Effect of an early neurocognitive rehabilitation on autonomic nervous system in critically ill patients

Introduction Recent clinical and electrophysiological studies reveal a high incidence of autonomic nervous system (ANS) dys- function in patients treated in ICU [1]. ANS disturbances may produce diverse and unexpected consequences. For instance, critically ill patients are at risk of neurocognitive impairments that may persist after hospital discharge. Among various pathophysiological mechanisms proposed, ANS dysfunction leading cholinergic deficiency seems one of the most viable to explain the development of long-term sequelae. Heart rate variability (HRV) has been related to the activity of the prefrontal cortex [2] hence, prefrontal activation could help to strengthen the auto- nomic nervous system integrity. We are interested in assessing the improvement of the ANS dysfunction through neural circuits’ activation. Thus, we propose a novel therapy that could allow the reinforcing of ANS through an early neurocognitive intervention targeted to improve prefrontal activation. Objectives The aim of this study was to explore if the integrity of the ANS, via cardiac vagal tone, measured by the HRV can be modified after early neurocognitive rehabilitation in ICU patients. Methods A total of 17 critically ill patients received a 20-minute Early Neurocognitive Rehabilitation (ENR) session in their own bed in the ICU. HRV was derived from the recorded ECG signal during pre-session, session and post-session. Power in the specific frequency bands related to sympathetic and parasympathetic systems was computed (PLF and PHF for low and high frequency bands, respectively). PLF was computed within the clas- sic band, while PHF was computed within a band cen- tered at respiratory rate. Changes in the HRV parameters from pre-session to session, and from pre- session to post-session were studied using Wilcoxon signed-rank test. Results Clinical data of the sample are summarized in table 1. Comparing with baseline values, 9 patients (53%) showed a decreased PLF in post-session, while 8 patients (47%) presented a higher PLF (p = .759). In 12 patients (71%), PHF increased after the ENR session, suggesting an increase of parasympathetic activity (p = .836). Conclusions Diagnosis, severity of illness or medication could explain the differential effect in the evolution of the HRV para- meters among different patients. Despite differences, an early neurocognitive rehabilitation seems to increase parasympathetic activity after the session in the majority of the patients. Clinical characteristics of the critical ill patients should be further studied to determinate which patients could be the best candidates for early neurocog- nitive intervention

The relevance of the SH2 domain for c-Src functionality in triple-negative breast cancer cells

The role of Src family kinases (SFKs) in human tumors has been always associated with tyrosine kinase activity and much less attention has been given to the SH2 and SH3 adapter domains. Here, we studied the role of the c-Src-SH2 domain in triple-negative breast cancer (TNBC). To this end, SUM159PT and MDA-MB-231 human cell lines were employed as model systems. These cells conditionally expressed, under tetracycline control (Tet-On system), a c-Src variant with point-inactivating mutation of the SH2 adapter domain (R175L). The expression of this mutant reduced the self-renewal capability of the enriched population of breast cancer stem cells (BCSCs), demonstrating the importance of the SH2 adapter domain of c-Src in the mammary gland carcinogenesis. In addition, the analysis of anchorage-independent growth, proliferation, migration, and invasiveness, all processes associated with tumorigenesis, showed that the SH2 domain of c-Src plays a very relevant role in their regulation. Furthermore, the transfection of two different aptamers directed to SH2-c-Src in both SUM159PT and MDA-MB-231 cells induced inhibition of their proliferation, migration, and invasiveness, strengthening the hypothesis that this domain is highly involved in TNBC tumorigenesis. Therefore, the SH2 domain of c-Src could be a promising therapeutic target and combined treatments with inhibitors of c-Src kinase enzymatic activity may represent a new therapeutic strategy for patients with TNBC, whose prognosis is currently very negative

FERO: Finding Extreme Relativistic Objects. I. Statistics of Relativistic Fe Kalpha lines in Radio-Quiet Type 1 AGN

Accretion models predict that fluorescence lines broadened by relativistic effects should arise from reflection of X-ray emission onto the inner region of the accretion disc surrounding the central black hole of active galactic nuclei (AGN). The theory behind the origin of relativistic lines is well established, and observational evidence from a moderate number of sources seems to support the existence of these lines. The aim of this work is to establish the fraction of AGN with relativistic Fe Kalpha lines, and study possible correlations with source physical properties. An XMM-Newton collection of 149 radio-quiet Type 1 AGN has been systematically and uniformly analyzed in order to search for significant evidence of a relativistically broadened Fe Kalpha line. To enable statistical studies, an almost complete, flux-limited subsample of 31 sources has been defined. The 2-10 keV spectra of the FERO sources have been compared with a complex model including most of the physical components observed in the X-ray spectra of Seyfert galaxies: a power law primary continuum modified by non-relativistic Compton reflection and warm absorption, plus a series of narrow Fe line reflection features. The observed fraction of sources in the flux-limited sample that show significant evidence of a relativistic Fe Kalpha line is 36%. The average line Equivalent Width (EW) is of the order of 100 eV, while the average disc inclination angle is 28+/-5 deg and the average power-law index of the radial disc emissivity law is 2.4+/-0.4. The spin value is well constrained only in 2 cases (MCG-6-30-15 and MRK509), and in the rest of the cases, whenever a constraint can be placed, it always implies the rejection of the static black hole solution. The Fe Kalpha line EW does not correlate with disc parameters or with system physical properties, such as black hole mass, accretion rate and hard X-ray luminosity.Comment: 22 pages, 7 figures. Accepted for publication in A&

The X-ray emission of local luminous infrared galaxies

We study the X-ray emission of a representative sample of 27 local luminous infrared galaxies (LIRGs). The median IR luminosity of our sample is log L_IR/L_sun = 11.2, thus the low-luminosity end of the LIRG class is well represented. We used new XMM-Newton data as well as Chandra and XMM-Newton archive data. The soft X-ray (0.5-2 keV) emission of most of the galaxies (>80%), including LIRGs hosting a Seyfert 2 nucleus, is dominated by star-formation related processes. These LIRGs follow the star-formation rate (SFR) versus soft X-ray luminosity correlation observed in local starbursts. We find that ~15% of the non-Seyfert LIRGs (3 out of 20) have an excess hard X-ray emission relative to that expected from star-formation that might indicate the presence of an obscured AGN. The rest of the non-Seyfert LIRGs follow the SFR versus hard X-ray (2-10 keV) luminosity correlation of local starbursts. The non-detection of the 6.4 keV Fe K alpha emission line in the non-Seyfert LIRGs allows us to put an upper limit to the bolometric luminosity of an obscured AGN, L_bol <1043 erg s-1 . That is, in these galaxies, if they hosted a low luminosity AGN, its contribution to total luminosity would be less than 10%. Finally we estimate that the AGN contribution to the total luminosity for our sample of local LIRGs is between 7% and 10%.Comment: Accepted for Publication in A&A, 22 pages, 9 figure

Estimation of Admission D-dimer Cut-off Value to Predict Venous Thrombotic Events in Hospitalized COVID-19 Patients: Analysis of the SEMI-COVID-19 Registry

Background: Venous thrombotic events (VTE) are frequent in COVID-19, and elevated plasma D-dimer (pDd) and dyspnea are common in both entities. Objective: To determine the admission pDd cut-off value associated with in-hospital VTE in patients with COVID-19. Methods: Multicenter, retrospective study analyzing the at-admission pDd cut-off value to predict VTE and anticoagulation intensity along hospitalization due to COVID-19. Results: Among 9386 patients, 2.2% had VTE: 1.6% pulmonary embolism (PE), 0.4% deep vein thrombosis (DVT), and 0.2% both. Those with VTE had a higher prevalence of tachypnea (42.9% vs. 31.1%; p = 0.0005), basal O2 saturation &lt;93% (45.4% vs. 33.1%; p = 0.0003), higher at admission pDd (median [IQR]: 1.4 [0.6–5.5] vs. 0.6 [0.4–1.2] µg/ml; p &lt; 0.0001) and platelet count (median [IQR]: 208 [158–289] vs. 189 [148–245] platelets × 109/L; p = 0.0013). A pDd cut-off of 1.1 µg/ml showed specificity 72%, sensitivity 49%, positive predictive value (PPV) 4%, and negative predictive value (NPV) 99% for in-hospital VTE. A cut-off value of 4.7 µg/ml showed specificity of 95%, sensitivity of 27%, PPV of 9%, and NPV of 98%. Overall mortality was proportional to pDd value, with the lowest incidence for each pDd category depending on anticoagulation intensity: 26.3% for those with pDd &gt;1.0 µg/ml treated with prophylactic dose (p &lt; 0.0001), 28.8% for pDd for patients with pDd &gt;2.0 µg/ml treated with intermediate dose (p = 0.0001), and 31.3% for those with pDd &gt;3.0 µg/ml and full anticoagulation (p = 0.0183). Conclusions: In hospitalized patients with COVID-19, a pDd value greater than 3.0 µg/ml can be considered to screen VTE and to consider full-dose anticoagulation. © 2021, Society of General Internal Medicine

Sex Differences in the Incidence and Outcomes of Acute Myocardial Infarction in Spain, 2016–2018: A Matched-Pair Analysis

(1) Background: Our aim was to analyze the incidence, procedures, and in-hospital outcomes of myocardial infarction (MI) in Spain (2016–2018) according to sex. (2) Methods: We estimated the incidence of an ST elevation myocardial infarction (STEMI) and non-ST elevation myocardial infarction (NSTEMI) according to sex using the Spanish National Hospital Discharge Database. A matched-pair analysis was used. (3) Results: MI was coded in 156,826 patients aged ≥18 years (111,842 men and 44,984 women). Men showed higher incidence rates (205.0 vs. 77.8 per 100,000; p < 0.001; IRR = 2.81(95%CI:2.78–2.84)). After matching, the use of coronary artery by-pass grafting (CABG) (1.0% vs. 0.7%; p < 0.001) and percutaneous coronary intervention (PCI) (57.8% vs. 52.3%; p < 0.001) was higher among men with an STEMI, whereas the in-hospital mortality (IHM) remained higher among women (11.2% vs. 10.1%; p < 0.001). Likewise, CABG (1.9% vs. 3.3%; p < 0.001) and PCI (33.8% vs. 41.9%; p < 0.001) were less often used among women with an NSTEMI, but no sex-related differences were found in IHM. After adjusting for confounders, IHM was more than twofold higher for both men and women with an STEMI than those with an NSTEMI. Women with an STEMI had a 21% higher mortality risk than men (OR = 1.21(95%CI:1.13–1.29). (4) Conclusion: Men had higher incidence rates of MI than women. Women underwent invasive procedures less often and had a higher IHM when admitted for an STEMI

Incidence and Outcomes of Hemorrhagic Stroke among Adults in Spain (2016–2018) According to Sex: A Retrospective, Cohort, Observational, Propensity Score Matched Study

(1) Background: We aim to analyze sex differences in the incidence, clinical characteristics and in-hospital outcomes of hemorrhagic stroke (HS) in Spain (2016–2018) using the National Hospital Discharge Database. (2) Methods: Retrospective, cohort, observational study. We estimated the incidence of HS in men and women. We analyzed comorbidity, treatments, procedures, and hospital outcomes. We matched each woman with a man by age, type of HS and medical conditions using propensity score matching. (3) Results: HS was coded in 57,227 patients aged ≥18 years (44.3% women). Overall, men showed higher incidence rates (57.3/105 vs. 43.0/105; p < 0.001; IRR = 1.60; 95% CI: 1.38–1.83). Women suffered more subarachnoid hemorrhages (25.2% vs. 14.6%), whereas men more often had intracerebral hemorrhages (55.7% vs. 54.1%). In-hospital mortality (IHM) was higher for intracerebral hemorrhage in both men and women. Women underwent decompressive craniectomy less often than men (5.0% vs. 6.2%; p < 0.001). After matching, IHM among women was higher (29.0% vs. 23.7%; p < 0.001). Increments in age, comorbidity and use of anticoagulants and antiplatelet agents prior to hospitalization were associated were higher IHM, and decompressive craniectomy was associated with lower IHM in both sexes. After multivariable adjustment, women had higher IHM (OR = 1.23; 95% CI: 1.18–1.28). (4) Conclusion: Men had higher incidence rates of HS than women. Women less often underwent decompressive craniectomy. IHM was higher among women admitted for HS than among men

The Use of Corticosteroids or Tocilizumab in COVID-19 Based on Inflammatory Markers

SEMI-COVID-19 Network.[Background] The inflammatory cascade is the main cause of death in COVID-19 patients. Corticosteroids (CS) and tocilizumab (TCZ) are available to treat this escalation but which patients to administer it remains undefined.[Objective] We aimed to evaluate the efficacy of immunosuppressive/anti-inflammatory therapy in COVID-19, based on the degree of inflammation. .[Design] A retrospective cohort study with data on patients collected and followed up from March 1st, 2020, to May 1st, 2021, from the nationwide Spanish SEMI-COVID-19 Registry. Patients under treatment with CS vs. those under CS plus TCZ were compared. Effectiveness was explored in 3 risk categories (low, intermediate, high) based on lymphocyte count, C-reactive protein (CRP), lactate dehydrogenase (LDH), ferritin, and d-dimer values.[Patients] A total of 21,962 patients were included in the Registry by May 2021. Of these, 5940 met the inclusion criteria for the present study (5332 were treated with CS and 608 with CS plus TCZ).[Main Measures] The primary outcome of the study was in-hospital mortality. Secondary outcomes were the composite variable of in-hospital mortality, requirement for high-flow nasal cannula (HFNC), non-invasive mechanical ventilation (NIMV), invasive mechanical ventilation (IMV), or intensive care unit (ICU) admission.[Key Results] A total of 5940 met the inclusion criteria for the present study (5332 were treated with CS and 608 with CS plus TCZ). No significant differences were observed in either the low/intermediate-risk category (1.5% vs. 7.4%, p=0.175) or the high-risk category (23.1% vs. 20%, p=0.223) after propensity score matching. A statistically significant lower mortality was observed in the very high–risk category (31.9% vs. 23.9%, p=0.049).[Conclusions] The prescription of CS alone or in combination with TCZ should be based on the degrees of inflammation and reserve the CS plus TCZ combination for patients at high and especially very high risk.Peer reviewe

Flavanol-anthocyanin condensed pigments in plant extracts

Pigments resulting from the direct condensation of anthocyanins and flavanols are usually associated with reactions taking place during processing and storage of plant-derived foods and beverages and have been particularly studied in aged red wines. In this paper, small amounts of flavanol-anthocyanin condensed pigments are found in different plant extracts. Structures are suggested for 10 such condensed pigments detected in extracts of strawberry, runner beans, purple corn and grape skins, based on their MS" fragmentation patterns, following analyses by electrospray tandem mass spectrometry. All of them correspond to dimers containing a flavan-3-ol [either (epi)afzelechin, (epi)catechin or (epi)gallocatechin] as the upper unit carbon-carbon linked to a lower anthocyanin unit consisting of different delphinidin, cyanidin, pelargonidin, peonidin or malvidin derivatives. The detection of these pigments in plant extracts may suggest that they are natural pigments and not products exclusively formed during storage and ageing of processed foods and beverages, as was previously assumed.Comissão Europeia (Fundo Social Europeu) e Governo Português através do Programa PRODEP (III) - ref.ª 5.3/N/199.006/00-Doutoramento

The XMM deep survey in the CDF-S V. Iron K lines from active galactic nuclei in the distant Universe

Context. X-ray spectroscopy of active galactic nuclei (AGN) offers the opportunity to directly probe the inner regions of the accretion disk. Reflection of the primary continuum on the circumnuclear accreting matter produces features in the X-ray spectrum that help to explore the physics and the geometry of the innermost region, close to the central black hole. Aims. We present the results of our analysis of average AGN XMM-Newton X-ray spectra in the Chandra Deep Field South observation (hereafter, XMM CDFS), in order to explore the Fe line features in distant AGN up to z ~ 3.5. Methods. We computed the average X-ray spectrum of a sample of 54 AGN with spectroscopic redshifts and signal-to-noise ratio in the 2–12 keV rest-frame band larger than 15 in at least one EPIC camera (for a total of 100 X-ray spectra and 181 623 net counts in the 2–12 keV rest-frame band). We have taken the effects of combining spectra from sources at different redshifts and from both EPIC-pn and EPIC-MOS cameras into account, as well as their spectral resolution; we checked our results using thorough simulations. We explored the iron line components of distant AGN focusing on the narrow core which arises from material far from the central BH and on the putative relativistic component emitted in the accretion disk. Results. The average spectrum shows a highly significant iron feature. Estimating its equivalent width (EW) with a model-independent method suggests a higher EW in a broader range. The line, modelled as an unresolved Gaussian, is significant at 6.8σ and has an EW = 95 ± 22 eV for the full sample. We find that our current data can be fitted equally welladding a relativistic profile to the narrow component (in the full sample, EW = 140 ± 120 eV and 67 ± 28 eV respectively for the relativistic and narrow lines). Conclusions. Thanks to the high quality of the XMM CDFS spectra and to the detailed modelling of the continuum and instrumental effects, we have shown that the most distant AGN exhibit a highly significant iron emission feature. It can be modelled both with narrow and broad lines which suggest that the EW becomes higher when a broader energy range around the line centroid is considered, provides tantalising evidence for reflection by material both very close and far away from the central engine. The EW of both features are similar to those observed in individual nearby AGN, hence they must be a widespread characteristic of AGN, since otherwise the average values would be smaller than observed