Research and Publication Trends in Pediatric Surgery in Latin America: A Bibliometric and Visual Analysis from 2012 to 2021.

INTRODUCTION: Pediatric surgery is a developing specialty with increasing volume in Latin America. However, the research and scientific activity trends carried out in this region in recent years are unknown. This study aimed to analyze and visualize Latin American research in pediatric surgery from 2012 to 2021. MATERIAL AND METHODS: Bibliometric cross-sectional study of scientific articles on pediatric surgery published by Latin American authors from 2012 to 2021 in Scopus was performed. Statistical and visual analysis was performed with R programming language and VOS viewer. RESULTS: 449 articles were found. Observational studies (44.7%; n = 201), case reports (20.4%; n = 92) and narrative reviews (11.4%; n = 51) were found to be the most common study designs. The published articles were predominantly monocentric (73.1%; n = 328), only 17% (n = 76) involved authors from 2 or more countries, and mostly there was no collaboration with high-income countries (80.6%; n = 362). The Journal of Pediatric Surgery was the journal with the highest volume of articles published (n = 37). The most used terms were Laparoscopy, Complications, and Liver Transplantation, and the countries with the highest number of articles published were Brazil and Argentina. CONCLUSIONS: This study found a progressive increase in the scientific activity of Latin authors in pediatric surgery from 2012 to 2021. The evidence produced was mainly from observational studies and case reports, predominantly conducted in Brazil. Multinational and international collaboration was low; the most frequent topics of interest were laparoscopy and minimally invasive surgery. LEVELS OF EVIDENCE: IV.

Dietary supplementation with spray-dried animal plasma improves vaccine protection in aged mice.

Background: Senescence is characterized by an aggravated inflammatory state that reduces vaccine responsiveness. Dietary supplementation with spray-dried porcine plasma (SDP) exerts anti-inflammatory effects in different mucosal areas. We aimed to determine if the anti-inflammatory properties of SDP improve the efficiency of immunization in senescent animals. Methods: Experiments were performed in 2-month-old and 6-month-old male SAMP8 mice fed control or SDP (8%) feeds for 4 months. The mice received nasal doses of 2.5 µg of Staphylococcus aureus enterotoxin B (SEB) or vehicle every 15 days (i.e., 3 times). Fifteen days after the last dose, a lethal shock was induced by intraperitoneal administration of SEB and LPS. Results: Immunization increased anti-SEB IgA in intestinal and bronchoalveolar fluid (p < 0.05). After the lethal shock, all immunized aged mice that were supplemented with SDP survived, in contrast to only 66% of those fed the control feed (p < 0.05). Moreover, after the lethal challenge, aged mice showed higher expression levels of pro-inflammatory cytokines (Il-6, Tnf-α, Ifn-γ, and Il-1ß) in jejunal and (Tnf-α, and Il-1ß) in lung tissues (p < 0.05), which were reduced by SDP supplementation (p < 0.05). Furthermore, in senescent mice, SDP supplementation augmented Il-4 and Il-10 expression in both tissues (p < 0.05). Conclusion: SDP reduces the mucosal inflammation associated with aging, improving vaccine protection in senescent mice.

The Neuroprotective Effects of Spray-Dried Porcine Plasma Supplementation Involve the Microbiota-Gut-Brain Axis.

Dietary supplementation with spray-dried porcine plasma (SDP) reduces the Alzheimer's disease (AD) hallmarks in SAMP8 mice. Since gut microbiota can play a critical role in the AD progression, we have studied if the neuroprotective effects of SDP involve the microbiota−gut−brain axis. Experiments were performed on two-month-old SAMP8 mice fed a standard diet and on six-month-old SAMP8 mice fed a control diet or an 8% SDP supplemented diet for four months. Senescence impaired short- and long-term memory, reduced cortical brain-derived neurotrophic factor (BDNF) abundance, increased interleukin (Il)-1ß, Il-6, and Toll-like receptor 2 (Tlr2) expression, and reduced transforming growth factor ß (Tgf-ß) expression and IL-10 concentration (all p < 0.05) and these effects were mitigated by SDP (all p < 0.05). Aging also increased pro-inflammatory cytokines in serum and colon (all p < 0.05). SDP attenuated both colonic and systemic inflammation in aged mice (all p < 0.05). SDP induced the proliferation of health-promoting bacteria, such as Lactobacillus and Pediococcus, while reducing the abundance of inflammation-associated bacteria, such as Johnsonella and Erysipelothrix (both q < 0.1). In conclusion, SDP has mucosal and systemic anti-inflammatory effects as well as neuroprotective properties in senescent mice; these effects are well correlated with SDP promotion of the abundance of probiotic species, which indicates that the gut−brain axis could be involved in the peripheral effects of SDP supplementation.

A cross-study analysis of drug response prediction in cancer cell lines.

To enable personalized cancer treatment, machine learning models have been developed to predict drug response as a function of tumor and drug features. However, most algorithm development efforts have relied on cross-validation within a single study to assess model accuracy. While an essential first step, cross-validation within a biological data set typically provides an overly optimistic estimate of the prediction performance on independent test sets. To provide a more rigorous assessment of model generalizability between different studies, we use machine learning to analyze five publicly available cell line-based data sets: National Cancer Institute 60, ancer Therapeutics Response Portal (CTRP), Genomics of Drug Sensitivity in Cancer, Cancer Cell Line Encyclopedia and Genentech Cell Line Screening Initiative (gCSI). Based on observed experimental variability across studies, we explore estimates of prediction upper bounds. We report performance results of a variety of machine learning models, with a multitasking deep neural network achieving the best cross-study generalizability. By multiple measures, models trained on CTRP yield the most accurate predictions on the remaining testing data, and gCSI is the most predictable among the cell line data sets included in this study. With these experiments and further simulations on partial data, two lessons emerge: (1) differences in viability assays can limit model generalizability across studies and (2) drug diversity, more than tumor diversity, is crucial for raising model generalizability in preclinical screening.

Reply to Nifli, A.-P. Comment on "Rosell-Cardona et al. Dietary Spray-Dried Porcine Plasma Reduces Neuropathological Alzheimer's Disease Hallmarks in SAMP8 Mice. Nutrients 2021, 13, 2369".

Thank you for your comments on our recent work of the effects of supplementation with spray-dried porcine plasma (SDP) on neuropathological markers of Alzheimer's disease (AD) [...].

Dietary Spray-Dried Porcine Plasma Reduces Neuropathological Alzheimer's Disease Hallmarks in SAMP8 Mice.

Alzheimer's disease (AD) is characterized by the aberrant processing of amyloid precursor protein (APP) and the accumulation of hyperphosphorylated tau, both of which are accompanied by neuroinflammation. Dietary supplementation with spray-dried porcine plasma (SDP) has anti-inflammatory effects in inflammation models. We investigated whether dietary supplementation with SDP prevents the neuropathological features of AD. The experiments were performed in 2- and 6-month-old SAMP8 mice fed a control diet, or a diet supplemented with 8% SDP, for 4 months. AD brain molecular markers were determined by Western blot and real-time PCR. Senescent mice showed reduced levels of p-GSK3ß (Ser9) and an increase in p-CDK5, p-tau (Ser396), sAPPß, and the concentration of Aß40, (all p < 0.05). SDP prevented these effects of aging and reduced Bace1 levels (all p < 0.05). Senescence increased the expression of Mme1 and Ide1 and pro-inflammatory cytokines (Il-17 and Il-18; all p < 0.05); these changes were prevented by SDP supplementation. Moreover, SDP increased Tgf-ß expression (p < 0.05). Furthermore, in aged mice, the gene expression levels of the microglial activation markers Trem2, Ym1, and Arg1 were increased, and SDP prevented these increases (all p < 0.05). Thus, dietary SDP might delay AD onset by reducing its hallmarks in senescent mice.

Dietary Supplementation with Spray-Dried Porcine Plasma Attenuates Colon Inflammation in a Genetic Mouse Model of Inflammatory Bowel Disease.

Dietary supplementation with spray-dried porcine plasma (SDP) can modulate the immune response of gut-associated lymphoid tissue. SDP supplementation reduces acute mucosal inflammation, as well as chronic inflammation associated with aging. The aim of this study was to analyze if SDP supplementation could ameliorate colitis in a genetic mouse model of inflammatory bowel disease (IBD). Wild-type mice and Mdr1a knockout (KO) mice were administered a control diet or an SDP-supplemented diet from day 21 (weaning) until day 56. The histopathological index, epithelial barrier, and intestinal immune system were analyzed in the colonic mucosa. KO mice had higher epithelial permeability, increased Muc1 and Muc4 expression, and lower abundance of E-cadherin and Muc2 (all p < 0.001). SDP prevented these effects (all p < 0.05) and decreased the colonic inflammation observed in KO mice, reducing neutrophil and monocyte infiltration and activation and the percentage of activated T helper lymphocytes in the colonic mucosa (all p < 0.05). SDP also diminished proinflammatory cytokine expression and increased the anti-inflammatory IL-10 concentration in the colonic mucosa (all p < 0.05). In conclusion, dietary supplementation with SDP enhances colon barrier function and reduces mucosal inflammation in a mouse model of IBD.

CANDLE/Supervisor: a workflow framework for machine learning applied to cancer research.

BACKGROUND: Current multi-petaflop supercomputers are powerful systems, but present challenges when faced with problems requiring large machine learning workflows. Complex algorithms running at system scale, often with different patterns that require disparate software packages and complex data flows cause difficulties in assembling and managing large experiments on these machines. RESULTS: This paper presents a workflow system that makes progress on scaling machine learning ensembles, specifically in this first release, ensembles of deep neural networks that address problems in cancer research across the atomistic, molecular and population scales. The initial release of the application framework that we call CANDLE/Supervisor addresses the problem of hyper-parameter exploration of deep neural networks. CONCLUSIONS: Initial results demonstrating CANDLE on DOE systems at ORNL, ANL and NERSC (Titan, Theta and Cori, respectively) demonstrate both scaling and multi-platform execution.

Predicting tumor cell line response to drug pairs with deep learning.

BACKGROUND: The National Cancer Institute drug pair screening effort against 60 well-characterized human tumor cell lines (NCI-60) presents an unprecedented resource for modeling combinational drug activity. RESULTS: We present a computational model for predicting cell line response to a subset of drug pairs in the NCI-ALMANAC database. Based on residual neural networks for encoding features as well as predicting tumor growth, our model explains 94% of the response variance. While our best result is achieved with a combination of molecular feature types (gene expression, microRNA and proteome), we show that most of the predictive power comes from drug descriptors. To further demonstrate value in detecting anticancer therapy, we rank the drug pairs for each cell line based on model predicted combination effect and recover 80% of the top pairs with enhanced activity. CONCLUSIONS: We present promising results in applying deep learning to predicting combinational drug response. Our feature analysis indicates screening data involving more cell lines are needed for the models to make better use of molecular features.

Cap-Score™ prospectively predicts probability of pregnancy.

Semen analysis (SA) poorly predicts male fertility, because it does not assess sperm fertilizing ability. The percentage of capacitated sperm determined by GM1 localization ("Cap-Score™"), differs between cohorts of fertile and potentially infertile men, and retrospectively, between men conceiving or failing to conceive by intrauterine insemination (IUI). Here, we prospectively tested whether Cap-Score can predict male fertility with the outcome being clinical pregnancy within ≤3 IUI cycles. Cap-Score and SA were performed (n = 208) with outcomes initially available for 91 men. Men were predicted to have either low (n = 47) or high (n = 44) chance of generating pregnancy using previously-defined Cap-Score reference ranges. Absolute and cumulative pregnancy rates were reduced in men predicted to have low pregnancy rates versus high ([absolute: 10.6% vs. 29.5%; p = 0.04]; [cumulative: 4.3% vs. 18.2%, 9.9% vs. 29.1%, and 14.0% vs. 32.8% for cycles 1-3; n = 91, 64, and 41; p = 0.02]). Only Cap-Score, not male/female age or SA results, differed significantly between outcome groups. Logistic regression evaluated Cap-Score and SA results relative to the probability of generating pregnancy (PGP) for men who were successful in, or completed, three IUI cycles (n = 57). Cap-Score was significantly related to PGP (p = 0.01). The model fit was then tested with 67 additional patients (n = 124; five clinics); the equation changed minimally, but fit improved (p < 0.001; margin of error: 4%). The Akaike Information Criterion found the best model used Cap-Score as the only predictor. These data show that Cap-Score provides a practical, predictive assessment of male fertility, with applications in assisted reproduction and treatment of male infertility.

Timing of sperm capacitation varies reproducibly among men.

Sperm must mature functionally in the process of capacitation to become able to fertilize. Capacitation depends on membrane lipid changes, and can be quantitatively assessed by redistribution of the ganglioside GM1 , the basis of the Cap-Score™ sperm function test. Here, differences in Cap-Score were compared among and within men at two time points. Ejaculates were liquefied, washed, and incubated for 3 hr under capacitating (Cap) conditions, then fixed and analyzed immediately (Day0); after being incubated 3 hr under Cap conditions then maintained 22-24 hr in fix (Day1-fix); or after 22-24 hr incubation under Cap conditions prior to fixation (Day1). In all cases, a light fixative previously shown to allow membrane lipid movements was used. Day1-fix and Day1 Cap-Scores were greater than Day0 (p < 0.001; n = 25), whereas Day1-fix and Day1 Cap-Scores were equivalent (p = 0.43; n = 25). In 123 samples from 52 fertile men, Cap-Score increased more than 1SD (7.7; calculated previously from a fertile cohort) from Day0 to Day1-fix in 44% (54/123) of the samples. To test whether timing of capacitation was consistent within an individual, 52 samples from 11 fertile men were classified into either "early" or "late" capacitation groups. The average capacitation group concordance within a donor was 81%. Median absolute deviation (MAD; in Cap-Score units) was used to assess the tightness of clustering of the difference from Day0 to Day1-fix within individuals. The average (2.21) and median (1.98) MAD confirmed consistency within individuals. Together, these data show that the timing of capacitation differed among men and was consistent within men.

Mediterranean Tomato-Based Sofrito Sauce Improves Fibroblast Growth Factor 21 (FGF21) Signaling in White Adipose Tissue of Obese ZUCKER Rats.

SCOPE: Obesity is a fibroblast growth factor 21 (FGF21)-resistant state. Since FGF21 production and signaling are regulated by some bioactive dietary compounds, we analyze the impact of Mediterranean tomato-based sofrito sauce on: (i) the FGF21 expression and signaling in visceral white adipose tissue (vWAT), and (ii) the insulin sensitivity of obese Zucker rats (OZR). METHODS AND RESULTS: OZR are fed with a sofrito-supplemented diet or control diet. Insulin sensitivity and FGF21 signaling are determined. We observed that sofrito is able to improve the responsiveness to both hormones in obese rats. Sofrito-supplemented diet increases FGF21 signaling in vWAT by inducing the expression of the FGF receptors (FGFR1 and FGFR4) that promotes the expression of canonical target genes, like Egr-1, c-Fos and uncoupling protein 1 (Ucp1). CONCLUSIONS: A sofrito-supplemented diet improves insulin and FGF21 sensitivity in OZR, explaining part of sofrito's healthy effects on glucose metabolism. In addition, induction of UCP1 and the unchanged body weight despite the hyperphagic behavior of the sofrito-fed rats suggests that the increase in FGF21 signaling correlates with an increase in energy expenditure (EE). Further studies in humans may help to understand whether sofrito consumption increases the EE in obese individuals.

Validation of a laboratory-developed test of human sperm capacitation.

Sperm must undergo capacitation to become fertilization competent. Here we validated that monosialotetrahexosylganglioside (GM1 ) localization patterns, which were assessed in the Cap-Score™ Sperm Function Test, reflect a capacitated state in human sperm. First, we defined patterns representing sperm that do or do not respond to stimuli for capacitation. Sperm with "capacitated" patterns had exposed acrosomal carbohydrates and underwent acrosome exocytosis in response to calcium ionophore (A23187). Precision was evaluated by percent change of the Cap-Score measured for 50, 100, 150, and 200 sperm. Changes of 11%, 6%, and 5% were observed (n ≥ 23); therefore, we counted ≥150 sperm per condition. Variance within and between readers was evaluated using 20 stitched image files generated from unique ejaculates. Two trained readers randomly resampled each image 20 times, reporting an average standard deviation of 3 Cap-Score units and coefficient of variation of 13% when rescoring samples, with no difference between readers. Semen liquefaction times ≤2 hr and mechanical liquefaction with Pasteur or wide-orifice transfer pipettes did not alter Cap-Score values. However, liquefaction with chymotrypsin (p = 0.002) and bromelain (p = 0.049) reduced response to capacitating stimuli and induced membrane damage, while counterintuitively improving sperm motility. Together, these data validate the Cap-Score assay for the intended purpose of providing information on sperm capacitation and male fertility. In addition to its clinical utility as a diagnostic tool, this test of sperm function can reveal the impact of common practices of semen handling on the ability of sperm to respond to capacitation stimuli.

Localization patterns of the ganglioside GM1 in human sperm are indicative of male fertility and independent of traditional semen measures.

Semen analysis lacks a functional component and best identifies extreme cases of infertility. The ganglioside GM1 is known to have functional roles during capacitation and acrosome exocytosis. Here, we assessed whether GM1 localization patterns (Cap-Score™) correspond with male fertility in different settings: Study 1 involved couples pursuing assisted reproduction in a tertiary care fertility clinic, while Study 2 involved men with known fertility versus those questioning their fertility at a local urology center. In Study 1, we examined various thresholds versus clinical history for 42 patients; 13 had Cap-Scores ≥39.5%, with 12 of these (92.3%) achieving clinical pregnancy by natural conception or ≤3 intrauterine insemination cycles. Of the 29 patients scoring <39.5%, only six (20.7%) attained clinical pregnancy by natural conception or ≤3 intrauterine insemination cycles. In Study 2, Cap-Scores were obtained from 76 fertile men (Cohort 1, pregnant partner or recent father) and compared to 122 men seeking fertility assessment (Cohort 2). Cap-Score values were normally distributed in Cohort 1, with 13.2% having Cap-Scores more than one standard deviation below the mean (35.3 ± 7.7%). Significantly, more men in Cohort 2 had Cap-Scores greater than one standard deviation below the normal mean (33.6%; p = 0.001). Minimal/no relationship was found between Cap-Score and sperm concentration, morphology, or motility. Together, these data demonstrate that Cap-Score provides novel, clinically relevant insights into sperm function and male fertility that complement traditional semen analysis. Furthermore, the data provide normal reference ranges for fertile men that can help clinicians counsel couples toward the most appropriate fertility treatment.

Multiclass Data Segmentation Using Diffuse Interface Methods on Graphs.

We present two graph-based algorithms for multiclass segmentation of high-dimensional data on graphs. The algorithms use a diffuse interface model based on the Ginzburg-Landau functional, related to total variation and graph cuts. A multiclass extension is introduced using the Gibbs simplex, with the functional's double-well potential modified to handle the multiclass case. The first algorithm minimizes the functional using a convex splitting numerical scheme. The second algorithm uses a graph adaptation of the classical numerical Merriman-Bence-Osher (MBO) scheme, which alternates between diffusion and thresholding. We demonstrate the performance of both algorithms experimentally on synthetic data, image labeling, and several benchmark data sets such as MNIST, COIL and WebKB. We also make use of fast numerical solvers for finding the eigenvectors and eigenvalues of the graph Laplacian, and take advantage of the sparsity of the matrix. Experiments indicate that the results are competitive with or better than the current state-of-the-art in multiclass graph-based segmentation algorithms for high-dimensional data.

Spectral clustering with epidemic diffusion.

Spectral clustering is widely used to partition graphs into distinct modules or communities. Existing methods for spectral clustering use the eigenvalues and eigenvectors of the graph Laplacian, an operator that is closely associated with random walks on graphs. We propose a spectral partitioning method that exploits the properties of epidemic diffusion. An epidemic is a dynamic process that, unlike the random walk, simultaneously transitions to all the neighbors of a given node. We show that the replicator, an operator describing epidemic diffusion, is equivalent to the symmetric normalized Laplacian of a reweighted graph with edges reweighted by the eigenvector centralities of their incident nodes. Thus, more weight is given to edges connecting more central nodes. We describe a method that partitions the nodes based on the componentwise ratio of the replicator's second eigenvector to the first and compare its performance to traditional spectral clustering techniques on synthetic graphs with known community structure. We demonstrate that the replicator gives preference to dense, clique-like structures, enabling it to more effectively discover communities that may be obscured by dense intercommunity linking.

Localized Overheating Phenomena and Optimization of Spark-Plasma Sintering Tooling Design.

The present paper shows the application of a three-dimensional coupled electrical, thermal, mechanical finite element macro-scale modeling framework of Spark Plasma Sintering (SPS) to an actual problem of SPS tooling overheating, encountered during SPS experimentation. The overheating phenomenon is analyzed by varying the geometry of the tooling that exhibits the problem, namely by modeling various tooling configurations involving sequences of disk-shape spacers with step-wise increasing radii. The analysis is conducted by means of finite element simulations, intended to obtain temperature spatial distributions in the graphite press-forms, including punches, dies, and spacers; to identify the temperature peaks and their respective timing, and to propose a more suitable SPS tooling configuration with the avoidance of the overheating as a final aim. Electric currents-based Joule heating, heat transfer, mechanical conditions, and densification are imbedded in the model, utilizing the finite-element software COMSOL™, which possesses a distinguishing ability of coupling multiple physics. Thereby the implementation of a finite element method applicable to a broad range of SPS procedures is carried out, together with the more specific optimization of the SPS tooling design when dealing with excessive heating phenomena.

[Shiitake dermatitis in a Spanish patient]. / Letter: Dermatitis shiitake en una paciente española.

Shiitake dermatitis is a toxicodermia that occurs after ingestion of raw or half-cooked shiitake. We present a Spanish patient who was referred to the emergency room after developing a pruritic, dermatographic, eruption that affected the trunk and neck region. The eruption occurred a few days after eating shiitake mushrooms.