Novel statistical approaches for non-normal censored immunological data: analysis of cytokine and gene expression data

Background: For several immune-mediated diseases, immunological analysis will become more complex in the future with datasets in which cytokine and gene expression data play a major role. These data have certain characteristics that require sophisticated statistical analysis such as strategies for non-normal distribution and censoring. Additionally, complex and multiple immunological relationships need to be adjusted for potential confounding and interaction effects. Objective: We aimed to introduce and apply different methods for statistical analysis of non-normal censored cytokine and gene expression data. Furthermore, we assessed the performance and accuracy of a novel regression approach in order to allow adjusting for covariates and potential confounding. Methods: For non-normally distributed censored data traditional means such as the Kaplan-Meier method or the generalized Wilcoxon test are described. In order to adjust for covariates the novel approach named Tobit regression on ranks was introduced. Its performance and accuracy for analysis of non-normal censored cytokine/gene expression data was evaluated by a simulation study and a statistical experiment applying permutation and bootstrapping. Results: If adjustment for covariates is not necessary traditional statistical methods are adequate for non-normal censored data. Comparable with these and appropriate if additional adjustment is required, Tobit regression on ranks is a valid method. Its power, type-I error rate and accuracy were comparable to the classical Tobit regression. Conclusion: Non-normally distributed censored immunological data require appropriate statistical methods. Tobit regression on ranks meets these requirements and can be used for adjustment for covariates and potential confounding in large and complex immunological datasets

Do Changes in the Pace of Events Affect One-Off Judgments of Duration?

Five experiments examined whether changes in the pace of external events influence people’s judgments of duration. In Experiments 1a–1c, participants heard pieces of music whose tempo accelerated, decelerated, or remained constant. In Experiment 2, participants completed a visuo-motor task in which the rate of stimulus presentation accelerated, decelerated, or remained constant. In Experiment 3, participants completed a reading task in which facts appeared on-screen at accelerating, decelerating, or constant rates. In all experiments, the physical duration of the to-be-judged interval was the same across conditions. We found no significant effects of temporal structure on duration judgments in any of the experiments, either when participants knew that a time estimate would be required (prospective judgments) or when they did not (retrospective judgments). These results provide a starting point for the investigation of how temporal structure affects one-off judgments of duration like those typically made in natural settings

Surgical physiology of inguinal hernia repair - a study of 200 cases

BACKGROUND: Current inguinal hernia operations are generally based on anatomical considerations. Failures of such operations are due to lack of consideration of physiological aspects. Many patients with inguinal hernia are cured as a result of current techniques of operation, though factors that are said to prevent hernia formation are not restored. Therefore, the surgical physiology of inguinal canal needs to be reconsidered. METHODS: A retrospective study is describer of 200 patients operated on for inguinal hernia under local anaesthesia by the author's technique of inguinal hernia repair. RESULTS: The posterior wall of the inguinal canal was weak and without dynamic movement in all patients. Strong aponeurotic extensions were absent in the posterior wall. The muscle arch movement was lost or diminished in all patients. The movement of the muscle arch improved after it was sutured to the upper border of a strip of the external oblique aponeurosis (EOA). The newly formed posterior wall was kept physiologically dynamic by the additional muscle strength provided by external oblique muscle to the weakened muscles of the muscle arch. CONCLUSIONS: A physiologically dynamic and strong posterior inguinal wall, and the shielding and compression action of the muscles and aponeuroses around the inguinal canal are important factors that prevent hernia formation or hernia recurrence after repair. In addition, the squeezing and plugging action of the cremasteric muscle and binding effect of the strong cremasteric fascia, also play an important role in the prevention of hernia

Prioritization strategies in clinical practice guidelines development: a pilot study

Objective: Few methodological studies address the prioritization of clinical topics for the development of Clinical Practice Guidelines (CPGs). The aim of this study was to validate a methodology for Priority Determination of Topics (PDT) of CPGs. Methods and results: Firstly, we developed an instrument for PDT with 41 criteria that were grouped under 10 domains, based on a comprehensive systematic search. Secondly, we performed a survey of stakeholders involved in CPGs development, and end users of guidelines, using the instrument. Thirdly, a pilot testing of the PDT procedure was performed in order to choose 10 guideline topics among 34 proposed projects; using a multicriteria analysis approach, we validated a mechanism that followed five stages: determination of the composition of groups, item/domain scoring, weights determination, quality of the information used to support judgments, and finally, topic selection. Participants first scored the importance of each domain, after which four different weighting procedures were calculated (including the survey results). The process of weighting was determined by correlating the data between them. We also reported the quality of evidence used for PDT. Finally, we provided a qualitative analysis of the process. The main domains used to support judgement, having higher quality scores and weightings, were feasibility, disease burden, implementation and information needs. Other important domains suc

Macrofossil evidence for a rapid and severe Cretaceous–Paleogene mass extinction in Antarctica

Debate continues about the nature of the Cretaceous–Paleogene (K–Pg) mass extinction event. An abrupt crisis triggered by a bolide impact contrasts with ideas of a more gradual extinction involving flood volcanism or climatic changes. Evidence from high latitudes has also been used to suggest that the severity of the extinction decreased from low latitudes towards the poles. Here we present a record of the K–Pg extinction based on extensive assemblages of marine macrofossils (primarily new data from benthic molluscs) from a highly expanded Cretaceous–Paleogene succession: the López de Bertodano Formation of Seymour Island, Antarctica. We show that the extinction was rapid and severe in Antarctica, with no significant biotic decline during the latest Cretaceous, contrary to previous studies. These data are consistent with a catastrophic driver for the extinction, such as bolide impact, rather than a significant contribution from Deccan Traps volcanism during the late Maastrichtian

Search for supersymmetric particles in scenarios with a gravitino LSP and stau NLSP

Sleptons, neutralinos and charginos were searched for in the context of scenarios where the lightest supersymmetric particle is the gravitino. It was assumed that the stau is the next-to-lightest supersymmetric particle. Data collected with the DELPHI detector at a centre-of-mass energy near 189 GeV were analysed combining the methods developed in previous searches at lower energies. No evidence for the production of these supersymmetric particles was found. Hence, limits were derived at 95% confidence level.Comment: 31 pages, 14 figure

Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts

Background Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes. Methods We constructed a polygenic risk score using a genome-wide association study of lung function (FEV1 and FEV1/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV1/FVC <0·7 and FEV1 <80% of predicted). Associations were tested using logistic regression models, adjusting for age, sex, height, smoking pack-years, and principal components of genetic ancestry. We assessed predictive performance of models by area under the curve. In a subset of studies, we also studied quantitative and qualitative CT imaging phenotypes that reflect parenchymal and airway pathology, and patterns of reduced lung growth. Findings The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81 [95% CI 1·74–1·88] and non-European (1·42 [1·34–1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56–9·72) in European ancestry and 4·83 (3·45–6·77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79–0·81] vs 0·76 [0·75–0·76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive emphysema subtypes. The polygenic risk score was associated with a reduced lung growth pattern. Interpretation A risk score comprised of genetic variants can identify a small subset of individuals at markedly increased risk for moderate-to-severe COPD, emphysema subtyp

Computational modelling of wound healing insights to develop new treatments

About 1% of the population will suffer a severe wound during their life. Thus, it is really important to develop new techniques in order to properly treat these injuries due to the high socioeconomically impact they suppose. Skin substitutes and pressure based therapies are currently the most promising techniques to heal these injuries. Nevertheless, we are still far from finding a definitive skin substitute for the treatment of all chronic wounds. As a first step in developing new tissue engineering tools and treatment techniques for wound healing, in silico models could help in understanding the mechanisms and factors implicated in wound healing. Here, we review mathematical models of wound healing. These models include different tissue and cell types involved in healing, as well as biochemical and mechanical factors which determine this process. Special attention is paid to the contraction mechanism of cells as an answer to the tissue mechanical state. Other cell processes such as differentiation and proliferation are also included in the models together with extracellular matrix production. The results obtained show the dependency of the success of wound healing on tissue composition and the importance of the different biomechanical and biochemical factors. This could help to individuate the adequate concentration of growth factors to accelerate healing and also the best mechanical properties of the new skin substitute depending on the wound location in the body and its size and shape. Thus, the feedback loop of computational models, experimental works and tissue engineering could help to identify the key features in the design of new treatments to heal severe wounds