Central leptin signaling deficiency induced by leptin receptor antagonist leads to hypothalamic proteomic remodeling.

AIMS: Leptin irresponsiveness, which is often associated with obesity, can have significant impacts on the hypothalamic proteome of individuals, including those who are lean. While mounting evidence on leptin irresponsiveness has focused on obese individuals, understanding the early molecular and proteomic changes associated with deficient hypothalamic leptin signaling in lean individuals is essential for early intervention and prevention of metabolic disorders. Leptin receptor antagonists block the binding of leptin to its receptors, potentially reducing its effects and used in cases where excessive leptin activity might be harmful. MATERIALS AND METHODS: In this work, we blocked the central actions of leptin in lean male adult Wistar rat by chronically administering intracerebroventricularly the superactive leptin receptor antagonist (SLA) (D23L/L39A/D40A/F41A) and investigated its impact on the hypothalamic proteome using label-free sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) for quantitative proteomics. KEY FINDINGS: Our results show an accumulation of proteins involved in mRNA processing, mRNA stability, and translation in the hypothalamus of SLA-treated rats. Conversely, hypothalamic leptin signaling deficiency reduces the representation of proteins implicated in energy metabolism, neural circuitry, and neurotransmitter release. SIGNIFICANCE: The alterations in the adult rat hypothalamic proteome contribute to dysregulate appetite, metabolism, and energy balance, which are key factors in the development and progression of obesity and related metabolic disorders. Additionally, using bioinformatic analysis, we identified a series of transcription factors that are potentially involved in the upstream regulatory mechanisms responsible for the observed signature.

Mirror Box as a tool for training users to achieve motor imagery.

To evaluate Mirror Visual Feedback (MVF) as a training tool for brain-computer interface (BCI) users. Because about 20%-30% of subjects need more training to operate a BCI system that uses motor imagery. Electroencephalograms (EEGs) were recorded from 18 healthy subjects, using event-related desynchronization (ERD) to observe the responses during the movement or movement intention of the hand for the conditions of Control, Imagination, and the MVF with the mirror box. Two groups of subjects were formed, Group 1: control, imagination, and MVF. Group 2: control, MVF, and imagination. There were significant differences in imagination conditions between groups using MVF before or after imagination (Right-hand p= 0.0403. Left-hand p=0.00939). The illusion of movement through MVF is not possible in all subjects, but even in those cases, we found an increase in imagination when the subject used the MVF previously. The increase in the r2s of imagination in the right and left hands suggests cross-learning. The increase in motor imagery recorded with EEG after MVF suggests that the mirror box made it easier to imagine movements. Our results provide evidence that the MVF could be used as a training tool to improve motor imagery.

Miettinen and Nurminen score statistics revisited.

It is commonly necessary to perform inferences on the difference, ratio, and odds ratio of two proportions p1 and p2 based on two independent samples. For this purpose, the most common asymptotic statistics are based on the score statistics (S-type statistics). As these do not correct the bias of the estimator of the product pi (1-pi), Miettinen and Nurminen proposed the MN-type statistics, which consist of multiplying the statistics S by (N-1)/N, where N is the sum of the two sample sizes. This paper demonstrates that the factor (N-1)/N is only correct in the case of the test of equality of two proportions, providing the estimation of the correct factor (AU-type statistics) and the minimum value of the same (AUM-type statistics). Moreover, this paper assesses the performance of the four-type statistics mentioned (S, MN, AU and AUM) in one and two-tailed tests, and for each of the three parameters cited (d, R and OR). We found that the AUM-type statistics are the best, followed by the MN type (whose performance was most similar to that of AU-type). Finally, this paper also provides the correct factors when the data are from a multinomial distribution, with the novelty that the MN and AU statistics are similar in the case of the test for the odds ratio.

Unbiased Phosphoproteome Mining Reveals New Functional Sites of Metabolite-Derived PTMs Involved in MASLD Development.

Post-translational modifications (PTMs) of proteins are paramount in health and disease. Phosphoproteome analysis by enrichment techniques is becoming increasingly attractive for biomedical research. Recent findings show co-enrichment of other phosphate-containing biologically relevant PTMs, but these results were obtained by closed searches focused on the modifications sought. Open searches are a breakthrough in high-throughput PTM analysis (OS-PTM), identifying practically all PTMs detectable by mass spectrometry, even unknown ones, with their modified sites, in a hypothesis-free and deep manner. Here we reanalyze liver phosphoproteome by OS-PTM, demonstrating its extremely complex nature. We found extensive Lys glycerophosphorylations (pgK), as well as modification with glycerylphosphorylethanolamine on Glu (gpetE) and flavin mononucleotide on His (fmnH). The functionality of these metabolite-derived PTMs is demonstrated during metabolic dysfunction-associated steatotic liver disease (MASLD) development in mice. MASLD elicits specific alterations in pgK, epgE and fmnH in the liver, mainly on glycolytic enzymes and mitochondrial proteins, suggesting an increase in glycolysis and mitochondrial ATP production from the early insulin-resistant stages. Thus, we show new possible mechanisms based on metabolite-derived PTMs leading to intrahepatic lipid accumulation during MASLD development and reinforce phosphoproteome enrichment as a valuable tool with which to study the functional implications of a variety of low-abundant phosphate-containing PTMs in cell physiology.

Assessment of Classical and Non-Classical Quantitative Electroencephalographic Measures in Patients with Substance Use Disorders.

Background: People diagnosed with substance use disorders (SUDs) are at risk for impairment of brain function and structure. However, physicians still do not have any clinical biomarker of brain impairment that helps diagnose or treat these patients when needed. The most common method to study these patients is the classical electroencephalographic (EEG) analyses of absolute and relative powers, but this has limited individual clinical applicability. Other non-classical measures such as frequency band ratios and entropy show promise in these patients. Therefore, there is a need to expand the use of quantitative (q)EEG beyond classical measures in clinical populations. Our aim is to assess a group of classical and non-classical qEEG measures in a population with SUDs. Methods: We selected 56 non-medicated and drug-free adult patients (30 males) diagnosed with SUDs and admitted to Rehabilitation Clinics. According to qualitative EEG findings, patients were divided into four groups. We estimated the absolute and relative powers and calculated the entropy, and the alpha/(delta + theta) ratio. Results: Our findings showed a significant variability of absolute and relative powers among patients with SUDs. We also observed a decrease in the EEG-based entropy index and alpha/(theta + delta) ratio, mainly in posterior regions, in the patients with abnormal qualitative EEG. Conclusions: Our findings support the view that the power spectrum is not a reliable biomarker on an individual level. Thus, we suggest shifting the approach from the power spectrum toward other potential methods and designs that may offer greater clinical possibilities.

Technological knowledge progress: Were famous laws almost correct in developing and emerging economies?

Do the famous laws of the motion of technological progress like the Moore's Law, Wright's Law, Goddard's Law, and their derivatives explain the technological knowledge progress of developing and emerging economies? The aim of this paper is to investigate that question. For that purpose, we rationalize an existing framework (Nagy et al. 2013) and employ it on a panel data set of 66 developing and emerging market economies over the 1995-2017 period. Empirical evidence is mixed. Some of the results confirm a positive relationship between technological knowledge progress and the progress of time. Other instances indicate that the slow rate of learning delays the doubling time by 18 years. Yet other results predict that this group of countries will double its rate of progress in 4-5 years. The explanatory power varies across the laws, with most laws suggesting acceptance of the hypotheses that the included variables affect the technological knowledge progress while others recommending that we "do not accept" the hypothesis that in-situ scale and hence cumulative GDP per capita explain the technological knowledge progress of these countries. Practical policy implications, which this group of countries can use to assess and address constraints to the technological knowledge progress, are also discussed.

Electro-optical Study of the Anomalous Rotational Diffusion in Polymer Solutions.

Brownian diffusion of spherical nanoparticles is usually exploited to ascertain the rheological properties of complex media. However, the behavior of the tracer particles is affected by a number of phenomena linked to the interplay between the dynamics of the particles and polymer coils. For this reason, the characteristic lengths of the dispersed entities, depletion phenomena, and the presence of sticking conditions have been observed to affect the translational diffusion of the probes. On the other hand, the retardation effect of the host fluid on the rotational diffusion of nonspherical particles is less understood. We explore the possibility of studying this phenomenon by analyzing the electro-orientation of the particles in different scenarios in which we vary the ratio between the particle and polymer characteristic size, and the geometry of the particles, including both elongated and oblate shapes. We find that the Stokes-Einstein relation only applies if the radius of gyration of the polymer is much shorter than the particle size and when some repulsive interaction between both is present.

Acceptability by End-users of a Standardized Structured Format for Reporting EEG.

The report of the electroencephalogram (EEG) results has traditionally been made using free-text formats with a huge variation in descriptions due to several factors. Recently, the International Federation of Clinical Neurophysiology (IFCN) endorsed the use of the Standardized Computer-based Organized Reporting of EEG (SCORE). This system has many advantages, but only some concerns have been investigated so far. This study aimed to assess the end-users acceptability of this proposed EEG report format. A 16-item electronic survey was sent to physicians who use EEG services of a medical diagnosis clinic. Physicians had been receiving the EEG reports in free-text formats from the same three board-certified electroencephalographers for the past three years. In January 2019, the report changed to the SCORE format. The survey assessed five main topics: physician information and historical use of EEG; personal preferences; comparative aspects of the formats; impact of the new format on clinical decision-making; and satisfaction. Thirty-two of 52 have responded to the survey (61%). On average, 81% of the responders have received enough reports with the new format to reliably complete the survey. Every responder prefers the standardized compared to the free-text format. Twenty-five responders like the inclusion of the head model, and interestingly, five suggest including another legend to differentiate "slow activity" from "other abnormal activity". Virtually all responders would recommend the new format, but one-third read only the conclusion. Our findings suggest high acceptability of this standardized report format. Despite the limitations of this study, we hope these findings contribute to the improvement and expansion of standardized EEG reporting systems.

Yield of Sleep Deprivation EEG in Suspected Epilepsy. A Retrospective Study.

Background. Sleep is an activation procedure and is considered the most potent and best-documented modulator of seizures and interictal epileptiform discharges (IEDs) on electroencephalogram (EEG). The precise role of sleep deprivation in the diagnostic process of epilepsy has not been fully clarified after more than 50 years of use. Sleep deprivation is a procedure that is accompanied by discomfort for patients and their families. Therefore, an accurate indication according to each patient-specific characteristic is needed. This study aims to assess the effectiveness of sleep deprivation EEG in the diagnostic process of patients with suspected epilepsy in our center. Methods. We included patients with a first unprovoked seizure and patients with paroxysmal events suspecting seizures who underwent a sleep deprivation EEG (sdEEG) or routine EEG (rEEG). All patients were subsequently classified with confirmed epilepsy or not. Results. We included 460 patients. The group with sdEEG consisted of 115 patients, while the group with rEEG comprised 345 patients. In the sdEEG group, 19 patients (17%) were confirmed with epilepsy, of which 17 presented interictal epileptiform discharges (IEDs). For the rEEG group, 66 patients (19%) were confirmed with epilepsy, of which 63 presented IEDs. The difference was not statistically significant. Conclusion. Our study failed to find a difference in the yield of sleep deprivation versus routine EEG in patients with epilepsy, but there are many significant confounders/sample biases that limit the generalizability of the findings, particularly to the majority of adult practices.

Grape seed extract supplementation modulates hepatic lipid metabolism in rats. Implication of PPARß/δ.

In mammals, the liver is involved in nutrient metabolism and in the regulation of lipid and glucose homeostasis. Multiple studies have described improvements in liver disorders after regular consumption of grape seed extract (GSE). GSE prevents or ameliorates hepatic metabolic dysfunction through AMPK activation, which reduces hepatic lipogenesis while enhancing hepatic lipid oxidation. However, the involvement of ChREBPß and PPARß/δ in these effects has not been fully elucidated. We aim to demonstrate that chronic consumption of GSE at low doses (25 mg kg-1 body weight per day) produces beneficial effects on hepatic glucose and lipid metabolism in young lean Wistar rats and that part of these effects involve ChREBPß inactivation and PPARß/δ activation. In our study, increased concentrations of structurally related (-)-(epi)catechin metabolites and 5-carbon ring fission metabolites were found in the serum of GSE-supplemented rats parallel with the reduction in triglycerides and leptin levels, hepatic cholesterol content and visceral adiposity. GSE supplementation inactivates ChREBP and GSK-3ß, which has been linked to improvements in hepatic lipid and glucose metabolism. Furthermore, the consumption of GSE promotes the expression of Pparß/δ, as well as Pgc-1α and Acox-1, which control hepatic lipid oxidation. Interestingly, pharmacological inhibition of PPARß/δ slowed the induction of Pgc-1α and Acox-1, as well as the activation of AMPK triggered by GSE consumption. Our data suggest that PPARß/δ activation is involved in the metabolic reprogramming effects of chronic GSE consumption in young rats, by modulating, at least, part of the transcriptional programs that maintain hepatic and systemic fuel homeostasis.

Ageing alters the lipid sensing process in the hypothalamus of Wistar rats. Effect of food restriction.

INTRODUCTION: Lipids regulate a wide range of biological processes. The mechanisms by which fatty acids (FA) and its metabolites influence the hypothalamic regulation of energy homeostasis have been highly studied. However, the effect of ageing and food restriction (FR) on this process is unknown. METHODS: Herein, we analyzed the gene expression, protein and phosphorylation levels of hypothalamic enzymes and transcription factors related to lipid metabolism. Experiments were performed in male Wistar rats of 3-, 8- and 24-month-old Wistar rats fed ad libitum (AL), as ageing model. Besides, 5- and 21-month-old rats were subjected to a moderate FR protocol (equivalent to ≈ 80% of normal food intake) for three months before the sacrifice. RESULTS: Aged Wistar rats showed a situation of chronic lipid excess as a result of an increase in de novo FA synthesis and FA levels that reach the brain, contributing likely to the development of central leptin and insulin resistance. We observe a hypothalamic downregulation of AMP-activated protein kinase (AMPK) and stearoyl-CoA desaturase (SCD1) and an increase of carnitine palmitoyltransferase-1c (CPT1c) expression. DISCUSSION: Our results suggest an impairment in the physiological lipid sensing system of aged Wistar rats, which would alter the balance of the intracellular mobilization and trafficking of lipids between the mitochondria and the Endoplasmic Reticulum (ER) in the hypothalamus, leading probably to the development of neurolipotoxicity in aged rats. Lastly, FR can only partially restore this imbalance.Schematic representation of the fate of LCFA-CoA in the hypothalamus of young and old rats. Blood circulating LCFAs in young Wistar rats reach the hypothalamus, where they are esterified to LCFA-CoA. Into glial cells or neurons, LCFA-CoA are driven to mitochondria (CPT1a) or ER (CPT1c) where could be desaturated by SDC1 and, thereby, converted into structural and signaling unsaturated lipids as oleic acid, related with neuronal myelinization and differentiation. However, the excess of LCFA that reach to the hypothalamus in old animals, could generate an increase in LCFA-CoA, which together with an increase in CPT1c levels, could favor the capture of LCFA-CoA to the ER. The decrease in the levels of SCD1 in old rats would decrease FA unsaturation degree that could trigger lipotoxicity process and neurodegeneration, both related to the development of neurodegenerative diseases linked to age.

Aging Induces Hepatic Oxidative Stress and Nuclear Proteomic Remodeling in Liver from Wistar Rats.

Aging is a continuous, universal, and irreversible process that determines progressive loss of adaptability. The liver is a critical organ that supports digestion, metabolism, immunity, detoxification, vitamin storage, and hormone signaling. Nevertheless, the relationship between aging and the development of liver diseases remains elusive. In fact, although prolonged fasting in adult rodents and humans delays the onset of the disease and increases longevity, whether prolonged fasting could exert adverse effects in old organisms remains incompletely understood. In this work, we aimed to characterize the oxidative stress and nuclear proteome in the liver of 3-month- and 24-month-old male Wistar rats upon 36 h of fasting and its adaptation in response to 30 min of refeeding. To this end, we analyzed the hepatic lipid peroxidation levels (TBARS) and the expression levels of genes associated with fat metabolism and oxidative stress during aging. In addition, to gain a better insight into the molecular and cellular processes that characterize the liver of old rats, the hepatic nuclear proteome was also evaluated by isobaric tag quantitation (iTRAQ) mass spectrometry-based proteomics. In old rats, aging combined with prolonged fasting had great impact on lipid peroxidation in the liver that was associated with a marked downregulation of antioxidant genes (Sod2, Fmo3, and Cyp2C11) compared to young rats. Besides, our proteomic study revealed that RNA splicing is the hepatic nuclear biological process markedly affected by aging and this modification persists upon refeeding. Our results suggest that aged-induced changes in the nuclear proteome could affect processes associated with the adaptative response to refeeding after prolonged fasting, such as those involved in the defense against oxidative stress.

Leptin, Acting at Central Level, Increases FGF21 Expression in White Adipose Tissue via PPARß/δ.

The altered function of adipose tissue can result in obesity, insulin resistance, and its metabolic complications. Leptin, acting on the central nervous system, modifies the composition and function of adipose tissue. To date, the molecular changes that occur in epididymal white adipose tissue (eWAT) during chronic leptin treatment are not fully understood. Herein we aimed to address whether PPARß/δ could mediate the metabolic actions induced by leptin in eWAT. To this end, male 3-month-old Wistar rats, infused intracerebroventricularly (icv) with leptin (0.2 µg/day) for 7 days, were daily co-treated intraperitoneally (ip) without or with the specific PPARß/δ receptor antagonist GSK0660 (1 mg/kg/day). In parallel, we also administered GSK0660 to control rats fed ad libitum without leptin infusion. Leptin, acting at central level, prevented the starvation-induced increase in circulating levels of FGF21, while induced markedly the endogenous expression of FGF21 and browning markers of eWAT. Interestingly, GSK0660 abolished the anorectic effects induced by icv leptin leading to increased visceral fat mass and reduced browning capacity. In addition, the pharmacological inhibition of PPARß/δ alters the immunomodulatory actions of central leptin on eWAT. In summary, our results demonstrate that PPARß/δ is involved in the up-regulation of FGF21 expression induced by leptin in visceral adipose tissue.

The nutrient sensing pathways FoxO1/3 and mTOR in the heart are coordinately regulated by central leptin through PPARß/δ. Implications in cardiac remodeling.

BACKGROUND: Cardiovascular disease in obese individuals with type 2 diabetes is often associated with hyperleptinemia and leptin resistance, while other studies support that leptin has cardioprotective effects. Besides, the role of leptin in regulating cardiac atrophy or hypertrophy remains to be clearly defined. In fact, in rats with normal leptin sensitivity, the molecular underpinnings of the effects of central leptin regulating cardiac structural pathways remain poorly understood. OBJECTIVE: Hence, we assessed the effects of intracerebroventricular (icv) leptin infusion on cardiac remodeling analyzing FOXO1/3 and mTORC1 pathways, focusing special attention to PPARß/δ as mediator of central leptin's effects on cardiac metabolism. METHODS: Male 3-months-old Wistar rats, infused with icv leptin (0.2 µg/day) for 7 days, were daily co-treated intraperitoneally with the specific PPARß/δ antagonist GSK0660, at 1 mg/kg per day along leptin treatment. RESULTS: Central leptin regulated dynamically, in an opposite manner, the network between FOXOs and mTORC1 and induced an atrophy-related gene program in cardiac tissue. Leptin activated the anti-hypertrophic kinase GSK3ß and increased the protein levels of muscle-specific ubiquitin ligases, muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx)/Atrogin-1 involved in limiting cardiac hypertrophy. FOXO1 activity and the expression of their target genes, Sod2 and Lpl, were also increased in the heart upon central leptin infusion. Besides, Beclin-1 and LC3B-II, gene products of the autophagic pathway response, were upregulated, while the content and expression levels of phenotypic markers of cardiac hypertrophy as ANP and ß-myosin heavy chain, gene product of Myh7 were significantly decreased. On the other hand, mTORC1 activity and OXPHOS protein levels were decreased suggesting a key role of central leptin preventing cardiac oxidative stress. In fact, the content of carbonylated proteins, TBARS and ROS/RSN were not increased in cardiac tissue in response to central leptin infusion. Finally, the pharmacological inhibition of PPARß/δ, via in vivo administration of the selective antagonist GSK0660, blunted the induction of FOXO1/3, Atrogin-1, MuRF1 and GSK3ß in the heart mediated by icv leptin infusion. CONCLUSIONS: Our results demonstrate that, in lean rats with normal leptin sensitivity, central leptin regulates nutrient sensing pathways in heart contributing to balance cardiac remodeling through the anti- and pro-hypertrophic programs, and in this process is involved PPARß/δ.

Emergence flow of weeds as the result of temperature and luminosity conditions in hilly areas / Fluxo de emergência de plantas daninhas em função de condições de temperatura e luminosidade em solo de coxilha

Levels of weed infestation can be inferred from climate information since every species requires specific conditions for its germination process. This study aimed to evaluate weed species and their emergence flow in hilly areas, when subjected to different environmental conditions of temperature and luminosity. Two experiments were carried out in a completely randomized design with four replications. In the first experiment, treatments used plastic films (no film; film just on top; partially closed film; and fully closed film), whereas the second experiment used black polyethylene covers (0; 35; 50; and 80%). Weed emergence in the area was monitored daily, until the establishment of the emergence flow. Soil temperature, solar radiation interception and soil moisture were also monitored. For the analysis of species subjected to every type and level of covers, phytosociological parameters and the emergence speed index were calculated. Data were submitted to analysis of covariance and, when they were significant, the Tukey test (p ≤ 0.05) was applied. A hierarchical cluster analysis was performed to relate factors and experimental levels to distribution intervals of climate covariates. Increase of 8.5°C in soil temperature favors the emergence of crabgrass, while reducing the emergence of alexander grass, morning glory, beggartick and sida. The main species that adapted to decrease in temperature and solar radiation are sida, alexander grass and crab grass. Besides, decrease in radiation increases the number of magnoliopsida species and enables all species to establish faster.

As informações climáticas permitem inferir qual será o nível de infestação de plantas daninhas, sendo que cada espécie exige requisitos específicos para ocorrência do processo germinativo. Objetivou-se avaliar as espécies infestantes e o fluxo de emergência de plantas daninhas em área de coxilha, quando submetidas a diferentes condições ambientais de temperatura e luz. Realizaram-se dois experimentos em delineamento inteiramente casualizado, com quatro repetições. No primeiro experimento os tratamentos foram definidos por cobertura com filme plástico (sem filme, filme somente em cima, parcialmente fechado e totalmente fechado) e, no segundo, por coberturas de polietileno preto (0; 35; 50; e 80%). A emergência de plantas daninhas na área foi monitorada diariamente, até estabelecimento do fluxo de emergência. Realizou-se também o monitoramento da temperatura do solo, interceptação da radiação solar e umidade do solo. Para a análise das espécies em cada tipo e nível de cobertura foram calculados os parâmetros fitossociológicos e o índice de velocidade de emergência. Os dados obtidos foram submetidos à análise de covariância e quando significativo procedeu-se o teste de Tukey (p≤0,05). Foi realizada análise de grupamento hierárquico para relacionar os fatores e os níveis experimentais aos intervalos da distribuição das covariáveis climáticas. O aumento em 8,5°C na temperatura do solo favorece a emergência de milhã, enquanto que reduz a emergência de papuã, corriola, picão-preto e guanxuma. As principais espécies a se adaptar as condições de redução da temperatura e radiação solar são guanxuma, papuã e milhã, sendo que a redução da radiação aumenta a frequência das espécies magnoliopsidas e proporciona o estabelecimento mais rápido de todas as espécies.

Two-tailed asymptotic inferences for the odds ratio in cross-sectional studies: evaluation of fifteen old and new methods of inference.

Various asymptotic methods of obtaining a confidence interval (CI) for the odds ratio (OR) have been proposed. Surprisingly, insofar as we know, the behavior of these methods has not been evaluated for data proceeding from a cross-sectional study (multinomial sampling), but only for data that originate in a prospective or retrospective study (two independent binomials sampling). The paper evaluates 15 different methods (10 classic ones and 5 new ones). Because the CI is obtained by inversion in θ of the two-tailed test for H0(θ): OR =[Formula: see text] (null hypothesis), this paper evaluates the tests for various values of θ, more than the CIs that are obtained. The following statements are valid only for the two-tailed inferences based on 20 ≤ n ≤ 200 and 0.05≤ OR≤20, since these are the limitations of the study. The two best methods are the classic Cornfield chi-squared method for 0.2≤ OR≤5 and, in other cases, the new method of Sterne for chi-squared; but the adjusted likelihood ratio method is a good alternative to the two previous methods, especially to the first when the sample size is large. The three methods require iterative calculations to obtain the CI. If one is looking for methods that are simple to apply (that is, ones that admit a simple, explicit solution), the best option is the Gart logit method for 1/3≤ OR≤3 and, if in other cases, the Agresti logit method. The Cornfield chi-squared and Gart logit methods should not be used outside the specified interval OR. The paper also selects the best methods for realizing the classic independence test (θ = 1).

Sesgo de muestreo y sus implicaciones en la evaluación a personas con riesgo genético de padecer esquizofrenia / Sampling bias and its implications in the evaluation of the population with genetic risk for schizophrenia

La esquizofrenia es considerada como un trastorno mental heterogéneo que abarca amplios rangos de expresión perceptiva, cognoscitiva, emocional, funcional, estructural y del comportamiento, que además se vincula a una importante susceptibilidad genética. Es por ello que investigar sobre esta enfermedad implique seleccionar cuidadosamente a la población de estudio para un adecuado análisis y generalización de los resultados. Este trabajo se propone exponer y discutir diversos sesgos de muestreo basados en evidencias empíricas que resultan, esencialmente, de la inclusión indiscriminada y generalizada de individuos en riesgo y de pacientes con esquizofrenia y/o trastornos relacionados, intentando proponer criterios de selección muestral más estrictos que garanticen una generalización confiable de los resultados. Consecuentemente, reflexionamos en particular sobre la relación entre pacientes con esquizofrenia y sus familiares de primer grado, debido a su similitud genética y las ventajas que esta ofrece para evaluar diversos factores ambientales vinculados a la aparición de la enfermedad

Schizophrenia is considered a heterogeneous mental disorder that encompasses wide ranges of perceptual, cognitive, emotional, functional, structural, and behavioural expressions, which is also associated with significant genetic susceptibility. For this reason, research on this disease involves carefully selecting the study population to perform an adequate analysis and generalisation of the results. This paper proposes to present and discuss various sampling biases based on empirical evidence that mainly result from the indiscriminate and widespread inclusion of at-risk individuals and patients with schizophrenia and/or related disorders, and at the same time trying to propose more stringent sample selection criteria that guarantee reliable results. Consequently, particularly focus is made on the relationship between patients with schizophrenia and their first-degree relatives, due to their genetic similarity and the advantages it offers to evaluate various environmental factors linked to the onset of the disease

Hubert's multi-rater kappa revisited.

There is a frequent need to measure the degree of agreement among R observers who independently classify n subjects within K nominal or ordinal categories. The most popular methods are usually kappa-type measurements. When R = 2, Cohen's kappa coefficient (weighted or not) is well known. When defined in the ordinal case while assuming quadratic weights, Cohen's kappa has the advantage of coinciding with the intraclass and concordance correlation coefficients. When R > 2, there are more discrepancies because the definition of the kappa coefficient depends on how the phrase 'an agreement has occurred' is interpreted. In this paper, Hubert's interpretation, that 'an agreement occurs if and only if all raters agree on the categorization of an object', is used, which leads to Hubert's (nominal) and Schuster and Smith's (ordinal) kappa coefficients. Formulae for the large-sample variances for the estimators of all these coefficients are given, allowing the latter to illustrate the different ways of carrying out inference and, with the use of simulation, to select the optimal procedure. In addition, it is shown that Schuster and Smith's kappa coefficient coincides with the intraclass and concordance correlation coefficients if the first coefficient is also defined assuming quadratic weights.

Sex-Specific Impact of Changes in Job Status on Suicidal Ideation.

Background: Around the globe, 800,000 people die from suicide every year. Despite being one of the leading causes of death, suicide remains a low public health priority. Korea has the second highest total suicide rate among Organisation for Economic Co-operation and Development (OECD) countries. Aims: The aim of this study was to explore how changes of job status influence suicidal risk in Korea, which lags behind other OECD countries in job security because temporary and part-time jobs are more prevalent in Korea. Method: We made use of a large longitudinal dataset, the Korea Health Panel (KHP). Results: Our findings revealed that a negative change in employment status increased the risk of suicide, but only for males. Limitations: Some individuals might intentionally change their job status, but the data do not indicate why the job status of an individual changes. Conclusion: These findings provide useful insights regarding the Korean labor market. In particular, tackling the issue of job stability, providing training polices for the unemployed and under-employed, and considering social insurance schemes may help to reduce suicide risk.