Functional Enrichment Analysis of Regulatory Elements

This work has been partially supported by FEDER/Junta de Andalucia-Consejeria de Economia y Conocimiento/(grant CV20-36723), grant PID2020-119032RB-I00, MCIN/AEI/10.13039/501100011033 and FEDER/Junta de Andalucia-Consejeria de Transformacion Economica, Industria, Conocimiento y Universidades (Grant P20_00335).Statistical methods for enrichment analysis are important tools to extract biological information from omics experiments. Although these methods have been widely used for the analysis of gene and protein lists, the development of high-throughput technologies for regulatory elements demands dedicated statistical and bioinformatics tools. Here, we present a set of enrichment analysis methods for regulatory elements, including CpG sites, miRNAs, and transcription factors. Statistical significance is determined via a power weighting function for target genes and tested by theWallenius noncentral hypergeometric distribution model to avoid selection bias. These new methodologies have been applied to the analysis of a set of miRNAs associated with arrhythmia, showing the potential of this tool to extract biological information from a list of regulatory elements. These new methods are available in GeneCodis 4, a web tool able to perform singular and modular enrichment analysis that allows the integration of heterogeneous information.FEDER/Junta de Andalucia-Consejeria de Economia y Conocimiento CV20-36723MCIN/AEI PID2020-119032RB-I00FEDER/Junta de Andalucia-Consejeria de Transformacion Economica, Industria, Conocimiento y Universidades P20_0033

The oxytocin analogue carbetocin prevents priming-induced reinstatement of morphine-seeking: Involvement of dopaminergic, noradrenergic and MOPr systems.

Relapse to illicit drug-seeking following abstinence is a major challenge for the treatment of addiction as no effective pharmacotherapy is available. We have recently shown that activating the central oxytocinergic system prevents emotional impairment and stress-induced reinstatement associated with opioid withdrawal. Here, we investigated whether the oxytocin analogue carbetocin (CBT) is able to reverse morphine-primed reinstatement of conditioned-place preference (CPP) in mice. The mechanism underlining the behavioural effect of CBT was investigated by assessing the involvement of the striatal noradrenergic and dopaminergic systems in CBT reversal of priming- and stress-induced reinstatement of opioid CPP. In addition, given recent evidence suggesting the presence of oxytocin receptor (OTR)-μ-opioid receptor (MOPr) interactions in the brain, we further explored these interactions by carrying out OTR autoradiographic binding in brain of mice lacking MOPr. CBT administration prevented priming-induced reinstatement of morphine CPP. While an acute effect of CBT in enhancing dopamine turnover was observed following stress- and priming-induced reinstatement, CBT significantly decreased striatal noradrenaline turnover only following priming-induced reinstatement. Moreover, a significant brain region- specific increase in OTR binding was observed in MOPr knockout mice, indicating the presence of a possible OTR-MOPr interaction, which may be involved in the modulation of relapse. These results support the oxytocinergic system as a promising target for the prevention of relapse to opioid use and highlight the differential involvement of monoaminergic systems on the effects of OTR stimulation in preventing stress- and priming-induced reinstatement of opioid CPP behaviour

Methamphetamine withdrawal induces activation of CRF neurons in the brain stress system in parallel with an increased activity of cardiac sympathetic pathways.

Methamphetamine (METH) addiction is a major public health problem in some countries. There is evidence to suggest that METH use is associated with increased risk of developing cardiovascular problems. Here, we investigated the effects of chronic METH administration and withdrawal on the activation of the brain stress system and cardiac sympathetic pathways. Mice were treated with METH (2 mg/kg, i.p.) for 10 days and left to spontaneous withdraw for 7 days. The number of corticotrophin-releasing factor (CRF), c-Fos, and CRF/c-Fos neurons was measured by immunohistochemistry in the paraventricular nucleus of the hypothalamus (PVN) and the oval region of the bed nucleus of stria terminalis (ovBNST), two regions associated with cardiac sympathetic control. In parallel, levels of catechol-o-methyl-transferase (COMT), tyrosine hydroxylase (TH), and heat shock protein 27 (Hsp27) were measured in the heart. In the brain, chronic-METH treatment enhanced the number of c-Fos neurons and the CRF neurons with c-Fos signal (CRF+/c-Fos+) in PVN and ovBNST. METH withdrawal increased the number of CRF+neurons. In the heart, METH administration induced an increase in soluble (S)-COMT and membrane-bound (MB)-COMT without changes in phospho (p)-TH, Hsp27, or pHsp27. Similarly, METH withdrawal increased the expression of S- and MB-COMT. In contrast to chronic treatment, METH withdrawal enhanced levels of (p)TH and (p)Hsp27 in the heart. Overall, our results demonstrate that chronic METH administration and withdrawal activate the brain CRF systems associated with the heart sympathetic control and point towards a METH withdrawal induced activation of sympathetic pathways in the heart. Our findings provide further insight in the mechanism underlining the cardiovascular risk associated with METH use and proposes targets for its treatment

International Consensus Document on Obstructive Sleep Apnea

El objetivo principal de este documento internacional de consenso sobre apnea obstructiva del sueno es proporcionar unas directrices que permitan a los profesionales sanitarios tomar las mejores decisiones en la asistencia de los pacientes adultos con esta enfermedad según un resumen crítico de la literatura más actualizada. El grupo de trabajo de expertos se ha constituido principalmente por 17 sociedades científicas y 56 especialistas con amplia representación geográfica (con la participación de 4 sociedades internacionales), además de un metodólogo experto y un documentalista del Centro Cochrane Iberoamer icano. El documento consta de un manuscrito principal, con las novedades más relevantes del DIC, y una serie de manuscritos online que recogen las búsquedas bibliográficas sistemáticas de cada uno de los apartados del DIC. Este documento no cubre la edad pediátrica ni el manejo del paciente en ventilación mecánica crónica no invasiva (que se publicarán en sendos documentos de consenso aparte)

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Short-term changes in klotho and FGF23 in heart failure with reduced ejection fraction—a substudy of the DAPA-VO2 study

The klotho and fibroblast growth factor 23 (FGF-23) pathway is implicated in cardiovascular pathophysiology. This substudy aimed to assess the changes in klotho and FGF-23 levels 1-month after dapagliflozin in patients with stable heart failure and reduced ejection fraction (HFrEF). The study included 29 patients (32.2% of the total), with 14 assigned to the placebo group and 15 to the dapagliflozin, as part of the double-blind, randomized clinical trial [DAPA-VO2 (NCT04197635)]. Blood samples were collected at baseline and after 30 days, and Klotho and FGF-23 levels were measured using ELISA Kits. Between-treatment changes (raw data) were analyzed by using the Mann-Whitney test and expressed as median (p25%–p75%). Linear regression models were utilized to analyze changes in the logarithm (log) of klotho and FGF-23. The median age was 68.3 years (60.8–72.1), with 79.3% male and 81.5% classified as NYHA II. The baseline medians of left ventricular ejection fraction, glomerular filtration rate, NT-proBNP, klotho, and FGF-23 were 35.8% (30.5–37.8), 67.4 ml/min/1.73 m2 (50.7–82.8), 1,285 pg/ml (898–2,305), 623.4 pg/ml (533.5–736.6), and 72.6 RU/ml (62.6–96.1), respectively. The baseline mean peak oxygen uptake was 13.1 ± 4.0 ml/kg/min. Compared to placebo, patients on dapagliflozin showed a significant median increase of klotho [Δ+29.5, (12.9–37.2); p = 0.009] and a non-significant decrease of FGF-23 [Δ−4.6, (−1.7 to −5.4); p = 0.051]. A significant increase in log-klotho (p = 0.011) and a decrease in log-FGF-23 (p = 0.040) were found in the inferential analysis. In conclusion, in patients with stable HFrEF, dapagliflozin led to a short-term increase in klotho and a decrease in FGF-23

COVID-19 Sequelae and the Host Pro-Inflammatory Response: An Analysis From the OnCovid Registry

Background: Fifteen percent of patients with cancer experience symptomatic sequelae, which impair post–COVID-19 outcomes. In this study, we investigated whether a proinflammatory status is associated with the development of COVID-19 sequelae. / Methods: OnCovid recruited 2795 consecutive patients who were diagnosed with Severe Acute Respiratory Syndrome Coronavirus 2 infection between February 27, 2020, and February 14, 2021. This analysis focused on COVID-19 survivors who underwent a clinical reassessment after the exclusion of patients with hematological malignancies. We evaluated the association of inflammatory markers collected at COVID-19 diagnosis with sequelae, considering the impact of previous systemic anticancer therapy. All statistical tests were 2-sided. / Results: Of 1339 eligible patients, 203 experienced at least 1 sequela (15.2%). Median baseline C-reactive protein (CRP; 77.5 mg/L vs 22.2 mg/L, P < .001), lactate dehydrogenase (310 UI/L vs 274 UI/L, P = .03), and the neutrophil to lymphocyte ratio (NLR; 6.0 vs 4.3, P = .001) were statistically significantly higher among patients who experienced sequelae, whereas no association was reported for the platelet to lymphocyte ratio and the OnCovid Inflammatory Score, which includes albumin and lymphocytes. The widest area under the ROC curve (AUC) was reported for baseline CRP (AUC = 0.66, 95% confidence interval [CI]: 0.63 to 0.69), followed by the NLR (AUC = 0.58, 95% CI: 0.55 to 0.61) and lactate dehydrogenase (AUC = 0.57, 95% CI: 0.52 to 0.61). Using a fixed categorical multivariable analysis, high CRP (odds ratio [OR] = 2.56, 95% CI: 1.67 to 3.91) and NLR (OR = 1.45, 95% CI: 1.01 to 2.10) were confirmed to be statistically significantly associated with an increased risk of sequelae. Exposure to chemotherapy was associated with a decreased risk of sequelae (OR = 0.57, 95% CI: 0.36 to 0.91), whereas no associations with immune checkpoint inhibitors, endocrine therapy, and other types of systemic anticancer therapy were found. / Conclusions: Although the association between inflammatory status, recent chemotherapy and sequelae warrants further investigation, our findings suggest that a deranged proinflammatory reaction at COVID-19 diagnosis may predict for sequelae development

SARS-CoV-2 omicron (B.1.1.529)-related COVID-19 sequelae in vaccinated and unvaccinated patients with cancer: results from the OnCovid registry

Background COVID-19 sequelae can affect about 15% of patients with cancer who survive the acute phase of SARS-CoV-2 infection and can substantially impair their survival and continuity of oncological care. We aimed to investigate whether previous immunisation affects long-term sequelae in the context of evolving variants of concern of SARS-CoV-2. Methods OnCovid is an active registry that includes patients aged 18 years or older from 37 institutions across Belgium, France, Germany, Italy, Spain, and the UK with a laboratory-confirmed diagnosis of COVID-19 and a history of solid or haematological malignancy, either active or in remission, followed up from COVID-19 diagnosis until death. We evaluated the prevalence of COVID-19 sequelae in patients who survived COVID-19 and underwent a formal clinical reassessment, categorising infection according to the date of diagnosis as the omicron (B.1.1.529) phase from Dec 15, 2021, to Jan 31, 2022; the alpha (B.1.1.7)-delta (B.1.617.2) phase from Dec 1, 2020, to Dec 14, 2021; and the pre-vaccination phase from Feb 27 to Nov 30, 2020. The prevalence of overall COVID-19 sequelae was compared according to SARS-CoV-2 immunisation status and in relation to post-COVID-19 survival and resumption of systemic anticancer therapy. This study is registered with ClinicalTrials.gov, NCT04393974. Findings At the follow-up update on June 20, 2022, 1909 eligible patients, evaluated after a median of 39 days (IQR 24-68) from COVID-19 diagnosis, were included (964 [ 50 center dot 7%] of 1902 patients with sex data were female and 938 [49 center dot 3%] were male). Overall, 317 (16 center dot 6%; 95% CI 14 center dot 8-18 center dot 5) of 1909 patients had at least one sequela from COVID-19 at the first oncological reassessment. The prevalence of COVID-19 sequelae was highest in the prevaccination phase (191 [19 center dot 1%; 95% CI 16 center dot 4-22 center dot 0] of 1000 patients). The prevalence was similar in the alpha-delta phase (110 [16 center dot 8%; 13 center dot 8- 20 center dot 3] of 653 patients, p=0 center dot 24), but significantly lower in the omicron phase (16 [6 center dot 2%; 3 center dot 5-10 center dot 2] of 256 patients, p<0 center dot 0001). In the alpha- delta phase, 84 (18 center dot 3%; 95% CI 14 center dot 6-22 center dot 7) of 458 unvaccinated patients and three (9 center dot 4%; 1 center dot 9- 27 center dot 3) of 32 unvaccinated patients in the omicron phase had sequelae. Patients who received a booster and those who received two vaccine doses had a significantly lower prevalence of overall COVID-19 sequelae than unvaccinated or partially vaccinated patients (ten [7 center dot 4%; 95% CI 3 center dot 5-13 center dot 5] of 136 boosted patients, 18 [9 center dot 8%; 5 center dot 8-15 center dot 5] of 183 patients who had two vaccine doses vs 277 [ 18 center dot 5%; 16 center dot 5-20 center dot 9] of 1489 unvaccinated patients, p=0 center dot 0001), respiratory sequelae (six [4 center dot 4%; 1 center dot 6-9 center dot 6], 11 [6 center dot 0%; 3 center dot 0-10 center dot 7] vs 148 [9 center dot 9%; 8 center dot 4- 11 center dot 6], p= 0 center dot 030), and prolonged fatigue (three [2 center dot 2%; 0 center dot 1-6 center dot 4], ten [5 center dot 4%; 2 center dot 6-10 center dot 0] vs 115 [7 center dot 7%; 6 center dot 3-9 center dot 3], p=0 center dot 037)

Epidemiological trends of HIV/HCV coinfection in Spain, 2015-2019

Altres ajuts: Spanish AIDS Research Network; European Funding for Regional Development (FEDER).Objectives: We assessed the prevalence of anti-hepatitis C virus (HCV) antibodies and active HCV infection (HCV-RNA-positive) in people living with HIV (PLWH) in Spain in 2019 and compared the results with those of four similar studies performed during 2015-2018. Methods: The study was performed in 41 centres. Sample size was estimated for an accuracy of 1%. Patients were selected by random sampling with proportional allocation. Results: The reference population comprised 41 973 PLWH, and the sample size was 1325. HCV serostatus was known in 1316 PLWH (99.3%), of whom 376 (28.6%) were HCV antibody (Ab)-positive (78.7% were prior injection drug users); 29 were HCV-RNA-positive (2.2%). Of the 29 HCV-RNA-positive PLWH, infection was chronic in 24, it was acute/recent in one, and it was of unknown duration in four. Cirrhosis was present in 71 (5.4%) PLWH overall, three (10.3%) HCV-RNA-positive patients and 68 (23.4%) of those who cleared HCV after anti-HCV therapy (p = 0.04). The prevalence of anti-HCV antibodies decreased steadily from 37.7% in 2015 to 28.6% in 2019 (p < 0.001); the prevalence of active HCV infection decreased from 22.1% in 2015 to 2.2% in 2019 (p < 0.001). Uptake of anti-HCV treatment increased from 53.9% in 2015 to 95.0% in 2019 (p < 0.001). Conclusions: In Spain, the prevalence of active HCV infection among PLWH at the end of 2019 was 2.2%, i.e. 90.0% lower than in 2015. Increased exposure to DAAs was probably the main reason for this sharp reduction. Despite the high coverage of treatment with direct-acting antiviral agents, HCV-related cirrhosis remains significant in this population