Paediatric population pharmacokinetics of itraconazole and its active metabolite hydroxy-itraconazole in cystic fibrosis and bone marrow transplant patients

Objectives: The aim of the study was to characterise the population pharmacokinetics (popPK) properties of itraconazole (ITRA) and its active metabolite hydroxy-ITRA in a representative paediatric population of cystic fibrosis (CF) and bone marrow transplant (BMT) patients. The goals were to determine the relative bioavailability between the two oral formulations, and to explore improved dosage regimens in these patients. Methods: All paediatric patients with CF taking oral ITRA for the treatment of allergic bronchopulmonary aspergillosis and patients undergoing BMT who were taking ITRA for prophylaxis of any fungal infection were eligible for the study. A minimum of two blood samples were drawn after the capsules and also after switching to oral solution, or vice versa. ITRA and hydroxy-ITRA plasma concentrations were measured by HPLC[1]. A nonlinear mixed-effect modelling approach (NONMEM 5.1.1) was used to describe the PK of ITRA and hydroxy-ITRA simultaneously. Simulations were used to assess dosing strategies in these patients. Results: Forty-nine patients (29CF, 20 BMT) were recruited to the study who provided 227 blood samples for the population analysis. A 1-compartment model with 1st order absorption and elimination best described ITRA kinetics, with 1st order conversion to hydroxy-ITRA. For ITRA, the apparent clearance (ClItra/F) and volume of distribution (Vitra/F) was 35.5L/h and 672L, respectively; the absorption rate constant for the capsule formulation was 0.0901 h-1 and for the oral solution formulation it was 0.959 h-1. The capsule comparative bioavailability (vs. solution) was 0.55. For hydroxy-ITRA, the apparent volume of distribution and clearance were 10.6 L and 5.28 L/h, respectively. Of several screened covariates only allometrically scaled total body weight significantly improved the fit to the data. No difference between the two populations was found. Conclusion: The developed popPK model adequately described the pharmacokinetics of ITRA and hydroxy-ITRA in paediatric patients with CF and patients undergoing BMT. High inter-patient variability confirmed previous data in CF[2], leukaemia and BMT[3] patients. From the population model, simulations showed the standard dose (5 mg/kg/day) needs to be doubled for the solution formulation and even 4 times more given of the capsules to achieve an adequate target therapeutic trough plasma concentration of 0.5 mg/L[4] in these patients.

Estimating ECAP threshold from the variability of the response

Electrical compound action potentials (ECAPs) of the cochlear nerve are used clinically for quick and efficient cochlear implant parameter setting. The ECAP is the aggregate response of nerve fibres at various distances from the recording electrode, and the magnitude of the ECAP is therefore related to the number of fibres excited by a particular stimulus. Current methods, such as the masker-probe or alternating polarity methods, use the ECAP magnitude at various stimulus levels to estimate the neural threshold, from which the parameters are calculated. However, the correlation between ECAP threshold and perceptual threshold is not always good, with ECAP threshold typically being much higher than perceptual threshold. The lower correlation is partly due to the very different pulse rates used for ECAPs (below 100 Hz) and clinical programs (hundreds of Hz up to several kHz). Here we introduce a new method of estimating ECAP threshold for cochlear implants based upon the variability of the response. At neural threshold, where some but not all fibers respond, there is a different response each trial. This inter-trial variability can be detected overlaying the constant variability of the system noise. The large stimulus artefact, which requires additional trials for artefact rejection in the standard ECAP magnitude methods, is not consequential, as it has little variability. The variability method therefore consists of simply presenting a pulse and recording the ECAP, and as such is quicker than other methods. It also has the potential to be run at high rates like clinical programs, potentially improving the correlation with behavioural threshold. Preliminary data is presented that shows a detectable variability increase shortly after probe offset, at probe levels much lower than those producing a detectable ECAP magnitude. Care must be taken, however, to avoid saturation of the recording amplifier saturation; in our experiments we found a gain of 300 to be optimal.

Examination variability in short-wavelength automated perimetry

The study evaluated sources of within- and between-subject variability in standard white-on-white (W-W) perimetry and short-wavelength automated perimetry (SWAP). The Influence of staircase strategy on the fatigue effect in W-W perimetry was investigated for a 4 dB single step, single reversal strategy; a variable step size, single reversal dynamic strategy; and the standard 4-2 dB double reversal strategy. The fatigue effect increased as the duration of the examination Increased and was greatest in the second eye for all strategies. The fatigue effect was lowest for the 4dB strategy, which exhibited the shortest examination time and was greatest for the 4-2 dB strategy, which exhibited the longest examination time. Staircase efficiency was lowest for the 4 dB strategy and highest for the dynamic strategy which thus offers a reduced examination time and low inter-subject variability. The normal between-subject variability of SWAP was determined for the standard 4-2 dB double reversal strategy and the 3 dB single reversal FASTPAC strategy and compared to that of W-W perimetry, The decrease in sensitivity with Increase in age was greatest for SWAP. The between-subject variability of SWAP was greater than W-W perimetry. Correction for the Influence of ocular media absorption reduced the between-subject variability of SWAP, The FASTPAC strategy yielded the lowest between-subject variability In SWAP, but the greatest between-subject variability In WoW perimetry. The greater between-subject variability of SWAP has profound Implications for the delineation of visual field abnormality, The fatigue effect for the Full Threshold strategy in SWAP was evaluated with conventional opaque, and translucent occlusion of the fellow eye. SWAP exhibited a greater fatigue effect than W-W perimetry. Translucent occlusion reduced the between-subject variability of W-W perimetry but Increased the between-subject variability of SWAP. The elevation of sensitivity was greater with translucent occlusion which has implications for the statistical analysis of W-W perimetry and SWAP. The influence of age-related cataract extraction and IOL implantation upon the visual field derived by WoW perimetry and SWAP was determined. Cataract yielded a general reduction In sensitivity which was preferentially greater in SWAP, even after the correction of SWAP for the attenuation of the stimulus by the ocular media. There was no correlation between either backward or forward light scatter and the magnitude of the attenuation of W-W or SWAP sensitivity. The post-operative mean deviation in SWAP was positive and has ramifications for the statistical Interpretation of SWAP. Short-wavelength-sensitive pathway isolation was assessed as a function of stimulus eccentricity using the two-colour Increment threshold method. At least 15 dB of SWS pathway Isolation was achieved for 440 nm, 450 nm and 460 nm stimuli at a background luminance of 100 cdm-2, There was a slight decrease In SWS pathway Isolation for all stimulus wavelengths with increasing eccentricity which was not of clinical significance. Adopting a 450 nm stimulus may reduce between-subject variability In SWAP due to a reduction In ocular media absorption and macular pigment absorption.

Population pharmacokinetic and pharmacogenetic analysis of tacrolimus in paediatric liver transplant patients

Aims - To build a population pharmacokinetic model that describes the apparent clearance of tacrolimus and the potential demographic, clinical and genetically controlled factors that could lead to inter-patient pharmacokinetic variability within children following liver transplantation. Methods - The present study retrospectively examined tacrolimus whole blood pre-dose concentrations (n = 628) of 43 children during their first year post-liver transplantation. Population pharmacokinetic analysis was performed using the non-linear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance and influential covariates. Results - The final model identified time post-transplantation and CYP3A5*1 allele as influential covariates on tacrolimus apparent clearance according to the following equation: TVCL = 12.9 x (Weight/13.2)0.35 x EXP (-0.0058 x TPT) x EXP (0.428 x CYP3A5) where TVCL is the typical value for apparent clearance, TPT is time post-transplantation in days and the CYP3A5 is 1 where *1 allele is present and 0 otherwise. The population estimate and inter-individual variability (%CV) of tacrolimus apparent clearance were found to be 0.977 l h−1 kg−1 (95% CI 0.958, 0.996) and 40.0%, respectively, while the residual variability between the observed and predicted concentrations was 35.4%. Conclusion Tacrolimus apparent clearance was influenced by time post-transplantation and CYP3A5 genotypes. The results of this study, once confirmed by a large scale prospective study, can be used in conjunction with therapeutic drug monitoring to recommend tacrolimus dose adjustments that take into account not only body weight but also genetic and time-related changes in tacrolimus clearance.

Localising the auditory N1m with event-related beamformers:localisation accuracy following bilateral and unilateral stimulation

The auditory evoked N1m-P2m response complex presents a challenging case for MEG source-modelling, because symmetrical, phase-locked activity occurs in the hemispheres both contralateral and ipsilateral to stimulation. Beamformer methods, in particular, can be susceptible to localisation bias and spurious sources under these conditions. This study explored the accuracy and efficiency of event-related beamformer source models for auditory MEG data under typical experimental conditions: monaural and diotic stimulation; and whole-head beamformer analysis compared to a half-head analysis using only sensors from the hemisphere contralateral to stimulation. Event-related beamformer localisations were also compared with more traditional single-dipole models. At the group level, the event-related beamformer performed equally well as the single-dipole models in terms of accuracy for both the N1m and the P2m, and in terms of efficiency (number of successful source models) for the N1m. The results yielded by the half-head analysis did not differ significantly from those produced by the traditional whole-head analysis. Any localisation bias caused by the presence of correlated sources is minimal in the context of the inter-individual variability in source localisations. In conclusion, event-related beamformers provide a useful alternative to equivalent-current dipole models in localisation of auditory evoked responses.

Inter-site and inter-scanner diffusion MRI data harmonization.

We propose a novel method to harmonize diffusion MRI data acquired from multiple sites and scanners, which is imperative for joint analysis of the data to significantly increase sample size and statistical power of neuroimaging studies. Our method incorporates the following main novelties: i) we take into account the scanner-dependent spatial variability of the diffusion signal in different parts of the brain; ii) our method is independent of compartmental modeling of diffusion (e.g., tensor, and intra/extra cellular compartments) and the acquired signal itself is corrected for scanner related differences; and iii) inter-subject variability as measured by the coefficient of variation is maintained at each site. We represent the signal in a basis of spherical harmonics and compute several rotation invariant spherical harmonic features to estimate a region and tissue specific linear mapping between the signal from different sites (and scanners). We validate our method on diffusion data acquired from seven different sites (including two GE, three Philips, and two Siemens scanners) on a group of age-matched healthy subjects. Since the extracted rotation invariant spherical harmonic features depend on the accuracy of the brain parcellation provided by Freesurfer, we propose a feature based refinement of the original parcellation such that it better characterizes the anatomy and provides robust linear mappings to harmonize the dMRI data. We demonstrate the efficacy of our method by statistically comparing diffusion measures such as fractional anisotropy, mean diffusivity and generalized fractional anisotropy across multiple sites before and after data harmonization. We also show results using tract-based spatial statistics before and after harmonization for independent validation of the proposed methodology. Our experimental results demonstrate that, for nearly identical acquisition protocol across sites, scanner-specific differences can be accurately removed using the proposed method.

Modeling long-term variability and change of soil moisture and groundwater level - from catchment to global scale

The water stored in and flowing through the subsurface is fundamental for sustaining human activities and needs, feeding water and its constituents to surface water bodies and supporting the functioning of their ecosystems. Quantifying the changes that affect the subsurface water is crucial for our understanding of its dynamics and changes driven by climate change and other changes in the landscape, such as in land-use and water-use. It is inherently difficult to directly measure soil moisture and groundwater levels over large spatial scales and long times. Models are therefore needed to capture the soil moisture and groundwater level dynamics over such large spatiotemporal scales. This thesis develops a modeling framework that allows for long-term catchment-scale screening of soil moisture and groundwater level changes. The novelty in this development resides in an explicit link drawn between catchment-scale hydroclimatic and soil hydraulics conditions, using observed runoff data as an approximation of soil water flux and accounting for the effects of snow storage-melting dynamics on that flux. Both past and future relative changes can be assessed by use of this modeling framework, with future change projections based on common climate model outputs. By direct model-observation comparison, the thesis shows that the developed modeling framework can reproduce the temporal variability of large-scale changes in soil water storage, as obtained from the GRACE satellite product, for most of 25 large study catchments around the world. Also compared with locally measured soil water content and groundwater level in 10 U.S. catchments, the modeling approach can reasonably well reproduce relative seasonal fluctuations around long-term average values. The developed modeling framework is further used to project soil moisture changes due to expected future climate change for 81 catchments around the world. The future soil moisture changes depend on the considered radiative forcing scenario (RCP) but are overall large for the occurrence frequency of dry and wet events and the inter-annual variability of seasonal soil moisture. These changes tend to be higher for the dry events and the dry season, respectively, than for the corresponding wet quantities, indicating increased drought risk for some parts of the world.

Variability and trends of downward surface global solar radiation over the Iberian Peninsula based on ERA-40 reanalysis

A climate study of the incidence of downward surface global solar radiation (SSRD) in the Iberian Peninsula (IP) based primarily on ERA-40 reanalysis is presented. NCEP/NCAR reanalysis and ground-based records from several Portuguese and Spanish stations have been also considered. The results showthat reanalysis can capture a similar inter-annual variability as compared to ground-based observations, especially on a monthly basis, even though annual ERA-40 (NCEP/NCAR) values tend to underestimate (overestimate) the observations with a mean relative difference of around 20Wm–2 (40Wm–2). On the other hand, ground-based measurements in Portuguese stations during the period 1964–1989 show a tendency to decrease until the mid-1970s followed by an increase up to the end of the study period, in line with the dimming/brightening phenomenon reported in the literature. Nevertheless, there are different temporal behaviours as a greater increase since the 1970s is observed in the south and less industrialized regions. Similarly, the ERA-40 reanalysis shows a noticeable decrease until the early 1970s followed by a slight increase up to the end of the 1990s, suggesting a dimming/brightening transition around the early 1970s, earlier in the south and centre and later in the north of the IP. Although there are slight differences in the magnitude of the trends as well as the turning year of the dimming/brightening periods, the decadal changes of ERA-40 fairly agree with the ground-based observations in Portugal and Spain, in contrast to most of the literature for other regions of the world, and is used in the climatology of the SSRD in the study area. NCEP/NCAR reanalysis does not capture the decadal variations of SSRD in the IP. The results show that part of the decadal variability of the global radiation in the IP is related to changes in cloud cover (represented in ERA-40).

The S.T.A.B. Trial - Standardised Testing of Artificial Blood. A comparative study of various products that may be used as artificial blood for high fidelity simulation training in the critical care setting

Aim: In the current climate of medical education, there is an ever-increasing demand for and emphasis on simulation as both a teaching and training tool. The objective of our study was to compare the realism and practicality of a number of artificial blood products that could be used for high-fidelity simulation. Method: A literature and internet search was performed and 15 artificial blood products were identified from a variety of sources. One product was excluded due to its potential toxicity risks. Five observers, blinded to the products, performed two assessments on each product using an evaluation tool with 14 predefined criteria including color, consistency, clotting, and staining potential to manikin skin and clothing. Each criterion was rated using a five-point Likert scale. The products were left for 24 hours, both refrigerated and at room temperature, and then reassessed. Statistical analysis was performed to identify the most suitable products, and both inter- and intra-rater variability were examined. Results: Three products scored consistently well with all five assessors, with one product in particular scoring well in almost every criterion. This highest-rated product had a mean rating of 3.6 of 5.0 (95% posterior Interval 3.4-3.7). Inter-rater variability was minor with average ratings varying from 3.0 to 3.4 between the highest and lowest scorer. Intrarater variability was negligible with good agreement between first and second rating as per weighted kappa scores (K = 0.67). Conclusion: The most realistic and practical form of artificial blood identified was a commercial product called KD151 Flowing Blood Syrup. It was found to be not only realistic in appearance but practical in terms of storage and stain removal.

Scatter difference NAP for SVM speaker recognition

This paper presents Scatter Difference Nuisance Attribute Projection (SD-NAP) as an enhancement to NAP for SVM-based speaker verification. While standard NAP may inadvertently remove desirable speaker variability, SD-NAP explicitly de-emphasises this variability by incorporating a weighted version of the between-class scatter into the NAP optimisation criterion. Experimental evaluation of SD-NAP with a variety of SVM systems on the 2006 and 2008 NIST SRE corpora demonstrate that SD-NAP provides improved verification performance over standard NAP in most cases, particularly at the EER operating point.

Image acquisition and manipulation protocols for CT-PET fusion to improve the accuracy of gross tumour volume localisation for 3D conformal radiotherapy for lung cancer

Aims: To develop clinical protocols for acquiring PET images, performing CT-PET registration and tumour volume definition based on the PET image data, for radiotherapy for lung cancer patients and then to test these protocols with respect to levels of accuracy and reproducibility. Method: A phantom-based quality assurance study of the processes associated with using registered CT and PET scans for tumour volume definition was conducted to: (1) investigate image acquisition and manipulation techniques for registering and contouring CT and PET images in a radiotherapy treatment planning system, and (2) determine technology-based errors in the registration and contouring processes. The outcomes of the phantom image based quality assurance study were used to determine clinical protocols. Protocols were developed for (1) acquiring patient PET image data for incorporation into the 3DCRT process, particularly for ensuring that the patient is positioned in their treatment position; (2) CT-PET image registration techniques and (3) GTV definition using the PET image data. The developed clinical protocols were tested using retrospective clinical trials to assess levels of inter-user variability which may be attributed to the use of these protocols. A Siemens Somatom Open Sensation 20 slice CT scanner and a Philips Allegro stand-alone PET scanner were used to acquire the images for this research. The Philips Pinnacle3 treatment planning system was used to perform the image registration and contouring of the CT and PET images. Results: Both the attenuation-corrected and transmission images obtained from standard whole-body PET staging clinical scanning protocols were acquired and imported into the treatment planning system for the phantom-based quality assurance study. Protocols for manipulating the PET images in the treatment planning system, particularly for quantifying uptake in volumes of interest and window levels for accurate geometric visualisation were determined. The automatic registration algorithms were found to have sub-voxel levels of accuracy, with transmission scan-based CT-PET registration more accurate than emission scan-based registration of the phantom images. Respiration induced image artifacts were not found to influence registration accuracy while inadequate pre-registration over-lap of the CT and PET images was found to result in large registration errors. A threshold value based on a percentage of the maximum uptake within a volume of interest was found to accurately contour the different features of the phantom despite the lower spatial resolution of the PET images. Appropriate selection of the threshold value is dependant on target-to-background ratios and the presence of respiratory motion. The results from the phantom-based study were used to design, implement and test clinical CT-PET fusion protocols. The patient PET image acquisition protocols enabled patients to be successfully identified and positioned in their radiotherapy treatment position during the acquisition of their whole-body PET staging scan. While automatic registration techniques were found to reduce inter-user variation compared to manual techniques, there was no significant difference in the registration outcomes for transmission or emission scan-based registration of the patient images, using the protocol. Tumour volumes contoured on registered patient CT-PET images using the tested threshold values and viewing windows determined from the phantom study, demonstrated less inter-user variation for the primary tumour volume contours than those contoured using only the patient’s planning CT scans. Conclusions: The developed clinical protocols allow a patient’s whole-body PET staging scan to be incorporated, manipulated and quantified in the treatment planning process to improve the accuracy of gross tumour volume localisation in 3D conformal radiotherapy for lung cancer. Image registration protocols which factor in potential software-based errors combined with adequate user training are recommended to increase the accuracy and reproducibility of registration outcomes. A semi-automated adaptive threshold contouring technique incorporating a PET windowing protocol, accurately defines the geometric edge of a tumour volume using PET image data from a stand alone PET scanner, including 4D target volumes.

Interactions between energy intake and expenditure in the development and treatment of obesity.

Summary There are four interactions to consider between energy intake (EI) and energy expenditure (EE) in the development and treatment of obesity. (1) Does sedentariness alter levels of EI or subsequent EE? and (2) Do high levels of EI alter physical activity or exercise? (3) Do exercise-induced increases in EE drive EI upwards and undermine dietary approaches to weight management and (4) Do low levels of EI elevate or decrease EE? There is little evidence that sedentariness alters levels of EI. This lack of cross-talk between altered EE and EI appears to promote a positive EB. Lifestyle studies also suggest that a sedentary routine actually offers the opportunity for over-consumption. Substantive changes in non exercise activity thermogenesis are feasible, but not clearly demonstrated. Cross talk between elevated EE and EI is initially too weak and takes too long to activate, to seriously threaten dietary approaches to weight management. It appears that substantial fat loss is possible before intake begins to track a sustained elevation of EE. There is more evidence that low levels of EI does lower physical activity levels, in relatively lean men under conditions of acute or prolonged semi-starvation and in dieting obese subjects. During altered EB there are a number of small but significant changes in the components of EE, including (i) sleeping and basal metabolic rate, (ii) energy cost of weight change alters as weight is gained or lost, (iii) exercise efficiency, (iv) energy cost of weight bearing activities, (v) during substantive overfeeding diet composition (fat versus carbohydrate) will influence the energy cost of nutrient storage by ~ 15%. The responses (i-v) above are all “obligatory” responses. Altered EB can also stimulate facultative behavioural responses, as a consequence of cross-talk between EI and EE. Altered EB will lead to changes in the mode duration and intensity of physical activities. Feeding behaviour can also change. The degree of inter-individual variability in these responses will define the scope within which various mechanisms of EB compensation can operate. The relative importance of “obligatory” versus facultative, behavioural responses -as components of EB control- need to be defined.

Statistical modeling to determine resonant frequency information present in combustion chamber pressure signals

A statistical modeling method to accurately determine combustion chamber resonance is proposed and demonstrated. This method utilises Markov-chain Monte Carlo (MCMC) through the use of the Metropolis-Hastings (MH) algorithm to yield a probability density function for the combustion chamber frequency and find the best estimate of the resonant frequency, along with uncertainty. The accurate determination of combustion chamber resonance is then used to investigate various engine phenomena, with appropriate uncertainty, for a range of engine cycles. It is shown that, when operating on various ethanol/diesel fuel combinations, a 20% substitution yields the least amount of inter-cycle variability, in relation to combustion chamber resonance.

The effects of muscle fatigue on knee function during landing

The human knee acts as a sophisticated shock absorber during landing movements. The ability of the knee to perform this function in the real world is remarkable given that the context of the landing movement may vary widely between performances. For this reason, humans must be capable of rapidly adjusting the mechanical properties of the knee under impact load in order to satisfy many competing demands. However, the processes involved in regulating these properties in response to changing constraints remain poorly understood. In particular, the effects of muscle fatigue on knee function during step landing are yet to be fully explored. Fatigue of the knee muscles is significant for 2 reasons. First, it is thought to have detrimental effects on the ability of the knee to act as a shock absorber and is considered a risk factor for knee injury. Second, fatigue of knee muscles provides a unique opportunity to examine the mechanisms by which healthy individuals alter knee function. A review of the literature revealed that the effect of fatigue on knee function during landing has been assessed by comparing pre and postfatigue measurements, with fatigue induced by a voluntary exercise protocol. The information is limited by inconsistent results with key measures, such as knee stiffness, showing varying results following fatigue, including increased stiffness, decreased stiffness or failure to detect any change in some experiments. Further consideration of the literature questions the validity of the models used to induce and measure fatigue, as well as the pre-post study design, which may explain the lack of consensus in the results. These limitations cast doubt on the usefulness of the available information and identify a need to investigate alternative approaches. Based on the results of this review, the aims of this thesis were to: • evaluate the methodological procedures used in validation of a fatigue model • investigate the adaptation and regulation of post-impact knee mechanics during repeated step landings • use this new information to test the effects of fatigue on knee function during a step-landing task. To address the aims of the thesis, 3 related experiments were conducted that collected kinetic, kinematic and electromyographic data from 3 separate samples of healthy male participants. The methodologies involved optoelectronic motion capture (VICON), isokinetic dynamometry (System3 Pro, BIODEX) and wireless surface electromyography (Zerowire, Aurion, Italy). Fatigue indicators and knee function measures used in each experiment were derived from the data. Study 1 compared the validity and reliability of repetitive stepping and isokinetic contractions with respect to fatigue of the quadriceps and hamstrings. Fifteen participants performed 50 repetitions of each exercise twice in randomised order, over 4 sessions. Sessions were separated by a minimum of 1 week’s rest, to ensure full recovery. Validity and reliability depended on a complex interaction between the exercise protocol, the fatigue indicator, the individual and the muscle of interest. Nevertheless, differences between exercise protocols indicated that stepping was less effective in eliciting valid and reliable changes in peak power and spectral compression, compared with isokinetic exercise. A key finding was that fatigue progressed in a biphasic pattern during both exercises. The point separating the 2 phases, known as the transition point, demonstrated superior between-test reliability during the isokinetic protocol, compared with stepping. However, a correction factor should be used to accurately apply this technique to the study of fatigue during landing. Study 2 examined alterations in knee function during repeated landings, with a different sample (N =12) performing 60 consecutive step landing trials. Each landing trial was separated by 1-minute rest periods. The results provided new information in relation to the pre-post study design in the context of detecting adjustments in knee function during landing. First, participants significantly increased or decreased pre-impact muscle activity or post-impact mechanics despite environmental and task constraints remaining unchanged. This is the 1st study to demonstrate this effect in healthy individuals without external feedback on performance. Second, single-subject analysis was more effective in detecting alterations in knee function compared to group-level analysis. Finally, repeated landing trials did not reduce inter-trial variability of knee function in some participants, contrary to assumptions underpinning previous studies. The results of studies 1 and 2 were used to modify the design of Study 3 relative to previous research. These alterations included a modified isokinetic fatigue protocol, multiple pre-fatigue measurements and singlesubject analysis to detect fatigue-related changes in knee function. The study design incorporated new analytical approaches to investigate fatiguerelated alterations in knee function during landing. Participants (N = 16) were measured during multiple pre-fatigue baseline trial blocks prior to the fatigue model. A final block of landing trials was recorded once the participant met the operational fatigue definition that was identified in Study 1. The analysis revealed that the effects of fatigue in this context are heavily dependent on the compensatory response of the individual. A continuum of responses was observed within the sample for each knee function measure. Overall, preimpact preparation and post-impact mechanics of the knee were altered with highly individualised patterns. Moreover, participants used a range of active or passive pre-impact strategies to adapt post-impact mechanics in response to quadriceps fatigue. The unique patterns identified in the data represented an optimisation of knee function based on priorities of the individual. The findings of these studies explain the lack of consensus within the literature regarding the effects of fatigue on knee function during landing. First, functional fatigue protocols lack validity in inducing fatigue-related changes in mechanical output and spectral compression of surface electromyography (sEMG) signals, compared with isokinetic exercise. Second, fatigue-related changes in knee function during landing are confounded by inter-individual variation, which limits the sensitivity of group-level analysis. By addressing these limitations, the 3rd study demonstrated the efficacies of new experimental and analytical approaches to observe fatigue-related alterations in knee function during landing. Consequently, this thesis provides new perspectives into the effects of fatigue in knee function during landing. In conclusion: • The effects of fatigue on knee function during landing depend on the response of the individual, with considerable variation present between study participants, despite similar physical characteristics. • In healthy males, adaptation of pre-impact muscle activity and postimpact knee mechanics is unique to the individual and reflects their own optimisation of demands such as energy expenditure, joint stability, sensory information and loading of knee structures. • The results of these studies should guide future exploration of adaptations in knee function to fatigue. However, research in this area should continue with reduced emphasis on the directional response of the population and a greater focus on individual adaptations of knee function.

Effects of different practice task constraints on fluctuations of player heart rate in small-sided football games

This paper analyzes effects of different practice task constraints on heart rate (HR) variability during 4v4 smallsided football games. Participants were sixteen football players divided into two age groups (U13, Mean age: 12.4±0.5 yrs; U15: 14.6±0.5). The task consisted of a 4v4 sub-phase without goalkeepers, on a 25x15 m field, of 15 minutes duration with an active recovery period of 6 minutes between each condition. We recorded players’ heart rates using heart rate monitors (Polar Team System, Polar Electro, Kempele, Finland) as scoring mode was manipulated (line goal: scoring by dribbling past an extended line; double goal: scoring in either of two lateral goals; and central goal: scoring only in one goal). Subsequently, %HR reserve was calculated with the Karvonen formula. We performed a time-series analysis of HR for each individual in each condition. Mean data for intra-participant variability showed that autocorrelation function was associated with more short-range dependence processes in the “line goal” condition, compared to other conditions, demonstrating that the “line goal” constraint induced more randomness in HR response. Relative to inter-individual variability, line goal constraints demonstrated lower %CV and %RMSD (U13: 9% and 19%; U15: 10% and 19%) compared with double goal (U13: 12% and 21%; U15: 12% and 21%) and central goal (U13: 14% and 24%; U15: 13% and 24%) task constraints, respectively. Results suggested that line goal constraints imposed more randomness on cardiovascular stimulation of each individual and lower inter-individual variability than double goal and central goal constraints.