Internal test sets studies in a group of antimalarials

Topological indices have been applied to build QSAR models for a set of 20 antimalarial cyclic peroxy cetals. In order to evaluate the reliability of the proposed linear models leave-n-out and Internal Test Sets (ITS) approaches have been considered. The proposed procedure resulted in a robust and consensued prediction equation and here it is shown why it is superior to the employed standard cross-validation algorithms involving multilinear regression models

What is the relationship between fear of falling and gait in well-functioning older persons aged 65 to 70 years?

OBJECTIVE: To investigate the association between fear of falling and gait performance in well-functioning older persons. DESIGN: Survey. SETTING: Community. PARTICIPANTS: Subjects (N=860, aged 65-70y) were a subsample of participants enrolled in a cohort study who underwent gait measurements. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Fear of falling and its severity were assessed by 2 questions about fear and related activity restriction. Gait performance, including gait variability, was measured using body-fixed sensors. RESULTS: Overall, 29.6% (210/860) of the participants reported fear of falling, with 5.2% (45/860) reporting activity restriction. Fear of falling was associated with reduced gait performance, including increased gait variability. A gradient in gait performance was observed from participants without fear to those reporting fear without activity restriction and those reporting both fear and activity restriction. For instance, stride velocity decreased from 1.15+/-.15 to 1.11+/-.17 to 1.00+/-.19 m/s (P<.001) in participants without fear, with fear but no activity restriction and with fear and activity restriction, respectively. In multivariate analysis, fear of falling with activity restriction remained associated with reduced gait performance, independent of sex, comorbidity, functional status, falls history, and depressive symptoms. CONCLUSIONS: In these well-functioning older people, those reporting fear of falling with activity restriction had reduced gait performance and increased gait variability, independent of health and functional status. These relationships suggest that early interventions targeting fear of falling might potentially help to prevent its adverse consequences on mobility and function in similar populations.

Early Variscan I-type pluton in the pre-Alpine basement of the Western Alps: The ca. 360 Ma Cogne diorite (NW-Italy)

Located at the internal border of the Grand-Saint-Bernard Zone, the diorite and its aureole lie on top of intensively studied Alpine eclogitic units but this pluton, poorly studied yet, has kept locally almost undeformed. The pluton intruded, at similar to 360 Ma, country-rocks mostly composed of dark shales with Na2O > K2O and minor mafic intercalations of tholeiitic basalt affinity. This association is characteristic of the Vanoise (France) basement series, where available age determinations suggest an Early Paleozoic age. Parts of the pluton, and of its hornfels aureole that is evidenced here for the first time, in the Punta Bioula section of Valsavaranche valley (NW-Italy), have been well-preserved from the Alpine deformation. Syn-emplacement hardening, dehydration-induced, probably prevented strain-enhanced Alpine recrystallization. Magmatic rock-types range continuously from subordinate mafic types at SiO2 similar to 48%, of hornblendite with cumulative or appinite affinities, to the main body of quartz diorite to quartz monzonite (SiO2 up to 62%). P-T estimates for the pluton emplacement, based on the abundance of garnet in the hornfelses, using also zircon and apatite saturation thermometry and Al-in-hornblende barometry, suggest T similar to 800-950 degrees C and minimum P in the 0.2-0.5 GPa range, with records of higher pressure conditions (up to 1-2 GPa?) in hornblendite phlogopite-cored amphibole. The high-K, Na > K, calcalkaline geochemistry is in line with a destructive plate-margin setting. Based on major element data and radiogenic isotope signature (epsilon Nd-360 Ma from -1.2 to + 0.9, Sr-87/Sr-86(360 MA) from 0.7054 to 0.7063), the parental magmas are interpreted in terms of deep-seated metabasaltic partial melts with limited contamination from shallower sources, the low radiogenic Nd-content excluding a major contribution from Vanoise tholeiites. There is no other preserved evidence for Variscan magmatism of similar age and composition in the Western Alps, but probable analogs are known in the western and northern parts of French Massif Central. Regarding the Alpine tectonics, not only the age of the pluton and its host-rocks (instead of the Permo-Carboniferous age previously believed), but also its upper mylonitic contact, suggest revisions of the Alpine nappe model. The Cogne diorite allegedly constituted the axial part of the E-verging ``pli en retour [backfold] du Valsavaranche'', a cornerstone of popular Alpine structural models: in fact, the alleged fold limbs, as attested here by field and geochemical data, do not belong to the same unit, and the backfold hypothesis is unfounded. (C) 2012 Elsevier B.V. All rights reserved.

Cross-cultural adaptations of the Oxford-12 HIP score to the French speaking population.

BACKGROUND: An objective measurement of surgical procedures outcomes is inherent to professional practices quality control; this especially applies in orthopaedics to joint replacement outcomes. A self-administered questionnaire offers an attractive alternative to surgeon's judgement but is infrequently used in France for these purposes. The British questionnaire, the 12-item Oxford Hip Score (OHS) was selected for this study because of its ease of use. HYPOTHESIS: The objective of this study was to validate the French translation of the self-assessment 12-item Oxford Hip Score and compare its results with those of the reference functional scores: the Harris Hip Score (HHS) and the Postel-Merle d'Aubigné (PMA) score. MATERIALS AND METHODS: Based on a clinical series of 242 patients who were candidates for total hip arthroplasty, the French translation of this questionnaire was validated. Its coherence was also validated by comparing the preoperative data with the data obtained from the two other reference clinical scores. RESULTS: The translation was validated using the forward-backward translation procedure from French to English, with correction of all differences or mistranslations after systematized comparison with the original questionnaire in English. The mean overall OHS score was 43.8 points (range, 22-60 points) with similarly good distribution of the overall value of the three scores compared. The correlation was excellent between the OHS and the HHS, but an identical correlation between the OHS and the PMA was only obtained for the association of the pain and function parameters, after excluding the mobility criterion, relatively over-represented in the PMA score. DISCUSSION AND CONCLUSION: Subjective questionnaires that contribute a personal appreciation of the results of arthroplasty by the patient can easily be applied on a large scale. This study made a translated and validated version of an internationally recognized, reliable self-assessment score available to French orthopaedic surgeons. The results obtained encourage us to use this questionnaire as a complement to the classical evaluation scores and methods.

A stratified approach for modeling the distribution of a threatened ant species in the Swiss National Park

We present models predicting the potential distribution of a threatened ant species, Formica exsecta Nyl., in the Swiss National Park ( SNP). Data to fit the models have been collected according to a random-stratified design with an equal number of replicates per stratum. The basic aim of such a sampling strategy is to allow the formal testing of biological hypotheses about those factors most likely to account for the distribution of the modeled species. The stratifying factors used in this study were: vegetation, slope angle and slope aspect, the latter two being used as surrogates of solar radiation, considered one of the basic requirements of F. exsecta. Results show that, although the basic stratifying predictors account for more than 50% of the deviance, the incorporation of additional non-spatially explicit predictors into the model, as measured in the field, allows for an increased model performance (up to nearly 75%). However, this was not corroborated by permutation tests. Implementation on a national scale was made for one model only, due to the difficulty of obtaining similar predictors on this scale. The resulting map on the national scale suggests that the species might once have had a broader distribution in Switzerland. Reasons for its particular abundance within the SNP might possibly be related to habitat fragmentation and vegetation transformation outside the SNP boundaries.

Hypoxia and vasculature in models of lung cancer: implications for targeted therapeutics

Estudi realitzat a partir d’una estada a la Stanford University School of Medicine. Division of Radiation Oncology, Estats Units, entre 2010 i 2012. Durant els dos anys de beca postdoctoral he estat treballant en dos projectes diferents. En primer lloc, i com a continuació d'estudis previs del grup, volíem estudiar la causa de les diferències en nivells d'hipòxia que havíem observat en models de càncer de pulmó. La nostra hipòtesi es basava en el fet que aquestes diferències es devien a la funcionalitat de la vasculatura. Vam utilitzar dos models preclínics: un en què els tumors es formaven espontàniament als pulmons i l'altre on nosaltres injectàvem les cèl•lules de manera subcutània. Vam utilitzar tècniques com la ressonància magnètica dinàmica amb agent de contrast (DCE-MRI) i l'assaig de perfusió amb el Hoeschst 33342 i ambdues van demostrar que la funcionalitat de la vasculatura dels tumors espontanis era molt més elevada comparada amb la dels tumors subcutanis. D'aquest estudi, en podem concloure que les diferències en els nivells d'hipòxia en els diferents models tumorals de càncer de pulmó podrien ser deguts a la variació en la formació i funcionalitat de la vasculatura. Per tant, la selecció de models preclínics és essencial, tant pels estudi d'hipòxia i angiogènesi, com per a teràpies adreçades a aquests fenòmens. L'altre projecte que he estat desenvolupant es basa en l'estudi de la radioteràpia i els seus possibles efectes a l’hora de potenciar l'autoregeneració del tumor a partir de les cèl•lules tumorals circulants (CTC). Aquest efecte s'ha descrit en alguns models tumorals preclínics. Per tal de dur a terme els nostres estudis, vam utilitzar una línia tumoral de càncer de mama de ratolí, marcada permanentment amb el gen de Photinus pyralis o sense marcar i vam fer estudis in vitro i in vivo. Ambdós estudis han demostrat que la radiació tumoral promou la invasió cel•lular i l'autoregeneració del tumor per CTC. Aquest descobriment s'ha de considerar dins d'un context de radioteràpia clínica per tal d'aconseguir el millor tractament en pacients amb nivells de CTC elevats.

Benefit of Cup Medialization in Total Hip Arthroplasty is Associated With Femoral Anatomy.

BACKGROUND: Medialization of the cup with a respective increase in femoral offset has been proposed in THA to increase abductor moment arms. Insofar as there are potential disadvantages to cup medialization, it is important to ascertain whether the purported biomechanical benefits of cup medialization are large enough to warrant the downsides; to date, studies regarding this question have disagreed. QUESTIONS/PURPOSES: The purpose of this study was to quantify the effect of cup medialization with a compensatory increase in femoral offset compared with anatomic reconstruction for patients undergoing THA. We tested the hypothesis that there is a (linear) correlation between preoperative anatomic parameters and muscle moment arm increase caused by cup medialization. METHODS: Fifteen patients undergoing THA were selected, covering a typical range of preoperative femoral offsets. For each patient, a finite element model was built based on a preoperative CT scan. The model included the pelvis, femur, gluteus minimus, medius, and maximus. Two reconstructions were compared: (1) anatomic position of the acetabular center of rotation, and (2) cup medialization compensated by an increase in the femoral offset. Passive abduction-adduction and flexion-extension were simulated in the range of normal gait. Muscle moment arms were evaluated and correlated to preoperative femoral offset, acetabular offset, height of the greater trochanter (relative to femoral center of rotation), and femoral antetorsion angle. RESULTS: The increase of muscle moment arms caused by cup medialization varied among patients. Muscle moment arms increase by 10% to 85% of the amount of cup medialization for abduction-adduction and from -35% (decrease) to 50% for flexion-extension. The change in moment arm was inversely correlated (R(2) = 0.588, p = 0.001) to femoral antetorsion (anteversion), such that patients with less femoral antetorsion gained more in terms of hip muscle moments. No linear correlation was observed between changes in moment arm and other preoperative parameters in this series. CONCLUSIONS: The benefit of cup medialization is variable and depends on the individual anatomy. CLINICAL RELEVANCE: Cup medialization with compensatory increase of the femoral offset may be particularly effective in patients with less femoral antetorsion. However, cup medialization must be balanced against its tradeoffs, including the additional loss of medial acetabular bone stock, and eventual proprioceptive implications of the nonanatomic center of rotation and perhaps joint reaction forces. Clinical studies should better determine the relevance of small changes of moment arms on function and joint reaction forces.

Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis.

Background Following the discovery that mutant KRAS is associated with resistance to anti-epidermal growth factor receptor (EGFR) antibodies, the tumours of patients with metastatic colorectal cancer are now profiled for seven KRAS mutations before receiving cetuximab or panitumumab. However, most patients with KRAS wild-type tumours still do not respond. We studied the effect of other downstream mutations on the efficacy of cetuximab in, to our knowledge, the largest cohort to date of patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab plus chemotherapy in the pre-KRAS selection era. Methods 1022 tumour DNA samples (73 from fresh-frozen and 949 from formalin-fixed, paraffin-embedded tissue) from patients treated with cetuximab between 2001 and 2008 were gathered from 11 centres in seven European countries. 773 primary tumour samples had sufficient quality DNA and were included in mutation frequency analyses; mass spectrometry genotyping of tumour samples for KRAS, BRAF, NRAS, and PIK3CA was done centrally. We analysed objective response, progression-free survival (PFS), and overall survival in molecularly defined subgroups of the 649 chemotherapy-refractory patients treated with cetuximab plus chemotherapy. Findings 40.0% (299/747) of the tumours harboured a KRAS mutation, 14.5% (108/743) harboured a PIK3CA mutation (of which 68.5% [74/108] were located in exon 9 and 20.4% [22/108] in exon 20), 4.7% (36/761) harboured a BRAF mutation, and 2.6% (17/644) harboured an NRAS mutation. KRAS mutants did not derive benefit compared with wild types, with a response rate of 6.7% (17/253) versus 35.8% (126/352; odds ratio [OR] 0.13, 95% CI 0.07-0.22; p<0.0001), a median PFS of 12. weeks versus 24 weeks (hazard ratio [HR] 1 98, 1.66-2.36; p<0.0001), and a median overall survival of 32 weeks versus 50 weeks (1.75, 1.47-2.09; p<0.0001). In KRAS wild types, carriers of BRAF and NRAS mutations had a significantly lower response rate than did BRAF and NRAS wild types, with a response rate of 8.3% (2/24) in carriers of BRAF mutations versus 38.0% in BRAF wild types (124/326; OR 0.15, 95% CI 0.02-0.51; p=0.0012); and 7.7% (1/13) in carriers of NRAS mutations versus 38.1% in NRAS wild types (110/289; OR 0.14, 0.007-0.70; p=0.013). PIK3CA exon 9 mutations had no effect, whereas exon 20 mutations were associated with a worse outcome compared with wild types, with a response rate of 0.0% (0/9) versus 36.8% (121/329; OR 0.00,0.00-0.89; p=0.029), a median PFS of 11.5 weeks versus 24 weeks (HR 2.52, 1.33-4.78; p=0.013), and a median overall survival of 34 weeks versus 51 weeks (3.29, 1.60-6.74; p=0.0057). Multivariate analysis and conditional inference trees confirmed that, if KRAS is not mutated, assessing BRAF, NRAS, and PIK3CA exon 20 mutations (in that order) gives additional information about outcome. Objective response rates in our series were 24.4% in the unselected population, 36.3% in the KRAS wild-type selected population, and 41.2% in the KRAS, BRAF, NRAS, and PIK3CA exon 20 wild-type population. Interpretation While confirming the negative effect of KRAS mutations on outcome after cetuximab, we show that BRAF, NRAS, and PIK3CA,exon 20 mutations are significantly associated with a low response rate. Objective response rates could be improved by additional genotyping of BRAF, NRAS, and PIK3CA exon 20 mutations in a KRAS wild-type population.

Association between GIS-based exposure to urban air pollution during pregnancy and birth weight in the INMA Sabadell Cohort

Background: There is growing evidence that traffic-related air pollution reduces birth weight. Improving exposure assessment is a key issue to advance in this research area.Objective: We investigated the effect of prenatal exposure to traffic-related air pollution via geographic information system (GIS) models on birth weight in 570 newborns from the INMA (Environment and Childhood) Sabadell cohort.Methods: We estimated pregnancy and trimester-specific exposures to nitrogen dioxide and aromatic hydrocarbons [benzene, toluene, ethylbenzene, m/p-xylene, and o-xylene (BTEX)] by using temporally adjusted land-use regression (LUR) models. We built models for NO2 and BTEX using four and three 1-week measurement campaigns, respectively, at 57 locations. We assessed the relationship between prenatal air pollution exposure and birth weight with linear regression models. We performed sensitivity analyses considering time spent at home and time spent in nonresidential outdoor environments during pregnancy.Results: In the overall cohort, neither NO2 nor BTEX exposure was significantly associated with birth weight in any of the exposure periods. When considering only women who spent < 2 hr/day in nonresidential outdoor environments, the estimated reductions in birth weight associated with an interquartile range increase in BTEX exposure levels were 77 g [95% confidence interval (CI), 7–146 g] and 102 g (95% CI, 28–176 g) for exposures during the whole pregnancy and the second trimester, respectively. The effects of NO2 exposure were less clear in this subset.Conclusions: The association of BTEX with reduced birth weight underscores the negative role of vehicle exhaust pollutants in reproductive health. Time–activity patterns during pregnancy complement GIS-based models in exposure assessment.

New validated prognostic models and prognostic calculators in patients with low-grade gliomas diagnosed by central pathology review: a pooled analysis of EORTC/RTOG/NCCTG phase III clinical trials.

Background In a previous study, the European Organisation for Research and Treatment of Cancer (EORTC) reported a scoring system to predict survival of patients with low-grade gliomas (LGGs). A major issue in the diagnosis of brain tumors is the lack of agreement among pathologists. New models in patients with LGGs diagnosed by central pathology review are needed. Methods Data from 339 EORTC patients with LGGs diagnosed by central pathology review were used to develop new prognostic models for progression-free survival (PFS) and overall survival (OS). Data from 450 patients with centrally diagnosed LGGs recruited into 2 large studies conducted by North American cooperative groups were used to validate the models. Results Both PFS and OS were negatively influenced by the presence of baseline neurological deficits, a shorter time since first symptoms (<30 wk), an astrocytic tumor type, and tumors larger than 5 cm in diameter. Early irradiation improved PFS but not OS. Three risk groups have been identified (low, intermediate, and high) and validated. Conclusions We have developed new prognostic models in a more homogeneous LGG population diagnosed by central pathology review. This population better fits with modern practice, where patients are enrolled in clinical trials based on central or panel pathology review. We could validate the models in a large, external, and independent dataset. The models can divide LGG patients into 3 risk groups and provide reliable individual survival predictions. Inclusion of other clinical and molecular factors might still improve models' predictions.

Src is activated by the nuclear receptor peroxisome proliferator-activated receptor β/δ in ultraviolet radiation-induced skin cancer.

Although non-melanoma skin cancer (NMSC) is the most common human cancer and its incidence continues to rise worldwide, the mechanisms underlying its development remain incompletely understood. Here, we unveil a cascade of events involving peroxisome proliferator-activated receptor (PPAR) β/δ and the oncogene Src, which promotes the development of ultraviolet (UV)-induced skin cancer in mice. UV-induced PPARβ/δ activity, which directly stimulated Src expression, increased Src kinase activity and enhanced the EGFR/Erk1/2 signalling pathway, resulting in increased epithelial-to-mesenchymal transition (EMT) marker expression. Consistent with these observations, PPARβ/δ-null mice developed fewer and smaller skin tumours, and a PPARβ/δ antagonist prevented UV-dependent Src stimulation. Furthermore, the expression of PPARβ/δ positively correlated with the expression of SRC and EMT markers in human skin squamous cell carcinoma (SCC), and critically, linear models applied to several human epithelial cancers revealed an interaction between PPARβ/δ and SRC and TGFβ1 transcriptional levels. Taken together, these observations motivate the future evaluation of PPARβ/δ modulators to attenuate the development of several epithelial cancers.

Change in physical activity after smoking cessation: the Coronary Artery Risk Development in Young Adults (CARDIA) study.

AIMS: To estimate physical activity trajectories for people who quit smoking, and compare them to what would have been expected had smoking continued. DESIGN, SETTING AND PARTICIPANTS: A total of 5115 participants in the Coronary Artery Risk Development in Young Adults Study (CARDIA) study, a population-based study of African American and European American people recruited at age 18-30 years in 1985/6 and followed over 25 years. MEASUREMENTS: Physical activity was self-reported during clinical examinations at baseline (1985/6) and at years 2, 5, 7, 10, 15, 20 and 25 (2010/11); smoking status was reported each year (at examinations or by telephone, and imputed where missing). We used mixed linear models to estimate trajectories of physical activity under varying smoking conditions, with adjustment for participant characteristics and secular trends. FINDINGS: We found significant interactions by race/sex (P = 0.02 for the interaction with cumulative years of smoking), hence we investigated the subgroups separately. Increasing years of smoking were associated with a decline in physical activity in black and white women and black men [e.g. coefficient for 10 years of smoking: -0.14; 95% confidence interval (CI) = -0.20 to -0.07, P < 0.001 for white women]. An increase in physical activity was associated with years since smoking cessation in white men (coefficient 0.06; 95% CI = 0 to 0.13, P = 0.05). The physical activity trajectory for people who quit diverged progressively towards higher physical activity from the expected trajectory had smoking continued. For example, physical activity was 34% higher (95% CI = 18 to 52%; P < 0.001) for white women 10 years after stopping compared with continuing smoking for those 10 years (P = 0.21 for race/sex differences). CONCLUSIONS: Smokers who quit have progressively higher levels of physical activity in the years after quitting compared with continuing smokers.

Wear of two artificial tooth materials in vivo: a 12-month pilot study.

STATEMENT OF PROBLEM: Wear of methacrylate artificial teeth resulting in vertical loss is a problem for both dentists and patients. PURPOSE: The purpose of this study was to quantify wear of artificial teeth in vivo and to relate it to subject and tooth variables. MATERIAL AND METHODS: Twenty-eight subjects treated with complete dentures received 2 artificial tooth materials (polymethyl methacrylate (PMMA)/double-cross linked PMMA fillers; 35%/59% (SR Antaris DCL, SR Postaris DCL); experimental 48%/46%). At baseline and after 12 months, impressions of the dentures were poured with improved stone. After laser scanning, the casts were superimposed and matched. Maximal vertical loss (mm) and volumetric loss (mm(3)) were calculated for each tooth and log-transformed to reduce variability. Volumetric loss was related to the occlusally active surface area. Linear mixed models were used to study the influence of the factors jaw, tooth, and material on adjusted (residual) wear values (alpha=.05). RESULTS: Due to drop outs (n=5) and unmatchable casts (n=3), 69% of all teeth were analyzed. Volumetric loss had a strong linear relationship to surface area (P<.001); this was less pronounced for vertical loss (P=.004). The factor showing the highest influence was the subject. Wear was tooth dependent (increasing from incisors to molars). However, these differences diminished once the wear rates were adjusted for occlusal area, and only a few remained significant (anterior versus posterior maxillary teeth). Another influencing factor was the age of the subject. CONCLUSIONS: Clinical wear of artificial teeth is higher than previously measured or expected. The presented method of analyzing wear of artificial teeth using a laser-scanning device seemed suitable.

Linking life-history traits, ecology, and niche breadth evolution in north american eriogonoids (polygonaceae).

Abstract Macroevolutionary and microevolutionary studies provide complementary explanations of the processes shaping the evolution of niche breadth. Macroevolutionary approaches scrutinize factors such as the temporal and spatial environmental heterogeneities that drive differentiation among species. Microevolutionary studies, in contrast, focus on the processes that affect intraspecific variability. We combine these perspectives by using macroevolutionary models in a comparative study of intraspecific variability. We address potential differences in rates of evolution of niche breadth and position in annual and perennial plants of the Eriogonoideae subfamily of the Polygonaceae. We anticipated higher rates of evolution in annuals than in perennials owing to differences in generation time that are paralleled by rates of molecular evolution. Instead, we found that perennial eriogonoid species present greater environmental tolerance (wider climate niche) than annual species. Niche breadth of perennial species has evolved two to four times faster than in annuals, while niche optimum has diversified more rapidly among annual species than among perennials. Niche breadth and average elevation of species are correlated. Moreover, niche breadth increases more rapidly with mean species elevation in perennials than in annuals. Our results suggest that both environmental gradients and life-history strategy influence rates and patterns of niche breadth evolution.

Time Series Input Selection using Multiple Kernel Learning

In this paper we study the relevance of multiple kernel learning (MKL) for the automatic selection of time series inputs. Recently, MKL has gained great attention in the machine learning community due to its flexibility in modelling complex patterns and performing feature selection. In general, MKL constructs the kernel as a weighted linear combination of basis kernels, exploiting different sources of information. An efficient algorithm wrapping a Support Vector Regression model for optimizing the MKL weights, named SimpleMKL, is used for the analysis. In this sense, MKL performs feature selection by discarding inputs/kernels with low or null weights. The approach proposed is tested with simulated linear and nonlinear time series (AutoRegressive, Henon and Lorenz series).