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The identification of causal relationships between specific genes and social, behavioral, and health outcomes is challenging due to environmental confounding from population stratification and dynastic genetic effects. Existing methods to eliminate environmental confounding leverage random genetic variation resulting from recombination and require within-family dyadic genetic data (i.e., parent-child and/or sibling pairs), meaning they can only be applied in relatively small and selected samples. We introduce the phenotype differences model and provide derivations showing that it-under plausible assumptions-provides consistent (and, in certain cases, unbiased) estimates of genetic effects using just a single individual's genotype. Then, leveraging distinct samples of fully and partially genotyped sibling pairs in the Wisconsin Longitudinal Study, we use polygenic indices and phenotypic data for 24 different traits to empirically validate the phenotype differences model. Finally, we utilize the model to test the effects of 40 polygenic indices on lifespan. After a 10% false discovery rate correction, we find that polygenic indices for three traits-body mass index, self-rated health, chronic obstructive pulmonary disease-have a statistically significant effect on an individual's lifespan., Competing Interests: Competing interests statement:The authors declare no competing interest.

The Strengths and Weaknesses of ADHD Symptoms and Normal Behaviour Scale (SWAN) measures the full spectrum of attention and activity symptoms, not just the negative end of the distribution. Previous studies revealed strong psychometric properties of the parent and teacher report versions; however, there is little research on the new self-report form of the SWAN. Therefore, our research aimed to explore the psychometric characteristics of the SWAN self-report. A non-clinical sample of young women ( N = 664, mean age: 20.01 years, SD : 3.08 years) completed the SWAN self-report, the Strengths and Difficulties Questionnaire (SDQ) and the Mental Health Continuum Short Form (MHC-SF). We tested several models using confirmatory factor analyses to assess the factorial validity of the SWAN self-report. Distributional characteristics, convergent, and predictive validity were assessed. A bifactor model with a general factor and a specific inattention factor (bifactor-1) provided the best fit in our data (CFI = 0.977, TLI/NFI = 0.972, RMSEA = 0.053 [90% CI: 0.047 - 0.059], SRMR = 0.061, ω = 0.90). The reliability of the general ADHD factor was good (ω h  = 0.87), and the specific inattention factor was acceptable (ω h = 0.73). The distribution of the SWAN self-report scores did not differ from the normal distribution. A strong correlation between the SWAN and the SDQ Hyperactivity subscale was found. The analyses revealed good predictive validity. Our results suggest that the SWAN self-report is a valuable tool for assessing symptoms of ADHD in adolescents and young adults., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Vajsz, Paulina, Trejo, Andaverde-Vega, Swanson and Miklósi.)

The initiation of the program Mental Health Support Program for Coronavirus Infection addressed the increased demand for mental health services in the province of Salamanca, resulting from the COVID-19 pandemic. The psychiatry service provided care for COVID-19 patients, their families, and healthcare workers who treated them, as these groups were identified as being at risk. This study aims to describe the assistance provided, including personnel and resources utilized, types of interventions carried out, and to assess the demand for mental health care and predominant symptoms and emotions experienced by patients. Billboards and the complex's intranet publicized the program. Specific clinical approach using telemedicine were provide from March 2020 to December 2021 to COVID-19 patients, their relatives, and healthcare workers. 216 patients were included with a mean age of 53.2 years, with women comprising 77.3% of this group. All the groups received treatment in similar proportions. Over a period of 730 h, a total of 1376 interventions were performed, with an average duration of 31.8 min per intervention. The program could treat 79.6% of these patients without requiring referrals to other services. When the program concluded, only 21 participants (9.7%) were discharged to the local mental health network to continue their mental health treatment. The program effectively reduced the burden on regular mental health services due to its ability to treat most patients without requiring referrals. The program was able to attend to most mental health requests with minimal involvement of the regular mental health service., (© 2024. The Author(s).)

Background: Lockdowns and other health protective measures, such as social distancing, imposed during the COVID-19 pandemic nurtured unprecedented levels of stress and social isolation around the world. This scenario triggered an increase in suicide thoughts and self-harm behaviours among children and young people. However, the longer-term impact of the pandemic on children's and adolescents' mental health, especially with regard to self-harm, is still to be fully discovered., Methods: We carried out a retrospective study where we collected data related to suicide ideation and self-harm behaviours in all patients aged under 18 that required on-call psychiatric services at the General Hospital Accident and Emergency (A&E) department in Salamanca, Spain, during 2019 (pre-pandemic) and in both 2021 and 2022 to capture possible variation at different time points during the post-pandemic period., Results: A total of 316 patients aged under 18 were seen by on-call psychiatric services at the A&E department during the three time periods: 78 in 2019, 98 in 2021 and 140 in 2022. The mean age was 15.12 (SD 2.25) and females represented more than twice the number of males each year. More than half of all patients assessed during 2022 disclosed suicide thoughts, whilst in 2019, it was near 25%. This increase in suicide ideation rates was more marked among females (X 2 = 15.127; p = 0.001), those aged over 15 (X 2 = 16.437; p < 0.001) and/or those with a previous history of mental health problems (X 2 = 17.823; p < 0.001). We identified an increase in the proportion of males with suicide ideas, especially between 2021 and 2022 (X 2 = 8.396; p = 0.015)., Conclusions: Our study suggests that children's and adolescents' demand for urgent mental healthcare and their clinical presentations in A&E departments with suicide thoughts and/or self-injuries do not seem to be declining after the pandemic but increasing over time. More research is warranted to understand possible factors involved in this sustained upward trend.

In 2014, the municipal water source in Flint, Michigan was switched, causing lead from aging pipes to leach into the city's drinking water. While lead exposure in Flint children increased modestly on average, some children were exposed to high lead levels. Surveys of Flint residents show the water crisis was also associated with increased levels of stress, anxiety, and depression. We use Michigan's administrative education data and utilize synthetic control methods to examine the impact of the crisis on Flint's school-age children. We find decreases in math achievement and increases in special needs classification, even among children living in homes with copper (rather than lead) water service lines. Low socioeconomic status students and younger students experienced the largest effects on math achievement, and boys experienced the largest effects on special needs classification. Our results point toward the broad negative effects of the crisis on children and suggest that existing estimates may substantially underestimate the overall societal cost of the crisis.

Birth weight is a robust predictor of valued life course outcomes, emphasizing the importance of prenatal development. But does birth weight act as a proxy for environmental conditions in utero, or do biological processes surrounding birth weight themselves play a role in healthy development? To answer this question, we leverage variation in birth weight that is, within families, orthogonal to prenatal environmental conditions: one's genes. We construct polygenic scores in two longitudinal studies (Born in Bradford, N  = 2008; Wisconsin Longitudinal Study, N  = 8488) to empirically explore the molecular genetic correlates of birth weight. A 1 standard deviation increase in the polygenic score is associated with an ~100-grams increase in birth weight and a 1.4 pp (22 percent) decrease in low birth weight probability. Sibling comparisons illustrate that this association largely represents a causal effect. The polygenic score-birth weight association is increased for children who spend longer in the womb and whose mothers have higher body mass index, though we find no differences across maternal socioeconomic status. Finally, the polygenic score affects social and cognitive outcomes, suggesting that birth weight is itself related to healthy prenatal development., (© The Author(s) 2024. Published by Oxford University Press on behalf of the University of North Carolina at Chapel Hill. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Despite substantial technical advances and wider clinical use, cochlear implant (CI) users continue to report high and elevated listening effort especially under challenging noisy conditions. Among all the objective measures to quantify listening effort, pupillometry is one of the most widely used and robust physiological measures. Previous studies with normally hearing (NH) and hearing-impaired (HI) listeners have shown that the relation between speech performance in noise and listening effort (as measured by peak pupil dilation) is not linear and exhibits an inverted-U shape. However, it is unclear whether the same psychometric relation exists in CI users, and whether individual differences in auditory sensitivity and central cognitive capacity affect this relation. Therefore, we recruited 17 post-lingually deaf CI adults to perform speech-in-noise tasks from 0 to 20 dB SNR with a 4 dB step size. Simultaneously, their pupillary responses and self-reported subjective effort were recorded. To characterize top-down and bottom-up individual variabilities, a spectro-temporal modulation task and a set of cognitive abilities were measured. Clinical word recognition in quiet and Quality of Life (QoL) were also collected. Results showed that at a group level, an inverted-U shape psychometric curve between task difficulty (SNR) and peak pupil dilation (PPD) was not observed. Individual shape of the psychometric curve was significantly associated with some individual factors: CI users with higher clinical word and speech-in-noise recognition showed a quadratic decrease of PPD over increasing SNRs; CI users with better non-verbal intelligence and lower QoL showed smaller average PPD. To summarize, individual differences in CI users had a significant impact on the psychometric relation between pupillary response and task difficulty, hence affecting the interpretation of pupillary response as listening effort (or engagement) at different task difficulty levels. Future research and clinical applications should further characterize the possible effects of individual factors (such as motivation or engagement) in modulating CI users' occurrence of 'tipping point' on their psychometric functions, and develop an individualized method for reliably quantifying listening effort using pupillometry., Competing Interests: YZ and FP are employees of Oticon Medical, manufacturer of the cochlear implants used by the patients in this study and receive salaries as part of their employment. MC-L’s research is funded by a Torres Quevedo grant from the Spanish Ministry of Science and Innovation (PTQ 2019-010594/AEI/10.13039/501100011033) and co-funded by Oticon Medical. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could cause a potential conflict of interest., (Copyright © 2023 Zhang, Callejón-Leblic, Picazo-Reina, Blanco-Trejo, Patou and Sánchez-Gómez.)

During the pandemic confinement, the WHO changed the term "social distancing" to "physical distancing", to help people deal with the lack of social contact. As a result, there was an increase in mental health problems, including insomnia and stress, with a negative impact on cardiovascular health. The objective of this research was to identify the association between insomnia and stress and cardiovascular risk (CVR) during the pandemic in a sample of the general population in Mexico; the participants were chosen using the non-probabilistic method. The data were obtained from an online questionnaire about medical histories focused on cardiovascular risk, according to the Official Mexican Standards and Regulations for patients' clinical records, NOM-004-SSA3-2012, along with an index for the severity of insomnia, measured with a seven-item guide, and an instrument to measure stress. The data were analyzed with descriptive statistics for several different variables: sociodemographics, stress, insomnia, and cardiovascular risk. Cardiovascular risk was compared to insomnia and stress variables, which led to statistically significant differences and correlations between the variables. Participants were divided into four groups with respect to CVR, from low to very high CVR. This research demonstrated that women were more susceptible to stress and cardiovascular risk. However, stress was a more major indicator of CVR than insomnia, but in the high and very high CVR groups, insomnia contributed along with stress; coping strategies reduced the risk in the high CVR group but did not function as expected with respect to reducing risk in the very high CVR group. These findings suggest that sleep patterns and mental health alterations present during the pandemic may persist even when the pandemic was declared as having ended and may contribute to increases in cardiovascular risk in the long-term.

We assessed the appropriateness of the bifactor model for a Mexican ADHD symptom questionnaire (BMQ-ADHD) applied to parents and teachers of elementary school children. With a sample of 765 reports of children's behavior (48.7% with ADHD A1 criteria, 42.6% girls, mean age 8.5 years [± 1.6 sd]), we examined construct validity, measurement invariance, differences for gender and school level, and the appropriateness of using summed scores. The BMQ-ADHD questionnaire was characterized by good construct validity for the bifactor model for parents' and teachers' reports. For both corpora, we detected invariance for gender and school level. There were differences in ADHD symptoms by gender, but not by school year. The summed scores may represent the factors accurately for females but may present difficulty for males in the parents' questionnaires. The present study revealed good BMQ-ADHD psychometric properties for a unidimensional-hierarchical ADHD scale segregated by gender for parents' and teachers' reports., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Although Burt provides a valuable critique of the scientific value of integrating genetic data into social science research, she reinforces rather than disrupts the age-old horserace between genetic effects and environmental effects. We must move past this false dichotomy to create a new ontology that recognizes the ways in which genetic and environmental processes are inextricably intertwined.

Objective: Since evidence of adults' cognition decline is based on standardized testing, we developed regression-based continuous norms by linear regression (LR) and nonlinear quantile regression (NQR) with years of schooling (YoS), age, and sex as covariates on the Mexican adaptation of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD-MX) and complementary tasks., Methods: 392 healthy, Spanish-speaking Mexican adults (50.25% women) aged 18-59 completed the 15 CERAD-MX cognitive tasks and complementary tasks. We used raw scores and examined YoS-related effects considering sex and age as covariates. For the NQR, we used calibrated scores for sex and age. While LR represents one line across the performance, NQR differentiated several nonlinear performance bands by quantiles., Results: LR showed positive relationships between YoS and cognitive performance with a funnel variance pattern. Therefore, this relationship is better represented with NQR than LR. A small, but significant, negative effect of age was found for this age range (18-59 years). The band with fewer years of schooling (1-6) showed greater variability in the cognitive measures than those with more years of schooling (16-22)., Conclusion: This study shows that NQR is useful for accurately positioning participants' performance relative to their peers. NQR accounts more than LR for the inconsistent variability of cognitive performance as a function of YoS by identifying the variability according to YoS (low, medium, high). Thus, NQR represents an appropriate way to construct norms for the cognitive performance of adults., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The objective of this project was to train future physicians to work effectively and thoughtfully with diverse populations by teaching them to employ Acceptance and Commitment Training (ACT) skills to increase cultural humility, with the goal of improving attitudes, knowledge, and beliefs about working with diverse patients. We developed ACT for cultural humility online interactive modules as part of an elective course to teach Medical Spanish to 4th-year medical students. Pre- and post-pilot data pertaining to the cultural humility training modules on the Work-Related Acceptance and Action questionnaire, Multidimensional Cultural Humility Scale, knowledge, attitudes, and beliefs were analyzed using paired samples t-tests and Wilcoxon signed-rank tests. We also included descriptive data pertaining to overall satisfaction with the cultural humility modules and intent to apply the material learned to patient care. Our data showed a significant increase in the cultural humility of our participants as well as an increase in psychological flexibility, a higher favorability rating toward various ethnicities, improvements in attitude, and positive changes in beliefs and knowledge following completion of the modules. The modules were well received by the medical students, with high social validity ratings. The ACT for cultural humility curriculum has great potential to enhance medical education in diversity, equity, and inclusion by increasing both the understanding and the cultural humility of medical students and future professionals to work with diverse populations. The current paper provides a framework that can be used by other programs to shape the education of the future medical workforce to help promote culturally humble care., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We investigate the factor structure, concurrent validity, internal consistency, measurement invariance (sex and parents' geographical/cultural background), and practical scoring practices of the Strengths and Weaknesses of Attention-deficit/Hyperactivity Disorder (ADHD)-Symptoms and Normal Behavior scale (SWAN) in junior high school students. With a sample of 650 parents of Mexican junior high school students (55.84% girls; mean age of 13.15 and SD = 0.97 years) who completed the SWAN scale, a bidirectional instrument, and the Barrios and Matute Questionnaire of ADHD symptoms (BMQ-ADHD), a traditional Mexican unidirectional instrument, we obtained SWAN' psychometric properties by a series of confirmatory factor analyses. Two and three-correlated factors of the SWAN and bifactor models fitted well to the data. The bifactor model with one general dimension and two specific dimensions (BF 2S) showed most favorable psychometric properties and was invariant regarding sex and cultural background. The analyses of the BF 2S revealed that only the general factor was sufficiently reliable for scoring. Percentiles divided by sex better approximated SWAN averaged-based scores to the general factor derived from the SWAN bifactor model, measuring the trait with acceptable precision for norms development. The study provides evidence that SWAN measures a trait best represented by a reliable general domain, that the average-based SWAN score is closer to the general SWAN trait when the score is segregated by sex, and that it is invariant with respect to sex and cultural background to be reliable in a culturally diverse population. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The aim of this study was to investigate the expression of apelin (APLN) and its receptor (APLNR) in visceral adipose tissue (VAT), and its effect on the downstream expression of endothelial nitric oxide synthase (eNOS) in individuals with class 3 obesity, with or without hypertension. Seventy-five unrelated individuals presenting obesity class 3 with or without hypertension were included. Gene expression of APLN, and APLNR were analyzed in VAT, by reverse transcription quantitative polymerase chain reaction. The APLN, APLNR and eNOS (total and phosphorylated) levels in VAT were evaluated by Western blot. Analysis of differences between groups of APLN, APLNR and eNOS were performed by a logistic regression adjusting by confounding factors. Forty-five individuals with hypertension formed the case group, and 30 individuals constituted the control group. The APLN mRNA and protein levels were higher in the group of individuals with hypertension versus individuals without hypertension (p = 0.027 and p = 0.036, respectively). Meanwhile, APLNR mRNA and protein levels in subjects with hypertension were lower versus the group of subjects without hypertension (p = 0.001 and p = 0.008, respectively). Further, the group with hypertension presented a lower level of phosphorylation of eNOS Ser1177, compared to the control group (p = 0.002). In conclusion, individuals with class 3 obesity and hypertension present a modified APLN/APLNR expression in visceral adipose tissue, which could be secondary to reduced eNOS phosphorylation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Colorectal cancer is the most frequent gastrointestinal malignancy worldwide. The value of adjuvant treatment is controversial in Stages I and II., Objective: The aim of this study was to construct post-operative prognostic models applicable to patients with stages I-II colon carcinoma (CC)., Methods: This is a retrospective cohort study of patients with Stage I-II CC treated over a 25-year period. Exposure was defined as clinical, histopathological, and immunohistochemical factors (including CDX2 and MUC2 expression). Patients were randomly allocated to either a “modeling set” or a “validation set”. Factors associated with recurrence, disease-free survival (DFS), and overall survival (OS) were defined in the “modeling set”. Their performances were tested in the “validation set”., Results: From a total of 556 recruited patients, 339 (61%) were allocated to the “modeling set” and 217 (39%) to the “validation set”. Three models explaining recurrence, DFS, and OS were described. Tumor location in the left colon (Hazards ratio [HR] = 1.57; 95% Confidence interval [CI] 0.99-2.48), lymphocyte (HR = 0.46; 96% CI 0.27-0.88) and monocyte (HR = 0.99; 95% CI 0.99-1) counts, neutrophil/platelet ratio (HR = 1.3; 95% CI 0.74-2.3, and HR = 2.3; 95% CI 1.3-4.1; for second and third category, respectively), albumin/monocyte ratio (HR = 0.43; 95% CI 0.21-0.87), and microscopic residual disease after surgery (HR = 8.7; 95% CI 3.1-24) were independently associated with OS. T classification and expression of CDX2 and/or MUC2 were not independently associated with recurrence or prognosis., Conclusion: These models are simple and readily available, and distinguish the risk and prognosis in patients with CC stages I and II; these models require cheaper processes than the use of more sophisticated molecular biology techniques. They may guide either the need for adjuvant therapy versus post-operative surveillance only, as well as aid in the design of clinical trials., (Copyright: © 2023 Permanyer.)

Among the different polymers (proteins, polysaccharides, etc.) that make up natural fibers, fibroin is a protein produced by silk spinning animals, which have developed an optimized system for the conversion of a highly concentrated solution of this protein into high-performance solid fibers. This protein undergoes a self-assembly process in the silk glands that result from chemical gradients and by the application of mechanical stresses during the last step of the process. In the quest for a process that could mimic natural spinning at massive scales, we have discovered that turbulence offers a novel and promising solution: a turbulent liquid jet can be formed by a chemically green and simple coagulating liquid (a diluted solution of acetic acid in etanol) co-flowing with a concentrated solution of fibroin in water by the use of a Flow Blurring nebulizer. In this system, (a) the co-flowing coagulant liquid extracts water from the original protein solution and, simultaneously, (b) the self-assembled proteins are subjected to mechanical actions, including splitting and stretching. Given the non-negligible produced content with the size and appearance of natural silk, the stochastic distribution of those effects in our process should contain the range of natural ones found in animals. The resulting easily functionalizable and tunable one-step material is 100% biocompatible, and our method a perfect candidate to large-scale, low-cost, green and sustainable processing of fibroin for fibres and textiles., (© 2022. The Author(s).)

Since the beginning of the COVID-19 pandemic, the need to implement protocols that respond to the mental health demands of the population has been demonstrated. The PASMICOR programme started in March 2020, involving a total of 210 requests for treatment. Out of those subjects, the intervention was performed in 53 patients with COVID-19 without history of past psychiatric illness, 57 relatives and 60 health professionals, all of them within the area of Salamanca (Spain). Interventions were carried out by professionals of the public mental health service mostly by telephone. Depending on clinical severity, patients received basic (level I) or complex psychotherapeutic care combined with psychiatric care (level II). The majority of attended subjects were women (76.5%). Anxious-depressive symptoms were predominant, although sadness was more frequent in patients, insomnia in relatives and anxiety and fear in health professionals. 80% of the sample, particularly most of the health professionals, required a high-intensity intervention (level II). Nearly 50% of the people treated were discharged after an average of 5 interventions. Providing early care to COVID-19 patients, relatives and professionals by using community mental health resources can help to reduce the negative impact of crises, such as the pandemic, on the most affected population groups., (© 2022. The Author(s).)

Studies of interaction effects are of great interest because they identify crucial interplay between predictors in explaining outcomes. Previous work has considered several potential sources of statistical bias and substantive misinterpretation in the study of interactions, but less attention has been devoted to the role of the outcome variable in such research. Here, we consider bias and false discovery associated with estimates of interaction parameters as a function of the distributional and metric properties of the outcome variable. We begin by illustrating that, for a variety of noncontinuously distributed outcomes (i.e., binary and count outcomes), attempts to use the linear model for recovery leads to catastrophic levels of bias and false discovery. Next, focusing on transformations of normally distributed variables (i.e., censoring and noninterval scaling), we show that linear models again produce spurious interaction effects. We provide explanations offering geometric and algebraic intuition as to why interactions are a challenge for these incorrectly specified models. In light of these findings, we make two specific recommendations. First, a careful consideration of the outcome's distributional properties should be a standard component of interaction studies. Second, researchers should approach research focusing on interactions with heightened levels of scrutiny. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Genotype-by-environment interaction (GxE) studies probe heterogeneity in response to risk factors or interventions. Popular methods for estimation of GxE examine multiplicative interactions between individual genetic and environmental measures. However, risk factors and interventions may modulate the total variance of an epidemiological outcome that itself represents the aggregation of many other etiological components. We expand the traditional GxE model to directly model genetic and environmental moderation of the dispersion of the outcome. We derive a test statistic, [Formula: see text], for inferring whether an interaction identified between individual genetic and environmental measures represents a more general pattern of moderation of the total variance in the phenotype by either the genetic or the environmental measure. We validate our method via extensive simulation, and apply it to investigate genotype-by-birth year interactions for Body Mass Index (BMI) with polygenic scores in the Health and Retirement Study (N = 11,586) and individual genetic variants in the UK Biobank (N = 380,605). We find that changes in the penetrance of a genome-wide polygenic score for BMI across birth year are partly representative of a more general pattern of expanding BMI variation across generations. Three individual variants found to be more strongly associated with BMI among later born individuals, were also associated with the magnitude of variability in BMI itself within any given birth year, suggesting that they may confer general sensitivity of BMI to a range of unmeasured factors beyond those captured by birth year. We introduce an expanded GxE regression model that explicitly models genetic and environmental moderation of the dispersion of the outcome under study. This approach can determine whether GxE interactions identified are specific to the measured predictors or represent a more general pattern of moderation of the total variance in the outcome by the genetic and environmental measures., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Despite the many social and ethical considerations in human genetics, researchers and communities remain largely siloed as for-profit, direct-to-consumer genetic testing and the application of polygenic scores to in vitro fertilization services become increasingly prevalent. The multifaceted challenges facing genomics, both empirical and ethical, require collaborations that foster critical dialogue and honest debate between communities inside and outside the research enterprise. This piece argues that in order to respond to the premature or inappropriate use of genomic data in industry, the scientific community needs to first embrace, understand, and be in dialogue about its disagreements. We introduce the research framework of adversarial collaboration as a way to celebrate disagreement and productively work toward policy-informed, ethical, and anticipatory genomics research., (© 2021 The Authors.)

Background and Objective: Collecting information from different raters is important for diagnosing ADHD, but several factors can lead to gathering discrepant information. Our aim was to determine the agreement between parent and teacher's when rating the list of ADHD symptoms (criterion A, DSM-IV) in a sample of Mexican school-age children. We explored whether inter-rater agreement varied by children's age and sex, and each symptom of inattention, hyperactivity, and impulsivity., Methods: A total of 789 children (335 girls) from six elementary school grades grouped as G1 [grades 1-2], G2 [grades 3-4], and G3 [grades 5-6]) were rated by their parents and teachers. We identified inter-rater reliability by using Cohen's kappa coefficient by school level, sex, and ADHD symptoms. We explored the presence of symptoms considering parents' and teachers' ratings, individually and collapsed, using the AND/OR rules., Results: Low inter-rater agreement was observed. Moderate levels were observed in G1, but not in G2 or G3. Both groups of informants reported that more boys than girls met these criteria, but agreement by sex was still low, as were the results of the analyses by individual symptoms. Among the children that met the ADHD criteria, an inattention symptom was the one most frequently reported by both raters, whereas among non-ADHD children, a hyperactive symptom was the one most often reported., Discussion: The exclusive use of questionnaires fails to provide convergent information between raters. We highlight the importance of conducting comprehensive clinical histories when diagnosing ADHD in order to explore what these discrepancies show about the relationship symptoms/context., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Chamorro et al.)

Introduction: Vulpian-Bernhardt syndrome (VBS) is an atypical rare clinical phenotype of amyotrophic lateral sclerosis (ALS) that causes a significant delay in diagnosis, and thus it is important to recognise its clinical and electrophysiological features., Materials and Methods: Retrospective cross-sectional study. We reviewed the clinical records of patients diagnosed with ALS in the period from January to December 2019. Those meeting criteria for VBS were included so as to describe their frequency as well as their clinical and electrophysiological features., Results: Twenty patients (15.8%) met criteria for VBS; 55% were female; age at onset of symptoms was 46.6 ± 12.9 years; 40% were smokers; median delay in diagnosis was 24 (12-96) months; median time to involvement of the second body segment was 24 (12-132) months, which was lumbosacral in 65%; mean Revised Amyotrophic Lateral Sclerosis Functional Rating Scale score was 27 ± 7 points; 45% met the El Escorial criteria for ALS defined at diagnosis and 58.8% met the Awaji criteria. There were 19 nerve conduction studies and 17 electromyograms, and an abductor digiti minimi-abductor pollicis brevis (ADM/APB) ratio < 0.6 was found in 63% (split hand)., Conclusions: There is a significant delay in the diagnosis of motor neuron diseases in general and more particularly in VBS. Calculating the ADM/APB ratio and applying the Awaji criteria in the electrophysiology study can be a valuable aid to increase diagnostic certainty in this clinical entity.

Background: The clinical characteristics of electrophysiological subtypes and prognostic factors of Mexican adults diagnosed with Guillain-Barré Syndrome (GBS) have not been described., Materials and Methods: A single center, ambispective, cohort study was performed (2015-2019). GBS was defined following the Asbury and Cornblath criteria. Electrodiagnosis was made according to Hadden criteria. Clinical, biochemical and electrodiagnostic parameters were described, compared and analyzed using a multivariate model. Only patients who completed a 3-month follow-up were included., Results: 137 GBS patients (92 males; mean age 46.6 ± 16.6).132 (96.3%) underwent an electrodiagnostic assessment.68 (51.5%) were classified as axonal GBS, with further classified into two groups: acute motor axonal neuropathy (AMAN) 45.4%, and acute motor and sensory axonal neuropathy (AMSAN) 8,6%. The following characteristics were lower in the AMAN group: Medical Research Counsel sumscore (MRC) 30.1 ± 16.3 vs 36.4 ± 14.4, unilateral facial palsy 10% vs 25.9% and albuminocytologic dissociation 41.3% vs. 71.7%.Multivariate analysis found AMAN as an independent predictor of an unfavorable outcome OR: 3.34 (p = 0.03) CONCLUSIONS: AMAN subtype is the most frequent presentation of GBS in Mexican adult patients and an independent predictor of inability to walk independently at 3 months after discharge., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

While over 240,000 American students experienced a school shooting in the last two decades, little is known about the impacts of these events on the mental health of surviving youth. Using large-scale prescription data from 2006 to 2015, we examine the effects of 44 school shootings on youth antidepressant use. Our empirical strategy compares the number of antidepressant prescriptions written by providers practicing 0 to 5 miles from a school that experienced a shooting (treatment areas) to the number of prescriptions written by providers practicing 10 to 15 miles away (reference areas), both before and after the shooting. We include month-by-year and school-by-area fixed effects in all specifications, thereby controlling for overall trends in antidepressant use and all time-invariant differences across locations. We find that local exposure to fatal school shootings increases youth antidepressant use by 21.4% in the following 2 y. These effects are smaller in areas with a higher density of mental health providers who focus on behavioral, rather than pharmacological, interventions., Competing Interests: The authors declare no competing interest.

Interest in the study of gene-environment interaction has recently grown due to the sudden availability of molecular genetic data-in particular, polygenic scores-in many long-running longitudinal studies. Identifying and estimating statistical interactions comes with several analytic and inferential challenges; these challenges are heightened when used to integrate observational genomic and social science data. We articulate some of these key challenges, provide new perspectives on the study of gene-environment interactions, and end by offering some practical guidance for conducting research in this area. Given the sudden availability of well-powered polygenic scores, we anticipate a substantial increase in research testing for interaction between such scores and environments. The issues we discuss, if not properly addressed, may impact the enduring scientific value of gene-environment interaction studies.

Observed genetic associations with educational attainment may be due to direct or indirect genetic influences. Recent work highlights genetic nurture , the potential effect of parents' genetics on their child's educational outcomes via rearing environments. To date, few mediating childhood environments have been tested. We used a large sample of genotyped mother-child dyads ( N = 2,077) to investigate whether genetic nurture occurs via the prenatal environment. We found that mothers with more education-related genes are generally healthier and more financially stable during pregnancy. Further, measured prenatal conditions explain up to one third of the associations between maternal genetics and children's academic and developmental outcomes at the ages of 4 to 7 years. By providing the first evidence of prenatal genetic nurture and showing that genetic nurture is detectable in early childhood, this study broadens our understanding of how parental genetics may influence children and illustrates the challenges of within-person interpretation of existing genetic associations.

Introduction: Refractory myasthenia gravis (MG) is defined as a failure to respond adequately to conventional therapies, the inability to reduce immunosuppressive therapy without clinical relapse or the need for ongoing rescue therapy, severe adverse effects from immunosuppressive therapy (treatment intolerant) or frequent myasthenic crisis even on therapy. Cyclophosphamide (CYC) is a DNA alkylating agent that causes important interference in transcription processes and DNA replication, it has been used in refractory MG with controversial results. We aim to determine the efficacy of CYC in refractory MG in the Mexican population., Methods: In an observational, longitudinal retrospective study, we identified eight refractory MG patients treated with 30-50 mg/kg monthly CYC for at least 6 months. The efficacy was assessed by Osserman scale considering significant improvement a ≥ 1 point reduction and Myasthenia Gravis Composite Scale. The relapse-free and remission-free period were also calculated using the Kaplan-Meier statistic., Results: Clinical improvement was achieved in 75% of the patients. According to the Kaplan-Meier analysis, the median progression-free survival (PFS) was 9 (6.2-11.5) months and the median time to progression (TTP) was 4 (1-8) months. Response was independent of patient's characteristics, except for the MG age of onset (p = 0.0025)., Conclusions: CYC was effective in all patients with refractory MG for a mean of 9 months, with worsening thereafter, which could be associated with low cumulative dose. The symptomatic improvement with CYC was noted within the 1st month. We conclude that CYC is effective as an induction to remission therapy, although our data suggest it is not effective as a long-term therapy.

We study theoretically the influence of viscoelasticity on the steady cone-jet mode of electrospray for small stress relaxation times. For this purpose, we numerically integrate the leaky-dielectric model together with the Oldroyd-B constitutive relationship and calculate both the base flow and linear eigenmodes characterizing its stability as a function of the governing parameters. We describe the effect of the polymeric stresses on both the cone-jet mode and the minimum flow rate stability limit. There are considerable differences between the Newtonian and viscoelastic electrospray realizations even for relatively small stress relaxation times due to the intense extensional deformation suffered by the fluid particles in the cone-jet transition region The axial polymeric stress shrinks the liquid meniscus and stabilizes it by pushing the fluid particle in the cone-to-jet transition region.

Background: The TNM classification does not completely reflect the prognosis of patients with colorectal cancer (CRC). Several clinical factors have been used to increase its prognostic value, but factors pertaining to the patient's immunonutritional status have not usually been addressed. The aim of this study is to evaluate the role of Prognostic nutritional index (PNI) and other well-known prognostic factors by multivariate analysis in a cohort of patients with CRC., Methods: This is a retrospective cohort study of consecutive patients with CRC managed in a cancer center between January 1992 and December 2016. Cox's model was used to define the association of the PNI and other factors with Overall survival (OS)., Results: A total of 3301 patients were included: 47.7% were female and 52.3% were male, with a mean age of 58.7 years. By bivariate analysis, PNI was strongly associated with OS (Risk ratio [RR] 0.968, 95% Confidence interval [CI] 0.962-0.974; P < 0.001). On multivariate analysis, PNI was an independent explanatory variable (as continuous variable and as categorized variable; RR 0.732, 95% CI 0.611-0.878; RR 0.656, 95% CI 0.529-0.813 and RR 0.646, 95% CI 0.521-0.802, for quintiles 2, 3, and 4-5, respectively); a biological gradient effect was demonstrated. The final prognostic model included PNI, location of the neoplasia in the colorectum, basal hemoglobin, lymphocyte count, neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, TNM stage, differentiation degree, R classification, and postoperative complications., Conclusions: PNI is a significant and independent prognostic factor in patients with CRC. Its prognostic value adds precision to the TNM staging system including specific subgroups of patients with CRC; it should be evaluated in prospective clinical studies., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Obesity increases the risk of developing hypertension. Since both pathological entities constitute public health problems, the aim of this study was to investigate RNA expression of adiponectin, leptin and their receptors in adipose tissue in women with class 3 obesity, with or without hypertension. Serum concentrations of these adipokines were also quantitated. Women with obesity and hypertension (n = 22) and with obesity without hypertension (n = 37) were included. All patients presented class 3 obesity, without diabetes mellitus. The expression of mRNA in: adiponectin, ADIPOR1 and ADIPOR2 was analyzed in visceral (VAT) and subcutaneous (SAT) adipose tissue; leptin and its receptor were only analyzed in SAT, by reverse transcription quantitative PCR. Measurements of adiponectin and leptin concentrations were performed using enzyme-linked immunosorbent assay kits. Analysis of mRNA expressions in VAT and SAT are presented as median and quartiles. Analysis of serum concentrations of adipokines are presented as median and percentiles 25th-75th. Women presenting a higher mean arterial pressure, had significantly higher levels of mRNA expression of adiponectin in SAT. Besides, we found several significant positive correlations of these adipokines and their receptors. In conclusion, we found that those women with a higher mean arterial pressure and receiving antihypertensive treatment, presented higher levels of mRNA expression of adiponectin in SAT., (Copyright © 2019. Published by Elsevier B.V.)

The stomach-derived hormone ghrelin mainly acts in the brain. Studies in mice have shown that the accessibility of ghrelin into the brain is limited and that it mainly takes place in some circumventricular organs, such as the median eminence. Notably, some known brain targets of ghrelin are distantly located from the circumventricular organs. Thus, we hypothesized that ghrelin could also access the brain via the blood-cerebrospinal fluid (CSF) barrier, which consists of the choroid plexus and the hypothalamic tanycytes. Using systemic injection of ghrelin or fluorescent-ghrelin in mice, we found that cells of the blood-CSF barrier internalize these molecules. In time-response studies, we found that peripherally injected fluorescent-ghrelin quickly reaches hypothalamic regions located in apposition to the median eminence and more slowly reaches the periventricular hypothalamic parenchyma, adjacent to the dorsal part of the third ventricle. Additionally, we found that CSF ghrelin levels increase after the systemic administration of ghrelin, and that central infusions of either an anti-ghrelin antibody, which immuno-neutralizes CSF ghrelin, or a scrambled version of ghrelin, which is also internalized by cells of the blood-CSF barrier, partially impair the orexigenic effect of peripherally injected ghrelin. Thus, current evidence suggests that the blood-CSF barrier can transport circulating ghrelin into the brain, and that the access of ghrelin into the CSF is required for its full orexigenic effect.

Background: Right-colon cancer (RCC) presents differences with Left-colon cancer (LCC) in terms of Overall survival (OS), but certain reports provide conflicting findings. Our objective is to define differences regarding prognostic factors in RCC and LCC by multivariate analysis., Methods: Retrospective cohort including patients treated from 1992-2016. The Kaplan-Meier and Cox models were used to define prognostic factors., Results: 871 patients had RCC and 748 LCC; mean age was 58.1. Location was associated with socioeconomic status, body mass, blood hemoglobin, serum albumin, lymphocyte count and Prognostic nutritional index (PNI). Distribution of TNM stages was similar between groups, as well as gender, age, surgical morbidity/mortality; 72.3% of RCC and 83.2% of LCC were well/moderately differentiated (p <0.0001). Mean surgical lymph-node retrieval was 19.3 (SD14.6) for RCC and 15.7 (SD13.1) for LCC (p <0.0001). Median OS was 5.2 (95% CI 3.9-6.5) for RCC, and 3.2 years (95% CI 2.1-4.4) for LCC (p = 0.426). OS was different between RCC and LCC by stratified analyses within PNI, TNM, differentiation and R classification. RCC presents different OS in stages IIIC, and IVB than LCC., Conclusion: Differences between RCC and LCC were mainly by immunonutritional variables. Differences in OS were found after stratified analysis of PNI, TNM stages, differentiation degree, and R classification. Location of the neoplasm in the colon should be considered in the design of clinical trials in patients with colon cancer., (Copyright © 2019 IMSS. Published by Elsevier Inc. All rights reserved.)

Background : The aim of this study was to investigate if serum concentrations of apelin-36, apelin-17, apelin-13 or apelin-12 were different in obesity class 3 individuals with hypertension, when compared to those without hypertension (normal or high-normal). Subjects and Methods : Twenty six individuals with obesity class 3-related hypertension and thirty three individuals without hypertension, who were divided in individuals with normal (n = 23) or with high-normal (n = 10) blood pressure (BP) were analyzed. All individuals presented obesity class 3, without diabetes mellitus. Measurements of all apelin isoforms were performed using enzyme-linked immunosorbent assay kits. Analysis of differences between groups of Apelin isoform concentrations was performed by a One-way ANOVA, with a Tukey test post hoc. Results : The individuals of the hypertensive group presented a slightly lower serum concentration of all apelin isoforms, but these differences were not statistically significant. These results were more evident when the group of patients without hypertension were divided based in normal and high-normal BP, observing that apelin-17 isoform were higher in individuals with high-normal BP in comparison to subjects with normal BP (P = 0.018); concentrations were also higher when compared to subjects with hypertension (P = 0.004). Conclusions : To our knowledge, this is the first study regarding the differences of apelin-17 isoform concentrations in individuals pertaining to different categories of BP, who presented obesity class 3. The group of patients that presented hypertension showed a lower concentration of all isoforms. This observation could be due to the fact that these patients were taking antihypertensive medication.

The objective of this study was to characterize an attention deficit hyperactivity disorder (ADHD) endophenotype in non-affected parents of adolescents with a history of ADHD, based on the relationship between performance on a sustained attention test (continuous performance task, or CPT) and polymorphisms of the DRD4 gene. In a sample of 25 non-affected parents of adolescents with ADHD history obtained from a longitudinal study of a nonclinical population, and 25 non-affected parents of adolescents with no ADHD history, four groups were evaluated with respect to the presence or absence of the long allele polymorphism of the DRD4 gene (i.e., over seven repeats). Comparisons of CPT performance among the four study groups included the number of commission errors, the number of omission errors, mean reaction time on correct responses (MRT), and reaction time (RT) variability (mean standard deviation of RT in each block [SDRT, as variability], and the sigma and tau components of the ex-Gaussian approach). The group of non-affected parents of adolescents with ADHD history and at least one long allele of the DRD4 gene showed greater RT variability (measured by SDRT), which is best explained by the greater frequency of abnormally slow responses (measured by tau). An association between the presence of the long allele of the DRD4 gene polymorphism and ADHD-like failure in CPT performance was evident in the non-affected parents of adolescents with ADHD in childhood. These findings suggest that certain traits of CPT performance could be considered an ADHD endophenotype., (© 2018 Wiley Periodicals, Inc.)

Di(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer that is metabolized to mono(2-ethylhexyl) phthalate (MEHP). Inhalation is an important exposure route for both phthalates, and their effects on lungs include inflammation, alteration of postnatal maturation (alveolarization), enlarged airspaces and cell differentiation changes, suggesting that alveolar epithelial cells-2 (AEC) are targets of phthalates. This study evaluated the cell progression, epithelial and mesenchymal markers, including surfactant secretion in A549 cells (AEC) that were exposed to DEHP (1-100 μM) or MEHP (1-50 μM) for 24-72 h. The results showed an increased cell proliferation at all concentrations of each phthalate at 24 and 48 h. Cell migration showed a concentration-dependent increase at 24 and 48 h of exposure to either phthalate and enlarged structures were seen. Decreased levels of both surfactants (SP-B/SP-C) were observed after the exposure to either phthalate at 48 h, and of SP-C positive cells exposed to MEHP, suggesting a loss of the epithelial phenotype. While a decrease in the epithelial marker E-cadherin and an increase in the mesenchymal marker fibronectin were observed following exposure to either phthalate. Our results showed that DEHP and MEHP altered the structure and migration of A549 cells and promoted the loss of the epithelial phenotype., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Genetic variants identified in genome-wide association studies of educational attainment have been linked with a range of positive life course development outcomes. However, it remains unclear whether school environments may moderate these genetic associations. We analyze data from two biosocial surveys that contain both genetic data and follow students from secondary school through mid- to late life. We test if the magnitudes of the associations with educational and occupational attainments varied across the secondary schools that participants attended or with characteristics of those schools. Although we find little evidence that genetic associations with educational and occupational attainment varied across schools or with school characteristics, genetic associations with any postsecondary education and college completion were moderated by school-level socioeconomic status. Along similar lines, we observe substantial between-school variation in the average level of educational attainment students achieved for a fixed genotype. These findings emphasize the importance of social context in the interpretation of genetic associations. Specifically, our results suggest that though existing measures of individual genetic endowment have a linear relationship with years of schooling that is relatively consistent across school environments, school context is crucial in connecting an individual's genotype to his or her likelihood of crossing meaningful educational thresholds.

Results from a genome-wide association study (GWAS) can be used to generate a polygenic score (PGS), an individual-level measure summarizing identified genetic influence on a trait dispersed across the genome. For complex, behavioral traits, the association between an individual's PGS and their phenotype may contain bias (from geographic, ancestral, and/or socioeconomic confounding) alongside the causal effect of the individual's genes. We formalize the introduction of a different source of bias in regression models using PGSs: the effects of parental genes on offspring outcomes, known as genetic nurture. GWAS do not discriminate between the various pathways through which genes become associated with outcomes, meaning existing PGSs capture both direct genetic effects and genetic nurture effects. We construct a theoretical model for genetic effects and show that the presence of genetic nurture biases PGS coefficients from both naïve OLS (between-family) and family fixed effects (within-family) regressions. This bias is in opposite directions; while naïve OLS estimates are biased away from zero, family fixed effects estimates are biased toward zero. We quantify this bias using two novel parameters: (1) the genetic correlation between the direct and nurture effects and (2) the ratio of the SNP heritabilities for the direct and nurture effects.

Inhalation injury causes a heterogeneous cascade of insults that increase morbidity and mortality among the burn population. Despite major advancements in burn care for the past several decades, there remains a significant burden of disease attributable to inhalation injury. For this reason, effort has been devoted to finding new therapeutic approaches to improve outcomes for patients who sustain inhalation injuries.The three major injury classes are the following: supraglottic, subglottic, and systemic. Treatment options for these three subtypes differ based on the pathophysiologic changes that each one elicits.Currently, no consensus exists for diagnosis or grading of the injury, and there are large variations in treatment worldwide, ranging from observation and conservative management to advanced therapies with nebulization of different pharmacologic agents.The main pathophysiologic change after a subglottic inhalation injury is an increase in the bronchial blood flow. An induced mucosal hyperemia leads to edema, increases mucus secretion and plasma transudation into the airways, disables the mucociliary escalator, and inactivates hypoxic vasocontriction. Collectively, these insults potentiate airway obstruction with casts formed from epithelial debris, fibrin clots, and inspissated mucus, resulting in impaired ventilation. Prompt bronchoscopic diagnosis and multimodal treatment improve outcomes. Despite the lack of globally accepted standard treatments, data exist to support the use of bronchoscopy and suctioning to remove debris, nebulized heparin for fibrin casts, nebulized N-acetylcysteine for mucus casts, and bronchodilators.Systemic effects of inhalation injury occur both indirectly from hypoxia or hypercapnia resulting from loss of pulmonary function and systemic effects of proinflammatory cytokines, as well as directly from metabolic poisons such as carbon monoxide and cyanide. Both present with nonspecific clinical symptoms including cardiovascular collapse. Carbon monoxide intoxication should be treated with oxygen and cyanide with hydroxocobalamin.Inhalation injury remains a great challenge for clinicians and an area of opportunity for scientists. Management of this concomitant injury lags behind other aspects of burn care. More clinical research is required to improve the outcome of inhalation injury.The goal of this review is to comprehensively summarize the diagnoses, treatment options, and current research.

The aim of the present study was to define the prognostic role of baseline serum albumin (BSA) in colorectal cancer (CRC) across tumor-node-metastasis (TNM) stages and other well defined prognostic factors. Many prognostic models in medicine employ BSA to define or refine treatments in very specific settings; in CRC, BSA has been found to be a prognostic factor as well. A retrospective cohort study of consecutive patients with CRC demonstrated by biopsy, who attended a cancer center during a 7-year period. Multivariate analysis was utilized to define prognostic factors associated with overall survival (OS) employing the Cox model. In this retrospective cohort study, 1465 patients were included; 46.6% were females and 53.4% males (mean age, 59.1 years). Mean BSA was inversely correlated with TNM stages. By multivariate analysis, it was an independent explanatory variable. TNM stages, "R" classification, age, lymphocyte count, neutrophil/platelet ratio, neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, postoperative morbidity, and BSA were independently associated with OS. Morbidities, surgery type, chemotherapy, and radiotherapy were considered confounders after adjusting by TNM stages. BSA is a significant and independent prognostic factor in patients with CRC, and its effect is maintained across TNM strata and other well known clinical prognostic factors. It can be easily used in prognostic models and should be employed to stratify prognosis in therapeutic randomized clinical trials.

This study formulated and characterized an antioxidant-rich concentrate of berries (BPC-350) produced in Chile, which was used to perform a crossover study aimed at determining the effect of the berries on the modulation of plasma postprandial oxidative stress and antioxidant status. Healthy male volunteers ( N = 11) were randomly assigned to three experimental meals: (1) 250 g of ground turkey burger (GTB) + 500 mL of water; (2) 250 g of GTB + 500 mL of 5% BPC-350; (3) 250 g of GTB prepared with 6% BPC-350 + 500 mL of 5% BPC-350. Venous blood samples were collected prior to meal intake and every hour for six hours after intake. Malondialdehyde (MDA), carbonyls in proteins, and DPPH (2,2-diphenyl-1-picrylhydrazyl) antioxidant capacity were quantified in plasma. Significant differences indicated that BPC-350 decreases MDA plasma concentration and protein carbonyls ( p < 0.05). Additionally, a significant increase in the DPPH antioxidant capacity was observed in Meals 2 and 3 when compared to Meal 1 ( p < 0.05). The results are discussed in terms of oxidative reactions that occur during digestion at the stomach level and the important effect of oxidative reactions that occur during the thermal processing of red meat., Competing Interests: The authors declare that there are no competing interests regarding the publication of this paper.

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal disease of unknown etiology. A growing body of evidence indicates that it may result from an aberrant activation of alveolar epithelium, which induces the expansion of the fibroblast population, their differentiation to myofibroblasts and the excessive accumulation of extracellular matrix. The mechanisms that activate the alveolar epithelium are unknown, but several studies indicate that smoking is the main environmental risk factor for the development of IPF. In this study we explored the effect of cigarette smoke on the gene expression profile and signaling pathways in alveolar epithelial cells. Lung epithelial cell line from human (A549), was exposed to cigarette smoke extract (CSE) for 1, 3, and 5 weeks at 1, 5 and 10% and gene expression was evaluated by complete transcriptome microarrays. Signaling networks were analyzed with the Ingenuity Pathway Analysis software. At 5 weeks of exposure, alveolar epithelial cells acquired a fibroblast-like phenotype. At this time, gene expression profile revealed a significant increase of more than 1000 genes and deregulation of canonical signaling pathways such as TGF-β and Wnt. Several profibrotic genes involved in EMT were over-expressed, and incomplete EMT was observed in these cells, and corroborated in mouse (MLE-12) and rat (RLE-6TN) epithelial cells. The secretion of activated TGF-β1 increased in cells exposed to cigarette smoke, which decreased when the integrin alpha v gene was silenced. These findings suggest that the exposure of alveolar epithelial cells to CSE induces the expression and release of a variety of profibrotic genes, and the activation of TGF-β1, which may explain at least partially, the increased risk of developing IPF in smokers.

The current trend of using recombinant antibody fragments in research to develop novel antidotes against scorpion stings has achieved excellent results. The polyclonal character of commercial antivenoms, obtained through the immunization of animals and which contain several neutralizing antibodies that recognize different epitopes on the toxins, guarantees the neutralization of the venoms. To avoid the use of animals, we aimed to develop an equivalent recombinant antivenom composed of a few neutralizing single chain antibody fragments (scFvs) that bind to two different epitopes on the scorpion toxins. In this study, we obtained scFv RU1 derived from scFv C1. RU1 showed a good capacity to neutralize the Cn2 toxin and whole venom of the scorpion Centruroides noxius. Previously, we had produced scFv LR, obtained from a different parental fragment (scFv 3F). LR also showed a similar neutralizing capacity. The simultaneous administration of both scFvs resulted in improved protection, which was translated as a rapid recovery of previously poisoned animals. The crystallographic structure of the ternary complex scFv LR-Cn2-scFv RU1 allowed us to identify the areas of interaction of both scFvs with the toxin, which correspond to non-overlapping sites. The epitope recognized by scFv RU1 seems to be related to a greater efficiency in the neutralization of the whole venom. In addition, the structural analysis of the complex helped us to explain the cross-reactivity of these scFvs and how they neutralize the venom., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

Labdane-related diterpenoids are natural products with potential pharmaceutical applications that are rarely found in bacteria. Here, a putative class I labdane-related diterpene synthase (LrdC) identified by genome mining in a streptomycete was successfully crystallized using the microbatch method. Crystals of the LrdC enzyme were obtained in a holo form with its natural cofactor Mg(2+) (LrdC-Mg(2+)) and in complex with inorganic pyrophosphate (PPi) (LrdC-Mg(2+)-PPi). Crystals of native LrdC-Mg(2+) diffracted to 2.50 Å resolution and belonged to the trigonal space group P3221, with unit-cell parameters a = b = 107.1, c = 89.2 Å. Crystals of the LrdC-Mg(2+)-PPi complex grown in the same conditions as the native enzyme with PEG 8000 diffracted to 2.36 Å resolution and also belonged to the trigonal space group P3221. Crystals of the LrdC-Mg(2+)-PPi complex grown in a second crystallization condition with PEG 3350 diffracted to 2.57 Å resolution and belonged to the monoclinic space group P21, with unit-cell parameters a = 49.9, b = 104.1, c = 66.5 Å, β = 111.4°. The structure was determined by the single-wavelength anomalous dispersion (SAD) technique using the osmium signal from a potassium hexachloroosmate (IV) derivative.

The aim of this study was to obtain the genotype and gene frequency from parents of children with attention-deficit/hyperactivity disorder (ADHD) and then assess the Hardy-Weinberg equilibrium of genotype frequency of the variable number tandem repeat (VNTR) III exon of the dopamine receptor D4 (DRD4) gene. The genotypes of the III exon of 48 bp VNTR repeats of the DRD4 gene were determined by polymerase chain reaction in a sample of 30 parents of ADHD cases. In the 60 chromosomes analyzed, the following frequencies of DRD4 gene polymorphisms were observed: six chromosomes (c) with two repeat alleles (r) (10%); 1c with 3r (1.5%); 36c with 4r (60%); 1c with 5r (1.5%); and 16c with 7r (27%). The genotypic distribution of the 30 parents was two parents (p) with 2r/2r (6.67%); 1p with 2r/4r (3.33%); 1p with 2r/5r (3.33%); 1p with 3r/4r (3.33%); 15p with 4r/4r (50%); 4p with 4r/7r (13.33); and 6p with 7r/7r (20%). A Hardy-Weinberg disequilibrium (χ (2)=13.03, P<0.01) was found due to an over-representation of the 7r/7r genotype. These results suggest that the 7r polymorphism of the DRD4 gene is associated with the ADHD condition in a Mexican population.