Unwinding Limb Development.

The molecular mechanisms underpinning vertebrate body plan evolution are beginning to be unravelled. In this issue of Cell, Kvon et al. spectacularly demonstrate how transplanting snake-specific genetic changes found uniquely in serpent enhancers leads to limb loss in mice.

Enhancer evolution across 20 mammalian species.

The mammalian radiation has corresponded with rapid changes in noncoding regions of the genome, but we lack a comprehensive understanding of regulatory evolution in mammals. Here, we track the evolution of promoters and enhancers active in liver across 20 mammalian species from six diverse orders by profiling genomic enrichment of H3K27 acetylation and H3K4 trimethylation. We report that rapid evolution of enhancers is a universal feature of mammalian genomes. Most of the recently evolved enhancers arise from ancestral DNA exaptation, rather than lineage-specific expansions of repeat elements. In contrast, almost all liver promoters are partially or fully conserved across these species. Our data further reveal that recently evolved enhancers can be associated with genes under positive selection, demonstrating the power of this approach for annotating regulatory adaptations in genomic sequences. These results provide important insight into the functional genetics underpinning mammalian regulatory evolution.

Phylogenetic modeling of enhancer shifts in African mole-rats reveals regulatory changes associated with tissue-specific traits.

Changes in gene regulation are thought to underlie most phenotypic differences between species. For subterranean rodents such as the naked mole-rat, proposed phenotypic adaptations include hypoxia tolerance, metabolic changes, and cancer resistance. However, it is largely unknown what regulatory changes may associate with these phenotypic traits, and whether these are unique to the naked mole-rat, the mole-rat clade, or are also present in other mammals. Here, we investigate regulatory evolution in the heart and liver from two African mole-rat species and two rodent outgroups using genome-wide epigenomic profiling. First, we adapted and applied a phylogenetic modeling approach to quantitatively compare epigenomic signals at orthologous regulatory elements and identified thousands of promoter and enhancer regions with differential epigenomic activity in mole-rats. These elements associate with known mole-rat adaptations in metabolic and functional pathways and suggest candidate genetic loci that may underlie mole-rat innovations. Second, we evaluated ancestral and species-specific regulatory changes in the study phylogeny and report several candidate pathways experiencing stepwise remodeling during the evolution of mole-rats, such as the insulin and hypoxia response pathways. Third, we report nonorthologous regulatory elements overlap with lineage-specific repetitive elements and appear to modify metabolic pathways by rewiring of HNF4 and RAR/RXR transcription factor binding sites in mole-rats. These comparative analyses reveal how mole-rat regulatory evolution informs previously reported phenotypic adaptations. Moreover, the phylogenetic modeling framework we propose here improves upon the state of the art by addressing known limitations of inter-species comparisons of epigenomic profiles and has broad implications in the field of comparative functional genomics.

Migration patterns and navigation cues of Atlantic salmon post-smolts migrating from 12 rivers through the coastal zones around the Irish Sea.

The freshwater phase of the first seaward migration of juvenile Atlantic salmon (Salmo salar) is relatively well understood when compared with our understanding of the marine phase of their migration. In 2021, 1008 wild and 60 ranched Atlantic salmon smolts were tagged with acoustic transmitters in 12 rivers in England, Scotland, Northern Ireland and Ireland. Large marine receiver arrays were deployed in the Irish Sea at two locations: at the transition of the Irish Sea into the North Atlantic between Ireland and Scotland, and between southern Scotland and Northern Ireland, to examine the early phase of the marine migration of Atlantic salmon smolts. After leaving their natal rivers' post-smolt migration through the Irish Sea was rapid with minimum speeds ranging from 14.03 to 38.56 km.day-1 for Atlantic salmon smolts that entered the Irish Sea directly from their natal river, to 9.69-39.94 km.day-1 for Atlantic salmon smolts that entered the Irish Sea directly from their natal estuary. Population minimum migration success through the study area was strongly correlated with the distance of travel, populations further away from the point of entry to the open North Atlantic exhibited lower migration success. Post-smolts from different populations experienced different water temperatures on entering the North Atlantic. This was largely driven by the timing of their migration and may have significant consequences for feeding and ultimately survivorship. The influence of water currents on post-smolt movement was investigated using data from previously constructed numerical hydrodynamic models. Modeled water current data in the northern Irish Sea showed that post-smolts had a strong preference for migrating when the current direction was at around 283° (west-north-west) but did not migrate when exposed to strong currents in other directions. This is the most favorable direction for onward passage from the Irish Sea to the continental shelf edge current, a known accumulation point for migrating post-smolts. These results strongly indicate that post-smolts migrating through the coastal marine environment are: (1) not simply migrating by current following (2) engage in active directional swimming (3) have an intrinsic sense of their migration direction and (4) can use cues other than water current direction to orientate during this part of their migration.

Determinants of riverine migration success by Atlantic salmon (Salmo salar) smolts from rivers across the UK and Ireland.

There is some evidence that the river migration success of Atlantic salmon smolts, on their first migration to sea, varies both spatially and temporally. However, we have only a poor understanding of what may be driving this variation. In this study, we used acoustic telemetry to quantify the spatial and temporal variations in river migration success in Atlantic salmon smolts on their first migration to sea. In total 4120 Atlantic salmon smolts migrating through 22 rivers in Scotland, England, Ireland, and Northern Ireland over multiple years were included in the study. Individuals were defined as successful migrants if detected leaving the river to enter marine waters. The results show significant temporal (up to 4 years) and spatial (river) variations in migration success, with overall between-river migration success varying from 3.4% to 97.0% and between years from 3.4% and 61.0%. Temporal variation in migration success was river specific, with some rivers being more temporally stable (exhibiting little variation between years) than others. Across all rivers and years, individual migration success was predicted positively by body condition and negatively by tag burden. The rate of migration success for a population (migration success standardized to a common river distance [proportion km-1]) was predicted by a number of environmental factors. The proportion of river catchment that comprised wetland and woodland positively predicted migration success, whereas the proportion of grassland and peatland in a catchment negatively predicted the rate of migration success. Although the mechanisms through which these effects may be operating were not directly examined in this study, we discuss some potential routes through which they may occur.

Inshore and offshore marine migration pathways of Atlantic salmon post-smolts from multiple rivers in Scotland, England, Northern Ireland, and Ireland.

The migratory behavior of Atlantic salmon (Salmo salar) post-smolts in coastal waters is poorly understood. In this collaborative study, 1914 smolts, from 25 rivers, in four countries were tagged with acoustic transmitters during a single seasonal migration. In total, 1105 post-smolts entered the marine study areas and 438 (39.6%) were detected on a network of 414 marine acoustic receivers and an autonomous underwater vehicle. Migration pathways (defined as the shortest distance between two detections) of up to 575 km and over 100 days at sea were described for all 25 populations. Post-smolts from different rivers, as well as individuals from the same river, used different pathways in coastal waters. Although difficult to generalize to all rivers, at least during the year of this study, no tagged post-smolts from rivers draining into the Irish Sea were detected entering the areas of sea between the Hebrides and mainland Scotland, which is associated with a high density of finfish aquaculture. An important outcome of this study is that a high proportion of post-smolts crossed through multiple legislative jurisdictions and boundaries during their migration. This study provides the basis for spatially explicit assessment of the impact risk of coastal pressures on salmon during their first migration to sea.

Effect of a Surgical Care Bundle on the Incidence of Surgical Site Infection in Colorectal Surgery: A Quasi-Experimental Intervention.

BACKGROUND: Surgical site infections (SSI) have an important impact on morbidity and mortality. OBJECTIVE: This study, therefore, sought to assess the effect of a surgical care bundle on the incidence of SSI in colorectal surgery. METHODS: We conducted a quasi-experimental intervention study with reference to the introduction of a surgical care bundle in 2011. Our study population, made up of patients who underwent colorectal surgery, was divided into the following two periods: 2007-2011 (pre-intervention) and 2012-2017 (post-intervention). The intervention's effect on SSI incidence was analyzed using adjusted odds ratios (OR). RESULTS: A total of 1,727 patients were included in the study. SSI incidence was 13.0% before versus 11.6% after implementation of the care bundle (OR: 0.88, 95% confidence interval: 0.66-1.17, p = 0.37). Multivariate analysis showed that cancer, chronic obstructive pulmonary disease, neutropenia, and emergency surgery were independently associated with SSI. In contrast, laparoscopic surgery proved to be a protective factor against SSI. CONCLUSIONS: Care bundles have proven to be very important in reducing SSI incidence since the measures that constitute these protocols are mutually reinforcing. In our study, the implementation of a care bundle reduced SSI incidence from 13% to 11.6%, though the reduction was not statistically significant.

Evolution of transcription factor binding in metazoans - mechanisms and functional implications.

Differences in transcription factor binding can contribute to organismal evolution by altering downstream gene expression programmes. Genome-wide studies in Drosophila melanogaster and mammals have revealed common quantitative and combinatorial properties of in vivo DNA binding, as well as marked differences in the rate and mechanisms of evolution of transcription factor binding in metazoans. Here, we review the recently discovered rapid 're-wiring' of in vivo transcription factor binding between related metazoan species and summarize general principles underlying the observed patterns of evolution. We then consider what might explain the differences in genome evolution between metazoan phyla and outline the conceptual and technological challenges facing this research field.

Codon-Driven Translational Efficiency Is Stable across Diverse Mammalian Cell States.

Whether codon usage fine-tunes mRNA translation in mammals remains controversial, with recent papers suggesting that production of proteins in specific Gene Ontological (GO) pathways can be regulated by actively modifying the codon and anticodon pools in different cellular conditions. In this work, we compared the sequence content of genes in specific GO categories with the exonic genome background. Although a substantial fraction of variability in codon usage could be explained by random sampling, almost half of GO sets showed more variability in codon usage than expected by chance. Nevertheless, by quantifying translational efficiency in healthy and cancerous tissues in human and mouse, we demonstrated that a given tRNA pool can equally well translate many different sets of mRNAs, irrespective of their cell-type specificity. This disconnect between variations in codon usage and the stability of translational efficiency is best explained by differences in GC content between gene sets. GC variation across the mammalian genome is most likely a result of the interplay between genome repair and gene duplication mechanisms, rather than selective pressures caused by codon-driven translational rates. Consequently, codon usage differences in mammalian transcriptomes are most easily explained by well-understood mutational biases acting on the underlying genome.

A role for insulator elements in the regulation of gene expression response to hypoxia.

Hypoxia inducible factor (HIF) up-regulates the transcription of a few hundred genes required for the adaptation to hypoxia. This restricted set of targets is in sharp contrast with the widespread distribution of the HIF binding motif throughout the genome. Here, we investigated the transcriptional response of GYS1 and RUVBL2 genes to hypoxia to understand the mechanisms that restrict HIF activity toward specific genes. GYS1 and RUVBL2 genes are encoded by opposite DNA strands and separated by a short intergenic region (~1 kb) that contains a functional hypoxia response element equidistant to both genes. However, hypoxia induced the expression of GYS1 gene only. Analysis of the transcriptional response of chimeric constructs derived from the intergenic region revealed an inhibitory sequence whose deletion allowed RUVBL2 induction by HIF. Enhancer blocking assays, performed in cell culture and transgenic zebrafish, confirmed the existence of an insulator element within this inhibitory region that could explain the differential regulation of GYS1 and RUVBL2 by hypoxia. Hence, in this model, the selective response to HIF is achieved with the aid of insulator elements. This is the first report suggesting a role for insulators in the regulation of differential gene expression in response to environmental signals.

DNA methylation patterns of transcription factor binding regions characterize their functional and evolutionary contexts.

BACKGROUND: DNA methylation is an important epigenetic modification which has numerous roles in modulating genome function. Its levels are spatially correlated across the genome, typically high in repressed regions but low in transcription factor (TF) binding sites and active regulatory regions. However, the mechanisms establishing genome-wide and TF binding site methylation patterns are still unclear. RESULTS: Here we use a comparative approach to investigate the association of DNA methylation to TF binding evolution in mammals. Specifically, we experimentally profile DNA methylation and combine this with published occupancy profiles of five distinct TFs (CTCF, CEBPA, HNF4A, ONECUT1, FOXA1) in the liver of five mammalian species (human, macaque, mouse, rat, dog). TF binding sites are lowly methylated, but they often also have intermediate methylation levels. Furthermore, biding sites are influenced by the methylation status of CpGs in their wider binding regions even when CpGs are absent from the core binding motif. Employing a classification and clustering approach, we extract distinct and species-conserved patterns of DNA methylation levels at TF binding regions. CEBPA, HNF4A, ONECUT1, and FOXA1 share the same methylation patterns, while CTCF's differ. These patterns characterize alternative functions and chromatin landscapes of TF-bound regions. Leveraging our phylogenetic framework, we find DNA methylation gain upon evolutionary loss of TF occupancy, indicating coordinated evolution. Furthermore, each methylation pattern has its own evolutionary trajectory reflecting its genomic contexts. CONCLUSIONS: Our epigenomic analyses indicate a role for DNA methylation in TF binding changes across species including that specific DNA methylation profiles characterize TF binding and are associated with their regulatory activity, chromatin contexts, and evolutionary trajectories.

Genome-wide identification of hypoxia-inducible factor binding sites and target genes by a probabilistic model integrating transcription-profiling data and in silico binding site prediction.

The transcriptional response driven by Hypoxia-inducible factor (HIF) is central to the adaptation to oxygen restriction. Hence, the complete identification of HIF targets is essential for understanding the cellular responses to hypoxia. Herein we describe a computational strategy based on the combination of phylogenetic footprinting and transcription profiling meta-analysis for the identification of HIF-target genes. Comparison of the resulting candidates with published HIF1a genome-wide chromatin immunoprecipitation indicates a high sensitivity (78%) and specificity (97.8%). To validate our strategy, we performed HIF1a chromatin immunoprecipitation on a set of putative targets. Our results confirm the robustness of the computational strategy in predicting HIF-binding sites and reveal several novel HIF targets, including RE1-silencing transcription factor co-repressor (RCOR2). In addition, mapping of described polymorphisms to the predicted HIF-binding sites identified several single-nucleotide polymorphisms (SNPs) that could alter HIF binding. As a proof of principle, we demonstrate that SNP rs17004038, mapping to a functional hypoxia response element in the macrophage migration inhibitory factor (MIF) locus, prevents induction of this gene by hypoxia. Altogether, our results show that the proposed strategy is a powerful tool for the identification of HIF direct targets that expands our knowledge of the cellular adaptation to hypoxia and provides cues on the inter-individual variation in this response.

[Adequacy of pre-surgical hand hygiene in an university teaching hospital in Madrid (Spain).] / Adecuación de la higiene prequirúrgica de manos en un hospital universitario de Madrid.

OBJECTIVE: We know the importance of hand hygiene in the prevention of healthcare-associated infections. However, its compliance is still a challenge. Moreover, when it is complied with, as in the case of preoperative hygiene, there are few studies on the proper performance of the technique. The aim of this paper is to assess adequacy of pre-surgical hand hygiene in operating room staff of different surgical specialities at a university teaching hospital in Madrid. METHODS: A cross-sectional study was made. Adequacy of pre-surgical hand hygiene was assessed in operating room staff of the different specialities and professional categories by direct covert observation. It was evaluated in 852 opportunities during the months of October, November and December 2020. A specific form was designed for data collection, following the recommendations of the World Health Organisation (WHO). Adequacy was described with frequency distributions of the different groups observed. Whether Chi-square or Fisher's exact tests were used to compare the different categories. RESULTS: Pre-surgical hand hygiene opportunities were evaluated, 75.5% in surgeons and 24.5% in nurses. Overall compliance with pre-surgical hand hygiene technique was 80.5 % (686). The most frequent surgical service evaluated was General Surgery with 240 observations. The professional category with the best adequacy was nursing (86.1%) and the surgical service one was Traumatology (90.2%). An stopwatch was used by some 25.8% of the evaluated professionals, with an adequate hygiene time of 96,8% (p<0,05) for that group. CONCLUSIONS: The overall adequacy of pre-surgical hand hygiene in the operating room professionals is high. Significant statistically differences in adequacy are found between professional categories and surgical specialities, with better compliance in nursing staff and in Traumatology. Better results are achieved by the use of an stopwatch.

OBJETIVO: Sabemos la importancia que tiene la higiene de manos en la prevención de infecciones asociadas a la asistencia sanitaria. Sin embargo, a día de hoy, su cumplimiento, es un reto. Además, cuando se cumple, como es el caso de en la higiene prequirúrgica, pocos estudios hay sobre la adecuada realización de la técnica. El objetivo de este estudio fue evaluar la adecuación de la higiene de manos prequirúrgica en profesionales de quirófano de un Hospital Universitario de Madrid. METODOS: Se realizó un estudio descriptivo trasversal. Se evaluó la adecuación de la higiene de manos prequirúrgica mediante observación directa y enmascarada en 852 oportunidades durante los meses de octubre, noviembre y diciembre de 2020. Se consideró adecuada la higiene de manos si ésta se realizaba según la técnica correcta y durante el tiempo indicado. La adecuación de la higiene de manos se describió con la distribución de frecuencias y las diferencias entre categorías se compararon con la prueba x2 de Pearson o prueba exacta de Fisher. RESULTADOS: Se evaluaron las oportunidades de higiene de manos prequirúrgica, el 75,5% en cirujanos y el 24,5% en personal de enfermería. La adecuación global de la higiene de manos fue del 80,5%. La categoría profesional con mejor adecuación fue Enfermería (86,1%) (p<0,05) y el servicio quirúrgico con mejor adecuación fue Traumatología (90,2%) (p<0,05). Un 25,8% de los profesionales evaluados utilizó el apoyo del cronómetro, consiguiendo este grupo una adecuación al tiempo de higiene del 96,8% (p<0,05). CONCLUSIONES: La adecuación global de la higiene de manos prequirúrgica en nuestros profesionales es muy alta. Se encuentran diferencias estadísticamente significativas de cumplimiento entre categorías profesionales y especialidades quirúrgicas, siendo mejor la adecuación en el personal de Enfermería y en la especialidad de Traumatología. El apoyo del cronómetro consigue mejores resultados en la adecuación al tiempo de higiene.

LINE retrotransposons characterize mammalian tissue-specific and evolutionarily dynamic regulatory regions.

BACKGROUND: To investigate the mechanisms driving regulatory evolution across tissues, we experimentally mapped promoters, enhancers, and gene expression in the liver, brain, muscle, and testis from ten diverse mammals. RESULTS: The regulatory landscape around genes included both tissue-shared and tissue-specific regulatory regions, where tissue-specific promoters and enhancers evolved most rapidly. Genomic regions switching between promoters and enhancers were more common across species, and less common across tissues within a single species. Long Interspersed Nuclear Elements (LINEs) played recurrent evolutionary roles: LINE L1s were associated with tissue-specific regulatory regions, whereas more ancient LINE L2s were associated with tissue-shared regulatory regions and with those switching between promoter and enhancer signatures across species. CONCLUSIONS: Our analyses of the tissue-specificity and evolutionary stability among promoters and enhancers reveal how specific LINE families have helped shape the dynamic mammalian regulome.

Incidence of surgical infection and risk factors in colorectal surgery - A prospective cohort study.

OBJECTIVE: The objective was to measure the incidence of surgical site infection (SSI) and identify risk factors, in patients undergoing elective surgery of the colon and rectum. MATERIALS AND METHODS: A prospective cohort study was performed from January 2017 to December 2018. RESULTS: A total of 130 patients were studied. The cumulative incidence of SSI was 12.3%. The 56.25% were superficial wound infections and the 31.25%, organ-space infection. The risk factors significantly associated with SSI were the non-administration of pre-operative oral nutrition, diabetes mellitus, heart disease, symptomatic state at the diagnosis of colorectal cancer (CRC), and ≥ 2 altered nutritional biochemical parameters at diagnosis. After multivariate , risk factors associated with SSI were: non-administration of preoperative enteral nutrition (odds ratio [OR] = 0.27; 95% confidence interval [CI]: 0.07-1.0), DM (OR = 3.0; 95% CI: 0.9-9.9), the heart disease (OR = 4.6; 95% CI: 1.1-18.6), and laparoscopic surgery (OR = 0.28; 95% CI: 0.08-0.97). The average stay was higher in patients with a diagnosis of SSI (11.9 vs. 9.2 days). CONCLUSIONS: Independent risk factors for SSI in CRC were the non-administration of pre-operative enteral nutrition, the existence of heart disease, and open surgery.

OBJETIVO: Estudiar la incidencia de infección del sitio quirúrgico y evaluar sus factores de riesgo en pacientes intervenidos de cirugía colorrectal electiva. MÉTODO: Se realizó un estudio de cohortes prospectivo desde enero de 2017 hasta diciembre de 2018. RESULTADOS: Se incluyeron 130 pacientes. La incidencia acumulada de infección del sitio quirúrgico fue del 12,3% (n = 16), siendo el 56,25% infecciones de herida y el 31,25% infecciones órgano-espacio. Los factores de riesgo asociados a infección del sitio quirúrgico con significación estadística fueron la no administración de nutrición oral preoperatoria, la diabetes mellitus, la enfermedad cardiaca, la presencia de síntomas en el momento del diagnóstico de cáncer colorrectal y tener al menos dos parámetros bioquímicos nutricionales alterados. Tras el análisis multivariante se asociaron la no administración de nutrición enteral preoperatoria (odds ratio [OR] = 0,27; intervalo de confianza del 95% [IC95%]: 0,07-1,0), la diabetes mellitus (OR = 3,0; IC95%: 0,9-9,9), la enfermedad cardiaca (OR = 4,6; IC95%: 1,1-18,6) y la cirugía laparoscópica (OR = 0,28; IC95%: 0,08-0,97). La estancia media fue mayor en los pacientes con diagnóstico de infección del sitio quirúrgico (11,9 frente a 9,2 días). CONCLUSIONES: Los factores de riesgo independientes para el desarrollo de infección del sitio quirúrgico en los pacientes con cáncer colorrectal fueron la no administración de nutrición oral preoperatoria, la enfermedad cardiaca y la cirugía abierta.

Antibiotic prophylaxis adequacy assessment and its influence on surgical site infection in peripheral vascular bypass surgery.

OBJECTIVE: We sought to assess the degree of antibiotic prophylaxis adequacy to our surgical antibiotic prophylaxis protocol among patients who underwent peripheral vascular bypass surgery. MATERIALS AND METHODS: Prospective cohort study. Adequacy to protocol was studied by comparing the different aspects of prophylaxis received by patients to those stipulated in the protocol in force at our hospital. Incidence of surgical wound infection was calculated and the effect of prophylaxis inadequacy on the incidence of surgical wound infection was estimated using the relative risk. RESULTS: The study covered 266 patients. Incidence of surgical site infection (SSI) after the follow-up period was 5.3% (95% Confidence interval [CI]: 3.0-9.4). Overall adequacy to the protocol of antibiotic prophylaxis was 91.0% (95% CI: 87.6-94.4). The most frequent cause of inadequacy to the protocol was time of initiation of antibiotic prophylaxis (94.1%). No relationship was found between SSI and antibiotic prophylaxis inadequacy (relative risk: 2.4; 95% CI: 0.49-12.5; p > 0.05). CONCLUSIONS: Global adequacy to protocol of antibiotic prophylaxis was high. The most frequent cause of inadequacy to the protocol was time of initiation of antibiotic prophylaxis.

OBJETIVO: Buscamos evaluar el grado de adecuación de la profilaxis antibiótica a nuestro protocolo de profilaxis antibiótica quirúrgica entre los pacientes sometidos a cirugía de bypass vascular periférico. MATERIAL Y MÉTODOS: Estudio de cohortes prospectivo. La adecuación al protocolo se estudió comparando los diferentes aspectos de la profilaxis recibida por los pacientes con los estipulados en el protocolo vigente en nuestro hospital. Se calculó la incidencia de infección de herida quirúrgica y se estimó el efecto de la inadecuación de la profilaxis sobre la incidencia de infección de herida quirúrgica mediante el riesgo relativo. RESULTADOS: El estudio abarcó 266 pacientes. La incidencia de infección del sitio quirúrgico (ISQ) tras el periodo de seguimiento fue del 5,3% (intervalo de confianza [IC] del 95%: 3,0-9,4). La adecuación global al protocolo de profilaxis antibiótica fue del 91,0% (IC 95%: 87,6-94,4). La causa más frecuente de inadecuación al protocolo fue el momento de inicio de la profilaxis antibiótica (94,1%). No se encontró relación entre ISQ e inadecuación de la profilaxis antibiótica (riesgo relativo: 2,4; IC 95%: 0,49-12,5; p > 0,05). CONCLUSIONES: La adecuación global al protocolo de la profilaxis antibiótica fue alta. La causa más frecuente de inadecuación al protocolo fue el momento de inicio de la profilaxis antibiótica.

The contribution of non-coding regulatory elements to cardiovascular disease.

Cardiovascular disease collectively accounts for a quarter of deaths worldwide. Genome-wide association studies across a range of cardiovascular traits and pathologies have highlighted the prevalence of common non-coding genetic variants within candidate loci. Here, we review genetic, epigenomic and molecular approaches to investigate the contribution of non-coding regulatory elements in cardiovascular biology. We then discuss recent insights on the emerging role of non-coding variation in predisposition to cardiovascular disease, with a focus on novel mechanistic examples from functional genomics studies. Lastly, we consider the clinical significance of these findings at present, and some of the current challenges facing the field.

Surgical site infection in hip arthroplasty in a 10-year follow-up prospective study: Risk and factors associated.

BACKGROUND: The increased demand for hip arthroplasty means a growing number of postsurgical complications. This study aims to assess the risk of surgical site infection (SSI) in a teaching hospital; develop regional, national and international external comparisons; and evaluate SSI-related risk factors, particularly according to the timing of surgery (urgent/unplanned or elective). METHODS: Prospective cohort study from January 2008 to December 2018. Patients were followed up to 90 days after surgery. Primary endpoint was SSI incidence according to the Centers for Disease Control and Prevention criteria. Multivariate analysis was conducted to find independently associated SSI risk factors. The association between risk factors and SSI incidence was assessed by reference to odds ratio (OR). Analyses were also performed among urgent/unplanned and elective patients to identify whether SSI risk factors differed between groups. RESULTS: The study population (n = 1,808) has an overall SSI rate of 3.0% (95% confidence interval [CI]: 2.4-3.9). Timing of surgery caused an effect modification, so surgery duration> 75th percentile (OR: 3.8; 95% CI: 1.5-9.8) and inadequate preparation (OR: 3.3; 95% CI: 1.1-10.0) were independent risk factors in the urgent/unplanned group; National Healthcare Safety Network risk index≥ 2 (OR: 6.3; 95% CI: 0.1-19.2) and transfusion (OR: 3.6; 95% CI: 1.1-11.9) in the elective group. CONCLUSIONS: Hospital infection surveillance systems allow identifying risk factors susceptible to change. Characterization of factors that caused an effect modification is key to identify areas of quality improvement, including reducing operating times, preventing perioperative blood transfusion, or improving patient preparation before surgery.

Adequacy of antibiotic prophylaxis protocol in appendectomies in children.

OBJECTIVE: To assess compliance of antibiotic prophylaxis in surgery for acute appendicitis in children and its effect on surgical site infection. METHODS: We carried out a prospective cohort study to evaluate compliance of antibiotic prophylaxis in appendectomies in children. An assessment of the level of compliance with prophylaxis was made, as well as the causes of non-compliance. The effect of non-compliance of antibiotic prophylaxis on the incidence of surgical site infection was studied with the adjusted relative risk (RR) with a backstep logistic regression model. RESULTS: The study included a total of 412 patients. Antibiotic prophylaxis was indicated in 348 patients, and administered in 95.7% of cases, with an overall protocol compliance of 90.7%. The principal cause of non-compliance was time of initiation. Cumulative incidence of surgical site infection was 2.7%. No relationship was found between inadequate prophylaxis compliance and infection (RR: 1.01; 95% confidence interval: 0.95-1.11; p = 0.61). CONCLUSIONS: Compliance of antibiotic prophylaxis was high, but could be improved. No relationship was found between prophylaxis compliance and surgical site infection rate.

OBJETIVO: Evaluar la adecuación de la profilaxis antibiótica en la cirugía de apendicitis aguda en niños y su efecto en la infección del sitio quirúrgico. MÉTODO: Estudio de cohortes prospectivo para evaluar la adecuación al protocolo de la profilaxis antibiótica en apendicectomías en población infantil. Se evaluaron la administración de la profilaxis y las causas de la inadecuación. Se estudió el efecto de la inadecuación en la incidencia de infección del sitio quirúrgico con el riesgo relativo (RR) ajustado con un modelo de regresión logística por pasos hacia atrás. RESULTADOS: Se estudiaron 412 pacientes. La profilaxis antibiótica estaba indicada en 348 pacientes y se administró en el 95.7% de los casos, con una adecuación global al protocolo del 90.7%. La causa principal del incumplimiento fue la hora de inicio. La incidencia acumulada de infección del sitio quirúrgico fue del 2.7%. No se encontró relación entre la adecuación de la profilaxis y la infección del sitio quirúrgico (RR: 1.01; intervalo de confianza del 95%: 0.95-1.11; p = 0.61). CONCLUSIONES: La adecuación de la profilaxis antibiótica fue alta, pero puede mejorarse. No se encontró relación entre la adecuación de la profilaxis antibiótica y la incidencia de infección del sitio quirúrgico.

Identification of a region on hypoxia-inducible-factor prolyl 4-hydroxylases that determines their specificity for the oxygen degradation domains.

HIFs [hypoxia-inducible (transcription) factors] are essential for the induction of an adaptive gene expression programme under low oxygen partial pressure. The activity of these transcription factors is mainly determined by the stability of the HIFalpha subunit, which is regulated, in an oxygen-dependent manner, by a family of three prolyl 4-hydroxylases [EGLN1-EGLN3 (EGL nine homologues 1-3)]. HIFalpha contains two, N- and C-terminal, independent ODDs (oxygen-dependent degradation domains), namely NODD and CODD, that, upon hydroxylation by the EGLNs, target HIFalpha for proteasomal degradation. In vitro studies indicate that each EGLN shows a differential preference for ODDs, However, the sequence determinants for such specificity are unknown. In the present study we showed that whereas EGLN1 and EGLN2 acted upon any of these ODDs to regulate HIF1alpha protein levels and activity in vivo, EGLN3 only acted on the CODD. With the aim of identifying the region within EGLNs responsible for their differential substrate preference, we investigated the activity and binding pattern of different EGLN deletions and chimaeric constructs generated by domain swapping between EGLN1 and EGLN3. These studies revealed a region of 97 residues that was sufficient to confer the characteristic substrate binding observed for each EGLN. Within this region, we identified the minimal sequence (EGLN1 residues 236-252) involved in substrate discrimination. Importantly, mapping of these sequences on the EGLN1 tertiary structure indicates that substrate specificity is determined by a region relatively remote from the catalytic site.