Timely radiographic detection of developmental dysplasia of the hip in family medicine residents. Educative intervention.

BACKGROUND: Developmental dysplasia of the hip (DDH) is a complex clinical entity that is usually underdiagnosed, if not detected and managed early, will turn the affected individual into a disabled being, with negative social, economic and emotional effects. OBJECTIVE: To determine the capacity for the timely radiographic detection of DDH before and after an educational intervention. METHOD: An educational intervention is carried out in family medicine resident, where they are given training on detection in DDH radiographic projections. Pre- and post-training evaluation is carried out. Statistical analysis is performed using Student's t and χ2, taking p ≤ 0.05 as significant. RESULTS: 94 residents participated. In the pre-intervention evaluation, 87.2% had no knowledge of the early detection protocol (p = 0.525). It was observed that 98.9% incorrectly drew the Perkins line (p = 0.427), 96.8% the Hilgenreiner line (p = 0.177) and 87.2% did not consider the data of bilateral dysplasia (p = 0.956). After the educational intervention, 87.2% correctly drew the Perkins line (p = 0.926), 97.8% the Hilgenreiner line (p = 0.325) and 78.7% if they considered the data of bilateral dysplasia (p = 0.826). CONCLUSIONS: After this training, 80% of family medicine residents were able to detect DDH in a timely manner.

ANTECEDENTES: La displasia del desarrollo de la cadera (DDC) constituye una entidad clínica compleja que suele ser infradiagnosticada que, de no ser precozmente detectadas y manejadas, convertirán al individuo afectado en un ser discapacitado, con efecto negativo social, económico y emocional. OBJETIVO: Determinar la capacidad para la detección radiográfica oportuna de la DDC antes y después de una intervención educativa en médicos residentes de medicina familiar. MÉTODO: Se realizó una intervención educativa en residentes de medicina familiar, en la que se les dio capacitación sobre detección de DDC en proyecciones radiográficas. Se realizó una evaluación previa y posterior a la capacitación. El análisis estadístico se realizó mediante pruebas t de Student y χ2, tomando como significativo un valor de p ≤ 0.05. RESULTADOS: Participaron 94 residentes. El 87.2% dijeron no conocer el protocolo radiológico de detección. En la evaluación preintervención, el 87.2% no tenían conocimiento del protocolo (p = 0.525). Se observó que el 98.9% trazaron de manera incorrecta la línea de Perkins (p = 0.427), el 96.8% la línea de Hilgenreiner (p = 0.177) y el 87.2% no consideraron los datos de displasia bilateral (p = 0.956). Posterior a la intervención educativa, el 87.2% trazaron de manera correcta la línea de Perkins (p = 0.926), el 97.8% la línea de Hilgenreiner (p = 0.325) y el 78.7% sí consideró los datos de displasia bilateral (p = 0.826). CONCLUSIONES: Tras la capacitación, el 80% de los médicos residentes de medicina familiar fueron capaces de detectar oportunamente la DDC.

Associations between Menopausal Hormone Therapy and Colorectal, Lung, or Melanoma Cancer Recurrence and Mortality: A Narrative Review.

Objective: to develop eligibility criteria for use in non-gynecological cancer patients. Methods: We searched all the articles published in peer-reviewed journals up to March 2021. We utilized the PICOS standards and the following selection criteria: menopausal women with a history of non-gynecological and non-breast cancer who underwent hormone replacement therapy (HRT) using various preparations (oestrogens alone or in combination with a progestogen, tibolone, or tissue selective oestrogen complex) and different routes of administration (including oral, transdermal, vaginal, or intra-nasal). We focused on randomized controlled trials as well as relevant extension studies or follow-up reports, specifically examining recurrence and mortality outcomes. Results: Women colorectal cancer survivors who use MHT have a lower risk of death from any cause than those survivors who do not use MHT. Women who are skin melanoma survivors using MHT have a longer survival rate than non-MHT survivors. There is no evidence that women lung cancer survivors who use MHT have a different survival rate than those who do not use MHT. Conclusions: MHT is safe for women who have a history of colorectal, lung, or skin melanoma cancers.

Nitazoxanide Inhibits the Bifunctional Enzyme GlG6PD::6PGL of Giardia lamblia: Biochemical and In Silico Characterization of a New Druggable Target.

Giardiasis, which is caused by Giardia lamblia infection, is a relevant cause of morbidity and mortality worldwide. Because no vaccines are currently available to treat giardiasis, chemotherapeutic drugs are the main options for controlling infection. Evidence has shown that the nitro drug nitazoxanide (NTZ) is a commonly prescribed treatment for giardiasis; however, the mechanisms underlying NTZ's antigiardial activity are not well-understood. Herein, we identified the glucose-6-phosphate::6-phosphogluconate dehydrogenase (GlG6PD::6PGL) fused enzyme as a nitazoxanide target, as NTZ behaves as a GlG6PD::6PGL catalytic inhibitor. Furthermore, fluorescence assays suggest alterations in the stability of GlG6PD::6PGL protein, whereas the results indicate a loss of catalytic activity due to conformational and folding changes. Molecular docking and dynamic simulation studies suggest a model of NTZ binding on the active site of the G6PD domain and near the structural NADP+ binding site. The findings of this study provide a novel mechanistic basis and strategy for the antigiardial activity of the NTZ drug.

Calcium and Integrin-binding protein 2 (CIB2) controls force sensitivity of the mechanotransducer channels in cochlear outer hair cells.

Calcium and Integrin-Binding Protein 2 (CIB2) is an essential subunit of the mechano-electrical transduction (MET) complex in mammalian auditory hair cells. CIB2 binds to pore-forming subunits of the MET channel, TMC1/2 and is required for their transport and/or retention at the tips of mechanosensory stereocilia. Since genetic ablation of CIB2 results in complete loss of MET currents, the exact role of CIB2 in the MET complex remains elusive. Here, we generated a new mouse strain with deafness-causing p.R186W mutation in Cib2 and recorded small but still measurable MET currents in the cochlear outer hair cells. We found that R186W variant causes increase of the resting open probability of MET channels, steeper MET current dependence on hair bundle deflection (I-X curve), loss of fast adaptation, and increased leftward shifts of I-X curves upon hair cell depolarization. Combined with AlphaFold2 prediction that R186W disrupts one of the multiple interacting sites between CIB2 and TMC1/2, our data suggest that CIB2 mechanically constraints TMC1/2 conformations to ensure proper force sensitivity and dynamic range of the MET channels. Using a custom piezo-driven stiff probe deflecting the hair bundles in less than 10 µs, we also found that R186W variant slows down the activation of MET channels. This phenomenon, however, is unlikely to be due to direct effect on MET channels, since we also observed R186W-evoked disruption of the electron-dense material at the tips of mechanotransducing stereocilia and the loss of membrane-shaping BAIAP2L2 protein from the same location. We concluded that R186W variant of CIB2 disrupts force sensitivity of the MET channels and force transmission to these channels.

Generating high-fidelity cochlear organoids from human pluripotent stem cells.

Mechanosensitive hair cells in the cochlea are responsible for hearing but are vulnerable to damage by genetic mutations and environmental insults. The paucity of human cochlear tissues makes it difficult to study cochlear hair cells. Organoids offer a compelling platform to study scarce tissues in vitro; however, derivation of cochlear cell types has proven non-trivial. Here, using 3D cultures of human pluripotent stem cells, we sought to replicate key differentiation cues of cochlear specification. We found that timed modulations of Sonic Hedgehog and WNT signaling promote ventral gene expression in otic progenitors. Ventralized otic progenitors subsequently give rise to elaborately patterned epithelia containing hair cells with morphology, marker expression, and functional properties consistent with both outer and inner hair cells in the cochlea. These results suggest that early morphogenic cues are sufficient to drive cochlear induction and establish an unprecedented system to model the human auditory organ.

Comprehensive rehabilitation and job reintegration of people with severe mental illness in a Latin American country: REINTEGRA study protocol.

BACKGROUND: Despite the increasing use of comprehensive rehabilitation models for people with severe mental illness (SMI), there are still limitations to their implementation and replicability in a consensual way, particularly in Latin American countries. The REINTEGRA program aims to be a standardized model of comprehensive rehabilitation focused on psychosocial and cognitive improvement through a set of interventions on different areas of people's functionality, with the goal of reintegrating people with SMI into the labour market. In this paper we summarize the protocol for its subsequent implementation in a mental health institution in Mexico. METHOD: The protocol is based on a quasi-experimental, prospective longitudinal study, with a pragmatic or naturalistic control group. It will be carried out in three phases. Phase 1 consists of a series of interventions focused on psychosocial improvement; Phase 2 focuses on cognitive and behavioral improvement treatments; and Phase 3 targets psychosocial recovery through rehabilitation and reintegration into the labour market. The overall procedure will be monitored with standarized evaluations at different stages of the program. DISCUSSION: This study presents a model of integral rehabilitation of people with SMI. At the moment, one of the obstacles to overcome is the organization and procedural control of the different actors needed for its implementation (nurses, psychologists, doctors, companies, institutions, etc.). REINTEGRA will be the first comprehensive rehabilitation model that includes systematized procedures for job reinsertion for people with SMI in Mexico, which aims to be a standardized tool of easy adaptation and the replicability for other mental health centers and institutions.

Hybrid allele-specific ChIP-seq analysis identifies variation in brassinosteroid-responsive transcription factor binding linked to traits in maize.

BACKGROUND: Genetic variation in regulatory sequences that alter transcription factor (TF) binding is a major cause of phenotypic diversity. Brassinosteroid is a growth hormone that has major effects on plant phenotypes. Genetic variation in brassinosteroid-responsive cis-elements likely contributes to trait variation. Pinpointing such regulatory variations and quantitative genomic analysis of the variation in TF-target binding, however, remains challenging. How variation in transcriptional targets of signaling pathways such as the brassinosteroid pathway contributes to phenotypic variation is an important question to be investigated with innovative approaches. RESULTS: Here, we use a hybrid allele-specific chromatin binding sequencing (HASCh-seq) approach and identify variations in target binding of the brassinosteroid-responsive TF ZmBZR1 in maize. HASCh-seq in the B73xMo17 F1s identifies thousands of target genes of ZmBZR1. Allele-specific ZmBZR1 binding (ASB) has been observed for 18.3% of target genes and is enriched in promoter and enhancer regions. About a quarter of the ASB sites correlate with sequence variation in BZR1-binding motifs and another quarter correlate with haplotype-specific DNA methylation, suggesting that both genetic and epigenetic variations contribute to the high level of variation in ZmBZR1 occupancy. Comparison with GWAS data shows linkage of hundreds of ASB loci to important yield and disease-related traits. CONCLUSION: Our study provides a robust method for analyzing genome-wide variations of TF occupancy and identifies genetic and epigenetic variations of the brassinosteroid response transcription network in maize.

Resilience, Stress, and Cortisol Predict Cognitive Performance in Older Adults.

OBJECTIVE: to determine the relationship between stress, resilience, and cognitive performance in older people without dementia. METHOD: multiple linear regressions were performed using measures of cognitive performance as dependent variables, and measures of stress and resilience as predictors in a sample of 63 Spanish elderly people. RESULTS: participants reported low levels of stress during their lifetime. In addition to socio-demographic variables, greater stress was related to better delayed recall and worse letter-number sequencing and block design. Higher capillary cortisol was associated with lower flexibility on the Stroop task. Regarding protective factors, we found that greater psychological resilience was related to higher scores on the Addenbrooke's Cognitive Examination-III, letter-number sequencing, and verbal fluency. CONCLUSION: in older people with low stress, apart from age, gender, and education, psychological resilience is a significant predictor of global cognitive status, working memory, and fluency. Likewise, stress is related to verbal memory functioning, working memory, and visuoconstructive abilities. Capillary cortisol level predicts cognitive flexibility. These findings may help to identify risk and protective factors for cognitive decline in older people. Training-based programs to reduce stress and increase psychological resilience may play an important role in preventing cognitive decline.

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Pyridyl Methylsulfinyl Benzimidazole Derivatives as Promising Agents against Giardia lamblia and Trichomonas vaginalis.

Protozoan parasites, such as Giardia lamblia and Trichomonas vaginalis, cause the most prevalent infections in humans in developing countries and provoke significant morbidity and mortality in endemic countries. Despite its side-effects, metronidazole is still the drug of choice as a giardiacidal and trichomonacidal tissue-active agent. However, the emergence of metronidazole resistance and its evolved strategies of parasites to evade innate host defenses have hindered the identification and development of new therapeutic strategies against these parasites. Here, we tested five synthesized benzimidazole derivatives as possible drugs for treating giardiasis and trichomoniasis, probing the bifunctional enzyme glucose 6-phosphate dehydrogenase::6-phosphogluconolactone from G. lamblia (GlG6PD::6PGL) and T. vaginalis (TvG6PD::6PGL) as a drug target. The investigated benzimidazole derivatives were H-B2M1, H-B2M2, H2N-BZM6, O2N-BZM7, and O2N-BZM9. The recombinant enzymes were used in inhibition assays, and in silico computational predictions and spectroscopic studies were applied to follow the structural alteration of the enzymes and identify the possible mechanism of inhibition. We identified two potent benzimidazole compounds (O2N-BZM7 and O2N-BZM9), which are capable of inhibiting both protozoan G6PD::6PGL enzymes and in vitro assays with these parasites, showing that these compounds also affect their viability. These results demonstrate that other therapeutic targets of the compounds are the enzymes GlG6PD::6PGL and TvG6PD::6PGL, which contribute to their antiparasitic effect and their possible use in antigiardial and trichomonacidal therapies.

Eligibility criteria for Menopausal Hormone Therapy (MHT): a position statement from a consortium of scientific societies for the use of MHT in women with medical conditions. MHT Eligibility Criteria Group.

This project aims to develop eligibility criteria for menopausal hormone therapy (MHT). The tool should be similar to those already established for contraception A consortium of scientific societies coordinated by the Spanish Menopause Society met to formulate recommendations for the use of MHT by women with medical conditions based on the best available evidence. The project was developed in two phases. As a first step, we conducted 14 systematic reviews and 32 metanalyses on the safety of MHT (in nine areas: age, time of menopause onset, treatment duration, women with thrombotic risk, women with a personal history of cardiovascular disease, women with metabolic syndrome, women with gastrointestinal diseases, survivors of breast cancer or of other cancers, and women who smoke) and on the most relevant pharmacological interactions with MHT. These systematic reviews and metanalyses helped inform a structured process in which a panel of experts defined the eligibility criteria according to a specific framework, which facilitated the discussion and development process. To unify the proposal, the following eligibility criteria have been defined in accordance with the WHO international nomenclature for the different alternatives for MHT (category 1, no restriction on the use of MHT; category 2, the benefits outweigh the risks; category 3, the risks generally outweigh the benefits; category 4, MHT should not be used). Quality was classified as high, moderate, low or very low, based on several factors (including risk of bias, inaccuracy, inconsistency, lack of directionality and publication bias). When no direct evidence was identified, but plausibility, clinical experience or indirect evidence were available, "Expert opinion" was categorized. For the first time, a set of eligibility criteria, based on clinical evidence and developed according to the most rigorous methodological tools, has been defined. This will provide health professionals with a powerful decision-making tool that can be used to manage menopausal symptoms.

Inspiratory Muscle Training in Patients with Chronic Obstructive Pulmonary Disease (COPD) as Part of a Respiratory Rehabilitation Program Implementation of Mechanical Devices: A Systematic Review.

Chronic Obstructive Pulmonary Disease (COPD) is a complex and heterogeneous disease, with pulmonary and extrapulmonary manifestations, which leads to the need to personalize the assessment and treatment of these patients. The latest updates of national and international guidelines for the management of COPD reveal the importance of respiratory rehabilitation (RR) and its role in improving symptoms, quality of life, and psychosocial sphere of patients. Within RR, the inspiratory muscle training (IMT) has received special interest, showing benefits in maximum inspiratory pressure, perception of well-being, and health status in patients with chronic heart disease, respiratory diseases, and dyspnea during exercise. The aim of this review is to assess the efficacy of IMT in COPD patients through the use of inspiratory muscle training devices, compared with respiratory rehabilitation programs without inspiratory muscle training. In the last years, many mechanical devices focused on inspiratory muscle training have been developed, some of them, such as the AirOFit PRO™, PowerBreath®, or FeelBreathe®, have shown clear benefits. The active search for candidate patients to undergo the RR program with inspiratory muscle training using this type of device in COPD patients represents an advance in the treatment of this disease, with direct benefits on the quality of life of the patients. In this article, we review the available evidence on IMT in these patients and describe the different devices used for it.

Immunogenicity and safety of booster CYD-TDV dengue vaccine after alternative primary vaccination schedules in healthy individuals aged 9-50 years: a randomised, controlled, phase 2, non-inferiority study.

BACKGROUND: Dengue is endemic in many countries throughout the tropics and subtropics, and the disease causes substantial morbidity and health-care burdens in these regions. We previously compared antibody responses after one-dose, two-dose, or three-dose primary regimens with the only approved dengue vaccine CYD-TDV (Dengvaxia; Sanofi Pasteur, Lyon, France) in individuals aged 9 years and older with previous dengue exposure. In this study, we assessed the need for a CYD-TDV booster after these primary vaccination regimens. METHODS: In this randomised, controlled, phase 2, non-inferiority study, healthy individuals aged 9-50 years recruited from three sites in Colombia and three sites in the Philippines (excluding those with the usual contraindications to vaccinations) were randomly assigned 1:1:1 via a permuted block method with stratification by site and by age group using an independent voice response system to receive, at 6-month intervals, three doses of CYD-TDV (three-dose group), one dose of placebo followed by two doses of CYD-TDV (two-dose group), or two doses of placebo followed by one dose of CYD-TDV (one-dose group). Participants were also randomly assigned (1:1) to receive a CYD-TDV booster at 1 year or 2 years after the last primary dose. Each CYD-TDV dose was 0·5 mL and administered subcutaneously in the deltoid region of the upper arm. The investigators and sponsor, study staff interacting with the investigators, and participants and their parents or legally acceptable representatives were masked to group assignment. Neutralising antibodies were measured by 50% plaque reduction neutralisation testing, and geometric mean titres (GMTs) were calculated. Due to a change in study protocol, only participants who were dengue seropositive at baseline in the Colombian cohort received a booster vaccination. The primary outcome was to show non-inferiority of the booster dose administered at 1 year or 2 years after the two-dose and three-dose primary regimens; non-inferiority was shown if the lower limit of the two-sided adjusted 95% CI of the between-group (day 28 post-booster dose GMT from the three-dose or two-dose group vs day 28 GMT post-dose three of the three-dose primary regimen [three-dose group]) geometric mean ratio (GMR) was higher than 0·5 for each serotype. Non-inferiority of the 1-year or 2-year booster was shown if all four serotypes achieved non-inferiority. Safety was assessed among all participants who received the booster. This trial is registered with ClinicalTrials.gov, NCT02628444, and is closed to accrual. FINDINGS: Between May 2 and Sept 16, 2016, we recruited and enrolled 1050 individuals who received either vaccine or placebo. Of the 350, 348, and 352 individuals randomly assigned to three-dose, two-dose, and one-dose groups, respectively, 108, 115, and 115 from the Colombian cohort were dengue seropositive at baseline and received a booster; 55 and 53 in the three-dose group received a booster after 1 year and 2 years, respectively, as did 59 and 56 in the two-dose group, and 62 and 53 in the one-dose group. After the three-dose primary schedule, non-inferiority was shown for serotypes 2 (GMR 0·746; 95% CI 0·550-1·010) and 3 (1·040; 0·686-1·570) but not serotypes 1 (0·567; 0·399-0·805) and 4 (0·647; 0·434-0·963) for the 1-year booster, and again for serotypes 2 (0·871; 0·673-1·130) and 3 (1·150; 0·887-1·490) but not serotypes 1 (0·688; 0·479-0·989) and 4 (0·655; 0·471-0·911) for the 2-year booster. Similarly, after the two-dose primary schedule, non-inferiority was shown for serotypes 2 (0·809; 0·505-1·300) and 3 (1·19; 0·732-1·940) but not serotypes 1 (0·627; 0·342-1·150) and 4 (0·499; 0·331-0·754) for the 1-year booster, and for serotype 3 (0·911; 0·573-1·450) but not serotypes 1 (0·889; 0·462-1·710), 2 (0·677; 0·402-1·140), and 4 (0·702; 0·447-1·100) for the 2-year booster. Thus, non-inferiority of the 1-year or 2-year booster was not shown after the three-dose or two-dose primary vaccination regimen in dengue-seropositive participants. No safety concerns occurred with the 1-year or 2-year CYD-TDV booster. INTERPRETATION: CYD-TDV booster 1 year or 2 years after the two-dose or three-dose primary vaccination regimen does not elicit a consistent, meaningful booster effect against all dengue serotypes in participants who are seropositive for dengue at baseline. FUNDING: Sanofi Pasteur. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

La superación profesional dirigida a docentes de Enfermería como vía para mejorar la atención del adulto mayor

RESUMEN El artículo constituye un acercamiento a las razones que respaldan la necesidad de resaltar el proceso de superación profesional para el tratamiento de estilos de vida saludables del adulto mayor en los docentes de la carrera de Enfermería, como una alternativa permanente encaminada al progreso profesional y humano que debe responder a las transformaciones que se requieren en los conocimientos, habilidades, prácticas y cualidades profesionales de educadores. Por la importancia del tema se persigue como objetivo valorar la pertinencia de una estrategia para la superación profesional de los docentes de la enseñanza de la carrera de Enfermería, sustentada en un modelo de igual denominación, que coherentemente atienda todo lo relacionado con el fomento de estilos de vida saludables del adulto mayor. Se emplearon los métodos investigativos como el análisis documental; análisis y síntesis; la inducción y deducción. Entre los resultados se destaca el perfeccionamiento del desempeño de los docentes, a partir del tratamiento integrado a la relación enfermedad - rehabilitación - estilos de vida saludables en el adulto mayor para favorecer el logro de una longevidad satisfactoria desde la integración hombre, familia y comunidad en la atención primaria de salud.

ABSTRACT The article constitutes an approach to the reasons that support the need to highlight the process of professional improvement for the treatment of healthy lifestyles of the elderly in Nursing teachers, as a permanent alternative aimed at professional and human progress that It must respond to the transformations that are required in the knowledge, skills, practices and professional qualities of educators Due to the importance of the subject, the objective is to reflect on the relevance of a strategy for the professional improvement of teachers of career teaching Nursing, based on a model of the same name, which consistently addresses everything related to the promotion of healthy lifestyles of the elderly. Investigative methods such as documentary analysis were used; analysis and synthesis; induction and deduction. Among the results, the improvement of the theoretical-practical experience of the teachers stands out, from the integrated treatment to the relationship between disease - rehabilitation - healthy lifestyles in the elderly to favor the achievement of a satisfactory longevity from the integration of man, family and community in primary health care.

Kinetic and Molecular Docking Studies to Determine the Effect of Inhibitors on the Activity and Structure of Fused G6PD::6PGL Protein from Trichomonas vaginalis.

Trichomoniasis is a sexually transmitted disease with a high incidence worldwide, affecting 270 million people. Despite the existence of a catalog of available drugs to combat this infection, their extensive use promotes the appearance of resistant Trichomonas vaginalis (T. vaginalis), and some side effects in treated people, which are reasons why it is necessary to find new alternatives to combat this infection. In this study, we investigated the impact of an in-house library comprising 55 compounds on the activity of the fused T. vaginalis G6PD::6PGL (TvG6PD::6PGL) protein, a protein mediating the first reaction step of the pentose phosphate pathway (PPP), a crucial pathway involved in the parasite's energy production. We found four compounds: JMM-3, CNZ-3, CNZ-17, and MCC-7, which inhibited the TvG6PD::6PGL protein by more than 50%. Furthermore, we determined the IC50, the inactivation constants, and the type of inhibition. Our results showed that these inhibitors induced catalytic function loss of the TvG6PD::6PGL enzyme by altering its secondary and tertiary structures. Finally, molecular docking was performed for the best inhibitors, JMM-3 and MCC-7. All our findings demonstrate the potential role of these selected hit compounds as TvG6PD::6PGL enzyme selective inhibitors.

Validation and Selection of New Reference Genes for RT-qPCR Analysis in Pediatric Glioma of Different Grades.

Gliomas are heterogeneous, solid, and intracranial tumors that originate from glial cells. Malignant cells from the tumor undergo metabolic alterations to obtain the energy required for proliferation and the invasion of the cerebral parenchyma. The alterations in the expression of the genes related to the metabolic pathways can be detected in biopsies of gliomas of different CNS WHO grades. In this study, we evaluated the expression of 16 candidate reference genes in the HMC3 microglia cell line. Then, statistical algorithms such as BestKeeper, the comparative ΔCT method, geNorm, NormFinder, and RefFinder were applied to obtain the genes most suitable to be considered as references for measuring the levels of expression in glioma samples. The results show that PKM and TPI1 are two novel genes suitable for genic expression studies on gliomas. Finally, we analyzed the expression of genes involved in metabolic pathways in clinical samples of brain gliomas of different CNS WHO grades. RT-qPCR analysis showed that in CNS WHO grade 3 and 4 gliomas, the expression levels of HK1, PFKM, GAPDH, G6PD, PGD1, IDH1, FASN, ACACA, and ELOVL2 were higher than those of CNS WHO grade 1 and 2 glioma biopsies. Hence, our results suggest that reference genes from metabolic pathways have different expression profiles depending on the stratification of gliomas and constitute a potential model for studying the development of this type of tumor and the search for molecular targets to treat gliomas.

Identification and In Silico Characterization of Novel Helicobacter pylori Glucose-6-Phosphate Dehydrogenase Inhibitors.

Helicobacter pylori (H. pylori) is a pathogen that can remain in the stomach of an infected person for their entire life. As a result, this leads to the development of severe gastric diseases such as gastric cancer. In addition, current therapies have several problems including antibiotics resistance. Therefore, new practical options to eliminate this bacterium, and its induced affections, are required to avoid morbidity and mortality worldwide. One strategy in the search for new drugs is to detect compounds that inhibit a limiting step in a central metabolic pathway of the pathogen of interest. In this work, we tested 55 compounds to gain insights into their possible use as new inhibitory drugs of H. pylori glucose-6-phosphate dehydrogenase (HpG6PD) activity. The compounds YGC-1; MGD-1, MGD-2; TDA-1; and JMM-3 with their respective scaffold 1,3-thiazolidine-2,4-dione; 1H-benzimidazole; 1,3-benzoxazole, morpholine, and biphenylcarbonitrile showed the best inhibitory activity (IC50 = 310, 465, 340, 204 and 304 µM, respectively). We then modeled the HpG6PD protein by homology modeling to conduct an in silico study of the chemical compounds and discovers its possible interactions with the HpG6PD enzyme. We found that compounds can be internalized at the NADP+ catalytic binding site. Hence, they probably exert a competitive inhibitory effect with NADP+ and a non-competitive or uncompetitive effect with G6P, that of the compounds binding far from the enzyme's active site. Based on these findings, the tested compounds inhibiting HpG6PD represent promising novel drug candidates against H. pylori.

Eligibility criteria for menopausal hormone therapy (MHT): A consortium of scientific societies for the use of MHT in women with medical conditions. Research protocol.

The objective of this project is to create eligibility criteria for the use of menopausal hormone therapy (MHT) similar to those established for contraceptive methods. A consortium of scientific societies coordinated by the Spanish Menopause Society met to formulate recommendations for the use of MHT by patients with medical conditions based on the best available evidence. The project protocol, which was registered in the Open Science Framework platform (DOI 10.17605/OSF.IO/J6WBC), will be conducted in two phases. As a first step we will conduct a series of systematic reviews on the safety of MHT, addressing eight clinical questions. The findings of these systematic reviews will help to inform a structured process in which a panel of experts will define the eligibility criteria according to a specific framework, which will facilitate the discussion and development process. For the first time, a set of eligibility criteria, based on clinical evidence and developed according to the most rigorous methodological tools, will be defined. This will provide health professionals with a powerful decision-making tool that can be used in the management of menopausal symptoms.

The da1 mutation in wheat increases grain size under ambient and elevated CO2 but not grain yield due to trade-off between grain size and grain number.

Grain size is potentially yield determining in wheat, controlled by the ubiquitin pathway and negatively regulated by ubiquitin receptor DA1. We analyzed whether increased thousand grain weight in wheat da1 mutant is translated into higher grain yield and whether additional carbon provided by elevated (e)CO2 can be better used by the da1, displaying higher grain sink strength and size. Yield-related, biomass, grain quality traits, and grain dimensions were analyzed by two-factorial mixed-model analysis, regarding genotype and eCO2. da1 increased grain size but reduced spikes and grains per plant, grains per spike, and spikelets per spike, independent of eCO2 treatment, leaving total grain yield unchanged. eCO2 increased yield and grain number additively and independently of da1 but did not overcome the trade-off between grain size and number observed for da1. eCO2 but not da1 impaired grain quality, strongly decreasing concentrations of several macroelement and microelement. In conclusion, intrinsic stimulation of grain sink strength and grain size, achieved by da1, is not benefitting total yield unless trade-offs between grain size and numbers can be overcome. The results reveal interactions of yield components in da1-wheat under ambient and eCO2, thereby uncovering limitations enhancing wheat yield potential.

Immunogenicity and safety of simplified vaccination schedules for the CYD-TDV dengue vaccine in healthy individuals aged 9-50 years (CYD65): a randomised, controlled, phase 2, non-inferiority study.

BACKGROUND: Three doses of the licensed tetravalent dengue vaccine CYD-TDV (Dengvaxia, Sanofi Pasteur, Lyon France) are immunogenic and effective against symptomatic dengue in individuals aged 9 years and older who are dengue seropositive. Previous trials have provided some evidence that antibody responses elicited after just one dose or two doses of CYD-TDV might be similar to those elicited after three doses. We compared antibody responses following one-dose, two-dose, and three-dose vaccination regimens in individuals who were dengue seropositive at baseline up to 1 year after the last injection. METHODS: In this randomised, controlled, phase 2, non-inferiority study (CYD65), healthy individuals aged 9-50 years were recruited from the community in three sites in Colombia and three sites in the Philippines. Participants were randomly assigned (1:1:1), using a permuted block method with stratification by site and age group, to receive, at 6-month intervals (on day 0, month 6, and month 12), three doses of CYD-TDV (three-dose group), one dose of placebo (on day 0) and two doses of CYD-TDV (at months 6 and 12; two-dose group), or two doses of placebo (on day 0 and month 6) and one dose of CYD-TDV (at month 12; one-dose group). Each dose of CYD-TDV was 0·5 mL, administered subcutaneously into the deltoid of the upper arm. Participants, study staff, investigators, and the funder were masked to group assignment. The co-primary endpoints were geometric mean titres (GMTs) of neutralising antibodies against each dengue virus serotype at 28 days and 1 year after the last vaccine injection. After a protocol amendment during the conduct of the study, the original co-primary objectives of non-inferiority of the one-dose and two-dose groups to the three-dose group were altered to include non-inferiority of the two-dose group to the three-dose group only, to be assessed in individuals who were dengue seropositive at baseline. Non-inferiority was shown if the lower limit of the 95% CI for the ratio of GMTs (GMR) at 28 days and 1 year between groups was more than 0·5 for each serotype. The analysis of the coprimary objectives was done in the per-protocol analysis dataset, which included all participants who had been vaccinated, had no protocol deviations, and had a valid serology test result for at least one dengue serotype at 28 days after the third injection. Safety was assessed throughout in all participants who received at least one injection of study drug, regardless of serostatus. This trial is registered with ClinicalTrials.gov, NCT02628444, and is closed to accrual. FINDINGS: Between May 2, 2016, and Sept 16, 2016, we recruited and enrolled 1050 individuals, of whom 1048 received at least one injection and 993 had at least one blood sample taken (full-analysis dataset; 333 in three-dose group, 328 in two-dose group, and 332 in one-dose group). 860 (86·6%) of 993 participants in the full-analysis dataset were dengue seropositive at baseline. Non-inferiority (two dose vs three dose) was shown for each serotype at both 28 days and 1 year among dengue-seropositive participants (number of participants assessed: 272 [two-dose group], 265 [three-dose group] at 28 days; and 190 [two-dose group], 185 [three-dose group] at 1 year). At 28 days after the last injection, neutralising antibody GMTs were 899 (95% CI 752-1075) in the two-dose group versus 822 (700-964) in the three dose group against dengue serotype 1 (GMR 1·09 [95% CI 0·86-1·39]); 869 (754-1002) versus 875 (770-995) against serotype 2 (GMR 0·99 [0·82-1·20]); 599 (524-685) versus 610 (535-694) against serotype 3 (GMR 0·98 [0·82-1·18]); and 510 (453-575) versus 531 (470-601) against serotype 4 (GMR 0·96 [0·81-1·14]). At year 1, GMTs had decreased but remained above baseline for all serotypes: 504 (95% CI 403-630) in the two-dose group versus 490 (398-604) in the three-dose group against serotype 1 (GMR 1·03 [0·76-1·40]); 737 (611-888) versus 821 (704-957) against serotype 2 (GMR 0·90 [0·71-1·14]); 437 (368-519) versus 477 (405-561) against serotype 3 (GMR 0·92 [0·72-1·16]); and 238 (205-277) versus 270 (235-310) against serotype 4 (GMR 0·88 [0·72-1·09]). Reactogenicity profiles were similar across treatment groups. Most unsolicited adverse events after any injection were non-serious and systemic in nature. During the study, 60 serious adverse events were reported in 58 participants (14 in three-dose group, 26 in two-dose group, 18 in one-dose group), mostly infection and infestations or injury, poisoning, and procedural complications. No serious adverse events of special interest or admissions to hospital for dengue occurred. Two deaths occurred, unrelated to study treatment. INTERPRETATION: A two-dose CYD-TDV regimen might be an alternative to the licensed three-dose regimen in individuals who are dengue seropositive at baseline and aged 9 years and older. Vaccination with a reduced number of doses could lead to improved vaccine compliance and coverage, especially in low-resource settings. FUNDING: Sanofi Pasteur.