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Abstract The druggable proteome refers to proteins that can bind to small molecules with appropriate chemical affinity, inducing a favorable clinical response. Predicting druggable proteins through screening and in silico modeling is imperative for drug design. To contribute to this field, we developed an accurate predictive classifier for druggable cancer-driving proteins using amino acid composition descriptors of protein sequences and 13 machine learning linear and non-linear classifiers. The optimal classifier was achieved with the support vector machine method, utilizing 200 tri-amino acid composition descriptors. The high performance of the model is evident from an area under the receiver operating characteristics (AUROC) of 0.975 ± 0.003 and an accuracy of 0.929 ± 0.006 (threefold cross-validation). The machine learning prediction model was enhanced with multi-omics approaches, including the target-disease evidence score, the shortest pathways to cancer hallmarks, structure-based ligandability assessment, unfavorable prognostic protein analysis, and the oncogenic variome. Additionally, we performed a drug repurposing analysis to identify drugs with the highest affinity capable of targeting the best predicted proteins. As a result, we identified 79 key druggable cancer-driving proteins with the highest ligandability, and 23 of them demonstrated unfavorable prognostic significance across 16 TCGA PanCancer types: CDKN2A, BCL10, ACVR1, CASP8, JAG1, TSC1, NBN, PREX2, PPP2R1A, DNM2, VAV1, ASXL1, TPR, HRAS, BUB1B, ATG7, MARK3, SETD2, CCNE1, MUTYH, CDKN2C, RB1, and SMARCA4. Moreover, we prioritized 11 clinically relevant drugs targeting these proteins. This strategy effectively predicts and prioritizes biomarkers, therapeutic targets, and drugs for in-depth studies in clinical trials. Scripts are available at https://github.com/muntisa/machine-learning-for-druggable-proteins .

Introducción: el niño al que se diagnostica una enfermedad como el cáncer se enfrenta a un amplio espectro de emociones: miedo, ira, soledad, depresión o ansiedad. Su nivel de desarrollo va a determinar la naturaleza del impacto emocional del cáncer y las estrategias que empleará para afrontar la enfermedad. Objetivo: examinar las repercusiones psicológicas del cáncer infantil y las principales intervenciones que los psicólogos pueden aplicar al paciente oncológico y su familia durante el diagnóstico, el curso de la enfermedad y el tratamiento médico. Método: se realizó una revisión en febrero del 2024 donde se obtuvo la información a través de la búsqueda online en SciELO, Google Académico y revistas de acceso abierto, donde se seleccionaron 32 artículos en idioma español e inglés. Resultado: la atención psicológica es un componente esencial del tratamiento integral del cáncer infantil. Es necesario comprender las necesidades emocionales y psicológicas del paciente y su entorno, por lo que se debe proporcionar un espacio seguro para que el niño exprese sus miedos, ansiedades y esperanzas, así como enseñar estrategias para manejar el estrés, la ansiedad y el dolor. Conclusiones: las características de la enfermedad y los efectos secundarios de los tratamientos pueden alterar de forma significativa la vida del niño y de su familia, por lo que se enfatiza la importancia de intervenir para reducir el impacto emocional del cáncer y facilitar la adaptación del enfermo y sus familiares a la nueva situación.

Objective: To describe a variation in the final osteosynthesis technique for total ankle replacement (TAR) implantation through lateral approach. Methods: We retrospectively reviewed a series of cases dated between January 2022 and May 2023 in which intramedullary nailing was used as the osteosynthesis technique for the fibula during TAR implantation via lateral approach. Results: In all cases, skin scarring and soft tissue recovery to baseline were achieved in one and a half month to three months. Consolidation of the fibula occurred at an average of three months. No material was removed in any of the cases to date. Finally, patients were satisfied, resuming their previous activities. Conclusion: To our knowledge, this study is the first to investigate a modification of the osteosynthesis technique in the lateral approach to TAR. We believe the intramedullary nail for the fibula may be a useful tool to prevent soft tissue complications, requiring prospective and comparative studies to evaluate its efficacy. Level of Evidence IV; Therapeutic Studies; Case Series.

Objectives To explore the relationship between physical activity over a 10-year period and current symptoms of insomnia, daytime sleepiness and estimated sleep duration in adults aged 39–67.Design Population-based, multicentre cohort study.Setting 21 centres in nine European countries.Methods Included were 4339 participants in the third follow-up to the European Community Respiratory Health Survey (ECRHS III), who answered questions on physical activity at baseline (ECRHS II) and questions on physical activity, insomnia symptoms, sleep duration and daytime sleepiness at 10-year follow-up (ECRHS III). Participants who reported that they exercised with a frequency of at least two or more times a week, for 1 hour/week or more, were classified as being physically active. Changes in activity status were categorised into four groups: persistently non-active; became inactive; became active; and persistently active.Main outcome measures Insomnia, sleep time and daytime sleepiness in relation to physical activity.Results Altogether, 37% of participants were persistently non-active, 25% were persistently active, 20% became inactive and 18% became active from baseline to follow-up. Participants who were persistently active were less likely to report difficulties initiating sleep (OR 0.60, 95% CI 0.45–0.78), a short sleep duration of ≤6 hours/night (OR 0.71, 95% CI 0.59–0.85) and a long sleep of ≥9 hours/night (OR 0.53, 95% CI 0.33–0.84) than persistently non-active subjects after adjusting for age, sex, body mass index, smoking history and study centre. Daytime sleepiness and difficulties maintaining sleep were not related to physical activity status.Conclusion Physically active people have a lower risk of some insomnia symptoms and extreme sleep durations, both long and short.

La enfermedad IgA lineal se trata de un trastorno autoinmune poco frecuente. En la infancia aparece sobre todo en edad preescolar, y en adultos es necesario realizar un buen diagnóstico diferencial con otras enfermedades ampollosas como la dermatitis herpetiforme o el penfigoide ampollar. Hasta un cuarto de los casos se relacionan con infecciones o con la toma de medicamentos entre los que destacan antibióticos y antiinflamatorios no esteroideos. El diagnóstico se basa en la clínica, biopsia cutánea e inmunofluorescencia. Típicamente se presenta como ampollas anulares tensas de morfología anular con imagen característica en collar de perlas. Al realizar el estudio de inmunofluorescencia directa se evidencia una banda lineal de IgA en la unión dermoepidérmica. Suele responder de forma completa a la retirada del fármaco causante y al tratamiento con Dapsona oral y glucocorticoides tópicos.

Abstract Background Migraine is one of the most prevalent and disabling medical diseases in the world. The periaqueductal gray matter and the red nucleus play an important role in its pathogenesis. Our aim was to evaluate the echogenicity of the periaqueductal gray matter and the red nucleus in patients with migraine, by means of transcranial ultrasound. Methods In this cross-sectional study, a group of patients with migraine (according to the International Classification of Headache Disorders) and a group of control subjects with comparable age-and-sex distribution were prospectively included. We evaluated the area and echogenicity of the periaqueductal gray matter and the red nucleus by means of transcranial ultrasound, both bedside and posteriorly analyzed with the medical image viewer Horos. Results We included 115 subjects: 65 patients with migraine (39 of them with chronic migraine and 26 with episodic migraine), and 50 controls. Median disease duration in patients with chronic migraine was 29 (IQR: 19; 40) years, with a median of 18 (IQR: 14; 27) days of migraine per month. The area of the periaqueductal gray matter was larger in patients with chronic migraine compared to episodic migraine and controls (0.15[95%CI 0.12;0.22]cm2; 0.11[95%CI 0.10;0.14]cm2 and 0.12[95%CI 0.09;0.15]cm2, respectively; p = 0.043). Chronic migraine patients showed an intensity of the periaqueductal gray matter echogenicity lower than controls (90.57[95%CI 70.87;117.26] vs 109.56[95%CI 83.30;122.64]; p = 0.035). The coefficient of variation of periaqueductal gray matter echogenicity was the highest in chronic migraine patients (p = 0.009). No differences were observed regarding the area or intensity of red nucleus echogenicity among groups. Conclusion Patients with chronic migraine showed a larger area of echogenicity of periaqueductal gray matter, a lower intensity of its echogenicity and a higher heterogenicity within this brainstem structure compared to patients with episodic migraine and controls. The echogenicity of the periaqueductal gray matter should be further investigated as a biomarker of migraine chronification.

Abstract Purpose This study used cone-beam computed tomography (CBCT) to analyze the prevalence of several maxillary anatomical/accessory structures, as well as variations within each type, assessing how accurate diagnosis can minimize the risk of intraoperative complications during implantological procedures in the oral cavity. Methods 212 CBCT scans of the maxilla were analyzed, captured over a period of 18 months for surgical planning purposes. The prevalence of posterior superior alveolar arteries (PSAA), maxillary sinus septa (MSS), and branches of the canalis sinuosus (CS) were evaluated, as were the diameter and location of each anatomical structure in horizontal and vertical planes. P

El síndrome de la bolsa de orina violeta es una entidad poco frecuente pero muy característica. Consiste en el cambio de coloración de la orina en la bolsa en pacientes portadores de sonda urinaria y en el contexto de una infección urinaria por determinados gérmenes. Esta coloración tan llamativa se produce por interacción entre pigmentos de índigo y/o indirrubina producidos por ciertas bacterias con los materiales sintéticos de la sonda y bolsa de orina. Presentamos un caso en el que ocurre este fenómeno.

During the COVID-19 pandemic, there were reports of heightened levels of anxiety and fear of contagion in the general population. Such psychological responses may be influenced by the socio-environmental context in which individuals reside. This study aimed to examine the relationship between socioeconomic and educational factors and the level of anxiety and fear related to COVID-19. A multicenter, cross-sectional design was used, including patients aged 18 years or older who attended primary care physician consultations at various primary health centers in Toledo, Spain, between October 2020 and January 2021. By means of a non-probabilistic sampling, a total of 150 participants were selected for the study, with 146 of them providing responses to the AMICO questionnaire The level of fear and anxiety associated with COVID-19 was assessed using the validated Anxiety and Fear of COVID-19 Assessment Scale (AMICO). A significant linear relationship was revealed between social class, employment status, and anxiety levels. Specifically, as social class decreased (p = 0.001) and employment situation worsened (unemployment) (p = 0.037), the proportion of participants reporting a high level of anxiety increased. During the second phase of the pandemic, more than half of the patients attending family medicine consultations exhibited a high level of fear and anxiety towards COVID-19, which was significantly associated with lower social class and unemployment.

Abstract The screening of the BCR::ABL1 kinase domain (KD) mutation has become a routine analysis in case of warning/failure for chronic myeloid leukemia (CML) and B-cell precursor acute lymphoblastic leukemia (ALL) Philadelphia (Ph)-positive patients. In this study, we present a novel DNA-based next-generation sequencing (NGS) methodology for KD ABL1 mutation detection and monitoring with a 1.0E−4 sensitivity. This approach was validated with a well-stablished RNA-based nested NGS method. The correlation of both techniques for the quantification of ABL1 mutations was high (Pearson r = 0.858, p

Abstract The mammalian inner ear has a limited capacity to regenerate its mechanosensory hair cells. This lack of regenerative capacity underlies the high incidence of age-related hearing loss in humans. In contrast, non-mammalian vertebrates can form new hair cells when damage occurs, a mechanism that depends on re-activation of expression of the pro-hair cell transcription factor Atoh1. Here, we show that members of the E2F transcription factor family, known to play a key role in cell cycle progression, regulate the expression of Atoh1. E2F1 activates chicken Atoh1 by directly interacting with a cis-regulatory region distal to the avian Atoh1 gene. E2F does not activate mouse Atoh1 gene expression, since this regulatory element is absent in mammals. We also show that E2F1 expression changes dynamically in the chicken auditory epithelium during ototoxic damage and hair cell regeneration. Therefore, we propose a model in which the mitotic regeneration of non-mammalian hair cells is due to E2F1-mediated activation of Atoh1 expression, a mechanism which has been lost in mammals.

Lamellar ichthyosis (LI) is a genodermatosis that injures the structure and function of the skin, affecting the appearance and self-esteem of patients, which may seriously impair their mental health and quality of life. In the present study, we determined anxiety, depression, and suicidal risk levels in patients with LI through the Beck anxiety and depression inventories (BAI and DBI-II, respectively) and the SAD PERSONS scale (SPS). We observed that anxiety, depression, and suicidal ideation were strongly associated with the LI (Cramér’s V = 0.429, 0.594, and 0.462, respectively). Furthermore, patients with LI showed a significant increase in the scores of anxiety, depression, and suicidal risk (p = 0.011, p = 0.02). Similarly, the increase in the BAI scores correlated with the score observed on the SPS. Our results indicate that patients with LI have higher levels of anxiety and depression compared to individuals without the disease, which could be associated with suicidal risk. Therefore, the collaborative involvement of skin and mental health professionals is necessary to manage patients with LI appropriately. We believe that psychiatric studies and individual evaluations must be performed in LI patients to determine a treatment that, in addition to reducing skin symptoms, focuses on reducing the levels of depression and anxiety and improving the quality of life to reduce the risk of suicide.

Abstract Silicosis is a diffuse interstitial lung disease caused by sustained inhalation of silica and silicates. Several cytokines are activated by their inhalation and can mediate the process of pulmonary fibrosis. The identification of biomarkers could allow an early diagnosis before the development of radiological alterations and help monitor the evolution of patients. The objetive of this study was to determine the clinical significance of specific biomarkers, to estimate their association with the development, severity and/or progression of silicosis, and identify determinants of this evolution. We conducted a prospective observational study in patients attending the pulmonology clinic from 2009 to 2018. Serum levels of the following inflammatory mediators were assessed: interleukin-6 (IL-6), interleukin 2 receptor subunit alpha (IL2R) interleukin 1 beta (IL1B), interleukin-8 (IL-8), tumour necrosis factor-alpha (TNF-α), transforming growth factor-beta1 (TGF-β1), alpha-1 antitrypsin (AAT), C-reactive protein (CRP), lactate dehydrogenase (LDH) and ferritin in subjects exposed to silica, with and without silicosis. Association between those inflammatory mediators with lung function measurements and radiological severity of disease and their impact on prognosis were analysed. 337 exposed to silica (278 with silicosis) and 30 subjects in the control group were included. IL-8, α1AT, ferritin, CRP and LDH levels were higher in silicosis than in those exposed to silica without silicosis. IL-8, LDH and AAT levels were associated with progression of silicosis and IL-6, IL-8, LDH, AAT, ferritin, and CRP with vital status. The results of the ROC analysis indicated the potential of IL-8 as a biomarker in the presence of silicosis and for the prediction of mortality.

Background: It is crucial to understand the benefits to human health from decarbonisation to galvanise action among decision makers. Most of our existing evidence comes from modelling studies and little is known about the extent to which the health co-benefits of climate change mitigation actions are realised upon implementation. We aim to analyse evidence from mitigation actions that have been implemented across a range of sectors and scales, to identify those that can improve and sustain health, while accelerating progress towards a zero-carbon economy. Objectives: To understand the implementation process of actions and the role of key actors; explain the contextual elements influencing these actions; summarise what effects, both positive and negative, planned and unplanned they may have on emissions of greenhouse gases and health; and to summarise environmental, social, or economic co-benefits. Data: We will review evidence collected through partnership with existing data holders and an open call for evidence. We will also conduct a hand search of reference lists from systematic reviews and websites of organisations relevant to climate change mitigation. Screening: Screening will be done by two reviewers according to a pre-defined inclusion and exclusion criteria. Analysis: We will identify gaps where implementation or evaluation of implementation of mitigation actions is lacking. We will synthesise the findings to describe how actions were implemented and how they achieved results in different contexts, identifying potential barriers and facilitators to their design, implementation, and uptake. We will also synthesise their effect on health outcomes and other co-benefits. Quantitative synthesis will depend on the heterogeneity of outcomes and metrics. Conclusions: Findings will be used to identify lessons that can be learned from successful and unsuccessful mitigation actions, to make inferences on replicability, scalability, and transferability and will contribute to the development of frameworks that can be used by policy makers.

Introduction In Mexico, a new COVID-19 case definition was released on 24 March 2020, this definition is no different from the one used for epidemiological surveillance of influenza-like illness since 2009. We aim to evaluate the effectiveness of the COVID-19 suspected case definition in identifying SARS-CoV-2 infection in Tijuana, a US-border city in Mexico. Methods A cross-sectional database study was conducted, including entries from 11 March to 1 May 2020. COVID-19 case definition was compared to RT-PCR results using 2×2 tables to estimate sensitivity, specificity, PPV, NPV, accuracy and likelihood ratios (LR). Categorical variables were analyzed using χ 2 test. Stratification by gender, age group, history of chronic disease and severity of presentation was performed to control for confounding. Results From a total of 10216 entries, 897 patients with results from RT-CPR for SARS-CoV-2 were included. There was no significant association between COVID-19 case definition and RT-PCR result (χ 2 =0.750, df=1, p=0.386). A sensitivity of 87.45%, specificity of 10.61%, PPV of 61.69%, and NPV of 33.96% were calculated, with an overall accuracy of 58.42%, LR+ was 0.98 and LR- was 1.18. Stratifying by age, homogeneity of OR=0.024 showed an association between case definition and test result particularly among those aged 16-39 years (p=0.014). Only 4 individual symptoms had a statistical association with RT-PCR result. These were dyspnea (p

Abstract Background Thyroid eye disease is an autoimmune disorder of the orbital retrobulbar tissue commonly associated with dysthyroid status. The most frequent condition is hyperthyroidism, although it is also present in hypothyroid and euthyroid patients. The prevalence of thyroid conditions in patients with thyroid eye disease had been previously evaluated; however, there is no consensus on a global prevalence. The study aims to estimate the prevalence of hyperthyroidism, hypothyroidism, and euthyroidism in patients with TED, through a systematic review of literature. Methods We conducted a systematic review of the literature following the PRISMA guidelines, in MEDLINE, COCHRANE, EMBASE, Science Direct, and LILACS databases. Inclusion criteria were primary studies of patients with a diagnosis of thyroid eye disease made by an ophthalmologist or with diagnosis criteria, with measurement of thyroid function (TSH, T3, and free T4), and diagnosis of the primary thyroid condition. A quality assessment was made through the Joanna Briggs Institute Quality tools. Finally, we extracted relevant details about the design, the results, and the prevalence of thyroid disorders in thyroid eye disease. Results The initial search revealed 916 studies, of which finally thirteen met inclusion criteria. Six studies were performed in Europe (Germany, Wales, and Spain), five in Asia (Iran, South Korea, Japan, and Singapore), one in North America (USA), and one in Africa (Ghana). The global prevalence, in patients of thyroid eye disease, was 10.36% for hypothyroidism, 7.9% for euthyroidism, and 86.2% for hyperthyroidism. Conclusions Professionals should be aware that thyroid eye disease can be present in patients with a normal thyroid function. The assessment for these patients is based on orbital images; serum TSH, T3, and free T4; antibody levels as thyrotropin receptor antibodies; and thyroperoxidase levels. Additionally, we want to encourage research in this field in other regions of the world such as Latin America. Systematic review registration PROSPERO ID CRD42020107167

Resumen Introducción y objetivo Los cambios anatómicos faciales que resultan como consecuencia del envejecimiento son uno de los principales motivos de consulta en Cirugía Estética facial. Nos proponemos determinar los cambios histológicos secundarios a la aplicación de carboxiterapia previa a la ritidoplastia, tomando en cuenta la aceptación de los pacientes en relación a mejora en la calidad de su piel facial tras el tratamiento. Material y método Aplicamos 10 sesiones de carboxiterapia facial 5 semanas antes de la intervención quirúrgica de ritidoplastia. Infiltramos el dióxido de carbono por vía percutánea alrededor de cara y cuello a excepción de las regiones pre y postauriculares derechas. La ritidpolastia fue realizada por diferentes cirujanos y codificamos y analizamos las muestras de piel tomadas de las áreas pre y postauriculares Resultados Llevamos a cabo el estudio en 7 pacientes. Histología: la disposición de las fibras de colágeno fue en espiral y nódulos en la zona preauricular derecha (área no tratada), mientras que en la zona preauricular izquierda la disposición de colágeno fue lineal, diferencia estadísticamente significativa (p=0.0052). La proliferación de tejido celular subcutáneo en la zona preauricular izquierda disminuyó de una manera evidente (p=0.03), mientras que el área postauricular no presentó este fenómeno (p=0.10). Conclusiones La carboxiterapia previa a la cirugía de ritidoplastia es un procedimiento seguro, que en nuestro estudio no prolongó el tiempo quirúrgico ni aumentó la respuesta inflamatoria. Los cambios histológicos hallados demostraron cambios en la disposición del colágeno en las áreas tratadas, con mayor elasticidad de la piel. Hubo también disminución en la proliferación celular en el área que recibió carboxiterapia sin alteración de la estructura de la dermis.

Objetivo: Describir las características demográficas y la proporción de sujetos sometidos a cirugía cardiovascular (CCV), que requieren ventilación mecánica prolongada (VMP) y analizar los factores asociados al desarrollo de dicha entidad. Materiales y método: Serie de casos. Se incluyeron sujetos mayores de 18 años que requirieron una CCV a través de esternotomía, entre julio de 2017 y noviembre de 2018. Se excluyeron sujetos con datos faltantes y se eliminaron quienes fallecieron durante la cirugía. Se llevó a cabo un análisis de regresión logística para determinar las variables predictoras de la ocurrencia de VMP. Resultados: De 70 sujetos analizados, 17,1% requirió VMP, cuya mortalidad fue de 41,7%. En el análisis univariado la obesidad, días de internación, tiempo de cirugía, necesidad de circulación extracorpórea (CEC), desarrollo de complicaciones posoperatorias (POP) y puntaje del score Sequential Organ Failure Assessment (SOFA) en el posquirúrgico inmediato, se asociaron significativamente a VMP. Conclusión: La proporción de sujetos con requerimiento de VMP fue superior a lo reportado en la literatura. El tiempo de cirugía, el SOFA en el POP inmediato, obesidad, necesidad de CEC, días de internación y desarrollo de complicaciones POP se asociaron con VMP.

Background Atrial fibrillation (AF) remain a prevalent undiagnosed condition frequently encountered in primary care. Objective We aimed to find the parameters that optimize the diagnostic accuracy of pulse palpation to detect AF. We also aimed to create a simple algorithm for selecting which individuals would benefit from pulse palpation and, if positive, receive an ECG to detect AF. Methods Nurses from four Cardiology outpatient clinics palpated 7,844 pulses according to a randomized list of arterial territories and durations of measure and immediately followed by a 12-lead ECG, which we used as the reference standard. We calculated the sensitivity and specificity of the palpation parameters. We also assessed whether diagnostic accuracy depended on the nurse’s experience or on a list of clinical factors of the patients. With this information, we estimated the positive predictive values and false omission rates according to very few clinical factors readily available in primary care (age, sex, and diagnosis of heart failure) and used them to create the algorithm. Results The parameters associated with the highest diagnostic accuracy were palpation of the radial artery and classifying as irregular those palpations in which the nurse was uncertain about pulse regularity or unable to palpate pulse (sensitivity = 79%; specificity = 86%). Specificity decreased with age. Neither the nurse’s experience nor any investigated clinical factor influenced diagnostic accuracy. We provide the algorithm to select the ≥40 years old individuals that would benefit from a pulse palpation screening: a) do nothing in Conclusions Opportunistic screening for AF using optimal pulse palpation in candidate individuals according to a simple algorithm may have high effectiveness in detecting AF in primary care.

Variation in floral displays, both between and within species, has been long known to be shaped by the mutualistic interactions that plants establish with their pollinators. However, increasing evidence suggests that abiotic selection pressures influence floral diversity as well. Here, we analyse the genetic and environmental factors that underlie patterns of floral pigmentation in wild sunflowers. While sunflower inflorescences appear invariably yellow to the human eye, they display extreme diversity for patterns of ultraviolet pigmentation, which are visible to most pollinators. We show that this diversity is largely controlled by cis-regulatory variation affecting a single MYB transcription factor, HaMYB111, through accumulation of ultraviolet (UV)-absorbing flavonol glycosides in ligules (the ‘petals’ of sunflower inflorescences). Different patterns of ultraviolet pigments in flowers are strongly correlated with pollinator preferences. Furthermore, variation for floral ultraviolet patterns is associated with environmental variables, especially relative humidity, across populations of wild sunflowers. Ligules with larger ultraviolet patterns, which are found in drier environments, show increased resistance to desiccation, suggesting a role in reducing water loss. The dual role of floral UV patterns in pollinator attraction and abiotic response reveals the complex adaptive balance underlying the evolution of floral traits.

Abstract Despite many cardioprotective interventions have shown to protect the heart against ischemia/reperfusion injury in the experimental setting, only few of them have succeeded in translating their findings into positive proof-of-concept clinical trials. Controversial and inconsistent experimental and clinical evidence supports the urgency of a disruptive paradigm shift for testing cardioprotective therapies. There is a need to evaluate experimental reproducibility before stepping into the clinical arena. The CIBERCV (acronym for Spanish network-center for cardiovascular biomedical research) has set up the “Cardioprotection Large Animal Platform” (CIBER-CLAP) to perform experimental studies testing the efficacy and reproducibility of promising cardioprotective interventions based on a pre-specified design and protocols, randomization, blinding assessment and other robust methodological features. Our first randomized, control-group, open-label blinded endpoint experimental trial assessing local ischemic preconditioning (IPC) in a pig model of acute myocardial infarction (n = 87) will be carried out in three separate sets of experiments performed in parallel by three laboratories. Each set aims to assess: (A) CMR-based outcomes; (B) histopathological-based outcomes; and (C) protein-based outcomes. Three core labs will assess outcomes in a blinded fashion (CMR imaging, histopathology and proteomics) and 2 methodological core labs will conduct the randomization and statistical analysis.

Objetivo de este trabajo fue demostrar la utilidad de la Evaluación Clínica Neonatal utilizando el CANS SCORE (Evaluación Clínica del Estado Nutricional), desarrollado y publicado por Mettcoff en 1994. Métodos Se realizó un estudio piloto transversal de marzo a junio de 2018, en el Hospital de Cochabamba nivel II, seleccionando 50 recién nacidos a término que presentasen signos clínicos para desnutrición según la escala de Mettcoff. Se realizaron mediciones antropométricas completas y exámenes de parámetros de laboratorio relacionados. Se utilizaron comparaciones de medias y regresiones logísticas con valores del score-Z calculado mediante la herramienta Intergrowth- 21st, para evaluar los datos. Resultados Se encontraron diferencias estadísticamente significativas entre los parámetros antropométricos básicos evaluados como peso, talla, perímetro cefálico. Además, la evaluación mediante la escala de Mettcoff permitió la detección de DESNUTRICIÓN FETAL en recién nacidos que de otra manera se clasificarían como de peso adecuado para la Edad Gestacional (AEG). En el laboratorio los hallazgos fueron: disminución o aumento de las concentraciones de algunos de los parámetros bioquímicos evaluados; los más llamativos fueron la disminución de los niveles de albúmina sérica; también disminución de las concentraciones de calcio en el 100% de la población estudiada y una elevación sistemática de los valores de creatinina en la mayoría del 80% de los casos. Conclusiones El puntaje CANS es una herramienta clínica útil, sencilla y de fácil aplicación que permite identificar con mayor precisión el grado de desnutrición en recién nacidos y podría validarse estadísticamente en series más amplias y estudios sistemáticos.

Dermal fillers are applied using a minimally invasive technique with a good safety profile. However, they can have side effects. We present the case of a patient who, 2 months after undergoing polycaprolactone (Ellansé®) injections, developed nodular facial and nodal lesions that were compatible with sarcoidosis on histology. This complication has not been previously described for polycaprolactone and could be the expression of an autoimmune syndrome induced by adjuvants.

Background: Identification of signaling pathways altered at early stages after cardiac ischemia/reperfusion (I/R) is crucial to develop timely therapies aimed at reducing I/R injury. The expression of G protein-coupled receptor kinase 2 (GRK2), a key signaling hub, is up-regulated in the long-term in patients and in experimental models of heart failure. However, whether GRK2 levels change at early time points following myocardial I/R and its functional impact during this period remain to be established. Methods: We have investigated the temporal changes of GRK2 expression and their potential relationships with the cardioprotective AKT pathway in isolated rat hearts and porcine preclinical models of I/R. Findings: Contrary to the maladaptive up-regulation of GRK2 reported at later times after myocardial infarction, successive GRK2 phosphorylation at specific sites during ischemia and early reperfusion elicits GRK2 degradation by the proteasome and calpains, respectively, thus keeping GRK2 levels low during early I/R in rat hearts. Concurrently, I/R promotes decay of the prolyl-isomerase Pin1, a positive regulator of AKT stability, and a marked loss of total AKT protein, resulting in an overall decreased activity of this pro-survival pathway. A similar pattern of concomitant down-modulation of GRK2/AKT/Pin1 protein levels in early I/R was observed in pig hearts. Calpain and proteasome inhibition prevents GRK2/Pin1/AKT degradation, restores bulk AKT pathway activity and attenuates myocardial I/R injury in isolated rat hearts. Interpretation: Preventing transient degradation of GRK2 and AKT during early I/R might improve the potential of endogenous cardioprotection mechanisms and of conditioning strategies. Keywords: GRK2, AKT, Ischemia-reperfusion, Cardioprotection, Pin1, Proteasome, Calpains

Introduction: Timely diagnosis and treatment of gestational diabetes (GD), as well as adequate control of associated risk factors, allows reducing its negative impact on maternal and perinatal health. Objectives: To determine the prevalence of GD in a tertiary care hospital in Colombia and identify the risk factors associated with this condition, as well as the maternal-perinatal outcomes in this population, following the implementation of the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. Materials and methods: Cross-sectional study in which a secondary data analysis was carried out. By means of consecutive sampling, 533 pregnant women with GD who gave birth at the Hospital Universitario San José in Popayán, Colombia, between July 2017 and March 2018, were included. Social, biological, and psychological variables were analyzed. To identify risk factors and associated maternal-perinatal outcomes, the Odds Ratio was used as a measure of association (CI:95%). In addition, a multivariate analysis was performed to control for confounding factors. Results: The prevalence of GD was 16.32% (95%CI:13.28-19.73). The following risk factors associated with GD were identified: age >35 (OR=2.26; 95%CI:1.23-4.14), indigenous race (OR=6.60; 95%CI:1.17-37.15), BMI >25 (OR=2. 26; 95%CI:1.23-4.14), history of fetal macrosomia (OR=10.07; 95%CI: 1.50-67.34), and family history of diabetes mellitus (OR=3.17; 95%CI:1.39-7.22). Regarding maternal-perinatal outcomes, a significant association was found with labor induction (OR=4.41; 95%CI:1.71-11.39), emergency cesarean section (OR=2.22; 95%CI:1.33-3.73), elective cesarean section (OR=2.79; 95%CI:1.51-5.18), fetal weight >90th percentile (OR=2.78; 95%CI:1.29-5.98), and neonatal hospitalization (OR=8.1; 95%CI:4.48-18.62). Conclusions: The prevalence of GD reported here is higher than the prevalence described in other studies conducted in Colombia, but similar to most studies that have followed the IADPSG criteria. Likewise, risk factors and maternal-perinatal outcomes that had a statistically significant association with GD here are similar to those described in most of the studies that were consulted.

BackgroundEfficient and early triage of hospitalized Covid-19 patients to detect those with higher risk of severe disease is essential for appropriate case management.MethodsWe trained, validated, and externally tested a machine-learning model to early identify patients who will die or require mechanical ventilation during hospitalization from clinical and laboratory features obtained at admission. A development cohort with 918 Covid-19 patients was used for training and internal validation, and 352 patients from another hospital were used for external testing. Performance of the model was evaluated by calculating the area under the receiver-operating-characteristic curve (AUC), sensitivity and specificity.ResultsA total of 363 of 918 (39.5%) and 128 of 352 (36.4%) Covid-19 patients from the development and external testing cohort, respectively, required mechanical ventilation or died during hospitalization. In the development cohort, the model obtained an AUC of 0.85 (95% confidence interval [CI], 0.82 to 0.87) for predicting severity of disease progression. Variables ranked according to their contribution to the model were the peripheral blood oxygen saturation (SpO2)/fraction of inspired oxygen (FiO2) ratio, age, estimated glomerular filtration rate, procalcitonin, C-reactive protein, updated Charlson comorbidity index and lymphocytes. In the external testing cohort, the model performed an AUC of 0.83 (95% CI, 0.81 to 0.85). This model is deployed in an open source calculator, in which Covid-19 patients at admission are individually stratified as being at high or non-high risk for severe disease progression.ConclusionsThis machine-learning model, applied at hospital admission, predicts risk of severe disease progression in Covid-19 patients.

Regionalization through the analysis of species groups offers important advantages in conservation biology, compared to the single taxon approach in areas of high species richness. We use a systematic framework for biogeographic regionalization at a regional scale based on species turnover and environmental drivers (climate variables and soil properties) mainly of herbaceous plant species richness. To identify phytogeographic regions in the Balsas Depression (BD), we use Asteraceae species, a family widely distributed in Seasonally Dry Tropical Forest (SDTF) and the most diverse of the vascular plants in Mexico. Occurrence records of 571 species were used to apply a quantitative analysis based on the species turnover, the rate of changes in their composition between sites (β-Simpson index) and the analysis of the identified environmental drivers. Also, the environmental predictors that influence species richness in the SDTF were determined with a redundancy analysis. We identified and named two phytogeographic districts within the SDTF of the BD (Upper Balsas and Lower Balsas). According to the multi-response permutation procedure, floristic composition of the two districts differs significantly, and the richness of exclusive species in Upper Balsas was higher (292 species) than in the Lower Balsas (32 species). The proportion of Mg and Ca in the soil and the precipitation of the driest three-month period were the environmental factors with greatest positive influence on species richness. The division of geographic districts subordinated to the province level, based on diverse families such as Asteraceae, proved to be appropriate to set up strategies for the conservation of the regional flora, since at this scale, variation in species richness is more evident. Our findings are consistent with a growing body of biogeographic literature that indicates that the identification of smaller biotic districts is more efficient for the conservation of biodiversity, particularly of endemic or rare plants, whose distribution responds more to microhabitats variation.

El uso de la manometría esofágica como subrogado de la presión pleural se encuentra ampliamente difundido en el campo de la investigación científica. Su valoración brinda información de relevancia en la totalidad de las fases de la ventilación mecánica, como así también durante la ventilación espontánea. Sin embargo, la baja disponibilidad de tecnología necesaria para la integración de las señales, las dificultades técnicas para la instrumentación y validación de los datos adquiridos y la experiencia necesaria para la correcta interpretación de la información hacen de la manometría esofágica una herramienta escasamente utilizada en la práctica clínica. Con objetivo de salvar algunas de las barreras para su implementación, en el presente paso a paso se describe la colocación del catéter esofágico y las estrategias para validación de la señal adquirida.

Macrophages (Mφs) produce factors that participate in cardiac repair and remodeling after myocardial infarction (MI); however, how these factors crosstalk with other cell types mediating repair is not fully understood. Here we demonstrated that cardiac Mφs increased the expression of Mmp14 (MT1-MMP) 7 days post-MI. We selectively inactivated the Mmp14 gene in Mφs using a genetic strategy (Mmp14f/f:Lyz2-Cre). This conditional KO (MAC-Mmp14 KO) resulted in attenuated post-MI cardiac dysfunction, reduced fibrosis, and preserved cardiac capillary network. Mechanistically, we showed that MT1-MMP activates latent TGFβ1 in Mφs, leading to paracrine SMAD2-mediated signaling in endothelial cells (ECs) and endothelial-to-mesenchymal transition (EndMT). Post-MI MAC-Mmp14 KO hearts contained fewer cells undergoing EndMT than their wild-type counterparts, and Mmp14-deficient Mφs showed a reduced ability to induce EndMT in co-cultures with ECs. Our results indicate the contribution of EndMT to cardiac fibrosis and adverse remodeling post-MI and identify Mφ MT1-MMP as a key regulator of this process.

Introducción: El edema por reexpansion pulmonar (ERP) ocurre debido a una rápida expansión pulmonar posterior al drenaje brusco de un derrame pleural de gran volumen. En casos severos puede desarrollarse hipoxemia refractaria. La ventilación pulmonar independiente y el posicionamiento son algunas de las estrategias propuestas. Debido a la similitud en su fisiopatología con el síndrome de distrés respiratorio agudo (SDRA). es posible que las intervenciones descritas para el sostén de pacientes con SDRA puedan resultar de utilidad. Sin embargo no hemos podido encontrar recomendaciones sobre su utilización en estos casos. El objetivo de esta presentación es describir las estrategias implementadas y los resultados obtenidos en un caso con ERP e hipoxemia refractaria. Presentación del caso: Joven de 24 años, que desarrolló ERP e hipoxemia refractaria durante el posoperatorio de cirugía de reemplazo valvular aórtico por un drenaje de un hemotórax masivo derecho. Se implementó una estrategia de ventilación protectora, monitorización de la mecánica pulmonar avanzada y posición prona. El paciente evolucionó favorablemente y el día 8 se logró extubar. Conclusión: Los resultados obtenidos permiten valorar la estrategia implementada como una alternativa a la ventilación pulmonar independiente en casos severos.

The nutritional and economic potentials of livestock systems are compromised by the emergence and spread of antimicrobial resistance. A major driver of resistance is the misuse and abuse of antimicrobial drugs. The likelihood of misuse may be elevated in low- and middle-income countries where limited professional veterinary services and inadequately controlled access to drugs are assumed to promote non-prudent practices (e.g., self-administration of drugs). The extent of these practices, as well as the knowledge and attitudes motivating them, are largely unknown within most agricultural communities in low- and middle-income countries. The main objective of this study was to document dimensions of knowledge, attitudes and practices related to antimicrobial use and antimicrobial resistance in livestock systems and identify the livelihood factors associated with these dimensions. A mixed-methods ethnographic approach was used to survey households keeping layers in Ghana (N = 110) and Kenya (N = 76), pastoralists keeping cattle, sheep, and goats in Tanzania (N = 195), and broiler farmers in Zambia (N = 198), and Zimbabwe (N = 298). Across countries, we find that it is individuals who live or work at the farm who draw upon their knowledge and experiences to make decisions regarding antimicrobial use and related practices. Input from animal health professionals is rare and antimicrobials are sourced at local, privately owned agrovet drug shops. We also find that knowledge, attitudes, and particularly practices significantly varied across countries, with poultry farmers holding more knowledge, desirable attitudes, and prudent practices compared to pastoralist households. Multivariate models showed that variation in knowledge, attitudes and practices is related to several factors, including gender, disease dynamics on the farm, and source of animal health information. Study results emphasize that interventions to limit antimicrobial resistance should be founded upon a bottom-up understanding of antimicrobial use at the farm-level given limited input from animal health professionals and under-resourced regulatory capacities within most low- and middle-income countries. Establishing this bottom-up understanding across cultures and production systems will inform the development and implementation of the behavioral change interventions to combat antimicrobial resistance globally.

Abstract Epidemiological studies have found a higher prevalence of allergic symptoms and positive prick tests in patients with Meniere’s disease (MD); however the effect of allergenic extracts in MD has not been established. Thus, this study aims to determine the effect of Aspergillus and Penicillium stimulation in cytokine release and gene expression profile in MD. Patients with MD showed higher basal levels of IL-1β, IL-1RA, IL-6 and TNF-α when compared to healthy controls. We observed that IL-1β levels had a bimodal distribution suggesting two different subgroups of patients, with low and high basal levels of cytokines. Gene expression profile in peripheral blood mononuclear cells (PBMC) showed significant differences in patients with high and low basal levels of IL-1β. We found that both mold extracts triggered a significant release of TNF-α in MD patients, which were not found in controls. Moreover, after mold stimulation, MD patients showed a different gene expression profile in PBMC, according to the basal levels of IL-1β. The results indicate that a subset of MD patients have higher basal levels of proinflammatory cytokines and the exposure to Aspergillus and Penicillium extracts may trigger additional TNF-α release and contribute to exacerbate inflammation.

Se presentó un caso de un paciente con colitis ulcerativa de varios años de evolución con un cuadro de oclusión intestinal por un adenocarcinoma de colon izquierdo. Durante el acto quirúrgico se constató la presencia de una tumoración en el ángulo esplénico del colon. Se realizó hemicolectomía izquierda con colostomía tipo Hartman.

La nefritis lúpica (NL) proliferativa es una de las complicaciones más graves del LES. La respuesta terapéutica con los esquemas clásicos no existe en el 20 al 70% de los casos, siendo la amplitud de dicho rango explicada por variaciones étnicas, falta de consenso en la definición de remisión, diferencias en los tiempos de tratamiento, seguimiento y en la clase de NL. En presencia de NL recidivante o refractaria los tratamientos y el nivel de evidencia sobre su eficacia son más limitados. Rituximab es un anticuerpo monoclonal quimérico (ratón-humano) dirigido contra el antígeno CD 20 localizado en la superficie celular de los linfocitos B. Estos participan en la patogénesis del LES a partir de su maduración en células plasmáticas, producción de anticuerpos, secreción de citoquinas proinflamatorias, presentación de autoantígenos a las células T y en la activación de células T. La administración de rituximab genera un rápido y sostenido descenso de los linfocitos B CD 20+ circulantes y una reducción de los títulos de auto-anticuerpos. Se reportó una disminución significativa en los niveles de antiDNA a partir de la semana 14 y de los niveles de IgM, sin compromiso de IgG ni de IgA. Se detectó droga activa en sangre periférica luego de la semana 24 de la última infusión. La depleción de linfocitos B se puede mantener por 6 meses, su reconstitución es heterogénea y puede tardar más de un año. Esta linfopenia selectiva tendría un valor predictivo de respuesta terapéutica, la remisión clínica prolongada tendría asociación con repoblación incompleta de células B de memoria varios años luego del tratamiento. En estudios observacionales realizados en pacientes con NL refractaria se reportó respuesta terapéutica con rituximab entre 67-77 % luego de 6 a 12 meses de seguimiento. Sin embargo los resultados del estudio Lupus Nephritis Assesment with Rituximab (LUNAR), randomizado controlado, a doble ciego, comparativo, rituximab + corticoides + micofenolato vs. corticoides + micofenolato + placebo, fueron menos alentadores ya que no logró demostrar superioridad en la rama rituximab tomando como objetivo primario la remisión parcial o total de la NL. No existe consenso sobre la dosis adecuada (375 mg/m²/ semana durante 4 sesiones o 1 g cada 2 semanas en 2 dosis) ni sobre los esquemas de inducción con rituximab (asociado a ciclofosfamida, micofenolato sódico o monodroga). El tratamiento con rituximab en NL puede ser efectivo pero hasta la fecha limitado a casos refractarios a terapia convencional. La experiencia con rituximab en embarazo también es limitada, lo que justifica el reporte todos los casos en que se hubiera realizado un adecuado seguimiento clínico.

The bacterium Myxococcus xanthus exhibits a complex multicellular life cycle. In the presence of nutrients, cells prey cooperatively. Upon starvation, they enter a developmental cycle wherein cells aggregate to produce macroscopic fruiting bodies filled with resistant myxospores. We used RNA-Seq technology to examine the transcriptome of the 96 hr developmental program. These data revealed that 1415 genes were sequentially expressed in 10 discrete modules, with expression peaking during aggregation, in the transition from aggregation to sporulation, or during sporulation. Analysis of genes expressed at each specific time point provided insights as to how starving cells obtain energy and precursors necessary for assembly of fruiting bodies and into developmental production of secondary metabolites. This study offers the first global view of developmental transcriptional profiles and provides important tools and resources for future studies.

Este artículo analiza el papel que la estructura etaria, la carga de trabajo médica y la duración de la estancia, relacionadas con el área de cirugía, tienen sobre la gerencia de una unidad médica de segundo nivel. Objetivo: Mostrar cómo los datos generados por las actividades quirúrgicas de la unidad informan a tomador de decisiones en función de las características demográficas en la población a la que sirve, así como de la provisión y requerimientos de los servicios quirúrgicos. Comprender la dinámica de estas características ayuda a detectar áreas de oportunidad para mejorar la gerencia presente, así como para prever necesidades futuras que requieren presupuestarse. Material y método: Se utiliza estadística descriptiva y análisis de varianza sobre los tipos de cirugías realizadas durante dos años en el hospital. Conclusiones: Se encuentran diferencias estadísticamente significativas entre ellas en términos de la edad, la concentración del trabajo y la estancia.

Glioblastoma multiforme (GBM) is a poor prognosis type of tumour due to its resistance to chemo and radiotherapy. SOCS1 and SOCS3 have been associated with tumour progression and response to treatments in different kinds of cancers, including GBM. In this study, cell lines of IDH-wildtype GBM from primary cultures were obtained, and the role of SOCS1 and SOCS3 in the radiotherapy response was analysed. Fifty-two brain aspirates from GBM patients were processed, and six new cell lines of IDH-wildtype GBM were established. These new cell lines were characterized according to the WHO classification of CNS tumours. SOCS1 and SOCS3 expression levels were determined, at mRNA level by Q-PCR, at protein level by immunocytochemistry, and Western blot analysis. The results showed that SOCS1 and SOCS3 are overexpressed in GBM, as compared to a non-tumoral brain RNA pool. SOCS1 and SOCS3 expression were reduced by siRNA, and it was found that SOCS3 inhibition increases radioresistance in GBM cell lines, suggesting a key role of SOCS3 in radioresistant acquisition. In addition, radioresistant clonal populations obtained by selective pressure on these cell cultures also showed a significant decrease in SOCS3 expression, while SOCS1 remained unchanged. Furthermore, the induction of SOCS3 expression, under a heterologous promoter, in a radiotherapy resistant GBM cell line increased its radiosensitivity, supporting an important implication of SOCS3 in radiotherapy resistance acquisition. Finally, the treatment with TSA in the most radioresistant established cell line produced an increase in the effect of radiotherapy, that correlated with an increase in the expression of SOCS3. These effects of TSA disappeared if the increase in the expression of SOCS3 prevented with an siRNA against SOCS3. Thus, SOCS3 signal transduction pathway (JAK/STAT) could be useful to unmask new putative targets to improve radiotherapy response in GBM.

Climatic conditions affect the growth, development and final crop production. As wheat is of paramount importance as a staple crop in the human diet, there is a growing need to study its abiotic stress adaptation through the performance of key breeding traits. New and complementary approaches, such as genome-wide association studies (GWAS) and genomic selection (GS), are used for the dissection of different agronomic traits. The present study focused on the dissection of agronomic and quality traits of interest (initial agronomic score, yield, gluten index, sedimentation index, specific weight, whole grain protein and yellow colour) assessed in a panel of 179 durum wheat lines (Triticum durum Desf.), grown under rainfed conditions in different Mediterranean environments in Southern Spain (Andalusia). The findings show a total of 37 marker-trait associations (MTAs) which affect phenotype expression for three quality traits (specific weight, gluten and sedimentation indexes). MTAs could be mapped on the A and B durum wheat subgenomes (on chromosomes 1A, 1B, 2A, 2B and 3A) through the recently available bread wheat reference assembly (IWGSC RefSeqv1). Two of the MTAs found for quality traits (gluten index and SDS) corresponded to the known Glu-B1 and Glu-A1 loci, for which candidate genes corresponding to high molecular weight glutenin subunits could be located. The GS prediction ability values obtained from the breeding materials analyzed showed promising results for traits as grain protein content, sedimentation and gluten indexes, which can be used in plant breeding programs.

PURPOSE:To determine if a novel analysis method will increase the diagnostic value of the multifocal electroretinogram (mfERG) in diagnosing early-stage multiple sclerosis (MS). METHODS:We studied the mfERG signals of OD (Oculus Dexter) eyes of fifteen patients diagnosed with early-stage MS (in all cases < 12 months) and without a history of optic neuritis (ON) (F:M = 11:4), and those of six controls (F:M = 3:3). We obtained values of amplitude and latency of N1 and P1 waves, and a method to assess normalized root-mean-square error (FNRMSE) between model signals and mfERG recordings was used. Responses of each eye were analysed at a global level, and by rings, quadrants and hemispheres. AUC (area under the ROC curve) is used as discriminant factor. RESULTS:The standard method of analysis obtains further discrimination between controls and MS in ring R3 (AUC = 0.82), analysing N1 waves amplitudes. In all of the retina analysis regions, FNRMSE value shows a greater discriminating power than the standard method. The highest AUC value (AUC = 0.91) was in the superior temporal quadrant. CONCLUSION:By analysing mfERG recordings and contrasting them with those of healthy controls it is possible to detect early-stage MS in patients without a previous history of ON.

BackgroundMetformin treatment (1000-2000 mg/day) over 6 months in pubertal children and/or adolescents with obesity and hyperinsulinism is associated with a reduction in body mass index (BMI) and the insulin resistance index (HOMA-IR). We aimed to ascertain if long-term treatment (24 months) with lower doses of metformin (850 mg/day) normalizes the endocrine-metabolic abnormalities, improves body composition, and reduces the carotid intima-media thickness (cIMT) in pre-puberal and early pubertal children with obesity.MethodsA pilot double-blind, placebo-controlled trial was conducted on 18 pre-puberal and early pubertal (Tanner stage I-II) children with obesity and risk markers for metabolic syndrome. Patients were randomly assigned (1:1) to receive metformin (850 mg/day) or placebo for 24 months. Clinical, biochemical (insulin, lipids, leptin, and high-sensitivity C-reactive protein [hsCRP]), and imaging (body composition [dual-energy X-ray absorptiometry and magnetic resonance imaging]) parameters as well as cIMT (ultrasonography) were assessed at baseline and at 6, 12, and 24 months.ResultsThe 12-month treatment tend to cause a reduction in weight standard deviation scores (SDS), BMI-SDS, leptin, leptin-to-high-molecular-weight (HMW) adiponectin ratio, hsCRP, cIMT, fat mass, and liver fat in metformin-treated children compared with placebo. The effect of metformin on the reduction of BMI-SDS, leptin, leptin-to-HMW adiponectin ratio, hsCRP, and liver fat seemed to be maintained after completing the 24 months of treatment. No changes in insulin sensitivity (HOMA-IR) or adverse effects were detected.ConclusionIn this pilot study, metformin treatment in pre-puberal and early pubertal children with obesity seemed to improve body composition and inflammation markers. Our data encourage the development of future fully powered trials using 850 mg/day metformin in young children, highlighting its excellent tolerance and potential long-term benefits.

[This corrects the article DOI: 10.1371/journal.pone.0212581.].

Dried fig is susceptible to infection by Aspergillus flavus, the major producer of the carcinogenic mycotoxins. This fruit may be contaminated by the fungus throughout the entire chain production, especially during natural sun-drying, post-harvest, industrial processing, storage, and fruit retailing. Correct management of such critical stages is necessary to prevent mould growth and mycotoxin accumulation, with temperature being one of the main factors associated with these problems. The effect of different temperatures (5, 16, 25, 30, and 37 °C) related to dried-fig processing on growth, one of the regulatory genes of aflatoxin pathway (aflR) and mycotoxin production by A. flavus, was assessed. Firstly, growth and aflatoxin production of 11 A. flavus strains were checked before selecting two strains (M30 and M144) for in-depth studies. Findings showed that there were enormous differences in aflatoxin amounts and related-gene expression between the two selected strains. Based on the results, mild temperatures, and changes in temperature during drying and storage of dried figs should be avoided. Drying should be conducted at temperatures >30 °C and close to 37 °C, while industry processing, storage, and retailing of dried figs are advisable to perform at refrigeration temperatures (