| 1. |
- Medina-Dols, Aina, et al.
(författare)
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Role of PATJ in stroke prognosis by modulating endothelial to mesenchymal transition through the Hippo/Notch/PI3K axis
- 2024
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Ingår i: Cell Death Discovery. - : Springer Nature. - 2058-7716. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Through GWAS studies we identified PATJ associated with functional outcome after ischemic stroke (IS). The aim of this study was to determine PATJ role in brain endothelial cells (ECs) in the context of stroke outcome. PATJ expression analyses in patient's blood revealed that: (i) the risk allele of rs76221407 induces higher expression of PATJ, (ii) PATJ is downregulated 24 h after IS, and (iii) its expression is significantly lower in those patients with functional independence, measured at 3 months with the modified Rankin scale ((mRS) <= 2), compared to those patients with marked disability (mRS = 4-5). In mice brains, PATJ was also downregulated in the injured hemisphere at 48 h after ischemia. Oxygen-glucose deprivation and hypoxia-dependent of Hypoxia Inducible Factor-1 alpha also caused PATJ depletion in ECs. To study the effects of PATJ downregulation, we generated PATJ-knockdown human microvascular ECs. Their transcriptomic profile evidenced a complex cell reprogramming involving Notch, TGF-ss, PI3K/Akt, and Hippo signaling that translates in morphological and functional changes compatible with endothelial to mesenchymal transition (EndMT). PATJ depletion caused loss of cell-cell adhesion, upregulation of metalloproteases, actin cytoskeleton remodeling, cytoplasmic accumulation of the signal transducer C-terminal transmembrane Mucin 1 (MUC1-C) and downregulation of Notch and Hippo signaling. The EndMT phenotype of PATJ-depleted cells was associated with the nuclear recruitment of MUC1-C, YAP/TAZ, beta-catenin, and ZEB1. Our results suggest that PATJ downregulation 24 h after IS promotes EndMT, an initial step prior to secondary activation of a pro-angiogenic program. This effect is associated with functional independence suggesting that activation of EndMT shortly after stroke onset is beneficial for stroke recovery.
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| 2. |
- Ferrando, Carlos, et al.
(författare)
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Effects of oxygen on post-surgical infections during an individualised perioperative open-lung ventilatory strategy : a randomised controlled trial
- 2020
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Ingår i: British Journal of Anaesthesia. - : ELSEVIER SCI LTD. - 0007-0912 .- 1471-6771. ; 124:1, s. 110-120
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Tidskriftsartikel (refereegranskat)abstract
- Background: We aimed to examine whether using a high fraction of inspired oxygen (FIO2) in the context of an individualised intra- and postoperative open-lung ventilation approach could decrease surgical site infection (SSI) in patients scheduled for abdominal surgery. Methods: We performed a multicentre, randomised controlled clinical trial in a network of 21 university hospitals from June 6, 2017 to July 19, 2018. Patients undergoing abdominal surgery were randomly assigned to receive a high (0.80) or conventional (0.3) FIO2 during the intraoperative period and during the first 3 postoperative hours. All patients were mechanically ventilated with an open-lung strategy, which included recruitment manoeuvres and individualised positive end-expiratory pressure for the best respiratory-system compliance, and individualised continuous postoperative airway pressure for adequate peripheral oxyhaemoglobin saturation. The primary outcome was the prevalence of SSI within the first 7 postoperative days. The secondary outcomes were composites of systemic complications, length of intensive care and hospital stay, and 6-month mortality. Results: We enrolled 740 subjects: 371 in the high FIO2 group and 369 in the low FIO2 group. Data from 717 subjects were available for final analysis. The rate of SSI during the first postoperative week did not differ between high (8.9%) and low (9.4%) FIO2 groups (relative risk [RR]: 0.94; 95% confidence interval [CI]: 0.59-1.50; P=0.90]). Secondary outcomes, such as atelectasis (7.7% vs 9.8%; RR: 0.77; 95% CI: 0.48-1.25; P=0.38) and myocardial ischaemia (0.6% [n=2] vs 0% [n=0]; P=0.47) did not differ between groups. Conclusions: An oxygenation strategy using high FIO2 compared with conventional FIO2 did not reduce postoperative SSIs in abdominal surgery. No differences in secondary outcomes or adverse events were found.
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| 3. |
- Ferrando, Carlos, et al.
(författare)
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Individualised perioperative open-lung approach versus standard protective ventilation in abdominal surgery (iPROVE) : a randomised controlled trial
- 2018
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Ingår i: The Lancet Respiratory Medicine. - : ELSEVIER SCI LTD. - 2213-2600 .- 2213-2619. ; 6:3, s. 193-203
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Tidskriftsartikel (refereegranskat)abstract
- Background The effects of individualised perioperative lung-protective ventilation (based on the open-lung approach [OLA]) on postoperative complications is unknown. We aimed to investigate the effects of intraoperative and postoperative ventilatory management in patients scheduled for abdominal surgery, compared with standard protective ventilation. Methods We did this prospective, multicentre, randomised controlled trial in 21 teaching hospitals in Spain. We enrolled patients who were aged 18 years or older, were scheduled to have abdominal surgery with an expected time of longer than 2 h, had intermediate-to-high-risk of developing postoperative pulmonary complications, and who had a body-mass index less than 35 kg/m(2). Patients were randomly assigned (1: 1: 1: 1) online to receive one of four lung-protective ventilation strategies using low tidal volume plus positive end-expiratory pressure (PEEP): open-lung approach (OLA)-iCPAP (individualised intraoperative ventilation [individualised PEEP after a lung recruitment manoeuvre] plus individualised postoperative continuous positive airway pressure [CPAP]), OLA-CPAP (intraoperative individualised ventilation plus postoperative CPAP), STD-CPAP (standard intraoperative ventilation plus postoperative CPAP), or STD-O-2 (standard intraoperative ventilation plus standard postoperative oxygen therapy). Patients were masked to treatment allocation. Investigators were not masked in the operating and postoperative rooms; after 24 h, data were given to a second investigator who was masked to allocations. The primary outcome was a composite of pulmonary and systemic complications during the first 7 postoperative days. We did the primary analysis using the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02158923. Findings Between Jan 2, 2015, and May 18, 2016, we enrolled 1012 eligible patients. Data were available for 967 patients, whom we included in the final analysis. Risk of pulmonary and systemic complications did not differ for patients in OLA-iCPAP (110 [46%] of 241, relative risk 0.89 [95% CI 0.74-1.07; p=0.25]), OLA-CPAP (111 [47%] of 238, 0.91 [0.76-1.09; p=0.35]), or STD-CPAP groups (118 [48%] of 244, 0.95 [0.80-1.14; p=0.65]) when compared with patients in the STD-O-2 group (125 [51%] of 244). Intraoperatively, PEEP was increased in 69 (14%) of patients in the standard perioperative ventilation groups because of hypoxaemia, and no patients from either of the OLA groups required rescue manoeuvres. Interpretation In patients who have major abdominal surgery, the different perioperative open lung approaches tested in this study did not reduce the risk of postoperative complications when compared with standard lung-protective mechanical ventilation.
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| 4. |
- Evangelou, Evangelos, et al.
(författare)
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Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:10, s. 1412-1425
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Tidskriftsartikel (refereegranskat)abstract
- High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
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| 5. |
- Ferrando, Carlos, et al.
(författare)
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Rationale and study design for an individualised perioperative open-lung ventilatory strategy with a high versus conventional inspiratory oxygen fraction (iPROVE-O2) and its effects on surgical site infection : study protocol for a randomised controlled trial
- 2017
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 7:7
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Surgical site infection (SSI) is a serious postoperative complication that increases morbidity and healthcare costs. SSIs tend to increase as the partial pressure of tissue oxygen decreases: previous trials have focused on trying to reduce them by comparing high versus conventional inspiratory oxygen fractions (FIO 2) in the perioperative period but did not use a protocolised ventilatory strategy. The open-lung ventilatory approach restores functional lung volume and improves gas exchange, and therefore it may increase the partial pressure of tissue oxygen for a given FIO 2. The trial presented here aims to compare the efficacy of high versus conventional FIO 2 in reducing the overall incidence of SSIs in patients by implementing a protocolised and individualised global approach to perioperative open-lung ventilation. Methods and analysis This is a comparative, prospective, multicentre, randomised and controlled two-arm trial that will include 756 patients scheduled for abdominal surgery. The patients will be randomised into two groups: (1) a high FIO 2 group (80% oxygen; FIO 2 of 0.80) and (2) a conventional FIO 2 group (30% oxygen; FIO 2 of 0.30). Each group will be assessed intra-and postoperatively. The primary outcome is the appearance of postoperative SSI complications. Secondary outcomes are the appearance of systemic and pulmonary complications. Ethics and dissemination The iPROVE-O2 trial has been approved by the Ethics Review Board at the reference centre (the Hospital Clinico Universitario in Valencia). Informed consent will be obtained from all patients before their participation. If the approach using high FIO 2 during individualised open-lung ventilation decreases SSIs, use of this method will become standard practice for patients scheduled for future abdominal surgery. Publication of the results is anticipated in early 2019.
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| 6. |
- Ferrando, Carlos, et al.
(författare)
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Rationale and study design for an individualized perioperative open lung ventilatory strategy (iPROVE) : study protocol for a randomized controlled trial
- 2015
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Ingår i: Trials. - : Springer Science and Business Media LLC. - 1745-6215. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Background: Postoperative pulmonary and non-pulmonary complications are common problems that increase morbidity and mortality in surgical patients, even though the incidence has decreased with the increased use of protective lung ventilation strategies. Previous trials have focused on standard strategies in the intraoperative or postoperative period, but without personalizing these strategies to suit the needs of each individual patient and without considering both these periods as a global perioperative lung-protective approach. The trial presented here aims at comparing postoperative complications when using an individualized ventilatory management strategy in the intraoperative and immediate postoperative periods with those when using a standard protective ventilation strategy in patients scheduled for major abdominal surgery. Methods: This is a comparative, prospective, multicenter, randomized, and controlled, four-arm trial that will include 1012 patients with an intermediate or high risk for postoperative pulmonary complications. The patients will be divided into four groups: (1) individualized perioperative group: intra-and postoperative individualized strategy; (2) intraoperative individualized strategy + postoperative continuous positive airway pressure (CPAP); (3) intraoperative standard ventilation + postoperative CPAP; (4) intra-and postoperative standard strategy (conventional strategy). The primary outcome is a composite analysis of postoperative complications. Discussion: The Individualized Perioperative Open-lung Ventilatory Strategy (iPROVE) is the first multicenter, randomized, and controlled trial to investigate whether an individualized perioperative approach prevents postoperative pulmonary complications.
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| 7. |
- Carrera, Caty, et al.
(författare)
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Validation of a clinical-genetics score to predict hemorrhagic transformations after rtPA.
- 2019
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Ingår i: Neurology. - 1526-632X. ; 93:9
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Tidskriftsartikel (refereegranskat)abstract
- To validate the Genot-PA score, a clinical-genetic logistic regression score that stratifies the thrombolytic therapy safety, in a new cohort of patients with stroke.We enrolled 1,482 recombinant tissue plasminogen activator (rtPA)-treated patients with stroke in Spain and Finland from 2003 to 2016. Cohorts were analyzed on the basis of ethnicity and therapy: Spanish patients treated with IV rtPA within 4.5 hours of onset (cohort A and B) or rtPA in combination with mechanical thrombectomy within 6 hours of onset (cohort C) and Finnish participants treated with IV rtPA within 4.5 hours of onset (cohort D). The Genot-PA score was calculated, and hemorrhagic transformation (HT) and parenchymal hematoma (PH) risks were determined for each score stratum.Genot-PA score was tested in 1,324 (cohort A, n = 726; B, n = 334; C, n = 54; and D, n = 210) patients who had enough information to complete the score. Of these, 213 (16.1%) participants developed HT and 85 (6.4%) developed PH. In cohorts A, B, and D, HT occurrence was predicted by the score (p = 2.02 × 10-6, p = 0.023, p = 0.033); PH prediction was associated in cohorts A through C (p = 0.012, p = 0.034, p = 5.32 × 10-4). Increased frequency of PH events from the lowest to the highest risk group was found (cohort A 4%-15.7%, cohort B 1.5%-18.2%, cohort C 0%-100%). The best odds ratio for PH prediction in the highest-risk group was obtained in cohort A (odds ratio 5.16, 95% confidence interval 1.46-18.08, p = 0.009).The Genot-PA score predicts HT in patients with stroke treated with IV rtPA. Moreover, in an exploratory study, the score was associated with PH risk in mechanical thrombectomy-treated patients.
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| 8. |
- Ferrando, Carlos, et al.
(författare)
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A noninvasive postoperative clinical score to identify patients at risk for postoperative pulmonary complications : the Air-Test Score
- 2020
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Ingår i: Minerva Anestesiologica. - : EDIZIONI MINERVA MEDICA. - 0375-9393 .- 1827-1596. ; 86:4, s. 404-415
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Postoperative pulmonary complications (PPCs) negatively affect morbidity, healthcare costs and postsurgical survival. Preoperative and intraoperative peripheral oxyhemoglobin saturation (SpO(2)) levels are independent risk factors for postoperative pulmonary complications (PPCs). The air-test assesses the value of SpO(2) while breathing room-air. We aimed at building a clinical score that includes the air-test for predicting the risk for PPCs. METHODS: This is a development and validation study in patients -randomly divided into two cohorts- from a large randomized clinical trial (iPROVE) that enrolled 964 intermediate-to-high risk patients scheduled for abdominal surgery. Arterial oxygenation was assessed on room-air in the preoperative period (preoperative air-test) and 3h after admission to the postoperative care unit (postoperative air-test). The air-test was defined as positive or negative if SpO(2) was <= 96% or >96%, respectively. Positive air-tests were stratified into weak (93-96%) or strong (<93%). The primary outcome was a composite of moderate-to-severe PPCs during the first seven postoperative days. RESULTS: A total of 902 patients were included in the final analysis (542 in the development cohort and 360 in the validation cohort). Regression analysis identified five independent risk factors for PPC: age. type of surgery, pre- and postoperative air-test, and atelectasis. The area under the receiver operating characteristic curve (AUC) was 0.79 (95% CI: 0.75-0.82) when including these five independent predictors. We built a simplified score termed "air-test score" by using only the pre- and postoperative SpO(2) , resulting in an AUC of 0.72 (95% CI: 0.67-0.76) for the derivation and 0.72 (95% CI: 0.66-0.78) for the validation cohort, respectively. The air-test score stratified patients into four levels of risk, with PPCs ranging from <15% to >75%. CONCLUSIONS: The simple, non-invasive and inexpensive bedside air-test score, evaluating pre- and postoperatively SpO(2) measured on room-air, helps to predict the risk for PPCs.
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| 9. |
- Ferrando, Carlos, et al.
(författare)
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The accuracy of postoperative, non-invasive Air-Test to diagnose atelectasis in healthy patients after surgery : a prospective, diagnostic pilot study
- 2017
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 7:5
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Tidskriftsartikel (refereegranskat)abstract
- Objective To assess the diagnostic accuracy of peripheral capillary oxygen saturation (SpO(2)) while breathing room air for 5 min (the 'Air-Test') in detecting postoperative atelectasis. Design Prospective cohort study. Diagnostic accuracy was assessed by measuring the agreement between the index test and the reference standard CT scan images. Setting Postanaesthetic care unit in a tertiary hospital in Spain. Participants Three hundred and fifty patients from 12 January to 7 February 2015; 170 patients scheduled for surgery under general anaesthesia who were admitted into the postsurgical unit were included. Intervention The Air-Test was performed in conscious extubated patients after a 30 min stabilisation period during which they received supplemental oxygen therapy via a venturi mask. The Air-Test was defined as positive when SpO(2) was >= 96% and negative when SpO(2) was >= 97%. Arterial blood gases were measured in all patients at the end of the Air-Test. In the subsequent 25 min, the presence of atelectasis was evaluated by performing a CT scan in 59 randomly selected patients. Main outcome measures The primary study outcome was assessment of the accuracy of the Air-Test for detecting postoperative atelectasis compared with the reference standard. The secondary outcome was the incidence of positive Air-Test results. Results The Air-Test diagnosed postoperative atelectasis with an area under the receiver operating characteristic curve of 0.90 (95% CI 0.82 to 0.98) with a sensitivity of 82.6% and a specificity of 87.8%. The presence of atelectasis was confirmed by CT scans in all patients (30/30) with positive and in 5 patients (17%) with negative Air-Test results. Based on the Air-Test, postoperative atelectasis was present in 36% of the patients (62 out of 170). Conclusion The Air-Test may represent an accurate, simple, inexpensive and non-invasive method for diagnosing postoperative atelectasis.
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| 10. |
- Jiménez-Balado, Joan, et al.
(författare)
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DNA methylation and stroke prognosis : an epigenome-wide association study
- 2024
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Ingår i: Clinical Epigenetics. - : BioMed Central (BMC). - 1868-7083. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Background and aimsStroke is the leading cause of adult-onset disability. Although clinical factors influence stroke outcome, there is a significant variability among individuals that may be attributed to genetics and epigenetics, including DNA methylation (DNAm). We aimed to study the association between DNAm and stroke prognosis.Methods and resultsTo that aim, we conducted a two-phase study (discovery-replication and meta-analysis) in Caucasian patients with ischemic stroke from two independent centers (BasicMar [discovery, N = 316] and St. Pau [replication, N = 92]). Functional outcome was assessed using the modified Rankin Scale (mRS) at three months after stroke, being poor outcome defined as mRS > 2. DNAm was determined using the 450K and EPIC BeadChips in whole-blood samples collected within the first 24 h. We searched for differentially methylated positions (DMPs) in 370,344 CpGs, and candidates below p-value < 10–5 were subsequently tested in the replication cohort. We then meta-analyzed DMP results from both cohorts and used them to identify differentially methylated regions (DMRs).After doing the epigenome-wide association study, we found 29 DMPs at p-value < 10–5 and one of them was replicated: cg24391982, annotated to thrombospondin-2 (THBS2) gene (p-valuediscovery = 1.54·10–6; p-valuereplication = 9.17·10–4; p-valuemeta-analysis = 6.39·10–9). Besides, four DMRs were identified in patients with poor outcome annotated to zinc finger protein 57 homolog (ZFP57), Arachidonate 12-Lipoxygenase 12S Type (ALOX12), ABI Family Member 3 (ABI3) and Allantoicase (ALLC) genes (p-value < 1·10–9 in all cases).DiscussionPatients with poor outcome showed a DMP at THBS2 and four DMRs annotated to ZFP57, ALOX12, ABI3 and ALLC genes. This suggests an association between stroke outcome and DNAm, which may help identify new stroke recovery mechanisms.
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