Moléculas inflamatorias y marcadores de lesión endotelial en la isquemia cerebral : participación en el deterioro neurológico y la transformación hemorrágiaca

Consultable des del TDXTítol obtingur de la portada digitalitzadaLos mecanismos implicados en el deterioro neurológico precoz (DNP) y en la transformación hemorrágica (TH) de la lesión isquémica cerebral no se conocen con exactitud. Estudios previos habían demostrado la asociación de niveles elevados de TNF-a e IL-6 con el DNP en pacientes con isquemia cerebral independientemente del mecanismo ictal. Sin embargo, los mecanismos relacionados con el DNP en pacientes con infarto lacunar no se conocían con exactitud. Con el objetivo de determinar si los mecanismos inflamatorios participaban en la progresión y el pronóstico funcional de estos pacientes se determinaron los niveles de TNF-a, IL-6 e ICAM-1 en el momento del ingreso en 113 pacientes con ictus lacunar de 14 pg/mL y de ICAM-1 > 208 pg/mL se asociaban de manera independiente tanto con el DNP como con el mal pronóstico funcional evaluado a los 3 meses. En cuanto a la TH, se había demostrado la asociación de niveles elevados de MMP-9 y la aparición de TH exclusivamente en pacientes con ictus de mecanismo cardioembólico por lo que se analizaron los niveles de esta molécula en 250 pacientes con ictus hemisférico de 14 pg/mL and ICAM-1 > 208 pg/mL were independently associated with both END and poor outcome at 3 months. On the other hand, the association between high levels of matrix metaloproteinase-9 (MMP-9) and secondary bleeding in patients with cardiembolic ischemic stroke had been already published. However, there were no data about the HT predictive capacity of MMP-9 in patients with other stroke subtypes. The association between high levels of MMP-9 and the development of HT was determined in 250 patients with hemispheric ischemic stroke within the first 24 hours of symptoms' onset. The results demonstrated that those patients with HT had significantly higher levels of MMP-9 at admission compared to those without secondary bleeding. Logistic regression analysis showed that MMP-9 levels ≥ 140 ng/mL were independently associated with HT after adjustment for potential confounders. Moreover, MMP-9 levels ≥ 140 ng/mL predicted the development of HT with a sensitivity, especificity, negative predictive value (NPV) and positive predictive value (PPV) of 87%, 90%, 61% and 97%, respectively. Finally, the association between the levels of cellular-Fibronectin (c-Fn), taken as a more specific marker of endothelial damage, and the development of HT in 87 patients who received thrombolytic treatment with rt-PA was evaluated. In order to compare the predictive capacity of MMP-9 and c-Fn levels, the levels of MMP-9 were also analyzed in this group of patients. The results demonstrated that patients with HT had significantly higher c-Fn as well as MMP-9 levels before the administration of the treatment. The levels of c-Fn were also higher in patients with symptomatic HT whereas no differences were found in MMP-9 levels between symptomatic and asymptomatic HT. Logistic regression analysis showed that c-Fn levels was the only variable associated with HT development after adjustment of potential confounders, which included MMP-9 levels. Levels of c-Fn ≥ 3.6 µg/mL predicted the development of hemorrhagic infarction type 2 and parenchymal hemorrhage (types of HT that has been reported to occur more often in patients treated with rt-PA) with a sensitivity of 100%, specificity of 96%, NPV of 44% and PPV of 100%, whereas the sensitivity, specificity, NPV and PPV of MMP-9 levels ≥ 140 ng/mL were 81%, 88%, 41% and 98%, respectively. These results were observed both in patients treated within 6 hours and within 3 hours from symptoms' onset. In conclusion, the results suggest that inflammation contributes to brain injury in patients with lacunar stroke and confirm that high plasma MMP-9 concentration is an independent predictor of HT in patients with acute ischemic stroke. Moreover, high plasma c-Fn levels are significantly associated with subsequent HT in stroke patients treated with rt-PA, so plasma c-Fn determinations might be useful in clinical practice to improve the risk/benefit ratio of thrombolytic treatment

Association of High Serum Levels of Growth Factors with Good Outcome in Ischemic Stroke: a Multicenter Study

The main objective of this research work was to study the association of serum levels of growth factors (GF) and SDF-1alpha with the functional outcome and reduction of lesion volume in ischemic stroke patients. In this multicenter study, 552 patients with non-lacunar stroke (male, 62.1%; mean age, 68.2 +/- 11.4) were included within 24 h from symptom onset. The main outcome variable was good functional outcome (modified Rankin Scale [mRS] </= 2) at 12 months. Secondary outcome variable was infarct volume (in mL) after 6 +/- 3 months. Serum levels of VEGF, Ang-1, G-CSF, BDNF, and SDF-1alpha were measured by ELISA at admission, 7 +/- 1 days, at 3 +/- 1 months, and 12 +/- 3 months. Except for BDNF, all GF and SDF-1alpha serum levels showed a peak value at day 7 and remained elevated during the first 3 months (all p < 0.01). High serum levels at day 7 of VEGF (OR, 19.3), Ang-1 (OR, 14.7), G-CSF (OR, 9.6), and SDF-1alpha (OR, 28.5) were independently associated with good outcome at 12 months (all p < 0.0001). On the other hand, serum levels of VEGF (B, - 21.4), G-CSF (B, - 14.0), Ang-1 (B, - 13.3), and SDF-1alpha (B, - 44.6) measured at day 7 were independently associated with lesion volume at 6 months (p < 0.01). In summary, high serum levels of VEGF, Ang-1, G-CSF, and SDF-1alpha at day 7 and 3 months after ischemic stroke are associated with good functional outcome and smaller residual lesion at 1 year of follow-up

Oral Anticoagulation and Risk of Symptomatic Hemorrhagic Transformation in Stroke Patients Treated With Mechanical Thrombectomy: Data From the Nordictus Registry

Introduction: We aimed to evaluate if prior oral anticoagulation (OAC) and its type determines a greater risk of symptomatic hemorrhagic transformation in patients with acute ischemic stroke (AIS) subjected to mechanical thrombectomy. Materials and Methods: Consecutive patients with AIS included in the prospective reperfusion registry NORDICTUS, a network of tertiary stroke centers in Northern Spain, from January 2017 to December 2019 were included. Prior use of oral anticoagulants, baseline variables, and international normalized ratio (INR) on admission were recorded. Symptomatic intracranial hemorrhage (sICH) was the primary outcome measure. Secondary outcome was the relation between INR and sICH, and we evaluated mortality and functional outcome at 3 months by modified Rankin scale. We compared patients with and without previous OAC and also considered the type of oral anticoagulants. Results: About 1.455 AIS patients were included, of whom 274 (19%) were on OAC, 193 (70%) on vitamin K antagonists (VKA), and 81 (30%) on direct oral anticoagulants (DOACs). Anticoagulated patients were older and had more comorbidities. Eighty-one (5.6%) developed sICH, which was more frequent in the VKA group, but not in DOAC group. OAC with VKA emerged as a predictor of sICH in a multivariate regression model (OR, 1.89 [95% CI, 1.01-3.51], p = 0.04) and was not related to INR level on admission. Prior VKA use was not associated with worse outcome in the multivariate regression model nor with mortality at 3 months. Conclusions: OAC with VKA, but not with DOACs, was an independent predictor of sICH after mechanical thrombectomy. This excess risk was associated neither with INR value by the time thrombectomy was performed, nor with a worse functional outcome or mortality at 3 months

NCAPH drives breast cancer progression and identifies a gene signature that predicts luminal a tumour recurrence

Background: Luminal A tumours generally have a favourable prognosis but possess the highest 10‐year recurrence risk among breast cancers. Additionally, a quarter of the recurrence cases occur within 5 years post‐diagnosis. Identifying such patients is crucial as long‐term relapsers could benefit from extended hormone therapy, while early relapsers might require more aggressive treatment. Methods: We conducted a study to explore non‐structural chromosome maintenance condensin I complex subunit H’s (NCAPH) role in luminal A breast cancer pathogenesis, both in vitro and in vivo, aiming to identify an intratumoural gene expression signature, with a focus on elevated NCAPH levels, as a potential marker for unfavourable progression. Our analysis included transgenic mouse models overexpressing NCAPH and a genetically diverse mouse cohort generated by backcrossing. A least absolute shrinkage and selection operator (LASSO) multivariate regression analysis was performed on transcripts associated with elevated intratumoural NCAPH levels. Results: We found that NCAPH contributes to adverse luminal A breast cancer progression. The intratumoural gene expression signature associated with elevated NCAPH levels emerged as a potential risk identifier. Transgenic mice overexpressing NCAPH developed breast tumours with extended latency, and in Mouse Mammary Tumor Virus (MMTV)‐NCAPH ErbB2 double‐transgenic mice, luminal tumours showed increased aggressiveness. High intratumoural Ncaph levels correlated with worse breast cancer outcome and subpar chemotherapy response. A 10‐gene risk score, termed Gene Signature for Luminal A 10 (GSLA10), was derived from the LASSO analysis, correlating with adverse luminal A breast cancer progression. Conclusions: The GSLA10 signature outperformed the Oncotype DX signature in discerning tumours with unfavourable outcomes, previously categorised as luminal A by Prediction Analysis of Microarray 50 (PAM50) across three independent human cohorts. This new signature holds promise for identifying luminal A tumour patients with adverse prognosis, aiding in the development of personalised treatment strategies to significantly improve patient outcomes.Ministry of Science and Innovation/State Research Agency (MCIN/AEI)European Regional Development Fund (ERDF) “A way of making Europe”Carlos III Health InstituteRegional Government of Castile and LeónDepto. de Estadística e Investigación OperativaFac. de FarmaciaTRUEpu

Additional file 1 of Statistical analysis plan for the multicenter, open, randomized controlled clinical trial to assess the efficacy and safety of intravenous tirofiban vs aspirin in acute ischemic stroke due to tandem lesion, undergoing recanalization therapy by endovascular treatment (ATILA trial)

Additional file 1: Supplementary Material 1. Minor Revision. Supplementary Material 2. DSMB. Supplementary Material 3. Full protocol

How do women living with HIV experience menopause? Menopausal symptoms, anxiety and depression according to reproductive age in a multicenter cohort

CatedresBackground: To estimate the prevalence and severity of menopausal symptoms and anxiety/depression and to assess the differences according to menopausal status among women living with HIV aged 45-60 years from the cohort of Spanish HIV/AIDS Research Network (CoRIS). Methods: Women were interviewed by phone between September 2017 and December 2018 to determine whether they had experienced menopausal symptoms and anxiety/depression. The Menopause Rating Scale was used to evaluate the prevalence and severity of symptoms related to menopause in three subscales: somatic, psychologic and urogenital; and the 4-item Patient Health Questionnaire was used for anxiety/depression. Logistic regression models were used to estimate odds ratios (ORs) of association between menopausal status, and other potential risk factors, the presence and severity of somatic, psychological and urogenital symptoms and of anxiety/depression. Results: Of 251 women included, 137 (54.6%) were post-, 70 (27.9%) peri- and 44 (17.5%) pre-menopausal, respectively. Median age of onset menopause was 48 years (IQR 45-50). The proportions of pre-, peri- and post-menopausal women who had experienced any menopausal symptoms were 45.5%, 60.0% and 66.4%, respectively. Both peri- and post-menopause were associated with a higher likelihood of having somatic symptoms (aOR 3.01; 95% CI 1.38-6.55 and 2.63; 1.44-4.81, respectively), while post-menopause increased the likelihood of having psychological (2.16; 1.13-4.14) and urogenital symptoms (2.54; 1.42-4.85). By other hand, post-menopausal women had a statistically significant five-fold increase in the likelihood of presenting severe urogenital symptoms than pre-menopausal women (4.90; 1.74-13.84). No significant differences by menopausal status were found for anxiety/depression. Joint/muscle problems, exhaustion and sleeping disorders were the most commonly reported symptoms among all women. Differences in the prevalences of vaginal dryness (p = 0.002), joint/muscle complaints (p = 0.032), and sweating/flush (p = 0.032) were found among the three groups. Conclusions: Women living with HIV experienced a wide variety of menopausal symptoms, some of them initiated before women had any menstrual irregularity. We found a higher likelihood of somatic symptoms in peri- and post-menopausal women, while a higher likelihood of psychological and urogenital symptoms was found in post-menopausal women. Most somatic symptoms were of low or moderate severity, probably due to the good clinical and immunological situation of these women

Effectiveness of the combination elvitegravir/cobicistat/tenofovir/emtricitabine (EVG/COB/TFV/FTC) plus darunavir among treatment-experienced patients in clinical practice : A multicentre cohort study

Background: The aim of this study was to investigate the effectiveness and tolerability of the combination elvitegravir/cobicistat/tenofovir/emtricitabine plus darunavir (EVG/COB/TFV/FTC + DRV) in treatment-experienced patients from the cohort of the Spanish HIV/AIDS Research Network (CoRIS). Methods: Treatment-experienced patients starting treatment with EVG/COB/TFV/FTC + DRV during the years 2014-2018 and with more than 24 weeks of follow-up were included. TFV could be administered either as tenofovir disoproxil fumarate or tenofovir alafenamide. We evaluated virological response, defined as viral load (VL) < 50 copies/ml and < 200 copies/ml at 24 and 48 weeks after starting this regimen, stratified by baseline VL (< 50 or ≥ 50 copies/ml at the start of the regimen). Results: We included 39 patients (12.8% women). At baseline, 10 (25.6%) patients had VL < 50 copies/ml and 29 (74.4%) had ≥ 50 copies/ml. Among patients with baseline VL < 50 copies/ml, 85.7% and 80.0% had VL < 50 copies/ml at 24 and 48 weeks, respectively, and 100% had VL < 200 copies/ml at 24 and 48 weeks. Among patients with baseline VL ≥ 50 copies/ml, 42.3% and 40.9% had VL < 50 copies/ml and 69.2% and 68.2% had VL < 200 copies/ml at 24 and 48 weeks. During the first 48 weeks, no patients changed their treatment due to toxicity, and 4 patients (all with baseline VL ≥ 50 copies/ml) changed due to virological failure. Conclusions: EVG/COB/TFV/FTC + DRV was well tolerated and effective in treatment-experienced patients with undetectable viral load as a simplification strategy, allowing once-daily, two-pill regimen with three antiretroviral drug classes. Effectiveness was low in patients with detectable viral loads

Quantitative Signal Intensity in Fluid-Attenuated Inversion Recovery and Treatment Effect in the WAKE-UP Trial

International audienceBackground and Purpose— Relative signal intensity of acute ischemic stroke lesions in fluid-attenuated inversion recovery (fluid-attenuated inversion recovery relative signal intensity [FLAIR-rSI]) magnetic resonance imaging is associated with time elapsed since stroke onset with higher intensities signifying longer time intervals. In the randomized controlled WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke Trial), intravenous alteplase was effective in patients with unknown onset stroke selected by visual assessment of diffusion weighted imaging fluid-attenuated inversion recovery mismatch, that is, in those with no marked fluid-attenuated inversion recovery hyperintensity in the region of the acute diffusion weighted imaging lesion. In this post hoc analysis, we investigated whether quantitatively measured FLAIR-rSI modifies treatment effect of intravenous alteplase. Methods— FLAIR-rSI of stroke lesions was measured relative to signal intensity in a mirrored region in the contralesional hemisphere. The relationship between FLAIR-rSI and treatment effect on functional outcome assessed by the modified Rankin Scale (mRS) after 90 days was analyzed by binary logistic regression using different end points, that is, favorable outcome defined as mRS score of 0 to 1, independent outcome defined as mRS score of 0 to 2, ordinal analysis of mRS scores (shift analysis). All models were adjusted for National Institutes of Health Stroke Scale at symptom onset and stroke lesion volume. Results— FLAIR-rSI was successfully quantified in stroke lesions in 433 patients (86% of 503 patients included in WAKE-UP). Mean FLAIR-rSI was 1.06 (SD, 0.09). Interaction of FLAIR-rSI and treatment effect was not significant for mRS score of 0 to 1 ( P =0.169) and shift analysis ( P =0.086) but reached significance for mRS score of 0 to 2 ( P =0.004). We observed a smooth continuing trend of decreasing treatment effects in relation to clinical end points with increasing FLAIR-rSI. Conclusions— In patients in whom no marked parenchymal fluid-attenuated inversion recovery hyperintensity was detected by visual judgement in the WAKE-UP trial, higher FLAIR-rSI of diffusion weighted imaging lesions was associated with decreased treatment effects of intravenous thrombolysis. This parallels the known association of treatment effect and elapsing time of stroke onset