Use of CYP2D6 substrates and inhibitors during pain management with analgesic opioids: Drug-drug interactions that lead to lack of analgesic effectiveness.

BACKGROUND: Several opioids have pharmacogenetic and drug-drug interactions which may compromise their analgesic effectiveness, but are not routinely implemented into supportive pain management. We hypothesized that CYP2D6 phenotypes and concomitant use of CYP2D6 substrates or inhibitors would correlate with opioid analgesic outcomes. MATERIALS AND METHODS: An observational cross-sectional study was conducted with 263 adult chronic non cancer pain (CNCP) patients from a real-world pain unit under long-term CYP2D6-related opioid treatment (tramadol, hydromorphone, tapentadol or oxycodone). Metabolizer phenotype (ultrarapid [UM], normal [NM], intermediate [IM] or poor [PM]) was determined by the CYP2D6 genotype. The socio-demographic (sex, age, employment status), clinical (pain intensity and relief, neuropathic component, quality of life, disability, anxiety and depression), pharmacological (opioid doses and concomitant pharmacotherapy) and safety (adverse events) variables were recorded. RESULTS: The whole population (66 % female, 65 (14) years old, 70 % retired and 63 % attended for low back pain) were classified as PM (5 %), IM (32 %), NM (56 %) and UM (6 %). Multiple linear and logistic regressions showed higher pain intensity and neuropathic component at younger ages when using any CYP2D6 substrate (p = 0.022) or inhibitor (p = 0.030) drug, respectively, with poorer pain relief when CYP2D6 inhibitors (p=0.030) were present. CONCLUSION: The concomitant use of CYP2D6 substrates or inhibitors during opioid therapy for CNCP may result in lack of analgesic effectiveness. This aspect could be relevant for pharmacological decision making during CNCP management.

Calidad de vida en pacientes con tumor vesical no músculo-invasivo sometidos a tratamiento adyuvante intravesical / Quality of life in patients with non-muscle invasive bladder tumor undergoing adjuvant intravesical treatment

Introducción El objetivo del estudio fue establecer posible relación entre los tratamientos con mitomicina-C (MMC) y bacilo de Calmette-Guérin (BCG) y la afectación en la calidad de vida. Material y métodos Estudio cuasiexperimental, prospectivo y longitudinal, recogiendo pacientes sometidos a tratamiento adyuvante en TVNMI. Se utilizaron los cuestionarios Short form-12 (SF-12) y Urogenital Distress Inventory-6 (UDI-6) para medir la calidad de vida. Se compararon las puntuaciones de los cuestionarios entre casos con MMC y BCG antes de iniciar la inducción (M1), a las 4 semanas (M2) y a los dos meses (M3). Resultados Se recogieron 90 pacientes, 54 en el grupo de BCG y 36 en el de MMC. Se comprobó que los pacientes con BCG percibían peor calidad de vida física comparados con los de MMC en M2 (OR:2,59, p=0,046). Además, se hallaron cambios significativos en la calidad de vida urinaria de los pacientes en tratamiento con MMC entre los diferentes momentos temporales (puntuación del UDI-6: 33,33 en M1, 27,78 en M2 y 16,67 en M3, p=0,001). Conclusiones No existen diferencias en la calidad de vida urinaria entre los pacientes tratados con MMC y BCG. Los pacientes con MMC muestran una recuperación significativa de la calidad de vida urinaria a partir de la finalización de la inducción, que aumenta aún más a los dos meses de la misma. Además, los pacientes tratados con BCG presentan peor calidad de vida física a las 4 semanas de tratamiento que aquellos tratados con MMC (AU)

Introduction The objective of the study was to establish a possible relationship between mitomycin-C (MMC) and bacillus Calmette-Guérin (BCG) treatments and quality of life impairment. Material and methods Quasi-experimental, prospective, and longitudinal study including patients undergoing adjuvant treatment in NMIBC. The Short form-12 (SF-12) and Urogenital Distress Inventory-6 (UDI-6) questionnaires were used to measure quality of life. Questionnaire scores were compared between cases with MMC and BCG before induction (M1), at 4 weeks (M2) and at 2 months (M3). Results Of the 90 patients enrolled, 54 were in the BCG group and 36 in the MMC group. It was found that BCG patients had worse perceived physical quality of life compared to MMC patients in M2 (OR:2.59, p=0.046). In addition, significant changes were found in the urinary quality of life of patients on MMC treatment between the different time points (UDI-6 score: 33.33 in M1, 27.78 in M2 and 16.67 in M3, p=0.001). Conclusions There are no differences in urinary quality of life between patients treated with MMC and BCG. Patients with MMC show a significant recovery of urinary quality of life from the completion of the induction course, which becomes even more significant after 2 months. In addition, BCG-treated patients have worse physical quality of life after 4 weeks of treatment than those treated with MMC (AU)

Quality of life in patients with non-muscle invasive bladder tumor undergoing adjuvant intravesical treatment.

INTRODUCTION: The objective of the study was to establish a possible relationship between mitomycin-C (MMC) and bacillus Calmette-Guérin (BCG) treatments and quality of life impairment. MATERIAL AND METHODS: Quasi-experimental, prospective, and longitudinal study including patients undergoing adjuvant treatment in NMIBC. The Short form-12 (SF-12) and Urogenital Distress Inventory-6 (UDI-6) questionnaires were used to measure quality of life. Questionnaire scores were compared between cases with MMC and BCG before induction (M1), at 4 weeks (M2) and at 2 months (M3). RESULTS: Of the 90 patients enrolled, 54 were in the BCG group and 36 in the MMC group. It was found that BCG patients had worse perceived physical quality of life compared to MMC patients in M2 (OR:2.59, p=0.046). In addition, significant changes were found in the urinary quality of life of patients on MMC treatment between the different time points (UDI-6 score: 33.33 in M1, 27.78 in M2 and 16.67 in M3, p=0.001). CONCLUSIONS: There are no differences in urinary quality of life between patients treated with MMC and BCG. Patients with MMC show a significant recovery of urinary quality of life from the completion of the induction course, which becomes even more significant after 2 months. In addition, BCG-treated patients have worse physical quality of life after 4 weeks of treatment than those treated with MMC.

Farmacogenética y respuesta analgésica: hacia una medicina personalizada con análisis de las diferencias por sexo / Pharmacogenetics in analgesic response: towards a sex-differences personalized medicine

El dolor crónico supone una epidemia silenciosa que afecta a 1 de cada 5 personas adultas en Europa. Este hecho convive con el abuso que realizan algunos pacientes de los medicamentos analgésicos, circunstancia que está limitando su prescripción en el dolor crónico no oncológico. El reto sería poder seleccionar las personas que, a priori, tendrían una mejor respuesta analgésica en base a una serie de condicionamientos intrínsecos. La presente revisión analiza las diferencias en base al sexo y a la presencia de ciertas variantes en los genes que codifican el receptor opioide mu (OPRM1), la enzima metabolizadora del citocromo CYP2D6 y la catecol-O-metiltransferasa (COMT) que degrada catecolaminas. El objetivo es suministrar potenciales elementos explicativos que puedan orientar al profesional clínico en la selección de una analgesia más personalizada.(AU)

Chronic pain is a silent epidemic, affecting 1 in 5 adults in Europe. This fact coexists with the abuse of analgesic drugs by some patients, a circumstance that is limiting their prescription in chronic non-cancer pain. The challenge would be to be able to select the people who, a priori, would have a better analgesic response based on a series of intrinsic conditions. This review analyzes the differences based on sex and the presence of certain variants in the genes that encode the mu opioid receptor (OPRM1), the cytochrome metabolizing enzyme CYP2D6 and the catechol-O-methyltransferase (COMT) that degrades catecholamines. The objective is to provide potentially explanatory elements that can guide the clinical professional in the selection of a more personalized analgesia.(AU)

Predicted COVID-19 molecular effects on endometrium reveal key dysregulated genes and functions.

COVID-19 exerts systemic effects that can compromise various organs and systems. Although retrospective and in silico studies and prospective preliminary analysis have assessed the possibility of direct infection of the endometrium, there is a lack of in-depth and prospective studies on the impact of systemic disease on key endometrial genes and functions across the menstrual cycle and window of implantation. Gene expression data have been obtained from (i) healthy secretory endometrium collected from 42 women without endometrial pathologies and (ii) nasopharyngeal swabs from 231 women with COVID-19 and 30 negative controls. To predict how COVID-19-related gene expression changes impact key endometrial genes and functions, an in silico model was developed by integrating the endometrial and COVID-19 datasets in an affected mid-secretory endometrium gene co-expression network. An endometrial validation set comprising 16 women (8 confirmed to have COVID-19 and 8 negative test controls) was prospectively collected to validate the expression of key genes. We predicted that five genes important for embryo implantation were affected by COVID-19 (downregulation of COBL, GPX3 and SOCS3, and upregulation of DOCK2 and SLC2A3). We experimentally validated these genes in COVID-19 patients using endometrial biopsies during the secretory phase of the menstrual cycle. The results generally support the in silico model predictions, suggesting that the transcriptomic landscape changes mediated by COVID-19 affect endometrial receptivity genes and key processes necessary for fertility, such as immune system function, protection against oxidative damage and development vital for embryo implantation and early development.

Breaking the ageing paradigm in endometrium: endometrial gene expression related to cilia and ageing hallmarks in women over 35 years.

STUDY QUESTION: Does age affect endometrial gene expression? SUMMARY ANSWER: Using unsupervised artificial intelligence methods, we report for the first time that endometrial gene expression changes from 35 years of age in women. WHAT IS KNOWN ALREADY: Female fertility declines with age, largely attributed to declining oocyte quality and ovarian reserve. Combined with other evidence, a longstanding paradigm holds that age does not affect the endometrial function and age has not been controlled for properly in endometrial studies. STUDY DESIGN, SIZE, DURATION: A retrospective in silico analysis was performed of endometrial transcriptomic data from the Gene Expression Omnibus (GEO) sample repository for 27 women of different ages. Results were validated in an independent gene expression dataset of 20 endometrial samples from women aged 23-43 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: A systematic search was performed in GEO from October 2016 to January 2019 to identify transcriptomic studies involving women of different ages. Included samples were from norm-ovulatory, women of reproductive age (23-49 years) with regular menstrual cycles who were free of endometriosis and used as controls in a previous endometrial study. We used raw gene expression data and metadata from these samples to investigate the effect of age on endometrial gene expression. Files were downloaded, pre-processed and explored for potential confounding variables and outliers. Artificial intelligence methods were applied to define age groups, and differential expression and functional analyses were applied to demonstrate and understand the effect of age on gene expression at the molecular level. Functional results were validated in an independent gene expression dataset of 20 endometrial samples from women aged 23-43 years. MAIN RESULTS AND THE ROLE OF CHANCE: Analysis of the initially retrieved endometrial datasets revealed the age of participants was not available (33.33%) or traceable (43.33%) in most studies. However, one study was suitable for age analysis (GSE4888, n = 27, 23-49 years). Samples showed different transcriptomic profiles according to age, beginning at 35 years. A total of 5778 differentially expressed genes and 27 significantly altered endometrial functions (false discovery rate (FDR) < 0.05) were associated with endometrial gene expression changes related to age. Interestingly, 81.48% of affected functions were related to up-regulation of ciliary processes, with 91 genes involved in cilia motility and ciliogenesis. Other functions included dysregulation of the vascular endothelial growth factor signalling pathway and inhibition of epithelial proliferation triggered by 37 genes involved in cell cycle arrest, angiogenesis, insulin signalling and telomere protection. These findings were validated in an independent dataset using a non-targeted approach; 20 up-regulated ciliary processes (FDR < 0.02) and 6 down-regulated functions related to cell cycle arrest were identified as affected by age, among other hallmarks of ageing such as DNA repair inhibition or sugar metabolism (FDR < 0.05). LARGE SCALE DATA: Data underlying this article are available in GEO, IDs: GSE4888 (main dataset) and GSE102131 (validation dataset). LIMITATIONS, REASONS FOR CAUTION: This study is limited in size, as are most studies of endometrial transcriptomics where whole-transcriptome analysis considers nearly 22 000 variables in a relatively small population. Yet, our study includes a main sample set and subsequent validation set that enhances reproducibility of our results and provides reasonable evidence for concluding that age affects endometrial gene expression. A larger study prospectively controlling for patient characteristics is needed to accurately describe changes related to age, with a higher sample size and across a wide age range. Additional studies also are necessary to determine the endometrial ageing contribution to infertility for ultimate translation to a clinical setting. WIDER IMPLICATIONS OF THE FINDINGS: Our findings support an influence of age on the endometrium in a genome-wide functional approach, breaking the endometrial ageing paradigm in human reproduction. To our knowledge, this work is the first to identify, using a genome-wide functional non-targeted approach, ciliary processes as the primary dysregulated function associated with maternal age. These results should guide the research community to control for age as a potential confounding variable in endometrial gene expression studies and to consider endometrial ageing in further studies as a potential cause of infertility in the clinical setting. The reported functional dysregulations could contribute to diminished embryo implantation with age and further studies will demonstrate if such dysregulation underlies some cases of implantation failure. Additionally, the discovery of these functional alterations could enable mechanistic studies, particularly around the age-related increase in uterine pathologies. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Instituto de Salud Carlos III through Miguel Servet programme (CP20/00118) granted to Patricia Diaz-Gimeno (Spanish Government) co-funded by FEDER; and by IVI Foundation (1706-FIVI-041-PD). A.D.-P. (FPU/15/01398) and A.P.-L. (FPU18/01777) are granted by the pre-doctoral programme fellowship from the Ministry of Science, Innovation and Universities (Spanish Government). The authors do not have any competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

A microfluidic sperm-sorting device reduces the proportion of sperm with double-stranded DNA fragmentation.

Sperm DNA fragmentation can be produced in one (ssSDF) or both (dsSDF) DNA strands, linked to difficulties in naturally achieving a pregnancy and recurrent miscarriages, respectively. The techniques more frequently used to select sperm require centrifugation, which may induce sperm DNA fragmentation (SDF). The objective of this study was to assess whether the microfluidic-based device FertileChip® (now ZyMot®ICSI) can diminish the proportion of sperm with dsSDF. First, in a blinded split pilot study, the semen of nine patients diagnosed with ≥60% dsSDF, was divided into three aliquots: not processed, processed with FertileChip®, and processed with swim up. The three aliquots were all analyzed using neutral COMET for the detection of dsSDF, resulting in a reduction of 46% (P < 0.001) with FertileChip® (dsSDF: 34.9%) compared with the ejaculate and the swim up (dsSDF: 65%). Thereafter, the FertileChip® was introduced into clinical practice and a cohort of 163 consecutive ICSI cycles of patients diagnosed with ≥60% dsSDF was analyzed. Fertilization rate was 75.41%. Pregnancy rates after the first embryo transfer were 53.2% (biochemical), 37.8% (clinical), 34% (ongoing) and the live birth rate was 28.8%. Cumulative pregnancy rates after one (65.4% of patients), two (27.6% of patients) or three (6.4% of patients) transfers were 66% (biochemical), 56.4% (clinical), 53.4% (ongoing) and the live birth rate was 42%. The selection of spermatozoa using Fertile Chip® significantly diminishes the percentage of dsSDF, compared with either the fresh ejaculate or after swim up. Its applicability in ICSI cycles of patients with high dsSDF resulted in good laboratory and clinical outcomes.

Identifying and optimizing human endometrial gene expression signatures for endometrial dating.

STUDY QUESTION: What are the key considerations for developing an enhanced transcriptomic method for secretory endometrial tissue dating? SUMMARY ANSWER: Multiple gene expression signature combinations can serve as biomarkers for endometrial dating, but their predictive performance is variable and depends on the number and identity of the genes included in the prediction model, the dataset characteristics and the technology employed for measuring gene expression. WHAT IS KNOWN ALREADY: Among the new generation of transcriptomic endometrial dating (TED) tools developed in the last decade, there exists variation in the technology used for measuring gene expression, the gene makeup and the prediction model design. A detailed study, comparing prediction performance across signatures for understanding signature behaviour and discrepancies in gene content between them, is lacking. STUDY DESIGN, SIZE, DURATION: A multicentre prospective study was performed between July 2018 and October 2020 at five different centres from the same group of clinics (Spain). This study recruited 281 patients and finally included in the gene expression analysis 225 Caucasian patients who underwent IVF treatment. After preprocessing and batch effect filtering, gene expression measurements from 217 patients were combined with artificial intelligence algorithms (support vector machine, random forest and k-nearest neighbours) allowing evaluation of different prediction models. In addition, secretory-phase endometrial transcriptomes from gene expression omnibus (GEO) datasets were analysed for 137 women, to study the endometrial dating capacity of genes independently and grouped by signatures. This provided data on the consistency of prediction across different gene expression technologies and datasets. PARTICIPANTS/MATERIALS, SETTING, METHODS: Endometrial biopsies were analysed using a targeted TruSeq (Illumina) custom RNA expression panel called the endometrial dating panel (ED panel). This panel included 301 genes previously considered relevant for endometrial dating as well as new genes selected for their anticipated value in detecting the secretory phase. Final samples (n = 217) were divided into a training set for signature discovery and an independent testing set for evaluation of predictive performance of the new signature. In addition, secretory-phase endometrial transcriptomes from GEO were analysed for 137 women to study endometrial dating capacity of genes independently and grouped by signatures. Predictive performance among these signatures was compared according to signature gene set size. MAIN RESULTS AND THE ROLE OF CHANCE: Testing of the ED panel allowed development of a model based on a new signature of 73 genes, which we termed 'TED' and delivers an enhanced tool for the consistent dating of the secretory phase progression, especially during the mid-secretory endometrium (3-8 days after progesterone (P) administration (P + 3-P + 8) in a hormone replacement therapy cycle). This new model showed the best predictive capacity in an independent test set for staging the endometrial tissue in the secretory phase, especially in the expected window of implantation (average of 114.5 ± 7.2 h of progesterone administered; range in our patient population of 82-172 h). Published sets of genes, in current use for endometrial dating and the new TED genes, were evaluated in parallel in whole-transcriptome datasets and in the ED panel dataset. TED signature performance was consistently excellent for all datasets assessed, frequently outperforming previously published sets of genes with a smaller number of genes for dating the endometrium in the secretory phase. Thus, this optimized set exhibited prediction consistency across datasets. LARGE SCALE DATA: The data used in this study is partially available at GEO database. GEO identifiers GSE4888, GSE29981, GSE58144, GSE98386. LIMITATIONS, REASONS FOR CAUTION: Although dating the endometrial biopsy is crucial for investigating endometrial progression and the receptivity process, further studies are needed to confirm whether or not endometrial dating methods in general are clinically useful and to guide the specific use of TED in the clinical setting. WIDER IMPLICATIONS OF THE FINDINGS: Multiple gene signature combinations provide adequate endometrial dating, but their predictive performance depends on the identity of the genes included, the gene expression platform, the algorithms used and dataset characteristics. TED is a next-generation endometrial assessment tool based on gene expression for accurate endometrial progression dating especially during the mid-secretory. STUDY FUNDING/COMPETING INTEREST(S): Research funded by IVI Foundation (1810-FIVI-066-PD). P.D.-G. visiting scientist fellowship at Oxford University (BEFPI/2010/032) and Josefa Maria Sanchez-Reyes' predoctoral fellowship (ACIF/2018/072) were supported by a program from the Generalitat Valenciana funded by the Spanish government. A.D.-P. is supported by the FPU/15/01398 predoctoral fellowship from the Ministry of Science, Innovation and Universities (Spanish Government). D.W. received support from the NIHR Oxford Biomedical Research Centre. The authors do not have any competing interests to declare.

Analysis of serum and endometrial progesterone in determining endometrial receptivity.

STUDY QUESTION: Is there a relationship between serum and endometrial progesterone (P4) levels, including P4 and metabolites (oestrone, oestradiol and 17α-hydroxyprogesterone), and endometrial receptivity? SUMMARY ANSWER: Serum P4 levels were not correlated with endometrial P4, nor associated with endometrial receptivity as determined by the ERA® test; however, endometrial P4 and 17α-hydroxyprogesterone levels were positively correlated and related to endometrial receptivity by ERA. WHAT IS KNOWN ALREADY: Acquisition of endometrial receptivity is governed by P4, which induces secretory transformation. A close relationship between serum P4 and pregnancy outcome is reported for hormone replacement therapy (HRT) cycles. However, the relationship between serum and uterine P4 levels has not been described, and it is unknown whether uterine receptivity depends more on serum or uterine P4 levels. STUDY DESIGN, SIZE, DURATION: A prospective cohort study was performed during March 2018-2019 in 85 IVF patients undergoing an evaluation-only HRT cycle with oestradiol valerate (6 mg/day) and micronised vaginal progesterone (400 mg/12 h). PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients were under 50 years of age, had undergone at least one failed IVF cycle, had no uterine pathology, and had adequate endometrial thickness (> 6.5 mm). The study was conducted at IVI Valencia and IVI Foundation. An endometrial biopsy and a blood sample were collected after 5 days of P4 vaginal treatment. Measures included serum P4 levels, ERA®-based evaluation of endometrial receptivity, and endometrial P4 levels along with metabolites (oestrone, oestradiol and 17α-hydroxyprogesterone) measured by ultra-performance liquid chromatography-tandem mass spectrometry. MAIN RESULTS AND THE ROLE OF CHANCE: Seventy-nine women were included (mean age: 39.9 ± 4.6, BMI: 24.2 ± 3.9 kg/m2, endometrial thickness: 8.2 ± 1.4 mm). The percentage of endometria indicated as receptive by ERA® was 40.5%. When comparing receptive versus non-receptive groups, no differences were observed in baseline characteristics nor in steroid hormones levels in serum or endometrium. No association between serum P4 and endometrial steroid levels or ERA result was found (P < 0.05). When the population was stratified according to metabolite concentration levels, endometrial P4 and 17α-hydroxyprogesterone were significantly associated with endometrial receptivity (P < 0.05). A higher proportion of receptive endometria by ERA was observed when endometrial P4 levels were higher than 40.07 µg/ml (relative maximum) and a lower proportion of receptive endometria was associated with endometrial 17α-hydroxyprogesterone lower than 0.35 ng/ml (first quartile). A positive correlation R2 = 0.67, P < 0.001 was observed between endometrial P4 and 17α-hydroxyprogesterone levels. LIMITATIONS, REASONS FOR CAUTION: This study did not analyse pregnancy outcomes. Further, the findings can only be extrapolated to HRT cycles with micronised vaginal progesterone for luteal phase support. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that the combined benefits of different routes of progesterone administration for luteal phase support could be leveraged to ensure an adequate concentration of progesterone both in the uterus and in the bloodstream. Further studies will confirm whether this method can optimise both endometrial receptivity and live birth rate. Additionally, targeted treatment to increase P4 endometrial levels may normalise the timing of the window of implantation without needing to modify the progesterone administration day. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the IVI-RMA Valencia (1706-VLC-051-EL) and Consellería d'Educació, Investigació, Cultura, i esport Generalitat Valenciana (Valencian Government, Spain, GV/2018//151). Almudena Devesa-Peiro (FPU/15/01398) and Cristina Rodriguez-Varela (FPU18/01657) were supported by the FPU program fellowship from the Ministry of Science, Innovation and Universities (Spanish Government). P.D.-G. is co-inventor on the ERA patent, with non-economic benefits. The other authors have no competing interests. TRIAL REGISTRATION NUMBER: NCT03456375.

Transcriptional changes through menstrual cycle reveal a global transcriptional derepression underlying the molecular mechanism involved in the window of implantation.

The human endometrium is a dynamic tissue that only is receptive to host the embryo during a brief time in the middle secretory phase, called the window of implantation (WOI). Despite its importance, regulation of the menstrual cycle remains incompletely understood. The aim of this study was to characterize the gene cooperation and regulation of menstrual cycle progression, to dissect the molecular complexity underlying acquisition of endometrial receptivity for a successful pregnancy, and to provide the scientific community with detailed gene co-expression information throughout the menstrual cycle on a user-friendly web-tool database. A retrospective gene co-expression analysis was performed based on the endometrial receptivity array (ERarray) gene signature from 523 human endometrial samples collected across the menstrual cycle, including during the WOI. Gene co-expression analysis revealed the WOI as having the significantly smallest proportion of negative correlations for transcriptional profiles associated with successful pregnancies compared to other cycle stages, pointing to a global transcriptional derepression being involved in acquisition of endometrial receptivity. Regulation was greatest during the transition between proliferative and secretory endometrial phases. Further, we prioritized nuclear hormone receptors as major regulators of this derepression and proved that some genes and transcription factors involved in this process were dysregulated in patients with recurrent implantation failure. We also compiled the wealth of gene co-expression data to stimulate hypothesis-driven single-molecule endometrial studies in a user-friendly database: Menstrual Cycle Gene Co-expression Network (www.menstrualcyclegcn.com). This study revealed a global transcriptional repression across the menstrual cycle, which relaxes when the WOI opens for transcriptional profiles associated with successful pregnancies. These findings suggest that a global transcriptional derepression is needed for embryo implantation and early development.

Sleep in autism: A biomolecular approach to aetiology and treatment.

People with autism spectrum disorder (ASD) commonly experience other comorbidities. Studies indicate that between 50% and 83% of individuals with ASD have sleep problems or disorders. The most commonly reported sleep problems are: (a) insomnia symptoms including the inability to get to sleep or stay asleep; and (b) circadian rhythm sleep-wake disorders, defined as a misalignment between the timing of endogenous circadian rhythms and the external environment. The circadian system provides timing information for the sleep-wake cycle that is regulated by the interaction of an endogenous processes (circadian - Process C, and homeostatic - Process S) and synchronizing agents (neurohormones and neurotransmitters), which produce somnogenic activity. A clinical priority in ASD is understanding the cause of these sleep problems in order to improve treatment outcomes. This review approaches sleep in autism from several perspectives: Sleep-wake mechanisms and problems, and brain areas and molecules controlling sleep (e.g., GABA and melatonin) and wake maintenance (e.g., serotonin, acetylcholine and glutamate). Specifically, this review examines how altered sleep structure could be related to neurobiological alterations or genetic mutations and the implications this may have for potential pharmacological treatments in individuals with ASD.

RECALMIN. Cuatro años de evolución de las Unidades de Medicina Interna del Sistema Nacional de Salud (2013-2016) / RECALMIN. Four years of growth of the internal medicine units of the Spanish National Health System (2013-2016)

Objetivos: Comparar la estructura, recursos y actividad de las Unidades de Medicina Interna (UMI) del Sistema Nacional de Salud (SNS) en 2013 y 2016. Analizar las diferencias entre UMI en 2016 por tamaño de hospital. Material y métodos: Comparativa de 2 estudios descriptivos transversales de UMI en hospitales generales de agudos del Sistema Nacional de Salud con datos referidos a 2013 y a 2016. Las variables fueron recogidas mediante un cuestionario «ad hoc» (encuesta RECALMIN). Resultados: Entre 2013 y 2016 aumentó notablemente la demanda asistencial (con un promedio anual del 11% en altas de hospitalización y del 16% en primeras consultas) y ligeramente la comorbilidad (2%). En el mismo período, aumentó un 16,7% la productividad media de las UMI (0,6+0,3 vs. 0,7+0,3; p=0,09) y la estancia media disminuyó un 10% (9+2,2 vs. 8,1+2,1 días; p=0,001). Los progresos en la implantación de buenas prácticas y de una atención sistemática al paciente crónico complejo fueron escasos. La variabilidad entre UMI y las notables diferencias entre UMI de hospitales de tamaño distinto fueron hallazgos de ambas encuestas. Conclusiones: Las UMI respondieron al aumento de la carga asistencial que soportaron en el período 2013-2016 mejorando su eficiencia y productividad, pero los avances en la implantación de buenas prácticas, incluyendo la atención al paciente crónico complejo, fueron escasos. La importante variabilidad en los indicadores de estructura, actividad y modelos de gestión encontrada en 2013 se mantuvo en 2016

Objectives: To compare the structure, resources and activity of the internal medicine units (IMUs) of the Spanish National Health System (SNHS) in 2013 and 2016. To analyse the differences between IMUs in 2016 by hospital size. Material and methods: We conducted a comparison of 2 descriptive cross-sectional studies of IMUs in general acute care hospitals of the Spanish National Health System, with data referring to 2013 and 2016. The variables were collected via an ad hoc questionnaire (RECALMIN survey). Results: Between 2013 and 2016, the demand for care increased dramatically (with an annual average of 11% in hospital discharges and 16% in first consultations), and comorbidity slightly increased (2%). During this period, the mean productivity of IMUs increased 16.7% (0.6±0.3 vs. 0.7±0.3; P=.09), and the mean stay decreased 10% (9±2.2 vs. 8.1±2.1 days; P=.001). Progress in implementing good practices and systematic care for complex chronic patients was scarce. Both surveys found variability among IMUs and marked differences among IMUs of hospitals of different sizes. Conclusions: IMUs responded to the increased burden of care they supported during 2013-2016 by improving their efficiency and productivity; however, advances in implementing good practices, including care for chronic complex patients, were scare. The significant variability in the indicators of structure, activity and management models found in 2013 remained in 2016

RECALMIN. Four years of growth of the internal medicine units of the Spanish National Health System (2013-2016). / RECALMIN. Cuatro años de evolución de las Unidades de Medicina Interna del Sistema Nacional de Salud (2013-2016).

OBJECTIVES: To compare the structure, resources and activity of the internal medicine units (IMUs) of the Spanish National Health System (SNHS) in 2013 and 2016. To analyse the differences between IMUs in 2016 by hospital size. MATERIAL AND METHODS: We conducted a comparison of 2 descriptive cross-sectional studies of IMUs in general acute care hospitals of the Spanish National Health System, with data referring to 2013 and 2016. The variables were collected via an ad hoc questionnaire (RECALMIN survey). RESULTS: Between 2013 and 2016, the demand for care increased dramatically (with an annual average of 11% in hospital discharges and 16% in first consultations), and comorbidity slightly increased (2%). During this period, the mean productivity of IMUs increased 16.7% (0.6±0.3 vs. 0.7±0.3; P=.09), and the mean stay decreased 10% (9±2.2 vs. 8.1±2.1 days; P=.001). Progress in implementing good practices and systematic care for complex chronic patients was scarce. Both surveys found variability among IMUs and marked differences among IMUs of hospitals of different sizes. CONCLUSIONS: IMUs responded to the increased burden of care they supported during 2013-2016 by improving their efficiency and productivity; however, advances in implementing good practices, including care for chronic complex patients, were scare. The significant variability in the indicators of structure, activity and management models found in 2013 remained in 2016.

Sperm telomere length in motile sperm selection techniques: A qFISH approach.

Several studies have associated telomere shortening with alterations in reproductive function. The objective of the present study was to determine telomere length (TL) in spermatozoa selected by either density-gradient centrifugation (DGC) or swim-up. The analysis of TL was performed using quantitative fluorescent in situ hybridisation (qFISH) using PNA probes in combination with a chromatin decompaction protocol in sperm cells. Results of TL were 24.64 ± 5.00 Kb and 24.95 ± 4.60 Kb before and after DGC, respectively, and 19.59 ± 8.02 Kb and 20.22 ± 5.18 Kb before and after swim-up respectively. Sperm selected by DGC or swim-up did not show any significant differences in TL as compared to nonselected sperm (p > .05). Negative correlations between TL and sperm motility (r = -.308; p = .049) and concentration (r = -.353; p = .028) were found. Furthermore, exposure of sperm to increasing concentrations of hydrogen peroxide during incubation resulted in a reduction in TL. These data indicate that oxidative stress may be one of the main factors involved in the reduction of TL in sperm. Preliminary clinical results from patients included in this study indicate that TL was shorter in spermatozoa from couples who never achieved a pregnancy compared to couples who did achieve at least one natural pregnancy (p < .05); however, the clinical utility of this biomarker still needs to be confirmed in further studies.

Actualización en la estratificación de riesgo del tromboembolismo pulmonar agudo sintomático / Update on the risk stratification of acute symptomatic pulmonary thromboembolism

La mortalidad precoz en pacientes con tromboembolia pulmonar (TEP) varía desde el 2% en pacientes normotensos al 30% en pacientes con shock cardiogénico. La estratificación actual de riesgo en la TEP sintomática incluye 4 grupos de pacientes y las estrategias terapéuticas recomendadas se basan en dicha estratificación. Los pacientes que se presentan con inestabilidad hemodinámica se consideran de alto riesgo y en ellos se recomienda el tratamiento fibrinolítico. En pacientes normotensos, la estratificación de riesgo ayuda a diferenciar entre aquellos de bajo riesgo, riesgo intermedio-bajo y riesgo intermedio-alto. Actualmente no existe suficiente evidencia sobre el beneficio de una monitorización intensiva y tratamiento fibrinolítico en pacientes con riesgo intermedio-alto. En pacientes de bajo riesgo, está indicada la anticoagulación estándar y podría considerarse la posibilidad de un alta precoz con manejo ambulatorio, aunque su beneficio no está todavía firmemente establecido (AU)

Early mortality in patients with pulmonary thromboembolism (PTE) varies from 2% in normotensive patients to 30% in patients with cardiogenic shock. The current risk stratification for symptomatic PTE includes 4 patient groups, and the recommended therapeutic strategies are based on this stratification. Patients who have haemodynamic instability are considered at high risk. Fibrinolytic treatment is recommended for these patients. In normotensive patients, risk stratification helps differentiate between those of low risk, intermediate-low risk and intermediate-high risk. There is currently insufficient evidence on the benefit of intensive monitoring and fibrinolytic treatment in patients with intermediate-high risk. For low-risk patients, standard anticoagulation is indicated. Early discharge with outpatient management may be considered, although its benefit has still not been firmly established (AU)

Update on the risk stratification of acute symptomatic pulmonary thromboembolism. / Actualización en la estratificación de riesgo del tromboembolismo pulmonar agudo sintomático.

Early mortality in patients with pulmonary thromboembolism (PTE) varies from 2% in normotensive patients to 30% in patients with cardiogenic shock. The current risk stratification for symptomatic PTE includes 4 patient groups, and the recommended therapeutic strategies are based on this stratification. Patients who have haemodynamic instability are considered at high risk. Fibrinolytic treatment is recommended for these patients. In normotensive patients, risk stratification helps differentiate between those of low risk, intermediate-low risk and intermediate-high risk. There is currently insufficient evidence on the benefit of intensive monitoring and fibrinolytic treatment in patients with intermediate-high risk. For low-risk patients, standard anticoagulation is indicated. Early discharge with outpatient management may be considered, although its benefit has still not been firmly established.

TREX-DM: a low-background Micromegas-based TPC for low-mass WIMP detection.

If Dark Matter is made of Weakly Interacting Massive Particles (WIMPs) with masses below [Formula: see text] GeV, the corresponding nuclear recoils in mainstream WIMP experiments are of energies too close, or below, the experimental threshold. Gas Time Projection Chambers (TPCs) can be operated with a variety of target elements, offer good tracking capabilities and, on account of the amplification in gas, very low thresholds are achievable. Recent advances in electronics and in novel radiopure TPC readouts, especially micro-mesh gas structure (Micromegas), are improving the scalability and low-background prospects of gaseous TPCs. Here we present TREX-DM, a prototype to test the concept of a Micromegas-based TPC to search for low-mass WIMPs. The detector is designed to host an active mass of [Formula: see text] kg of Ar at 10 bar, or alternatively [Formula: see text] kg of Ne at 10 bar, with an energy threshold below 0.4 keVee, and is fully built with radiopure materials. We will describe the detector in detail, the results from the commissioning phase on surface, as well as a preliminary background model. The anticipated sensitivity of this technique may go beyond current experimental limits for WIMPs of masses of 2-8 GeV.

Tumor de células gigantes óseo. Noventa y siete casos con seguimiento medio de 12 años / Giant cell tumour of bone: a series of 97 cases with a mean follow-up of 12 years

Objetivo. Describir una serie de tumores óseos de células gigantes con largo seguimiento, mostrando los resultados obtenidos con nuestro protocolo terapéutico. Material y método. Entre 1982-2009, 97 pacientes con lesiones histológicamente confirmadas como tumores óseos de células gigantes fueron tratados en nuestro centro con un seguimiento medio de 12 años (2-27 años). El tratamiento recibido lo determinó la clasificación de Campanacci. La serie la formaron 53 mujeres (54,6%) y 44 hombres (54,4%) con una edad media de 34,16 años (15-71 años). Los datos recogidos se centraron en la presentación clínica, localización, estadio, extensión, recurrencias y complicaciones. Resultados. El tratamiento más utilizado en los estadios i y ii de Campanacci fue escisión intralesional con fresado a alta velocidad y rellenado con injerto homólogo, mientras que en los estadios iii que no podían ser tratados con este método se abogó por la resección en bloque. Se halló una recurrencias global del 25,8%. Siete casos (7,2%) presentaron malignización. La tasa de exitus fue del 2,1% (2 casos). Conclusión. La opción terapéutica presentada para los tumores óseos de células gigantes que consiste en legrado con fresado a alta velocidad y aporte de injerto óseo en los grados i y ii de Campanacci obtiene resultados comparables con literatura actual. Los tumores de grado iii, que no pueden ser tratados con la opción terapéutica mencionada anteriormente, requieren resección en bloque y reconstrucción posterior (AU)

Purpose. To describe our series of patients with giant cell tumour of bone with a long-term follow-up to show the results obtained with our treatment protocol. Material and methods. A total of 97 histologically confirmed giant cell tumour of bone were treated in our center between 1982 and 2009. The mean follow-up period was 12 years (2-27 years). The treatment received was determined by the radiological grade based on the Campanacci classification. The series consisted of 53 women (54.6%) and 44 men (54.4%) with a median age of 34.16 years (15-71 years). The data collected was focused on the clinical presentation, location, phase, extension, recurrences, and complications. Results. The treatment most used in Campanacci grades i and ii was intralesional excision with high velocity drilling and filling with a graft. In grades iii that could not be treated with the aforementioned method, it was decided to perform en bloc resection. An overall recurrence rate of around 25.8% was observed. Seven cases (7.2%) presented with a recurrence of the malignancy. The death rate at the end of follow-up was 2.1% (2 cases). Conclusions. Curettage with a high-velocity drill and a bone graft in giant cell tumour of bone Campanacci grades i and ii obtain good results after long-term follow-up. Some grade iii giant cell tumour of bone that cannot be treated with this therapeutic option require en bloc resection and reconstruction (AU)

[Giant cell tumour of bone: a series of 97 cases with a mean follow-up of 12 years]. / Tumor de células gigantes óseo. Noventa y siete casos con seguimiento medio de 12 años.

PURPOSE: To describe our series of patients with giant cell tumour of bone with a long-term follow-up to show the results obtained with our treatment protocol. MATERIAL AND METHODS: A total of 97 histologically confirmed giant cell tumour of bone were treated in our center between 1982 and 2009. The mean follow-up period was 12 years (2-27 years). The treatment received was determined by the radiological grade based on the Campanacci classification. The series consisted of 53 women (54.6%) and 44 men (54.4%) with a median age of 34.16 years (15-71 years). The data collected was focused on the clinical presentation, location, phase, extension, recurrences, and complications. RESULTS: The treatment most used in Campanacci grades i and ii was intralesional excision with high velocity drilling and filling with a graft. In grades iii that could not be treated with the aforementioned method, it was decided to perform en bloc resection. An overall recurrence rate of around 25.8% was observed. Seven cases (7.2%) presented with a recurrence of the malignancy. The death rate at the end of follow-up was 2.1% (2 cases). CONCLUSIONS: Curettage with a high-velocity drill and a bone graft in giant cell tumour of bone Campanacci grades i and ii obtain good results after long-term follow-up. Some grade iii giant cell tumour of bone that cannot be treated with this therapeutic option require en bloc resection and reconstruction.

Nuclear degraded sperm subpopulation is affected by poor chromatin compaction and nuclease activity.

There is an interest in the nuclear degraded sperm subpopulation because, although it is present in a low percentage in all semen samples, patient groups such as varicocele and rearranged genome carriers show high levels of these degraded spermatozoa. This study is designed with two objectives in mind: first, incubations of H2 O2 and nuclease on DTT-treated and untreated samples to show the aetiology of this subpopulation and second, assessment of the correlation between the protamine ratio and nuclear degraded spermatozoa. A very high increase in the nuclear degraded subpopulation has been found with nuclease incubation, and it is even higher when it has been merged with nuclear decompaction using DTT. Alternatively, incubation with H2 O2 with and without DTT did not show such a significant increase in nuclear degraded spermatozoa. The protamine ratio correlated with this subpopulation, showing, in patients, that poor nuclear compaction would turn the sperm susceptible to degradation. Then, the assessment of nuclear degraded spermatozoa might not be only a measure of DNA degradation but also an indicator of chromatin compaction in the spermatozoa. Different patient groups would fit this model for sperm nuclear degradation, such as varicocele patients, who show a high percentage of immature spermatozoa and nuclear degraded spermatozoa, and reorganised genome carriers, where reorganisation might also cause poor chromatin compaction on the sperm nucleus.