Understanding complex predictive models with ghost variables

The version of record of this article, first published in Test, is available online at Publisher’s website: http://dx.doi.org/10.1007/s11749-022-00826-xFramed in the literature on Interpretable Machine Learning, we propose a new procedure to assign a measure of relevance to each explanatory variable in a complex predictive model. We assume that we have a training set to fit the model and a test set to check its out-of-sample performance. We propose to measure the individual relevance of each variable by comparing the predictions of the model in the test set with those obtained when the variable of interest is substituted (in the test set) by its ghost variable, defined as the prediction of this variable by using the rest of explanatory variables. In linear models it is shown that, on the one hand, the proposed measure gives similar results to leave-one-covariate-out (loco, with a lowest computational cost) and outperforms random permutations, and on the other hand, it is strongly related to the usual F-statistic measuring the significance of a variable. In nonlinear predictive models (as neural networks or random forests) the proposed measure shows the relevance of the variables in an efficient way, as shown by a simulation study comparing ghost variables with other alternative methods (including loco and random permutations, and also knockoff variables and estimated conditional distributions). Finally, we study the joint relevance of the variables by defining the relevance matrix as the covariance matrix of the vectors of effects on predictions when using every ghost variable. Our proposal is illustrated with simulated examples and the analysis of a large real data set.Peer ReviewedPostprint (author's final draft

High-Fat-Diet-Induced Obesity Produces Spontaneous Ventricular Arrhythmias and Increases the Activity of Ryanodine Receptors in Mice

Ventricular arrhythmias are a common cause of sudden cardiac death, and their occurrence is higher in obese subjects. Abnormal gating of ryanodine receptors (RyR2), the calcium release channels of the sarcoplasmic reticulum, can produce ventricular arrhythmias. Since obesity promotes oxidative stress and RyR2 are redox-sensitive channels, we investigated whether the RyR2 activity was altered in obese mice. Mice fed a high fat diet (HFD) became obese after eight weeks and exhibited a significant increase in the occurrence of ventricular arrhythmias. Single RyR2 channels isolated from the hearts of obese mice were more active in planar bilayers than those isolated from the hearts of the control mice. At the molecular level, RyR2 channels from HFD-fed mice had substantially fewer free thiol residues, suggesting that redox modifications were responsible for the higher activity. Apocynin, provided in the drinking water, completely prevented the appearance of ventricular arrhythmias in HFD-fed mice, and normalized the activity and content of the free thiol residues of the protein. HFD increased the expression of NOX4, an isoform of NADPH oxidase, in the heart. Our results suggest that HFD increases the activity of RyR2 channels via a redox-dependent mechanism, favoring the appearance of ventricular arrhythmias.Fil: Pecchi Sanchez, Gina Angela. Universidad de Chile. Facultad de Medicina. Institutos de Ciencias Biomédicas; ChileFil: Araneda, Felipe. Universidad de Chile. Facultad de Medicina. Institutos de Ciencias Biomédicas; ChileFil: Peña, Juan Pedro. Universidad de Viña del Mar. Escuela de Ciencias Veterinarias; ChileFil: Finkelstein, Jose Pablo. Universidad de Chile. Facultad de Medicina. Institutos de Ciencias Biomédicas; ChileFil: Riquelme, Jaime A.. Universidad de Chile; ChileFil: Montecinos, Luis. Universidad de Chile. Facultad de Medicina. Institutos de Ciencias Biomédicas; ChileFil: Barrientos, Genaro. Universidad de Chile. Facultad de Medicina. Institutos de Ciencias Biomédicas; ChileFil: LLanos, Paola. Universidad de Chile; ChileFil: Pedrozo, Zully. Universidad de Chile. Facultad de Medicina. Institutos de Ciencias Biomédicas; ChileFil: Said, Maria Matilde. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; ArgentinaFil: Bull, Ricardo. Universidad de Chile. Facultad de Medicina. Institutos de Ciencias Biomédicas; ChileFil: Donoso, Paulina. Universidad de Chile. Facultad de Medicina. Institutos de Ciencias Biomédicas; Chil

Early dysfunction of functional connectivity in healthy elderly with subjective memory complaints

It is still an open question whether subjective memory complaints (SMC) can actually be considered to be clinically relevant predictors for the development of an objective memory impairment and even dementia. There is growing evidence that suggests that SMC are associated with an increased risk of dementia and with the presence of biological correlates of early Alzheimer's disease. In this paper, in order to shed some light on this issue, we try to discern whether subjects with SMC showed a different profile of functional connectivity compared with subjects with mild cognitive impairment (MCI) and healthy elderly subjects. In the present study, we compare the degree of synchronization of brain signals recorded with magnetoencephalography between three groups of subjects (56 in total): 19 with MCI, 12 with SMC and 25 healthy controls during a memory task. Synchronization likelihood, an index based on the theory of nonlinear dynamical systems, was used to measure functional connectivity. Briefly, results show that subjects with SMC have a very similar pattern of connectivity to control group, but on average, they present a lower synchronization value. These results could indicate that SMC are representing an initial stage with a hypo-synchronization (in comparison with the control group) where the brain system is still not compensating for the failing memory networks, but behaving as controls when compared with the MCI subjects

In Urinary Incontinence Rehabilitation treated there is clinical improvement and decrease in electromyographic values with age

Introduction. The pelvic floor (SP) is formed by a set of muscular structures, which together with the fascias and ligaments make up the pelvic diaphragm. The function of the SP is the support of the pelvic organs and maintain a correct position of these, influencing urination, intercourse, childbirth and defecation. A weakness or injury of these structures predisposes to the appearance of a symptomatology that can occur in isolation or in combination, one of the main problems being UI urinary incontinence and pelvic organ prolapse POP(1). It is estimated a prevalence of UI in adults between 15 and 30%, presenting in all ages, detecting a progressive increase as age advances and POP in 50% of women who have had at least one vaginal delivery.(2-4) Objectives. Evaluate both clinically and electromyographically a group of women diagnosed with UI and / or POP, after performing a rehabilitative treatment and one year of follow-up. Material and methods. This is a longitudinal, analytical observational study of a prospective cohort type, where women aged between 18 and 85 years were evaluated in a period of time between January 2008 and January 2012. The variables used In the present study, they differed in clinical and electromyographic variables. For the evaluation of the MSP an intravaginal surface EMG was performed, which consisted in a quantitative muscular diagnostic evaluation and in which some known muscle parameters were obtained. A rehabilitation treatment protocol was designed, following the guidelines established according to scientific evidence. Results. In the present study a total of 241 women were included, whose average age was 50.4 years (SD = 12.3), the mean BMI was 27.7 kg / m2, the average duration of symptoms was 6.9 years (SD = 8.9). 88% of women consulted by IU and 29% by POP. The most frequent diagnosis was that of IUM in 118 women (49.0%), followed by SUI in 65 women (27.0%). 49.4% were menopausal, 85.1% had vaginal delivery, only 2.9% were nulliparous. The mean number of deliveries was 2.4 (SD = 1.1) and in 89% of the cases they suffered episiotomy. 92.1% of the women in the sample had urine leaks, 96.4% of them related to the effort. Of the total sample, 189 patients (78.4%) performed treatment in the SP Unit. The average number of sessions was 14.2 (SD = 7.8). At the end of the rehabilitation treatment, 92.3% of the patients reported finding themselves better, 42% of the women presented voiding urgencies, and 47.6% suffered from UUI. The analysis of repeated measures of the electromyographic variables before and after the rehabilitation treatment and during the year of follow-up, statistically significant increases were observed in the maximum values of the phasic contractions, the average values of the tonic contractions, the duration of the tonic contraction selected and the total power of the ttonic contraction. When the means of the maximum values of the phasic contractions were compared, the maximum values of the tonic contractions and the average values of the tonic contractions with the degrees of the modified Oxford scale obtained statistically significant results. Conclusions. The rehabilitation treatment has achieved an improvement perceived by the patients in 92% of them after finishing the treatment and an improvement in 75% at one year of follow-up. There is a decrease in the maximum values recorded in the EMG by age, decade by decade, experiencing a significant drop in the group of women ≥70 years

Band Depopulation of Graphene Nanoribbons Induced by Chemical Gating with Amino Groups

Altres ajuts: Xunta de Galicia (ED431G/09); Gobierno Vasco (IT1246-19, IT-1255-19); Diputación Foral de Gipuzkoa (RED 2019-096); CERCA Program/Generalitat de Catalunya; Program Interreg V-A España-Francia-Andorra (194/16 TNI)The electronic properties of graphene nanoribbons (GNRs) can be precisely tuned by chemical doping. Here we demonstrate that amino (NH) functional groups attached at the edges of chiral GNRs (chGNRs) can efficiently gate the chGNRs and lead to the valence band (VB) depopulation on a metallic surface. The NH-doped chGNRs are grown by on-surface synthesis on Au(111) using functionalized bianthracene precursors. Scanning tunneling spectroscopy resolves that the NH groups significantly upshift the bands of chGNRs, causing the Fermi level crossing of the VB onset of chGNRs. Through density functional theory simulations we confirm that the hole-doping behavior is due to an upward shift of the bands induced by the edge NH groups

Citrus tristeza virus p23: a unique protein mediating key virus-host interactions

This Document is Protected by copyright and was first published by Frontiers. All rights reserved. it is reproduced with permission[EN] The large RNA genome of Citrus tristeza virus (CTV; ca. 20 kb) contains 12 open reading frames, with the 3 -terminal one corresponding to a protein of 209 amino acids (p23) that is expressed from an abundant subgenomic RNA. p23, an RNA-binding protein with a putative zinc-finger domain and some basic motifs, is unique to CTV because no homologs have been found in other closteroviruses, including the type species of the genus Beet yellows virus (despite both viruses having many homologous genes). Consequently, p23 might have evolved for the specific interaction of CTV with its citrus hosts. From a functional perspective p23 has been involved in many roles: (i) regulation of the asymmetrical accumulation of CTV RNA strands, (ii) induction of the seedling yellows syndrome in sour orange and grapefruit, (iii) intracellular suppression of RNA silencing, (iv) elicitation of CTV-like symptoms when expressed ectopically as a transgene in several Citrus spp., and (v) enhancement of systemic infection (and virus accumulation) in sour orange and CTV release from the phloem in p23-expressing transgenic sweet and sour orange. Moreover, transformation of Mexican lime with intron-hairpin constructs designed for the co-inactivation of p23 and the two other CTV silencing suppressors results in complete resistance against the homologous virus. From a cellular point of view, recent data indicate that p23 accumulates preferentially in the nucleolus, being the first closterovirus protein with such a subcellular localization, as well as in plasmodesmata. These major accumulation sites most likely determine some of the functional roles of p23.Research on CTV has been supported by a grant (Prometeo/2008/121) from the Generalitat Valenciana (GV), and by a grant (AGL2009-08052) from the Ministerio de Ciencia e Innovacion (MICINN)-Fondo Europeo de Desarrollo Regional. Susana Ruiz-Ruiz has been additionally supported by a postdoctoral contract from the GV (APOSTD/2012/020, Program VALi+d), Nuria Soler by a predoctoral fellowship from the IVIA, and Carmen Fagoaga by a postdoctoral contract "Ramon y Cajal" from the MICINN.Flores Pedauye, R.; Ruiz Ruiz, S.; Soler, N.; Sanchez Navarro, JA.; Fagoaga García, CC.; López Del Rincón, C.; Navarro Lucas, L.... (2013). Citrus tristeza virus p23: a unique protein mediating key virus-host interactions. Frontiers in Microbiology. 4(98):1-9. https://doi.org/10.3389/fmicb.2013.00098S1949

Conservative management of perforated duodenal diverticulum: a case report and review of the literature

Duodenal diverticula are a relatively common condition. They are asymptomatic, unless they become complicated, with perforation being the rarest but most severe complication. Surgical treatment is the most frequently performed approach. We report the case of a patient with a perforated duodenal diverticulum, which was diagnosed early and treated conservatively with antibiotics and percutaneous drainage of secondary retroperitoneal abscesses. We suggest this method could be an acceptable option for the management of similar cases, provided that the patient is in good general condition and without septic signs

Tocilizumab in refractory Caucasian Takayasu's arteritis: a multicenter study of 54 patients and literature review

Objective: To assess the efficacy and safety of tocilizumab (TCZ) in Caucasian patients with refractory Takayasu's arteritis (TAK) in clinical practice. Methods: A multicenter study of Caucasian patients with refractory TAK who received TCZ. The outcome variables were remission, glucocorticoid-sparing effect, improvement in imaging techniques, and adverse events. A comparative study between patients who received TCZ as monotherapy (TCZMONO) and combined with conventional disease modifying anti-rheumatic drugs (cDMARDs) (TCZCOMBO) was performed. Results: The study comprised 54 patients (46 women/8 men) with a median [interquartile range (IQR)] age of 42.0 (32.5-50.5) years. TCZ was started after a median (IQR) of 12.0 (3.0-31.5) months since TAK diagnosis. Remission was achieved in 12/54 (22.2%), 19/49 (38.8%), 23/44 (52.3%), and 27/36 (75%) patients at 1, 3, 6, and 12 months, respectively. The prednisone dose was reduced from 30.0 mg/day (12.5-50.0) to 5.0 (0.0-5.6) mg/day at 12 months. An improvement in imaging findings was reported in 28 (73.7%) patients after a median (IQR) of 9.0 (6.0-14.0) months. Twenty-three (42.6%) patients were on TCZMONO and 31 (57.4%) on TCZCOMBO: MTX (n = 28), cyclosporine A (n = 2), azathioprine (n = 1). Patients on TCZCOMBO were younger [38.0 (27.0-46.0) versus 45.0 (38.0-57.0)] years; difference (diff) [95% confidence interval (CI) = -7.0 (-17.9, -0.56] with a trend to longer TAK duration [21.0 (6.0-38.0) versus 6.0 (1.0-23.0)] months; diff 95% CI = 15 (-8.9, 35.5), and higher c-reactive protein [2.4 (0.7-5.6) versus 1.3 (0.3-3.3)] mg/dl; diff 95% CI = 1.1 (-0.26, 2.99). Despite these differences, similar outcomes were observed in both groups (log rank p = 0.862). Relevant adverse events were reported in six (11.1%) patients, but only three developed severe events that required TCZ withdrawal. Conclusion: TCZ in monotherapy, or combined with cDMARDs, is effective and safe in patients with refractory TAK of Caucasian origin.Funding: This work was partially supported by RETICS Programs, RD08/0075 (RIER), RD12/0009/0013 and RD16/0012 from “Instituto de Salud Carlos III” (ISCIII) (Spain)

Low NKp30, NKp46 and NKG2D expression and reduced cytotoxic activity on NK cells in cervical cancer and precursor lesions

<p>Abstract</p> <p>Background</p> <p>Persistent high risk HPV infection can lead to cervical cancer, the second most common malignant tumor in women worldwide. NK cells play a crucial role against tumors and virus-infected cells through a fine balance between activating and inhibitory receptors. Expression of triggering receptors NKp30, NKp44, NKp46 and NKG2D on NK cells correlates with cytolytic activity against tumor cells, but these receptors have not been studied in cervical cancer and precursor lesions. The aim of the present work was to study NKp30, NKp46, NKG2D, NKp80 and 2B4 expression in NK cells from patients with cervical cancer and precursor lesions, in the context of HPV infection.</p> <p>Methods</p> <p>NKp30, NKp46, NKG2D, NKp80 and 2B4 expression was analyzed by flow cytometry on NK cells from 59 patients with cervical cancer and squamous intraepithelial lesions. NK cell cytotoxicity was evaluated in a 4 hour CFSE/7-AAD flow cytometry assay. HPV types were identified by PCR assays.</p> <p>Results</p> <p>We report here for the first time that NK cell-activating receptors NKp30 and NKp46 are significantly down-regulated in cervical cancer and high grade squamous intraepithelial lesion (HGSIL) patients. NCRs down-regulation correlated with low cytolytic activity, HPV-16 infection and clinical stage. NKG2D was also down-regulated in cervical cancer patients.</p> <p>Conclusion</p> <p>Our results suggest that NKp30, NKp46 and NKG2D down-regulation represent an evasion mechanism associated to low NK cell activity, HPV-16 infection and cervical cancer progression.</p