Economic implications of step-down outpatient management for fever and neutropenia episodes in pediatric cancer patients: a cost minimization analysis.

BACKGROUND: The management of febrile neutropenia (FN) in pediatric cancer patients has traditionally been conducted in a hospital setting. However, recent evidence has indicated that outpatient management of FN can be equally effective compared to inpatient care. Based on this evidence, we conducted a cost-minimization analysis (CMA) specifically focused on pediatric cancer patients in Mexico. METHODS: A piggy-back study was conducted during the execution of a non-inferiority clinical trial that compared outpatient treatment to inpatient treatment for FN in children with cancer. A CMA was performed from a societal perspective using patient-level data. In the previous study, we observed that step-down oral outpatient management of low-risk FN was as safe and effective as inpatient intravenous management. Direct and indirect costs were collected prospectively. The costs were adjusted for inflation and converted to US dollars, with values standardized to July 2022 costs. Statistical analysis using bootstrap methods was employed to obtain robust estimations for decision-making within the Mexican public health care system. RESULTS: A total of 117 FN episodes were analyzed, with 60 in the outpatient group and 57 in the inpatient group; however, complete cost data were available for only 115 FN episodes. The analysis revealed an average savings of $1,087 per FN episode managed on an outpatient basis, representing a significant 92% reduction in total cost per FN episode compared to inpatient treatment. Length of hospital stay and inpatient consultations emerged as the primary cost drivers within the inpatient care group. CONCLUSION: This CMA demonstrates that the step-down outpatient management approach is cost-saving when compared to inpatient management of FN in pediatric cancer patients. The mean difference observed between the treatment groups provides support for decision-making within the public health care system, as outpatient management of FN allows for substantial cost savings without compromising patient health.

Familial bilateral macronodular adrenal hyperplasia due to a novel ARMC 5 germline mutation: Clinical status and possible association with other neoplasms.

INTRODUCTION/OBJECTIVES: Mutations in the ARMC5 (armadillo repeat containing 5, OMIM 615549) gene, a putative tumor suppressor gene, have recently been identified as a common cause of sporadic and familial bilateral macronodular adrenal hyperplasia (BMAH). Familial BMAH is thought to be caused by two mutations, one germline and the other somatic, as suggested by the 2-hit theory. The objective is to describe a new mutation and develop its clinical characteristics and implications. METHODS, RESULTS AND CONCLUSIONS: We present an affected family with 11 members carrying a novel mutation of the ARMC5 gene (NM_001288767.1): c.2162T>C p. (Leu721Pro). Two of the carriers developed clinical Cushing's syndrome (CS), two mild autonomous cortisol secretion (MACS) and one presented with autonomous cortisol secretion (ACS). Four patients developed other tumors, three of whom died from this cause. It is not known whether these tumors could be related to the described mutation.

Estimativa de Produtividade Perdida Atribuída a Doenças Cardiovasculares na América do Sul / Estimated Loss of Productivity Attributed to Cardiovascular Diseases in South America

Resumo Fundamento: As doenças cardiovasculares (DCV) têm ônus sanitário e econômico significativos. Na América do Sul (AS), a perda de produtividade relacionada a estas enfermidades ainda não foi bem explorada. Objetivo: Estimar os anos de vida produtiva perdidos (AVPP) e a perda de produtividade relacionados a mortalidade prematura associada as DCV na AS, em 2019. Métodos: Empregou-se dados de mortalidade disponíveis no Global Burden of Disease Study 2019 na estimativa da carga de doença atribuível a DCV. Para os cálculos monetários da perda da produtividade usou-se uma proxy da abordagem de capital humano. Estratificou-se por sexo, nas faixas etárias de trabalho. Resultados: O número total de mortes por DCV na AS no ano de 2019 foi de 754.324 e os AVPP foram 2.040.973. A perda permanente de produtividade total foi de aproximadamente US$ 3,7 bilhões e US$ 7,8 bilhões em paridade do poder de compra, equivalente a 0,11% do produto interno bruto. O custo por morte foi de US$ 22.904, e a razão desse custo por óbito, entre homens e mulheres foi 1,45. A variação dos cenários aponta robustez nas estimativas, mesmo com diferenças importantes entre os países. Conclusões: As DCV impõem um ônus econômico significativo a este bloco de países. A caracterização deste fardo pode amparar os governos na alocação de recursos destinados ao planejamento e execução de políticas e intervenções sanitárias, sejam de promoção, prevenção ou recuperação.

Abstract Background: Cardiovascular diseases (CVD) have significant health and economic burdens. In South America, the loss of productivity related to these diseases has not yet been well explored. Objective: Estimate the potentially productive years of life lost (PPYLL) and loss of productivity related to premature mortality associated with CVD in South America, in 2019. Methods: Mortality data available from the 2019 Global Burden of Disease Study were used to estimate the burden of disease attributable to CVD. For monetary calculations of productivity loss, a proxy of the human capital approach was used. Data were stratified by sex, in working age groups. Results: The total number of deaths due to CVD in South America in 2019 was 754,324, and the total number of PPYLL was 2,040,973. The total permanent loss of productivity was approximately US$ 3.7 billion and US$ 7.8 billion in purchasing power parity, equivalent to 0.11% of the gross domestic product. The cost per death was US$ 22,904, and the ratio between men and women for the cost per death was 1.45. The variation in scenarios indicates that the estimates are robust, even with important differences between countries. Conclusions: CVD impose a significant economic burden on countries in South America. The characterization of this burden can support governments in the allocation of resources for the planning and execution of health policies and interventions in promotion, prevention, and recovery.

Effect of olive leaf phytochemicals on the anti-acetylcholinesterase, anti-cyclooxygenase-2 and ferric reducing antioxidant capacity.

In this study, the phytochemical profile of fifty olive leaves (OL) extracts from Spain, Italy, Greece, Portugal, and Morocco was characterized and their anti-cholinergic, anti-inflammatory, and antioxidant activities were evaluated. Luteolin-7-O-glucoside, isoharmnentin, and apigenin were involved in the acetylcholinesterase (AChE) inhibitory activity, while oleuropein and hydroxytyrosol showed noteworthy potential. Secoiridoids contributed to the cyclooxygenase-2 inhibitory activity and antioxidant capacity. Compounds such as oleuropein, ligstroside and luteolin-7-O-glucoside, may exert an important role in the ferric reducing antioxidant capacity. It should be also highlighted the role of hydroxytyrosol, hydroxycoumarins, and verbascoside concerning the antioxidant activity. This research provides valuable insights and confirms that specific compounds within OL extracts contribute to distinct anti-cholinergic, anti-inflammatory, and anti-oxidative effects.

Breast Cancer in Pregnant Young Women: Clinicopathological Profile, Survival, and Pregnancy Outcomes.

Background Breast cancer is one of the most common cancer types diagnosed during pregnancy; the presence of any neoplasm in pregnant women faces clinical dilemmas and challenges in cancer and pregnancy management. Pregnancy-associated breast cancer (PABC) is defined as breast cancer diagnosed during pregnancy or within one year after delivery. The aim of this study was to describe tumor clinicopathological characteristics and pregnancy outcomes in PABC patients. Materials and methods This is a retrospective cohort assessing PABC patients. Qualitative variables were compared using Fisher's exact test. Kaplan-Meier method was used to calculate survival. Cox regression and logistic regression methods were used to estimate the hazard ratio (HR) and odds ratio (OR), respectively. Results We assessed 16 PABC patients. Women ≤ 35 years of age were mainly diagnosed at advanced stage (88.8%) with ER-negative disease (77.8%). Patients with >4 pathological lymph nodes (25%; p = 0.001) and ER-negative disease (50%; p = 0.646) showed poor five-year overall survival (OS). In the multivariate analysis, nodal involvement was the main predictor associated with poorer OS (HR = 1.4, 90% confidence interval [CI]: 1.14 to 1.8). The following risk factors might influence the risk of preterm delivery: maternal older age, gestational age at diagnosis, and intrauterine exposure to chemotherapy, but an adjusted OR of 0.61 (90% CI: 0.34 to 1), 0.80 (90% CI: 0.66 to 0.9), and 0.013 (90% CI: 0.00 to 0.9), respectively, did not statistically support such an effect. Conclusions Younger women with PABC had a more aggressive pathological profile that might partly explain the poor OS. Obstetrical adverse events related to preterm delivery should be avoided with better planning of specialized strategies.

Infections and risk factors for infection-related mortality after pediatric allogeneic hematopoietic stem cell transplantation in Mexico: A single center retrospective study.

OBJECTIVE: To identify the type of infections and risk factors for infection-related mortality (IRM) after allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: Retrospective cohort study of patients <16 years of age treated in 2010-2019 was conducted. Unadjusted hazard ratios (HR) and adjusted hazard ratios (aHR) with 95% confidence intervals (95% CIs) were estimated using Cox regression. Cumulative incidence was calculated. RESULTS: Data for 99 pediatric patients were analyzed. The myeloablative conditioning was the most used regimen (78.8%) and the hematopoietic stem cell source was predominantly peripheral blood (80.8%). Primary graft failure occurred in 19.2% of patients. Frequency of acute graft-versus-host disease was 46.5%. Total of 136 infectious events was recorded, the most common of which were bacterial (76.4%) followed by viral infection (15.5%) and then fungal infection (8.1%). The best predictors for infection subtypes where the following: a) for bacterial infection (the age groups of 10.1-15 years: aHR = 3.33; 95% CI: 1.62-6.85 and. >15 years: aHR = 3.34; 95% CI: 1.18-9.45); b) for viral infection (graft versus host disease: aHR = 5.36; 95% CI: 1.62-17.68), however, for fungal infection statistically significant predictors were not identified. Related mortality was 30% (n = 12). Increased risk for infection-related mortality was observed in patients with unrelated donor and umbilical cord stem cells recipients (HR = 3.12; 95% CI: 1.00-9.85). CONCLUSIONS: Frequencies of infections and infection-related mortality appear to be similar to those reported. Unrelated donors and stem cells from umbilical cord recipients were associated with a high risk of mortality.

Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy.

Non-small lung cancers (NSCLC) frequently (∼30%) harbor KRAS driver mutations, half of which are KRASG12C. KRAS-mutant NSCLC with comutated STK11 and/or KEAP1 is particularly refractory to conventional, targeted, and immune therapy. Development of KRASG12C inhibitors (G12Ci) provided a major therapeutic advance, but resistance still limits their efficacy. To identify genes whose deletion augments efficacy of the G12Cis adagrasib (MRTX-849) or adagrasib plus TNO155 (SHP2i), we performed genome-wide CRISPR/Cas9 screens on KRAS/STK11-mutant NSCLC lines. Recurrent, potentially targetable, synthetic lethal (SL) genes were identified, including serine-threonine kinases, tRNA-modifying and proteoglycan synthesis enzymes, and YAP/TAZ/TEAD pathway components. Several SL genes were confirmed by siRNA/shRNA experiments, and the YAP/TAZ/TEAD pathway was extensively validated in vitro and in mice. Mechanistic studies showed that G12Ci treatment induced gene expression of RHO paralogs and activators, increased RHOA activation, and evoked ROCK-dependent nuclear translocation of YAP. Mice and patients with acquired G12Ci- or G12Ci/SHP2i-resistant tumors showed strong overlap with SL pathways, arguing for the relevance of the screen results. These findings provide a landscape of potential targets for future combination strategies, some of which can be tested rapidly in the clinic. SIGNIFICANCE: Identification of synthetic lethal genes with KRASG12C using genome-wide CRISPR/Cas9 screening and credentialing of the ability of TEAD inhibition to enhance KRASG12C efficacy provides a roadmap for combination strategies. See related commentary by Johnson and Haigis, p. 4005.

Dietary antioxidants and lifespan: Relevance of environmental conditions, diet, and genotype of experimental models.

The rise of life expectancy in current societies is not accompanied, to date, by a similar increase in healthspan, which represents a great socio-economic problem. It has been suggested that aging can be manipulated and then, the onset of all age-associated chronic disorders can be delayed because these pathologies share age as primary underlying risk factor. One of the most extended ideas is that aging is consequence of the accumulation of molecular damage. According to the oxidative damage theory, antioxidants should slow down aging, extending lifespan and healthspan. The present review analyzes studies evaluating the effect of dietary antioxidants on lifespan of different aging models and discusses the evidence on favor of their antioxidant activity as anti-aging mechanisms. Moreover, possible causes for differences between the reported results are evaluated.

In vivo metabolomics identifies CD38 as an emergent vulnerability in LKB1 -mutant lung cancer.

LKB1/STK11 is a serine/threonine kinase that plays a major role in controlling cell metabolism, resulting in potential therapeutic vulnerabilities in LKB1-mutant cancers. Here, we identify the NAD + degrading ectoenzyme, CD38, as a new target in LKB1-mutant NSCLC. Metabolic profiling of genetically engineered mouse models (GEMMs) revealed that LKB1 mutant lung cancers have a striking increase in ADP-ribose, a breakdown product of the critical redox co-factor, NAD + . Surprisingly, compared with other genetic subsets, murine and human LKB1-mutant NSCLC show marked overexpression of the NAD+-catabolizing ectoenzyme, CD38 on the surface of tumor cells. Loss of LKB1 or inactivation of Salt-Inducible Kinases (SIKs)-key downstream effectors of LKB1- induces CD38 transcription induction via a CREB binding site in the CD38 promoter. Treatment with the FDA-approved anti-CD38 antibody, daratumumab, inhibited growth of LKB1-mutant NSCLC xenografts. Together, these results reveal CD38 as a promising therapeutic target in patients with LKB1 mutant lung cancer. SIGNIFICANCE: Loss-of-function mutations in the LKB1 tumor suppressor of lung adenocarcinoma patients and are associated with resistance to current treatments. Our study identified CD38 as a potential therapeutic target that is highly overexpressed in this specific subtype of cancer, associated with a shift in NAD homeostasis.

Early posttraumatic brain injury tranexamic acid prevents blood-brain barrier hyperpermeability and improves surrogates of neuroclinical recovery.

BACKGROUND: Tranexamic acid (TXA) given early, but not late, after traumatic brain injury (TBI) appears to improve survival. This may be partly related to TXA-driven profibrinolysis and increased leukocyte (LEU)-mediated inflammation when administered late post-injury. We hypothesized that early TXA (1 hour post-TBI), blunts penumbral, blood-brain barrier (BBB) leukocyte-endothelial cell (LEU-EC) interactions and microvascular permeability, in vivo when compared with late administration (24 hours post-TBI). METHODS: CD1 male mice (n = 35) were randomized to severe TBI (injury by controlled cortical impact; injury: velocity, 6 m/s; depth, 1 mm; diameter, 3 mm) or sham craniotomy followed by intravenous saline (placebo) at 1 hour, or TXA (30 mg/kg) at 1 hour or 24 hours. At 48 hours, in vivo pial intravital microscopy visualized live penumbral LEU-EC interactions and BBB microvascular fluorescent albumin leakage. Neuroclinical recovery was assessed by the Garcia Neurological Test (motor, sensory, reflex, and balance assessments) and body weight loss recovery at 1 and 2 days after injury. Analysis of variance with Bonferroni correction assessed intergroup differences ( p < 0.05). RESULTS: One-hour, but not 24-hour, TXA improved Garcia Neurological Test performance on day 1 post-TBI compared with placebo. Both 1 hour and 24 hours TXA similarly improved day 1 weight loss recovery, but only 1 hour TXA significantly improved weight loss recovery on day 2 compared with placebo ( p = 0.04). No intergroup differences were found in LEU rolling or adhesion between injured animal groups. Compared with untreated injured animals, only TXA at 1 hour reduced BBB permeability. CONCLUSION: Only early post-TBI TXA consistently improves murine neurological recovery. Tranexamic acid preserves BBB integrity but only when administered early. This effect appears independent of LEU-EC interactions and demonstrates a time-sensitive effect that supports only early TXA administration.

Microwave-Assisted Hydrodistillation of Essential Oil from Plectranthus amboinicus: Evaluation of Its Antifungal Effect and Chemical Composition.

Fusarium wilt, a vascular syndrome in a wide range of plants, is caused by the pathogen Fusarium Oxysporum. The objective of this investigation was to evaluate the antifungal effect of four essential oils (EOs) (Plectranthus amboinicus, Syzygium aromaticum, Lippia alba, and Rosmarinus officinalis), which were obtained by using microwave-assisted hydrodistillation (MAH), against F. oxysporum. The yield obtained from P. amboinicus with the use of MAH was 0.2%, which was higher than that of a conventional extraction; its extraction time was also shorter. For concentrations of 100 and 300 µL/L, P. amboinicus caused an inhibition rate of 27.2 and 55.7%, respectively, while S. aromaticum caused an inhibition rate of 23.1 and 87.3%, respectively. It was observed that increasing the concentration also increased the % inhibition rate. The extracts of L. alba and R. officinalis caused an inhibition rate of 14.5 and 14.7% at 500 µL/L, respectively, at 10 days of incubation, while at this concentration, P. amboinicus and S. aromaticum achieved 100%. The major chemical compounds of P. amboinicus were carvacrol (41.20%), o-cymene (11.61%), caryophyllene (11.45%), α-bergamotene (7.71%), and caryophyllene oxide (4.62%), and these monoterpene hydrocarbons were responsible for the biological activity. The essential oil of P. amboinicus in appropriate concentrations is a potent antifungal agent that could be used for the control of F. oxysporum.

Marine biogenic emissions of benzene and toluene and their contribution to secondary organic aerosols over the polar oceans.

Reactive trace gas emissions from the polar oceans are poorly characterized, even though their effects on atmospheric chemistry and aerosol formation are crucial for assessing current and preindustrial aerosol forcing on climate. Here, we present seawater and atmospheric measurements of benzene and toluene, two gases typically associated with pollution, in the remote Southern Ocean and the Arctic marginal ice zone. Their distribution suggests a marine biogenic source. Calculated emission fluxes were 0.023 ± 0.030 (benzene) and 0.039 ± 0.036 (toluene) and 0.023 ± 0.028 (benzene) and 0.034 ± 0.041 (toluene) µmol m-2 day-1 for the Southern Ocean and the Arctic, respectively. Including these average emissions in a chemistry-climate model increased secondary organic aerosol mass concentrations only by 0.1% over the Arctic but by 7.7% over the Southern Ocean, with transient episodes of up to 77.3%. Climate models should consider the hitherto overlooked emissions of benzene and toluene from the polar oceans.

Involvement of redox signalling in tumour cell dormancy and metastasis.

Decades of research on oncogene-driven carcinogenesis and gene-expression regulatory networks only started to unveil the complexity of tumour cellular and molecular biology. This knowledge has been successfully implemented in the clinical practice to treat primary tumours. In contrast, much less progress has been made in the development of new therapies against metastasis, which are the main cause of cancer-related deaths. More recently, the role of epigenetic and microenviromental factors has been shown to play a key role in tumour progression. Free radicals are known to communicate the intracellular and extracellular compartments, acting as second messengers and exerting a decisive modulatory effect on tumour cell signalling. Depending on the cellular and molecular context, as well as the intracellular concentration of free radicals and the activation status of the antioxidant system of the cell, the signalling equilibrium can be tilted either towards tumour cell survival and progression or cell death. In this regard, recent advances in tumour cell biology and metastasis indicate that redox signalling is at the base of many cell-intrinsic and microenvironmental mechanisms that control disseminated tumour cell fate and metastasis. In this manuscript, we will review the current knowledge about redox signalling along the different phases of the metastatic cascade, including tumour cell dormancy, making emphasis on metabolism and the establishment of supportive microenvironmental connections, from a redox perspective.

[Associating prognostic factors with clinical results in locally advanced breast cancer]. / Asociando factores pronósticos con resultados clínicos en cáncer de mama localmente avanzado.

Background: Breast cancer is the most frequent malignant tumor in women. Objective: To identify clinico-pathological and molecular markers as predictors of survival in patients with locally advanced breast cancer (LABC). Methods: Retrospective and observational study. The clinical factors of clinico-pathological and molecular predictors in relation with overall survival (OS) were assessed by the survival function, baseline hazard with smoothing and Cox regression. Results: 126 patients were assessed. OS at five years was significantly superior in patients with clinical stage IIIA (87%; p < 0.001), grade 2 tumor (81%; p < 0.001), pathological node stage (ypN0: 90%; p < .001), low-risk Nottingham prognostic index (86%; p < 0.001) and luminal A subtype (88%; p = 0.022). Baseline hazard with smoothing exhibited an increase in the mortality rate at 50 months for the luminal B/ HER2+ subtype compared with other subtypes. The multivariate analysis ascertained that the stage ypN2-3 (hazard ratio [HR] = 7.3; 95% confidence interval [95% CI]: 2.2 to 23.9) and the HER2+ nonluminal (HR = 7.8; 95% CI: 2 to 29.6) and triple negative (HR = 5.4; 95% CI: 1.7 to 17.2) subtypes were associated with a poor OS. Conclusions: The comprehensive evaluation of the molecular marker and clinico-pathological factors provides more accurate predictive and prognostic information. The nodal stage and molecular subtype are suitable clinical parameters on survival for LABC patients.

Introducción: el cáncer de mama es el tumor maligno más frecuente en las mujeres. Objetivo: identificar marcadores clínico-patológicos y moleculares como predictores de la supervivencia en pacientes con cáncer de mama localmente avanzado (CMLA). Material y métodos: estudio retrospectivo y observacional. Los factores clínico-patológicos y moleculares fueron evaluados en relación con la supervivencia global (SG) mediante la función de supervivencia, riesgo basal con suavizamiento y regresión de Cox. Resultados: 126 pacientes fueron evaluadas. La SG a cinco años fue significativamente superior en pacientes con estadio clínico IIIA (87%; p < 0.001), tumor de grado 2 (81%; p < 0.001), ausencia de ganglios patológicos (ypN0: 90%; p < 0.001) y en el subtipo luminal A (88%; p = 0.022). El riesgo basal con suavizamiento exhibió un incremento en la tasa de mortalidad a los 50 meses para el subtipo luminal B/ HER2+ comparado con los otros subtipos. En el análisis multivariado, el estadio ypN2-3 (razón de riesgo [RR] = 7.3; intervalo de confianza del 95% [IC 95%]: 2.2 a 23.9) y los subtipos HER2+ (RR = 7.8; IC 95%: 2 a 29.6) y triple negativo (RR= 5.4; IC 95%: 1.7 a 17.2) se asociaron con una pobre SG. Conclusiones: la evaluación integral del marcador molecular y de los factores clínico-patológicos proporciona información predictiva y pronóstica más precisa. El estadio ganglionar y subtipo molecular son parámetros adecuados con un impacto pronóstico en la SG para las pacientes con CMLA.

Is colostomy closure without mechanical bowel preparation safe in pediatric patients? A randomized clinical trial.

BACKGROUND: Mechanical bowel preparation (MBP) is largely used worldwide prior to colostomy closure in children, although its benefits are questioned by scientific evidence, and its use can cause adverse reactions. We hypothesized that colostomy closure procedures in children are not associated with increased complications (surgical site infection [SSI] and anastomotic leakage) when performed without MBP. Thus, we conducted a noninferiority trial to compare the safety and efficacy of colostomy takedown with and without MBP. METHODS: A randomized noninferiority clinical trial was conducted at Hospital Infantil de Mexico in Mexico City from 2015 to 2019, in which the experimental group did not receive MBP prior to colostomy closure. A total of 79 patients were analyzed, and the primary outcomes were safety-related. Data were analyzed using the chi-squared test, Student's t-test, or Mann-Whitney U test as appropriate. RESULTS: The demographics in both groups were comparable. Statistical analysis revealed equivalence in safety outcomes (superficial SSI, 22.5% vs 15.3% p = 0.420; deep SSI, 7.5% vs 0% p = 0.081; reoperation, p = 0.320; intestinal occlusion, p = 0.986); no anastomotic leakage was observed in any group. Secondary outcomes such as fasting time and length of hospital stay after surgery were also similar between the groups. However, patients who received MBP were admitted 2 days before surgery. CONCLUSIONS: Our findings indicate that withholding MBP prior to colostomy takedowns in children is not associated with increased complications. Omitting MBP also leads to less discomfort and shortens hospital length of stay, suggesting that it has safer and more effective procedures. LEVEL OF EVIDENCE: Randomized controlled clinical trial with adequate statistical power.

Costs associated with adverse events from remission induction for children with Acute Lymphoblastic Leukemia (ALL).

BACKGROUND: ALL is the most frequent hematological tumor in children, so during remission induction chemotherapy protocol (RICP) adverse events (AEs) may appear. The public program in Mexico in charge of financial support to oncologic children without social security delivered a fix amount for ALL chemotherapy, but additional money needed to treat any other unexpected condition should be taken from the budget of the oncologic healthcare providers. So the purpose of our study was to estimate and evaluate the direct medical costs associated to EAs during RICP in children with ALL. METHODS: This study was retrospective, longitudinal, and observational based on medical records review of patients in RICP. The CTCAE was used to identify and classify AEs according to a SOC category. We focused on extracting resources data that were consumed both for inpatients and outpatients AEs. A micro-costing approach was adopted which involve quantification of each healthcare resource consumed by the hospital multiplying them by unit cost. The probability distributions of data were evaluated to identify the appropriated statistical tests to be used for comparisons between groups that were performed with Wilcoxon rank sum test. Generalized linear models (GLM) were adjusted to evaluate the effects of patient characteristics on total cost. RESULTS: Forty patients accumulated 204 inpatient and 81 outpatient AEs during RICP. Comparison of total costs between groups showed an incremental cost of $7,460.23 likewise attributable to AEs. The total cost of a pediatric patient undergoing RICP without adverse events was $3,078.36 and the total cost of a patient with AEs exceeds it threefold. CONCLUSIONS: The costs associated with AEs during RICP in Mexican children with ALL representing a high burden for the healthcare provider. Generalized linear models showed that variables such as sex, risk category and alive status are associated with the total costs of AEs. This is the first study aiming to analyze the effect of ALL-related AEs on health care costs in pediatric population, so our results may help not only to local decision making but also it may contribute to the research agenda in this field.

Oxidative Stress Amelioration of Novel Peptides Extracted from Enzymatic Hydrolysates of Chinese Pecan Cake.

Pecan (Carya cathayensis) is an important economic crop, and its hydrolyzed peptides have been evidenced to reduce the effect of oxidative stress due to their antioxidant capacity. Hence, the protocols of ultrafiltration and gel filtration chromatography were established to obtain bioactive peptides from by-products of C. cathayensis (pecan cake). As measured by DPPH/ABTS radical scavenging, the peptides with less molecular weight (MW) possess higher antioxidant capacity. PCPH-III (MW < 3 kDa) presented higher radical scavenging capacity than PCPH-II (3 kDa < MW < 10 kDa) and PCPH-I (MW > 10 kDa) measured by DPPH (IC50: 111.0 µg/ mL) and measured by ABTs (IC50: 402.9 µg/mL). The secondary structure and amino acid composition varied by their MW, in which PCPH-II contained more α-helices (26.71%) and ß-sheets (36.96%), PCPH-III contained higher ratios of ß-turns (36.87%), while the composition of different secondary of PCPH-I was even 25 ± 5.76%. The variation trend of α-helix and random experienced slightly varied from PCPH-I to PCPH-II, while significantly decreased from PCPH-II to PCPH-III. The increasing antioxidant capacity is followed by the content of proline, and PCPH-III had the highest composition (8.03%). With regard to the six peptides identified by LC-MS/MS, two of them (VYGYADK and VLFSNY) showed stronger antioxidant capacity than others. In silico molecular docking demonstrated their combining abilities with a transcription factor Kelch-like ECH-associated protein 1 (Keap1) and speculated that they inhibit oxidative stress through activating the Keap1-Nrf2-ARE pathway. Meanwhile, increased activity of SOD and CAT­antioxidant markers­were found in H2O2-induced cells. The residue of tyrosine was demonstrated to contribute the most antioxidant capacity of VYGYADK and its position affected less. This study provided a novel peptide screening and by-product utilization process that can be applied in natural product developments.

HP0953 - hypothetical virulence factor overexpresion and localization during Helicobacter pylori infection of gastric epithelium.

BACKGROUND: The high prevalence and persistence of Helicobacter pylori (H. pylori) infection, as well as the diversity of pathologies related to it, suggest that the virulence factors used by this microorganism are varied. Moreover, as its proteome contains 340 hypothetical proteins, it is important to investigate them to completely understand the mechanisms of its virulence and survival. We have previously reported that the hypothetical protein HP0953 is overexpressed during the first hours of adhesion to inert surfaces, under stress conditions, suggesting its role in the environmental survival of this bacterium and perhaps as a virulence factor. AIM: To investigate the expression and localization of HP0953 during adhesion to an inert surface and against gastric (AGS) cells. METHODS: Expression analysis was performed for HP0953 during H. pylori adhesion. HP0953 expression at 0, 3, 12, 24, and 48 h was evaluated and compared using the Kruskal-Wallis equality-of-populations rank test. Recombinant protein was produced and used to obtain polyclonal antibodies for immunolocalization. Immunogold technique was performed on bacterial sections during adherence to inert surfaces and AGS cells, which was analyzed by transmission electron microscopy. HP0953 protein sequence was analyzed to predict the presence of a signal peptide and transmembrane helices, both provided by the ExPASy platform, and using the GLYCOPP platform for glycosylation sites. Different programs, via, I-TASSER, RaptorX, and HHalign-Kbest, were used to perform three-dimensional modeling. RESULTS: HP0953 exhibited its maximum expression at 12 h of infection in gastric epithelium cells. Immunogold technique revealed HP0953 localization in the cytoplasm and accumulation in some peripheral areas of the bacterial body, with greater expression when it is close to AGS cells. Bioinformatics analysis revealed the presence of a signal peptide that interacts with the transmembrane region and then allows the release of the protein to the external environment. The programs also showed a similarity with the Tip-alpha protein of H. pylori. Tip-alpha is an exotoxin that penetrates cells and induces tumor necrosis factor alpha production, and HP0953 could have a similar function as posttranslational modification sites were found; modifications in turn require enzymes located in eukaryotic cells. Thus, to be functional, HP0953 may necessarily need to be translocated inside the cell where it can trigger different mechanisms producing cellular damage. CONCLUSION: The location of HP0953 around infected cells, the probable posttranslational modifications, and its similarity to an exotoxin suggest that this protein is a virulence factor.

Differences reported in the lifespan and aging of male Wistar rats maintained on diets containing fat with different fatty acid profiles (virgin olive, sunflower or fish oils) are not reflected by histopathological lesions found at death in central nervous and endocrine systems.

The present study was designed to examine if dietary fat sources that have shown differences in lifespan and if some aging-related aspects can modulate the range of histopathologic changes in central nervous and endocrine systems that occur during the lifespan of Wistar rats. Moreover, it was attempted to gain insight into the relationship between longevity and the development of the different pathological changes, as well as possible interaction with diet. In order to achieve this, male Wistar rats were randomly assigned to three experimental groups fed semisynthetic and isoenergetic diets from weaning until death with different dietary fat sources, namely virgin olive, sunflower, or fish oil. An individual follow-up until death of each animal was performed. Incidence, severity, and burden of specific or group (i.e., neoplastic or non-neoplastic proliferative and non-proliferative) of lesions was calculated along with individual's disease and individual organ lesion burden. Most of the histopathological lesions found have been described in previous studies. Neoplasms, and in particular pituitary adenomas followed by brain tumors, were the most prevalent lesions found in the rats and the main cause of death involving both systems. Incidence of brain lesions was associated with age-at-death. Assayed dietary fats did not present differential effects on pathological changes occurring in endocrine and central nervous systems throughout rat lifespan.