comparison with the alternative built-in CUSUM estimator, more accurate and precise estimates are obtained by the Bayesian estimator. These superiorities are enhanced when probability quantification, flexibility and generalizability of the Bayesian change point detection model are also considered.

Ocular surface changes with short-term contact lens wear

Contact lenses are a common method for the correction of refractive errors of the eye. While there have been significant advancements in contact lens designs and materials over the past few decades, the lenses still represent a foreign object in the ocular environment and may lead to physiological as well as mechanical effects on the eye. When contact lenses are placed in the eye, the ocular anatomical structures behind and in front of the lenses are directly affected. This thesis presents a series of experiments that investigate the mechanical and physiological effects of the short-term use of contact lenses on anterior and posterior corneal topography, corneal thickness, the eyelids, tarsal conjunctiva and tear film surface quality. The experimental paradigm used in these studies was a repeated measures, cross-over study design where subjects wore various types of contact lenses on different days and the lenses were varied in one or more key parameters (e.g. material or design). Both, old and newer lens materials were investigated, soft and rigid lenses were used, high and low oxygen permeability materials were tested, toric and spherical lens designs were examined, high and low powers and small and large diameter lenses were used in the studies. To establish the natural variability in the ocular measurements used in the studies, each experiment also contained at least one “baseline” day where an identical measurement protocol was followed, with no contact lenses worn. In this way, changes associated with contact lens wear were considered in relation to those changes that occurred naturally during the 8 hour period of the experiment. In the first study, the regional distribution and magnitude of change in corneal thickness and topography was investigated in the anterior and posterior cornea after short-term use of soft contact lenses in 12 young adults using the Pentacam. Four different types of contact lenses (Silicone hydrogel/ Spherical/–3D, Silicone Hydrogel/Spherical/–7D, Silicone Hydrogel/Toric/–3D and HEMA/Toric/–3D) of different materials, designs and powers were worn for 8 hours each, on 4 different days. The natural diurnal changes in corneal thickness and curvature were measured on two separate days before any contact lens wear. Significant diurnal changes in corneal thickness and curvature within the duration of the study were observed and these were taken into consideration for calculating the contact lens induced corneal changes. Corneal thickness changed significantly with lens wear and the greatest corneal swelling was seen with the hydrogel (HEMA) toric lens with a noticeable regional swelling of the cornea beneath the stabilization zones, the thickest regions of the lenses. The anterior corneal surface generally showed a slight flattening with lens wear. All contact lenses resulted in central posterior corneal steepening, which correlated with the relative degree of corneal swelling. The corneal swelling induced by the silicone hydrogel contact lenses was typically less than the natural diurnal thinning of the cornea over this same period (i.e. net thinning). This highlights why it is important to consider the natural diurnal variations in corneal thickness observed from morning to afternoon to accurately interpret contact lens induced corneal swelling. In the second experiment, the relative influence of lenses of different rigidity (polymethyl methacrylate – PMMA, rigid gas permeable – RGP and silicone hydrogel – SiHy) and diameters (9.5, 10.5 and 14.0) on corneal thickness, topography, refractive power and wavefront error were investigated. Four different types of contact lenses (PMMA/9.5, RGP/9.5, RGP/10.5, SiHy/14.0), were worn by 14 young healthy adults for a period of 8 hours on 4 different days. There was a clear association between fluorescein fitting pattern characteristics (i.e. regions of minimum clearance in the fluorescein pattern) and the resulting corneal shape changes. PMMA lenses resulted in significant corneal swelling (more in the centre than periphery) along with anterior corneal steepening and posterior flattening. RGP lenses, on the other hand, caused less corneal swelling (more in the periphery than centre) along with opposite effects on corneal curvature, anterior corneal flattening and posterior steepening. RGP lenses also resulted in a clinically and statistically significant decrease in corneal refractive power (ranging from 0.99 to 0.01 D), large enough to affect vision and require adjustment in the lens power. Wavefront analysis also showed a significant increase in higher order aberrations after PMMA lens wear, which may partly explain previous reports of "spectacle blur" following PMMA lens wear. We further explored corneal curvature, thickness and refractive changes with back surface toric and spherical RGP lenses in a group of 6 subjects with toric corneas. The lenses were worn for 8 hours and measurements were taken before and after lens wear, as in previous experiments. Both lens types caused anterior corneal flattening and a decrease in corneal refractive power but the changes were greater with the spherical lens. The spherical lens also caused a significant decrease in WTR astigmatism (WRT astigmatism defined as major axis within 30 degrees of horizontal). Both the lenses caused slight posterior corneal steepening and corneal swelling, with a greater effect in the periphery compared to the central cornea. Eyelid position, lid-wiper and tarsal conjunctival staining were also measured in Experiment 2 after short-term use of the rigid and SiHy contact lenses. Digital photos of the external eyes were captured for lid position analysis. The lid-wiper region of the marginal conjunctiva was stained using fluorescein and lissamine green dyes and digital photos were graded by an independent masked observer. A grading scale was developed in order to describe the tarsal conjunctival staining. A significant decrease in the palpebral aperture height (blepharoptosis) was found after wearing of PMMA/9.5 and RGP/10.5 lenses. All three rigid contact lenses caused a significant increase in lid-wiper and tarsal staining after 8 hours of lens wear. There was also a significant diurnal increase in tarsal staining, even without contact lens wear. These findings highlight the need for better contact lens edge design to minimise the interactions between the lid and contact lens edge during blinking and more lubricious contact lens surfaces to reduce ocular surface micro-trauma due to friction and for. Tear film surface quality (TFSQ) was measured using a high-speed videokeratoscopy technique in Experiment 2. TFSQ was worse with all the lenses compared to baseline (PMMA/9.5, RGP/9.5, RGP/10.5, and SiHy/14) in the afternoon (after 8 hours) during normal and suppressed blinking conditions. The reduction in TFSQ was similar with all the contact lenses used, irrespective of their material and diameter. An unusual pattern of change in TFSQ in suppressed blinking conditions was also found. The TFSQ with contact lens was found to decrease until a certain time after which it improved to a value even better than the bare eye. This is likely to be due to the tear film drying completely over the surface of the contact lenses. The findings of this study also show that there is still a scope for improvement in contact lens materials in terms of better wettability and hydrophilicity in order to improve TFSQ and patient comfort. These experiments showed that a variety of changes can occur in the anterior eye as a result of the short-term use of a range of commonly used contact lens types. The greatest corneal changes occurred with lenses manufactured from older HEMA and PMMA lens materials, whereas modern SiHy and rigid gas permeable materials caused more subtle changes in corneal shape and thickness. All lenses caused signs of micro-trauma to the eyelid wiper and palpebral conjunctiva, although rigid lenses appeared to cause more significant changes. Tear film surface quality was also significantly reduced with all types of contact lenses. These short-term changes in the anterior eye are potential markers for further long term changes and the relative differences between lens types that we have identified provide an indication of areas of contact lens design and manufacture that warrant further development.

Do anti-inflammatory agents promote linear ablation lesion discontinuities? : an electrophysiological examination

Background: Catheter ablation for atrial fibrillation (AF) is more efficacious than antiarrhythmic therapy. Post ablation recurrences reduce ablation effectiveness and are contributed by lesion discontinuity in the fibrotic linear ablation lesions. The anti-fibrotic role of statins in reducing AF is being assessed in current trials. By reducing the chronic pathological fibrosis that occurs in AF they may reduce AF. However if statins also have an effect on the acute therapeutic fibrosis of an ablation, this could exacerbate lesion discontinuity and AF recurrence. We tested the hypothesis that statins attenuate ablation lesion continuity in a recognised pig atrial linear ablation model. Aims: To assess whether Atorvastatin diminishes the bi-directional conduction block produced by a linear atrial ablation lesion. Methods: Sixteen pigs were randomised to statin (n=8) or placebo (n=8) with drug pre-treatment for 3 days and a further 4 weeks. At initial electrophysiological study (EPS1) 3D right atrium (RA) mapping and a vertical ablation linear lesion in the posterior RA with bidirectional conduction block were completed (Gepstein Circ 1999). Follow-up electrophysiological assessment (EPS2) at 28 days assessed bidirectional conduction block maintenance. Results: Data of 15/16 (statin=7) pigs were analysed. Mean lesion length was 3.7 ± 0.8cm with a mean of 17.9 ± 5.7 lesion applications. Bi-directional conduction block was confirmed in 15/15 pigs (100%) at EPS1 and EPS2. Conclusions: Atorvastatin did not affect ablation lesion continuity in this pig atrial linear ablation model. If patients are on long-term statins for AF reduction, periablation cessation is probably not necessary.

Eye shape and retinal shape, and their relation to peripheral refraction

Purpose: We provide an account of the relationships between eye shape, retinal shape and peripheral refraction. Recent findings: We discuss how eye and retinal shapes may be described as conicoids, and we describe an axis and section reference system for determining shapes. Explanations are given of how patterns of retinal expansion during the development of myopia may contribute to changing patterns of peripheral refraction, and how pre-existing retinal shape might contribute to the development of myopia. Direct and indirect techniques for determining eye and retinal shape are described, and results are discussed. There is reasonable consistency in the literature of eye length increasing at a greater rate than height and width as the degree of myopia increases, so that eyes may be described as changing from oblate/spherical shapes to prolate shapes. However, one study indicates that the retina itself, while showing the same trend, remains oblate in shape for most eyes (discounting high myopia). Eye shape and retinal shape are not the same and merely describing an eye shape as being prolate or oblate is insufficient without some understanding of the parameters contributing to this; in myopia a prolate eye shape is likely to involve both a steepening retina near the posterior pole combined with a flattening (or a reduction in steepening compared with an emmetrope) away from the pole.

Ambient temperature and cardiorespiratory morbidity : a systematic review and meta-analysis

BACKGROUND: The effect of extreme temperature has become an increasing public health concern. Evaluating the impact of ambient temperature on morbidity has received less attention than its impact on mortality. METHODS: We performed a systematic literature review and extracted quantitative estimates of the effects of hot temperatures on cardiorespiratory morbidity. There were too few studies on effects of cold temperatures to warrant a summary. Pooled estimates of effects of heat were calculated using a Bayesian hierarchical approach that allowed multiple results to be included from the same study, particularly results at different latitudes and with varying lagged effects. RESULTS: Twenty-one studies were included in the final meta-analysis. The pooled results suggest an increase of 3.2% (95% posterior interval = -3.2% to 10.1%) in respiratory morbidity with 1°C increase on hot days. No apparent association was observed for cardiovascular morbidity (-0.5% [-3.0% to 2.1%]). The length of lags had inconsistent effects on the risk of respiratory and cardiovascular morbidity, whereas latitude had little effect on either. CONCLUSIONS: The effects of temperature on cardiorespiratory morbidity seemed to be smaller and more variable than previous findings related to mortality.

Empirical evaluation of alternative approaches in identifying crash hot spots

This study proposes a framework of a model-based hot spot identification method by applying full Bayes (FB) technique. In comparison with the state-of-the-art approach [i.e., empirical Bayes method (EB)], the advantage of the FB method is the capability to seamlessly integrate prior information and all available data into posterior distributions on which various ranking criteria could be based. With intersection crash data collected in Singapore, an empirical analysis was conducted to evaluate the following six approaches for hot spot identification: (a) naive ranking using raw crash data, (b) standard EB ranking, (c) FB ranking using a Poisson-gamma model, (d) FB ranking using a Poisson-lognormal model, (e) FB ranking using a hierarchical Poisson model, and (f) FB ranking using a hierarchical Poisson (AR-1) model. The results show that (a) when using the expected crash rate-related decision parameters, all model-based approaches perform significantly better in safety ranking than does the naive ranking method, and (b) the FB approach using hierarchical models significantly outperforms the standard EB approach in correctly identifying hazardous sites.

Hotspot Identification: A Full Bayesian Hierarchical Modeling Approach

This study proposes a full Bayes (FB) hierarchical modeling approach in traffic crash hotspot identification. The FB approach is able to account for all uncertainties associated with crash risk and various risk factors by estimating a posterior distribution of the site safety on which various ranking criteria could be based. Moreover, by use of hierarchical model specification, FB approach is able to flexibly take into account various heterogeneities of crash occurrence due to spatiotemporal effects on traffic safety. Using Singapore intersection crash data(1997-2006), an empirical evaluate was conducted to compare the proposed FB approach to the state-of-the-art approaches. Results show that the Bayesian hierarchical models with accommodation for site specific effect and serial correlation have better goodness-of-fit than non hierarchical models. Furthermore, all model-based approaches perform significantly better in safety ranking than the naive approach using raw crash count. The FB hierarchical models were found to significantly outperform the standard EB approach in correctly identifying hotspots.

Effects of enhanced somatosensory information on postural stability in older people and people with Parkinson’s disease

The somatosensory system plays an important role in balance control and age-related changes to this system have been implicated in falls. Parkinson’s disease (PD) is a chronic and progressive disease of the brain, characterized by postural instability and gait disturbance. Previous research has shown that deficiencies in somatosensory feedback may contribute to the poorer postural control demonstrated by PD individuals. However, few studies have comprehensively explored differences in somatosensory function and postural control between PD participants and healthy older individuals. The soles of the feet contain many cutaneous mechanoreceptors that provide important somatosensory information sources for postural control. Different types of insole devices have been developed to enhance this somatosensory information and improve postural stability, but these devices are often too complex and expensive to integrate into daily life. Textured insoles provide a more passive intervention that may be an inexpensive and accessible means to enhance the somatosensory input from the plantar surface of the feet. However, to date, there has been little work conducted to test the efficacy of enhanced somatosensory input induced by textured insoles in both healthy and PD populations during standing and walking. Therefore, the aims of this thesis were to determine: 1) whether textured insole surfaces can improve postural stability by enhancing somatosensory information in younger and older adults, 2) the differences between healthy older participants and PD participants for measures of physiological function and postural stability during standing and walking, 3) how changes in somatosensory information affect postural stability in both groups during standing and walking; and 4), whether textured insoles can improve postural stability in both groups during standing and walking. To address these aims, Study 1 recruited seven older individuals and ten healthy young controls to investigate the effects of two textured insole surfaces on postural stability while performing standing balance tests on a force plate. Participants were tested under three insole surface conditions: 1) barefoot; 2) standing on a hard textured insole surface; and 3), standing on a soft textured insole surface. Measurements derived from the centre of pressure displacement included the range of anterior-posterior and medial-lateral displacement, path length and the 90% confidence elliptical area (C90 area). Results of study 1 revealed a significant Group*Surface*Insole interaction for the four measures. Both textured insole surfaces reduced postural sway for the older group, especially in the eyes closed condition on the foam surface. However, participants reported that the soft textured insole surface was more comfortable and, hence, the soft textured insoles were adopted for Studies 2 and 3. For Study 2, 20 healthy older adults (controls) and 20 participants with Parkinson’s disease were recruited. Participants were evaluated using a series of physiological assessments that included touch sensitivity, vibratory perception, and pain and temperature threshold detection. Furthermore, nerve function and somatosensory evoked potentials tests were utilized to provide detailed information regarding peripheral nerve function for these participants. Standing balance and walking were assessed on different surfaces using a force plate and the 3D Vicon motion analysis system, respectively. Data derived from the force plate included the range of anterior-posterior and medial-lateral sway, while measures of stride length, stride period, cadence, double support time, stance phase, velocity and stride timing variability were reported for the walking assessment. The results of this study demonstrated that the PD group had decrements in somatosensory function compared to the healthy older control group. For electrodiagnosis, PD participants had poorer nerve function than controls, as evidenced by slower nerve conduction velocities and longer latencies in sural nerve and prolonged latency in the P37 somatosensory evoked potential. Furthermore, the PD group displayed more postural sway in both the anterior-posterior and medial-lateral directions relative to controls and these differences were increased when standing on a foam surface. With respect to the gait assessment, the PD group took shorter strides and had a reduced stride period compared with the control group. Furthermore, the PD group spent more time in the stance phase and had increased cadence and stride timing variability than the controls. Compared with walking on the firm surface, the two groups demonstrated different gait adaptations while walking on the uneven surface. Controls increased their stride length and stride period and decreased their cadence, which resulted in a consistent walking velocity on both surfaces. Conversely, while the PD patients also increased their stride period and decreased their cadence and stance period on the uneven surface, they did not increase their stride length and, hence walked slower on the uneven surface. In the PD group, there was a strong positive association between decreased somatosensory function and decreased clinical balance, as assessed by the Tinetti test. Poorer somatosensory function was also strongly positively correlated with the temporospatial gait parameters, especially shorter stride length. Study 3 evaluated the effects of manipulating the somatosensory information from the plantar surface of the feet using textured insoles in the same populations assessed in Study 2. For this study, participants performed the standing and walking balance tests under three footwear conditions: 1) barefoot; 2) with smooth insoles; and 3), with textured insoles. Standing balance and walking were evaluated using a force plate and a Vicon motion analysis system and the data were analysed in the same way outlined for Study 2. The findings showed that the smooth and textured insoles caused different effects on postural control during both the standing and walking trials. Both insoles decreased medial-lateral sway to the same level on the firm surface. The greatest benefits were observed in the PD group while wearing the textured insole. When standing under a more challenging condition on the foam surface with eyes closed, only the textured insole decreased medial-lateral sway in the PD group. With respect to the gait trials, both insoles increased walking velocity, stride length and stride time and decreased cadence, but these changes were more pronounced for the textured insoles. The effects of the textured insoles were evident under challenging conditions in the PD group and increased walking velocity and stride length, while decreasing cadence. Textured insoles were also effective in reducing the time spent in the double support and stance phases of the gait cycle and did not increase stride timing variability, as was the case for the smooth insoles for the PD group. The results of this study suggest that textured insoles, such as those evaluated in this research, may provide a low-cost means of improving postural stability in high-risk groups, such as people with PD, which may act as an important intervention to prevent falls.

Secondary curve behavior in Lenke Type 1C adolescent idiopathic scoliosis after thoracoscopic selective anterior thoracic fusion

Study Design. Analysis of a case series of 24 Lenke 1C adolescent idiopathic scoliosis (AIS) patients receiving selective thoracoscopic anterior scoliosis correction. Objective. To report the behaviour of the compensatory lumbar curve in a group of Lenke IC AIS patients following thoracoscopic anterior scoliosis correction, and to compare the results of this study with previously published data. Summary of Background Data. Several prior studies have reported spontaneous lumbar curve correction for both anterior and posterior selective fusion in Lenke 1C/King-Moe II patients; however to our knowledge no previous studies have reported outcomes of thoracoscopic anterior correction for this curve type. Methods. All AIS patients with a curve classification of Lenke 1C and a minimum of 24 months follow-up were retrieved from a consecutive series of 190 AIS patients who underwent thoracoscopic anterior instrumented fusion. Cobb angles of the major curve, instrumented levels, compensatory lumbar curve, and T5-T12 kyphosis were recorded, as well as coronal spinal balance, T1 tilt angle and shoulder balance. All radiographic parameters were measured before surgery and at 2, 6, 12 and 24 months after surgery. Results. Twenty-four female patients with right thoracic curves had a mean thoracic Cobb angle of 53.0° before surgery, decreasing to 24.9° two years after surgery. The mean lumbar compensatory Cobb angle was 43.5° before surgery, spontaneously correcting to 25.4° two years after surgery, indicating balance between the thoracic and lumbar scoliotic curves. The lumbar correction achieved (41.8%) compares favourably to previous studies. Conclusions. Selective thoracoscopic anterior fusion allows spontaneous lumbar curve correction and achieves coronal balance of main thoracic and compensatory lumbar curves, good cosmesis and patient satisfaction. Correction and balance are maintained 24 months after surgery.

The 3D kinematics of the single leg flat and decline squat

Background: Pre-participation screening is commonly used to measure and assess potential intrinsic injury risk. The single leg squat is one such clinical screening measure used to assess lumbopelvic stability and associated intrinsic injury risk. With the addition of a decline board, the single leg decline squat (SLDS) has been shown to reduce ankle dorsiflexion restrictions and allowed greater sagittal plane movement of the hip and knee. On this basis, the SLDS has been employed in the Cricket Australia physiotherapy screening protocols as a measure of lumbopelvic control in the place of the more traditional single leg flat squat (SLFS). Previous research has failed to demonstrate which squatting technique allows for a more comprehensive assessment of lumbopelvic stability. Tenuous links are drawn between kinematics and hip strength measures within the literature for the SLS. Formal evaluation of subjective screening methods has also been suggested within the literature. Purpose: This study had several focal points namely 1) to compare the kinematic differences between the two single leg squatting conditions, primarily the five key kinematic variables fundamental to subjectively assess lumbopelvic stability; 2) determine the effect of ankle dorsiflexion range of motion has on squat kinematics in the two squat techniques; 3) examine the association between key kinematics and subjective physiotherapists’ assessment; and finally 4) explore the association between key kinematics and hip strength. Methods: Nineteen (n=19) subjects performed five SLDS and five SLFS on each leg while being filmed by an 8 camera motion analysis system. Four hip strength measures (internal/external rotation and abd/adduction) and ankle dorsiflexion range of motion were measured using a hand held dynamometer and a goniometer respectively on 16 of these subjects. The same 16 participants were subjectively assessed by an experienced physiotherapist for lumbopelvic stability. Paired samples t-tests were performed on the five predetermined kinematic variables to assess the differences between squat conditions. A Bonferroni correction for multiple comparisons was used which adjusted the significance value to p = 0.005 for the paired t-tests. Linear regressions were used to assess the relationship between kinematics, ankle range of motion and hip strength measures. Bivariate correlations between hip strength measures and kinematics and pelvic obliquity were employed to investigate any possible relationships. Results: 1) Significant kinematic differences between squats were observed in dominant (D) and non-dominant (ND) end of range hip external rotation (ND p = <0.001; D p = 0.004) and hip adduction kinematics (ND p = <0.001; D p = <0.001). With the mean angle, only the non-dominant leg observed significant differences in hip adduction (p = 0.001) and hip external rotation (p = <0.001); 2) Significant linear relationships were observed between clinical measures of ankle dorsiflexion and sagittal plane kinematic namely SLFS dominant ankle (p = 0.006; R2 = .429), SLFS non-dominant knee (p = 0.015; R2 = .352) and SLFS non-dominant ankle (p = 0.027; R2 = .305) kinematics. Only the dominant ankle (p = 0.020; R2 = .331) was found to have a relationship with the decline squat. 3) Strength measures had tenuous associations with the subjective assessments of lumbopelvic stability with no significant relationships being observed. 4) For the non-dominant leg, external rotation strength and abduction strength were found to be significantly correlated with hip rotation kinematics (Newtons r = 0.458 p = 0.049; Normalised for bodyweight: r = 0.469; p = 0.043) and pelvic obliquity (normalised for bodyweight: r = 0.498 p = 0.030) respectively for the SLFS only. No significant relationships were observed in the dominant leg for either squat condition. Some elements of the hip strength screening protocols had linear relationships with kinematics of the lower limb, particularly the sagittal plane movements of the knee and ankle. Strength measures had tenuous associations with the subjective assessments of lumbopelvic stability with no significant relationships being observed; Discussion: The key finding of this study illustrated that kinematic differences can occur at the hip without significant kinematic differences at the knee as a result of the introduction of a decline board. Further observations reinforce the role of limited ankle dorsiflexion range of motion on sagittal plane movement of the hip and knee and in turn multiplanar kinematics of the lower limb. The kinematic differences between conditions have clinical implications for screening protocols that employ frontal plane movement of the knee as a guide for femoral adduction and rotation. Subjects who returned stronger hip strength measurements also appeared to squat deeper as characterised by differences in sagittal plane kinematics of the knee and ankle. Despite the aforementioned findings, the relationship between hip strength and lower limb kinematics remains largely tenuous in the assessment of the lumbopelvic stability using the SLS. The association between kinematics and the subjective measures of lumbopelvic stability also remain tenuous between and within SLS screening protocols. More functional measures of hip strength are needed to further investigate these relationships. Conclusion: The type of SLS (flat or decline) should be taken into account when screening for lumbopelvic stability. Changes to lower limb kinematics, especially around the hip and pelvis, were observed with the introduction of a decline board despite no difference in frontal plane knee movements. Differences in passive ankle dorsiflexion range of motion yielded variations in knee and ankle kinematics during a self-selected single leg squatting task. Clinical implications of removing posterior ankle restraints and using the knee as a guide to illustrate changes at the hip may result in inaccurate screening of lumbopelvic stability. The relationship between sagittal plane lower limb kinematics and hip strength may illustrate that self-selected squat depth may presumably be a useful predictor of the lumbopelvic stability. Further research in this area is required.

CT and X-Ray analysis of sagittal curve changes following thoracoscopic anterior scoliosis surgery

Normal thoracic kyphosis Cobb angle for T5-T12 is most commonly reported as a range of 20-40º [1]. Patients with adolescent idiopathic scoliosis (AIS) exhibit a reduced thoracic kyphosis or hypokyphosis [2] accompanying the coronal and rotary distortion components. As a result, surgical restoration of the thoracic kyphosis while maintaining lumbar lordosis and overall sagittal balance is a critical aspect of achieving good clinical outcomes in AIS patients. Previous studies report an increase in thoracic kyphosis after anterior surgical approaches [3] and a flattening of sagittal contours following posterior approaches [4]. Difficulties with measuring sagittal parameters on radiographs are avoided with reformatted sagittal CT reconstructions due to the superior endplate clarity afforded by this imaging modality and are the subject of analysis in this study.

CT and radiographic analysis of sagittal profile changes after thoracoscopic anterior scoliosis surgery

Background. Previous studies report an increase in thoracic kyphosis after anterior approaches and a flattening of sagittal contours following posterior approaches. Difficulties with measuring sagittal parameters on radiographs are avoided with reformatted sagittal CT reconstructions due to the superior endplate clarity afforded by this imaging modality. Methods. A prospective study of 30 Lenke 1 adolescent idiopathic scoliosis (AIS) patients receiving selective thoracoscopic anterior spinal fusion (TASF) was performed. Participants had ethically approved low dose CT scans at minimum 24 months after surgery in addition to their standard care following surgery. The change in sagittal contours on supine CT was compared to standing radiographic measurements of the same patients and with previous studies. Inter-observer variability was assessed as well as whether hypokyphotic and normokyphotic patient groups responded differently to the thoracoscopic anterior approach. Results. Mean T5-12 kyphosis Cobb angle increased by 11.8 degrees and lumbar lordosis increased by 5.9 degrees on standing radiographs two years after surgery. By comparison, CT measurements of kyphosis and lordosis increased by 12.3 degrees and 7.0 degrees respectively. 95% confidence intervals for inter-observer variability of sagittal contour measurements on supine CT ranged between 5-8 degrees. TASF had a slightly greater corrective effect on patients who were hypokyphotic before surgery compared with those who were normokyphotic. Conclusions. Restoration of sagittal profile is an important goal of scoliosis surgery, but reliable measurement with radiographs suffers from poor endplate clarity. TASF significantly improves thoracic kyphosis and lumbar lordosis while preserving proximal and distal junctional alignment in thoracic AIS patients. Supine CT allows greater endplate clarity for sagittal Cobb measurements and linear relationships were found between supine CT and standing radiographic measurements. In this study, improvements in sagittal kyphosis and lordosis following surgery were in agreement with prior anterior surgery studies, and add to the current evidence suggesting that anterior correction is more capable than posterior approaches of addressing the sagittal component of both the instrumented and adjacent non instrumented segments following surgical correction of progressive Lenke 1 idiopathic scoliosis.

Bayesian experimental design for models with intractable likelihoods

In this paper we present a methodology for designing experiments for efficiently estimating the parameters of models with computationally intractable likelihoods. The approach combines a commonly used methodology for robust experimental design, based on Markov chain Monte Carlo sampling, with approximate Bayesian computation (ABC) to ensure that no likelihood evaluations are required. The utility function considered for precise parameter estimation is based upon the precision of the ABC posterior distribution, which we form efficiently via the ABC rejection algorithm based on pre-computed model simulations. Our focus is on stochastic models and, in particular, we investigate the methodology for Markov process models of epidemics and macroparasite population evolution. The macroparasite example involves a multivariate process and we assess the loss of information from not observing all variables.

GABAergic modification of myopic and hyperopic ocular tissue effects on scleral fibroblast growth

Purpose: Myopia is a common eye disorder affecting up to 90% of children in South East Asia and 30% of the population worldwide. Myopia of high severity is a leading cause of blindness around the world (4th to 5th most common). Changes and remodelling of the sclera i.e. increase cellular proliferation & increase protein synthesis within scleral cells (↑ scleral DNA) and thinning and lose of extracellular matrix of sclera (↓ scleral GAG synthesis) have been linked to myopic eye growth in animal models. Signals acting on the sclera are thought to originate in the retina, and are modulated by the retinal pigment epithelium (RPE) with limited evidence suggesting that the RPE can modify scleral cell growth in culture. However, the mechanism of retinal signal transmission and the role of posterior eye cup tissue, including the RPE, in mediating changes in scleral fibroblast growth during myopia development are unclear. Retinal transmitter systems are critically involved in pathways regulating eye growth, which ultimately lead to alterations in the sclera if eye size is to change. A dopaminergic agonist and muscarinic antagonists decrease the proliferation of scleral chondrocytes when co-cultured with chick’s retinal pigment epithelium (RPE). GABA receptors have recently been localised to chick sclera. We therefore hypothesised that posterior eye cup tissue from myopic eyes would stimulate and from hyperopic eyes would inhibit growth of scleral fibroblasts in vitro and that GABAergic agents could directly interact with scleral cells or indirectly modify the effects of myopic and hyperopic posterior eye cup tissue on scleral fibroblast growth. Method: Fibroblastic cells obtained from 8-day-old chick sclera were used to establish cell banks. Two major experiments were performed. Experiment 1: To determine if posterior eye cup tissues from myopic eye stimulates and hyperopic eye inhibits scleral cell proliferation, when co-cultured with scleral cells in vitro. This study comprised two linked experiments, i) monocular visual treatments of FDM (form-deprivation myopia), LIM (lens-induced myopia) and LIH (lens-induced hyperopia) with assessment of the effect of full punch eye cup tissue on DNA and GAG synthesis by cultured chick scleral fibroblasts, and ii) binocular visual treatments comprising LIM and LIH with assessment of the effect of individual layers of eye cup tissues (neural retina, RPE and choroid) on cultured chick scleral fibroblasts. Visual treatment was applied for 3 days. Experiment 2: To determine the direct interaction of GABA agents on scleral cell growth and to establish whether GABA agents modify the stimulatory/inhibitory effect of myopic and hyperopic posterior eye cup tissues on cultured scleral cell growth in vitro. Two linked experiments were performed. i) GABA agonists (muscimol and baclofen) and GABA antagonists (bicuculine (-), CGP46381 and TPMPA) were added to scleral cell culture medium to determine their direct effect on scleral cells. ii) GABAergic agents (agonists and antagonists) were administered to scleral fibroblasts co-cultured with posterior eye cup tissue (retina, RPE, retina/RPE, RPE/choroid). Ocular tissues were obtained from chick eyes wearing +15D (LIH) or -15D lenses (LIM) for 3 days. In both experiments, tissues were added to hanging cell culture insert (pore size 1.0ìm) placed over each well of 24 well plates while scleral cells were cultured in DMEM/F12, Glutamax (Gibco) plus 10% FBS and penicillin/streptomycin (50U/ml)) and fungizone (1.25ug/ml) (Gibco), at seeding density of 30,000 cells/well at the bottom of the well and allowed to grow for 3 days. Scleral cells proliferation rate throughout the study was evaluated by determining GAG and DNA content of scleral cells using Dimethylmethylene blue (DMMB) dye and Quant-iTTm Pico Green® dsDNA reagent respectively. Results and analysis: Based on DNA and GAG content, there was no significant difference in tissue effect of LIM and LIH eyes on scleral fibroblast growth (DNA: 8.4 ± 1.1μg versus 9.3 ± 2.3 μg, p=0.23; GAG: 10.13 ± 1.4 μg versus 12.67 ± 1.2 μg, F2,23=6.16, p=0.0005) when tissues were obtained from monocularly treated chick eyes (FDM or +15D lens or -15D lens over right eyes with left eyes untreated) and co-cultured as full punch. When chick eyes were treated binocularly with -15D lens (LIM) right eye and +15D lens (LIH) left eyes and tissue layers were separated, the retina from LIM eyes did not stimulate scleral cell proliferation compared to LIH eyes (DNA: 27.2 ± 6.7 μg versus 23.2 ± 1.5 μg, p=0.23; GAG: 28.1 ±3.7 μg versus 28.7 ± 4.2 μg, p=0.21). Similarly, the LIH and LIM choroid did not produce a differential effect based on DNA (LIM 46.9 ± 6.4 μg versus LIH 53.5 ± 4.7 μg, p=0.18), however the choroid from LIH eyes induced higher scleral GAG content than from LIM eyes (32.5 ± 6.7 μg versus 18.9 ± 1.2 μg, p=0.023). In contrast, the RPE from LIM eyes caused a significant increase in fibroblast proliferation whereas the RPE from LIH eyes was relatively inhibitory (72.4 ± 6.3 μg versus 27.9 ± 2.3 μg, F1, 6=69.99, p=0.0005). GAG data were opposite to DNA data e.g. the RPE from LIH eyes increased (33.7 ± 7.9 μg) while the RPE from LIM eyes decreased (28.2 ± 3.0 μg) scleral cell growth (F1, 6=13.99, p=0.010). Based on DNA content, GABA agents had a small direct effect on scleral cell growth; GABA agonists increased (21.4 ± 1.0% and 18.3 ± 1.0% with muscimol and baclofen, p=0.0021), whereas GABA antagonists decreased fibroblast proliferation (-23.7 ± 0.9% with bicuculine & CGP46381 and -28.1 ± 0.5% with TPMPA, p=0.0004). GABA agents also modified the effect of LIM and LIH tissues (p=0.0005).The increase in proliferation rate of scleral fibroblasts co-cultured with tissues (RPE, retina, RPE/retina and RPE/choroid) from LIM treated eyes was enhanced by GABA agonists (muscimol: 27.4 ± 1.2%, 35.8 ± 1.6%, 8.4 ± 0.3% and 11.9 ± 0.6%; baclofen: 27.0 ± 1.0%, 15.8 ± 1.5%, 16.8 ± 1.2% and 15.4 ± 0.4%, p=0.014) whereas GABA antagonists further reduced scleral fibroblasts growth (bicuculine: -52.5 ± 2.5%, -36.9 ± 1.4%, -37.5 ± 0.6% and -53.7 ± 0.9%; TPMPA: 57.3 ± 1.3%, -15.7 ± 1.2%, -33.5 ± 0.4% and -45.9 ± 1.5%; CGP46381: -51.9 ± 1.6%, -28.5 ± 1.5%, -25.4 ± 2.0% and -45.5 ± 1.9% respectively, p=0.0034). GAG data were opposite to DNA data throughout the experiment e.g. GABA agonists further inhibited while antagonists relatively enhanced scleral fibroblasts growth for both LIM and LIH tissue co-culture. The effect of GABA agents was relatively lower (p=0.0004) for tissue from LIH versus LIM eyes but was in a similar direction. There was a significant drug effect on all four tissue types e.g. RPE, retina, RPE/retina and RPE/choroid for both LIM and LIH tissue co-culture (F20,92=3.928, p=0.0005). However, the effect of GABA agents was greatest in co-culture with RPE tissue (F18,36=4.865, p=0.0005). Summary and Conclusion: 1) Retinal defocus signals are transferred to RPE and choroid which then exert their modifying effect on scleral GAG and DNA synthesis either through growth stimulating factors or directly interacting with scleral cells in process of scleral remodeling during LIM and LIH visual conditions. 2) GABAergic agents affect the proliferation of scleral fibroblasts both directly and when co-cultured with ocular tissues in vitro.