Questioning the role of phenology shifts and trophic mismatching in a planktonic food web

In a warming climate, differential shifts in the seasonal timing of predators and prey have been suggested to lead to trophic ‘‘mismatches’’ that decouple primary, secondary and tertiary production. We tested this hypothesis using a 25-year time-series of weekly sampling at the Plymouth L4 site, comparing 57 plankton taxa spanning 4 trophic levels. During warm years, there was a weak tendency for earlier timings of spring taxa and later timings of autumn taxa. While this is in line with many previous findings, numerous exceptions existed and only a few taxa (e.g. Gyrodinium spp., Pseudocalanus elongatus, and Acartia clausi) showed consistent, strong evidence for temperature-related timing shifts, revealed by all 4 of the timing indices that we used. Also, the calculated offsets in timing i.e. ‘‘mismatches’’) between predator and prey were no greater in extreme warm or cold years than during more average years. Further, the magnitude of these offsets had no effect on the ‘‘success’’ of the predator, in terms of their annual mean abundance or egg production rates. Instead numerous other factors override, including: inter-annual variability in food quantity, high food baseline levels, turnover rates and prolonged seasonal availability, allowing extended periods of production. Furthermore many taxa, notably meroplankton, increased well before the spring bloom. While theoretically a chronic mismatch, this likely reflects trade-offs for example in predation avoidance. Various gelatinous taxa (Phaeocystis, Noctiluca, ctenophores, appendicularians, medusae) may have reduced these predation constraints, with variable, explosive population outbursts likely responding to improved conditions. The match–mismatch hypothesis may apply for highly seasonal, pulsed systems or specialist feeders, but we suggest that the concept is being over-extended to other marine systems where multiple factors compensate.

Design and physicochemical characterisation of a bioadhesive patch for dose-controlled topical delivery of imiquimod

Clinical use of the imidazoquinoline immunomodulator imiquimod for the topical treatment of dysplastic and neoplastic lesions has increased markedly in recent years. However, despite guidance from the manufacturer of the proprietary imiquimod cream, there seems to be little consensus between clinicians as to the topically applied dose. Given that patients often apply the cream themselves at home, further dosing variability is expected and, consequently, accurate comparison of the results of different published studies is dif?cult. This paper describes, for the ?rst time, the formulation and physicochemical characterisation of a bioadhesive patch for dose-controlled topical delivery of imiquimod as well as a new HPLC method for sensitive ?uorescence determination of imiquimod released from such systems. Patches containing imiquimod loadings of 4.75, 9.50 and 12.50 mg cm-2 all released signi?cantly more drug across a model membrane than the proprietary cream over a period of 6 h. Inclusion of imiquimod in patches did not adversely affect their physicochemical properties. Of major importance, patches contained de?ned drug loadings per unit area; therefore, their use could reduce inter-clinician variability. This would make critical comparison of clinical studies and determination of an appropriate imiquimod dose for successful treatment much simpler. Since bioadhesive formulations are capable of adhering to body tissues in moist environments, the use of a bioadhesive patch system may allow extension of the clinical uses of imiquimod to the treatment of neoplastic conditions of the oral cavity and cervix, as well as the vulva. © 2005 Elsevier B.V. All rights reserved.

Assisted Diagnosis of Cervical Intraepithelial Neoplasia (CIN)

This paper introduces an automated computer- assisted system for the diagnosis of cervical intraepithelial neoplasia (CIN) using ultra-large cervical histological digital slides. The system contains two parts: the segmentation of squamous epithelium and the diagnosis of CIN. For the segmentation, to reduce processing time, a multiresolution method is developed. The squamous epithelium layer is first segmented at a low (2X) resolution. The boundaries are further fine tuned at a higher (20X) resolution. The block-based segmentation method uses robust texture feature vectors in combination with support vector machines (SVMs) to perform classification. Medical rules are finally applied. In testing, segmentation using 31 digital slides achieves 94.25% accuracy. For the diagnosis of CIN, changes in nuclei structure and morphology along lines perpendicular to the main axis of the squamous epithelium are quantified and classified. Using multi-category SVM, perpendicular lines are classified into Normal, CIN I, CIN II, and CIN III. The robustness of the system in term of regional diagnosis is measured against pathologists' diagnoses and inter-observer variability between two pathologists is considered. Initial results suggest that the system has potential as a tool both to assist in pathologists' diagnoses, and in training.

Sex differences in fetal habituation

There is some evidence for sex differences in habituation in the human fetus, but it is unknown whether this is due to differences in central processing (habituation) or in more peripheral processes, sensory or motor, involved in the response. This study examined whether the sex of the fetus influenced auditory habituation at 33weeks of gestation, and whether this was due to differences in habituation or in the sensory or motor components using a set of four experiments. The first experiment found that female fetuses required significantly fewer stimulus presentations to habituate than males. The second experiment revealed no difference in the spontaneous motor behaviour of male and female fetuses. The third experiment examined auditory intensity thresholds for the stimuli used to habituate the fetus. No differences in thresholds were found between males and females, although there was inter-individual variability in thresholds. A final experiment, using stimuli individualized for that particular fetus' auditory intensity threshold, found that female fetuses habituated faster than males. In combination, the studies reveal that habituation in the human fetus is affected by sex and this is due to a difference in central 'information processing' of the stimuli rather than peripheral aspects of the response. It is argued that male and female fetuses present different neurobehavioural developmental trajectories, with females more advanced at 33weeks than males. This study suggests that research examining prenatal behaviour should consider the factor of fetal sex. This may be particularly pertinent where there is an intention to use the results diagnostically. © 2012 Blackwell Publishing Ltd.

Decoding semantics across fMRI sessions with different stimulus modalities:a practical MVPA study

Both embodied and symbolic accounts of conceptual organization would predict partial sharing and partial differentiation between the neural activations seen for concepts activated via different stimulus modalities. But cross-participant and cross-session variability in BOLD activity patterns makes analyses of such patterns with MVPA methods challenging. Here, we examine the effect of cross-modal and individual variation on the machine learning analysis of fMRI data recorded during a word property generation task. We present the same set of living and non-living concepts (land-mammals, or work tools) to a cohort of Japanese participants in two sessions: the first using auditory presentation of spoken words; the second using visual presentation of words written in Japanese characters. Classification accuracies confirmed that these semantic categories could be detected in single trials, with within-session predictive accuracies of 80-90%. However cross-session prediction (learning from auditory-task data to classify data from the written-word-task, or vice versa) suffered from a performance penalty, achieving 65-75% (still individually significant at p « 0.05). We carried out several follow-on analyses to investigate the reason for this shortfall, concluding that distributional differences in neither time nor space alone could account for it. Rather, combined spatio-temporal patterns of activity need to be identified for successful cross-session learning, and this suggests that feature selection strategies could be modified to take advantage of this.

On sea level change in the North Sea influenced by the North Atlantic Oscillation: local and remote steric effects

In this study, contributions of both local steric and remote baroclinic effects (i.e., steric variations external to the region of interest) to the inter-annual variability of winter sea level in the North Sea, with respect to the North Atlantic Oscillation (NAO), for the period of 1953–2010 are investigated. On inter-annual time scales in this period, the NAO is significantly correlated to sea level variations in the North Sea only in the winter months (December–March), while its correlation to sea temperature over much of the North Sea is only significant in January and February. The discrepancy in sea level between observations and barotropic tide and surge models forced by tides and local atmospheric forcing, i.e., local atmospheric pressure effects and winds, in the present study are found to be consistent with previous studies. In the North Sea, local thermosteric effects caused by thermal expansion play a minor role on winter-mean NAO related sea level variability compared with atmospheric forcing. This is particularly true in the southeastern North Sea where water depths are mostly less than 25 m. Our calculations demonstrate that the discrepancy can be mostly explained by remote baroclinic effects, which appear as water mass exchanges on the continental shelf and are therefore only apparent in ocean bottom pressure. In the North Sea, NAO related sea level variations seem to be a hybrid of barotropic and baroclinic processes. Hence, they can only be adequately modelled with three-dimensional baroclinic ocean models that include contributions of baroclinic effects and large-scale atmospheric forcing external to the region of interest.

Comparison of Microbiomes from Different Niches of Upper and Lower Airways in Children and Adolescents with Cystic Fibrosis

Changes in the airway microbiome may be important in the pathophysiology of chronic lung disease in patients with cystic fibrosis. However, little is known about the microbiome in early cystic fibrosis lung disease and the relationship between the microbiomes from different niches in the upper and lower airways. Therefore, in this cross-sectional study, we examined the relationship between the microbiome in the upper (nose and throat) and lower (sputum) airways from children with cystic fibrosis using next generation sequencing. Our results demonstrate a significant difference in both α and β-diversity between the nose and the two other sampling sites. The nasal microbiome was characterized by a polymicrobial community while the throat and sputum communities were less diverse and dominated by a few operational taxonomic units. Moreover, sputum and throat microbiomes were closely related especially in patients with clinically stable lung disease. There was a high inter-individual variability in sputum samples primarily due to a decrease in evenness linked to increased abundance of potential respiratory pathogens such as Pseudomonas aeruginosa. Patients with chronic Pseudomonas aeruginosa infection exhibited a less diverse sputum microbiome. A high concordance was found between pediatric and adult sputum microbiomes except that Burkholderia was only observed in the adult cohort. These results indicate that an adult-like lower airways microbiome is established early in life and that throat swabs may be a good surrogate in clinically stable children with cystic fibrosis without chronic Pseudomonas aeruginosa infection in whom sputum sampling is often not feasible.

Determining the optimal current direction of transcranial magnetic stimulation to induce motor responses in the tongue: A preliminary study of neurologically healthy individuals

Objective
To determine the optimal transcranial magnetic stimulation (TMS) coil direction for inducing motor responses in the tongue in a group of non-neurologically impaired participants.
Methods
Single-pulse TMS was delivered using a figure-of-eight Magstim 2002 TMS coil. Study 1 investigated the effect of eight different TMS coil directions on the motor-evoked potentials elicited in the tongue in eight adults. Study 2 examined active motor threshold levels at optimal TMS coil direction compared to a customarily-used ventral-caudal direction. Study 3 repeated the procedure of Study 1 at five different sites across the tongue motor cortex in one adult.
Results
Inter-individual variability in optimal direction was observed, with an optimal range of directions determined for the group. Active motor threshold was reduced when a participant's own optimal TMS coil direction was used compared to the ventral-caudal direction. A restricted range of optimal directions was identified across the five cortical positions tested.
Conclusions
There is a need to identify each individual's own optimal TMS coil direction in investigating tongue motor cortex function. A recommended procedure for determining optimal coil direction is described.
Significance
Optimized TMS procedures are needed so that TMS can be utilized in determining the underlying neurophysiological basis of various motor speech disorders.

Serum Cytokines and Adipokines in Periodontitis

Objective: To investigate whether there was an association between serum levels of pro-inflammatory cytokines, adipokines and periodontitis in 60-70 year-old men in Northern Ireland. Methods: Test subjects (n=61) with established periodontitis, categorised by loss of periodontal attachment (PAL) and pocketing of at least 5mm, were matched for age, smoking and BMI with controls (n=60) who were periodontitis resistant (no PAL or pocketing over 3mm). Serum levels of IL 1 alpha, TNF alpha, IL 6, adiponectin, resistin, leptin and C-reactive protein (CRP) were measured from serum using a multiplex array (Randox, UK). Mann Whitney analysis was used with the level of significance set at p<0.05. Results: There was considerable inter-individual variability in all the analytes measured. There was a significantly higher level of IL 6 in men with periodontitis (3.25 pg/ml, SD 2.29) than in those with no periodontitis (2.38 pg/ml, SD1.62), p=0.0041 (after Bonferroni correction for multiple testing p=0.029). Serum IL 6 was strongly correlated with CRP: r=0.52 (95% CI 0.38-0.64), p<0.0001. There was a lower serum level of adiponectin in men with periodontitis (3662.1 ng/ml, SD 2383.4) compared with those who were periodontitis resistant (4265.9 ng/ml, SD 2266.0), which just escaped statistical significance at p=0.068. There were no significant differences in the serum levels of any of the other analytes measured in relation to periodontal status. Conclusions: There was evidence in the 60-70 year-old male population investigated that periodontitis was associated with an increased serum level of IL 6.

Left ventricle functional analysis from coronary CT angiography

Coronary CT angiography is widely used in clinical practice for the assessment of coronary artery disease. Several studies have shown that the same exam can also be used to assess left ventricle (LV) function. LV function is usually evaluated using just the data from end-systolic and end-diastolic phases even though coronary CT angiography (CTA) provides data concerning multiple cardiac phases, along the cardiac cycle. This unused wealth of data, mostly due to its complexity and the lack of proper tools, has still to be explored in order to assess if further insight is possible regarding regional LV functional analysis. Furthermore, different parameters can be computed to characterize LV function and while some are well known by clinicians others still need to be evaluated concerning their value in clinical scenarios. The work presented in this thesis covers two steps towards extended use of CTA data: LV segmentation and functional analysis. A new semi-automatic segmentation method is presented to obtain LV data for all cardiac phases available in a CTA exam and a 3D editing tool was designed to allow users to fine tune the segmentations. Regarding segmentation evaluation, a methodology is proposed in order to help choose the similarity metrics to be used to compare segmentations. This methodology allows the detection of redundant measures that can be discarded. The evaluation was performed with the help of three experienced radiographers yielding low intraand inter-observer variability. In order to allow exploring the segmented data, several parameters characterizing global and regional LV function are computed for the available cardiac phases. The data thus obtained is shown using a set of visualizations allowing synchronized visual exploration. The main purpose is to provide means for clinicians to explore the data and gather insight over their meaning, as well as their correlation with each other and with diagnosis outcomes. Finally, an interactive method is proposed to help clinicians assess myocardial perfusion by providing automatic assignment of lesions, detected by clinicians, to a myocardial segment. This new approach has obtained positive feedback from clinicians and is not only an improvement over their current assessment method but also an important first step towards systematic validation of automatic myocardial perfusion assessment measures.

Estudo comparativo entre criança com e sem joelhos valgos praticantes de hóquei em patins utilizando diferentes sistemas de análise

O presente estudo tem como objetivo comparar experimentalmente duas crianças praticantes de Hóquei em Patins, uma normal e uma com a patologia dos joelhos valgos, avaliando qualitativamente as diferenças posturais, estáticas e dinâmicas, decorrentes da utilização dos patins específicos desta modalidade, através do sistema de análise da Força de Reação do Solo (FRS), de Eletromiografia (EMG), de captura de movimento, e de modelação e simulação. Para atingir o objetivo definiu-se um protocolo de ensaios com as seguintes tarefas: repouso com e sem patins, marcha, corrida, deslizar com os dois pés apoiados e deslizar com o pé esquerdo levantado. No repouso avaliou-se a variação do ponto de aplicação da FRS da criança normal e patológica, com e sem patins. Ainda na tarefa de repouso avaliou-se também as componentes médio-lateral, antero-posterior individualmente e a componente vertical da FRS, juntamente com a atividade muscular dos músculos Gastrocnémio Medial (GM), Recto Femoral (RF), Vasto Medial (VM), Vasto Lateral (VL), Bicípete Femoral (BF), Semitendinoso (ST), Tensor da Fascia Lata (TFL), Gastrocnémio Lateral (GL), de forma a comparar os valores de intensidade de FRS e da atividade muscular dos diferentes instantes de tempo desta tarefa. Para as restantes tarefas apenas se avaliou individualmente as componentes médio-lateral e antero-posterior da FRS e a componente vertical da FRS juntamente com a atividade muscular dos referidos músculos, salientando as diferenças evidentes entre as curvas da criança normal e as curvas da criança patológica durante os diferentes instantes do movimento. Todas as tarefas referidas, exceto a tarefa de repouso com patins, foram ainda simuladas recorrendo a modelos músculo-esqueléticos. A partir destas simulações do movimento obtiveram-se os ângulos articulares e efetuou-se a respetiva análise. No final dos resultados obtidos apresentou-se uma tabela de resumo com o cálculo dos coeficientes de variação de cada grandeza, exceto nos gráficos da posição no espaço da FRS, onde se constatou que existe uma grande variabilidade inter-individuo em cada tarefa. A análise dos resultados de cada tarefa permite concluir que a utilização de patins pode trazer uma maior ativação muscular para a criança patológica, embora se verifique instabilidade articular. Apesar dessa instabilidade pode-se inferir que, uma maior ativação muscular decorrente da utilização de patins, tal como acontece na prática do hóquei em patins, pode trazer uma melhoria, a longo prazo, na estabilidade da articulação do joelho e na sustentação corporal, proporcionada pelo fortalecimento muscular.

Derivation and consistency checking of models in early software product line engineering

Dissertação para obtenção do Grau de Doutor em Engenharia Informática

Quantifying consistency of Event Related Potentials across subjects based on single-trial topographic analysis

Introduction: Non-invasive brain imaging techniques often contrast experimental conditions across a cohort of participants, obfuscating distinctions in individual performance and brain mechanisms that are better characterised by the inter-trial variability. To overcome such limitations, we developed topographic analysis methods for single-trial EEG data [1]. So far this was typically based on time-frequency analysis of single-electrode data or single independent components. The method's efficacy is demonstrated for event-related responses to environmental sounds, hitherto studied at an average event-related potential (ERP) level. Methods: Nine healthy subjects participated to the experiment. Auditory meaningful sounds of common objects were used for a target detection task [2]. On each block, subjects were asked to discriminate target sounds, which were living or man-made auditory objects. Continuous 64-channel EEG was acquired during the task. Two datasets were considered for each subject including single-trial of the two conditions, living and man-made. The analysis comprised two steps. In the first part, a mixture of Gaussians analysis [3] provided representative topographies for each subject. In the second step, conditional probabilities for each Gaussian provided statistical inference on the structure of these topographies across trials, time, and experimental conditions. Similar analysis was conducted at group-level. Results: Results show that the occurrence of each map is structured in time and consistent across trials both at the single-subject and at group level. Conducting separate analyses of ERPs at single-subject and group levels, we could quantify the consistency of identified topographies and their time course of activation within and across participants as well as experimental conditions. A general agreement was found with previous analysis at average ERP level. Conclusions: This novel approach to single-trial analysis promises to have impact on several domains. In clinical research, it gives the possibility to statistically evaluate single-subject data, an essential tool for analysing patients with specific deficits and impairments and their deviation from normative standards. In cognitive neuroscience, it provides a novel tool for understanding behaviour and brain activity interdependencies at both single-subject and at group levels. In basic neurophysiology, it provides a new representation of ERPs and promises to cast light on the mechanisms of its generation and inter-individual variability.

The P450 oxidoreductase genotype is associated with CYP3A activity in vivo as measured by the midazolam phenotyping test.

CYP3A4, CYP3A5 and CYP3A7 are hepatic enzymes that metabolize about 50% of drugs on the market, with a large overlap in their specificities. We investigated the genetic bases that contribute to the variation of CYP3A activity. We phenotyped 251 individuals from two independent studies (182 patients treated with methadone and 69 patients with clozapine) for CYP3A activity using the midazolam phenotyping test and genotyped them for CYP3A4, CYP3A5, and CYP3A7 genetic variants, including the single nucleotide polymorphism (SNP) rs4646437C>T in intron 7 of CYP3A4. Owing to the fact that CYP enzymes require electron transfer through the P450 oxidoreductase (POR), and functional impairment has been shown for the POR*28 SNP, this polymorphism was also analysed. We show that CYP3A4, CYP3A5 and CYP3A7 genotypes, including the SNP rs4646437C>T, do not reflect the inter-individual variability of CYP3A activity (P>0.1). In contrast, POR*28 TT genotype presents a 1.6-fold increase in CYP3A activity compared with POR*28C carriers (n = 182, P = 0.004). This finding was replicated in the second independent dataset (n = 69, P = 0.04). The SNP POR*28 seems to be a better genetic marker of the variability of total CYP3A activity in vivo than CYP3A4, CYP3A5 and CYP3A7 genetic variants.

Correlations between imatinib pharmacokinetics, pharmacodynamics, adherence, and clinical response in advanced metastatic gastrointestinal stromal tumor (GIST): An emerging role for drug blood level testing?

Imatinib is the standard of care for patients with advanced metastatic gastrointestinal stromal tumors (GIST), and is also approved for adjuvant treatment in patients at substantial risk of relapse. Studies have shown that maximizing benefit from imatinib depends on long-term administration at recommended doses. Pharmacokinetic (PK) and pharmacodynamic factors, adherence, and drug-drug interactions can affect exposure to imatinib and impact clinical outcomes. This article reviews the relevance of these factors to imatinib's clinical activity and response in the context of what has been demonstrated in chronic myelogenous leukemia (CML), and in light of new data correlating imatinib exposure to response in patients with GIST. Because of the wide inter-patient variability in drug exposure with imatinib in both CML and GIST, blood level testing (BLT) may play a role in investigating instances of suboptimal response, unusually severe toxicities, drug-drug interactions, and suspected non-adherence. Published clinical data in CML and in GIST were considered, including data from a PK substudy of the B2222 trial correlating imatinib blood levels with clinical responses in patients with GIST. Imatinib trough plasma levels <1100ng/mL were associated with lower rates of objective response and faster development of progressive disease in patients with GIST. These findings have been supported by other analyses correlating free imatinib (unbound) levels with response. These results suggest a future application for imatinib BLT in predicting and optimizing therapeutic response. Nevertheless, early estimates of threshold imatinib blood levels must be confirmed prospectively in future studies and elaborated for different patient subgroups.