Hospital Universitario Virgen del Rocío

Background Co‐morbid Alzheimer’s disease (AD) pathology is a major risk factor for cognitive impairment (CI) in PD, but whether and how AD co‐pathology affects the clinical phenotype of PD‐CI is incompletely understood. Recently validated plasma biomarkers for AD pathology, such as ptau217, hold great promise to revolutionize the diagnosis of neurodegenerative diseases. Here, we used plasma ptau217 to detect AD co‐pathology in a well‐characterized cohort of PD patients with CI and examine its associations with APOE4 genotype, cognitive profile, and cerebral hypometabolism on FDG‐PET. Method Eighty‐eight PD patients were stratified into PD‐CI (N=50; 24 PD‐MCI, 26 PDD) and PD with normal cognition (PD‐CN; N=38) using neuropsychological testing with the PD‐Cognitive Rating Scale. All patients had a blood draw and an FDG‐PET scan at study inclusion. Plasma ptau217 levels were measured using the ALZpath ptau217 Simoa immunoassay, and patients were classified as ptau217(+) and ptau217(‐) using an established threshold (0.4 pg/mL). APOE4 alleles were genotyped and coded as a binary variable. FDG‐PET data was processed using SPM12 and brain‐wide hypometabolism patterns (vs PD‐CN) were assessed across 52 atlas‐defined brain regions. In addition, we explicitly tested whether PD‐CI‐ptau217(+) had specifically more pronounced hypometabolism in an a‐priori region‐of‐interest (ROI) composed of temporo‐parietal areas typically affected in AD. Result Fourteen PD‐CI (28%) and 5 PD‐CN (13%) were classified as ptau217(+). PD‐CN‐ptau217(+) were excluded from further analyses. Compared to PD‐CI‐ptau217(‐), PD‐CI‐ptau217(+) had a higher prevalence of APOE4 carriers (50% vs 16%, p=0.04) and more impaired memory scores (p=0.03), although global cognition (MoCA) was not significantly different (p=0.10) (Table 1). When compared to PD‐CN, both PD‐CI‐ptau217(‐) and PD‐CI‐ptau217(+) showed significant hypometabolism in posterior‐occipital, temporal, and frontal areas (p<0.05, FDR‐corrected), but hypometabolism in PD‐CI‐ptau217(+) was considerably more extensive, particularly in temporo‐parietal areas (Fig‐1). ROI‐based analysis confirmed significantly more pronounced hypometabolism of AD‐related regions in PD‐CI‐ptau217(+) compared to PD‐CI‐ptau217(‐) (p=0.01), whereas occipital hypometabolism, typical for PD‐CI, did not differ (p=0.83). Conclusion AD co‐pathology results in a more memory‐predominant cognitive profile and AD‐like neurodegeneration phenotype in PD‐CI. Novel plasma biomarkers may significantly facilitate clinical detection of AD co‐pathology, which may have important implications for personalized diagnosis, prognosis, and treatment of PD patients.

Objective This study aimed to evaluate clinical control in chronic obstructive pulmonary disease (COPD), the consequences in terms of treatment decisions, and their potentially associated factors during follow-up of patients in real-life clinical practice. Methods EPOCONSUL 2021 is a cross-sectional audit that evaluated the outpatient care provided to patients with a diagnosis of COPD in respiratory clinics in Spain and multivariable logistic regression models to assess the relationships between clinical control and clinical inertia. Results 4225 patients from 45 hospitals in Spain were audited. Clinical control was analyzed in 1804 (42.7%) patients who met all the Spanish COPD Guidelines (GesEPOC) criteria. 49.1% of patients were classified as uncontrolled, and 42.2% of patients disagreed with the level of control determined by their doctor, which was reported as good during the visit. There was therapeutic inertia (TI), in other words not making any change or taking any action in the treatment of COPD, in 68.4% of uncontrolled patients and no action was taken during the visit for 9.1% of uncontrolled patients. Factors associated with TI in uncontrolled patients were disagreement with the degree of control reported by the doctor who performed the examination ☯physician classifies and reports disease as controlled versus uncontrolled, OR: 3.37 (2.33–4.88), p<0.001] and having a lower burden of associated comorbidities ☯Charlson comorbidity index ≥3 versus <3, OR 0.8 (0.1–3.0), p = 0.014]. The probability of disagreeing with the physician’s classification of the degree of COPD control in uncontrolled patients was lower in patients with severe exacerbations ☯OR 0.3 (0.17–0.78), p = 0.009] and those with more exacerbations in the last year ☯OR 0.6 (0.4–0.9), p = 0.019]. Conclusions Therapeutic inertia exists in more than half of uncontrolled patients and is more likely when there is disagreement with the assessment of the physician responsible for the visit, who reported there being good disease control, a situation that was more likely in patients with less history of exacerbations.

Objective To evaluate the main outcomes of disease activity and their association with other measures of activity, damage, and quality of life in patients with idiopathic inflammatory myopathy (IIM) according to time since diagnosis and positivity to antisynthetase autoantibodies (ASAs). Methods Cross-sectional multicenter study within the Spanish Myo-Spain registry. Cases were classified as incident (≤ 12 months since diagnosis) and prevalent. The main outcomes of disease activity were the Myositis Disease Activity Assessment visual analogue scale (MYOACT), the Manual Muscle Test 8 (MMT-8), physician global activity (PhGA), and extramuscular activity. Other measures of activity, damage, and quality of life included patient global disease activity, MYOACT muscular, creatine phosphokinase, Health Assessment Questionnaire, physician and patient global damage, global damage of the Myositis Damage Index, and the 12-item Short-Form Health Survey (SF-12). We analyzed associations using a multivariate generalized linear model and a simple linear regression model. Results A total of 554 patients with different diagnostic subgroups of IIM were included (136 incident and 418 prevalent cases), with 215 ASA-positive patients (58 incident and 157 prevalent cases). All measures of disease activity were higher in the incident cases (p < 0.05), except for MYOACT muscular and creatine phosphokinase, for which no differences were recorded in ASA-positive patients. No differences were found between incident and prevalent cases for measures of damage. Values for the physical component of the SF-12 were higher in the prevalent cases (p < 0.05). The multivariate model was initially significant overall for the main activity outcomes. Positivity to ASAs was positively and negatively associated with the MYOACT index and MMT-8, respectively (p < 0.05), although no association was recorded with PhGA and extramuscular activity. Prevalent cases were negatively associated with the main outcomes of activity, except with MMT-8, for which the association was positive (p < 0.05). Conclusions The main activity outcomes validated in polymyositis and dermatomyositis could also be used in other subtypes of IIM, such as antisynthetase syndrome. Recent diagnosis is associated with greater disease activity, as assessed based on these activity outcomes. PhGA and extramuscular activity are not modified by ASA positivity, thus supporting their preferred use for assessing treatment response in IIM with ASAs.

Obesity and iron deficiency (ID) are widespread health issues, with subclinical inflammation in obesity potentially contributing to ID through unclear mechanisms. The aim of the present work was to elucidate how obesity-associated inflammation disturb iron metabolism and to investigate the effect of intravenous (IV) iron supplementation on absolute iron deficient pre-obese (BMI 25.0–29.9 kg/m²) and obese (BMI > 30 kg/m²) individuals compared to healthy weight (HW) group (BMI 18.5–24.9 kg/m²). Iron-related, hematological and inflammatory biomarkers along with erythropoietin (EPO) were studied based on body mass index (BMI) in a Spanish cohort of non-anemic participants (n = 721; 67% women; median age of 48 years [IQR: 39–57]) and in a subgroup of subjects (n = 110) with absolute ID (ferritin < 50 ng/mL) after completing an IV iron therapy. Obese group exhibited higher levels of ferritin, hemoglobin (Hb), soluble transferrin receptor (sTfR) and hepcidin compared to HW group. Elevated BMI was independently associated with increased sTfR levels. While no statistical differences were found in EPO among groups, obese showed increased levels that inversely correlated with Hb only in pre-obese and obese groups. IV iron therapy on obese participants had significant improvements on iron-related parameters and Hb levels. Notable obesity-associated disturbances in iron metabolism are described and indicate a mixed ID among both, women and men. These findings highlight the importance of tailored interventions to correctly address ID in obese population.

Background and Purpose Embolization is the first-line treatment for dural arteriovenous fistulas (dAVF). The precipitating hydrophobic injectable liquid (PHIL) embolic agent is a non-adhesive copolymer with specific features and endovascular behavior. This study assessed its safety and efficacy in a prospective real-life cohort. Methods The PHIL-dAVF study was a prospective single-arm open-label observational multicenter study conducted between October 2017 and November 2019 in 14 European centers. Patients with a single intracranial dAVF intended for PHIL embolization were included. Previously partially treated or multiple dAVFs were excluded. Additional devices and embolic agents were permitted as complementary techniques or second-line strategies. Primary endpoints were functional outcome changes from baseline and complete cure rate at 3–6 months after the last embolization. Safety was assessed by adverse events (AE) incidence. Results A total of 67 patients (77 endovascular procedures; 70.1% men, mean age 61±14 years) were included. Most DAVFs were unruptured (71.6%), located in the transverse/sigmoid sinus (53.7%) and Cognard grade III or IV (56.7%). Sixty patients (89.6%) received one single embolization. Additional devices were used in 31.2% of procedures. Complete angiographic cure rate was 86.9% at the 3–6 month DSA follow-up after the last endovascular treatment. At least one AE was recorded in 37.3% of patients during follow-up, of which 52.9% were related to the procedure. The procedural rates of AE and serious AE were 32.5% and 15.6%, respectively. Five AEs were related to PHIL. Transient functional deterioration occurred in three patients (4.5%), all resolved by the last follow-up. Conclusion The PHIL-dAVF study provides evidence about the efficacy and safety of PHIL in the treatment of intracranial dAVFs, with outcomes comparable to existing liquid embolic agents reported in the literature.

Filamin A (FLNA) is an actin-binding protein that has been reported to interact with STIM1 modulating the activation of Orai1 channels. Cleaving of FLNA by calpain leads to a C-terminal fragment that is involved in a variety of functional and pathological events, including pro-oncogenic activity in different types of cancer. Here we show that full-length FLNA is downregulated in samples from colon cancer patients as well as in the adenocarcinoma cell line HT-29. This is consistent with an increased calpain-dependent FLNA cleaving with enhanced expression of the C-terminal FLNA fragment accompanied by enhanced expression of Orai1 and STIM1, as well as store-operated Ca ²⁺ entry (SOCE). To further explore the mechanism underlying the enhancement of SOCE by the C-terminal FLNA fragment we expressed in HEK-293 cells the C-terminal FLNA region encompassing repeats 16–24 (FLNA ¹⁶⁻²⁴ fragment), which enhanced both Orai1 and STIM1 as well as SOCE. Transfection of the FLNA ¹⁶⁻²⁴ fragment attenuates Orai1 and STIM1 protein degradation, and, specifically, abrogates Orai1α lysosomal degradation and retains this channel in the plasma membrane. However, the C-terminal FLNA fragment did not induce a detectable modification in Orai1β degradation. Due to the relevance of SOCE in cell physiology, our results provide evidence of a novel mechanism for the regulation of Ca ²⁺ influx with relevant pathophysiological implications.

Small fetuses, with estimated fetal weight (EFW) below the tenth percentile, are classified as fetal growth restriction (FGR) or small for gestational age (SGA) based on prenatal ultrasound. FGR fetuses have a greater risk of stillbirth and perinatal complications and may benefit from serial ultrasound scans to guide early delivery. Abnormal serum angiogenic factors, such as the soluble fms-like tyrosine kinase-1 (sFlt-1):placental growth factor (PlGF) ratio, have shown potential to more accurately distinguish FGR from SGA, with fewer false positives. This randomized controlled trial compared a management protocol based on the sFlt-1:PlGF with EFW and Doppler ultrasound in avoiding adverse perinatal outcomes in small fetuses after 36 weeks of gestation. A total of 1,088 pregnant women with singleton pregnancies were randomized to either the Doppler-based (control) or the sFlt-1:PlGF-based (intervention) protocol. The primary outcome, neonatal acidosis or Cesarean delivery as a result of abnormal cardiotocography, was assessed in 1,013 participants. The incidence was 10.5% in the intervention group and 10.0% in the control group (absolute difference, 0.53 (−3.21 to 4.26)), with the upper limit of the confidence interval <8.5%, confirming noninferiority. Thus, the sFlt-1:PlGF was noninferior to EFW and Doppler ultrasound in avoiding neonatal acidosis or Cesarean delivery owing to nonreassuring fetal status in small fetuses after 36 weeks (ClinicalTrials.gov registration: NCT04502823).

Cognition plays a central role in the diagnosis and characterization of dementia with Lewy bodies (DLB). However, the complex associations among cognitive deficits in different domains in DLB are largely unknown. To characterize these associations, we investigated and compared the cognitive connectome of DLB patients, healthy controls (HC), and Alzheimer’s disease patients (AD). We obtained data from the National Alzheimer’s Coordinating Center. We built cognitive connectomes for DLB (n = 104), HC (n = 3703), and AD (n = 1985) using correlations among 24 cognitive measures mapping multiple cognitive domains. Connectomes were compared using global and nodal graph measures of centrality, integration, and segregation. For global measures, DLB showed a higher global efficiency (integration) and lower transitivity (segregation) than HC and AD. For nodal measures, DLB showed higher global efficiency in most measures, higher participation (centrality) in free-recall memory, processing speed/attention, and executive measures, and lower local efficiency (segregation) than HC. Compared with AD, DLB showed lower nodal strength and local efficiency, especially in memory consolidation. The cognitive connectome of DLB shows a loss of segregation, leading to a loss of cognitive specialization. This study provides the data to advance the understanding of cognitive impairment and clinical phenotype in DLB, with implications for differential diagnosis.

The complex and variable anatomy of complex double outlet right ventricle makes it imperative to understand the spatial anatomic structures to determine whether it is feasible to repair the anomaly in a biventricular or univentricular fashion. Biventricular repair should be aimed for but is not always feasible. Choosing the correct surgical technique is of great importance in surgical planning of biventricular repair. Conventional imaging is typically insufficient to predict feasibility and technique of biventricular repair. The gap between virtual images and spatial reality can be filled using 3D prints. Retrospective observational study of all available imaging including 3D prints and operative reports in 13 patients. 3D-prints enabled accurate prediction of biventricular repair in 8 cases and of univentricular repair in 2 cases. In 2 patients, no precise prediction was possible. One 3D-print was created post repair. 3D-prints accurately predicted the optimal technique for achieving biventricular repair in 8 cases. Conventional imaging could not accurately predict biventricular repair of optimal surgical technique in any patient. In complex double outlet right ventricle, 3D-printing can predict feasibility of biventricular repair better than conventional imaging. Additionally, 3D-prints can predict the type of surgical technique better. 3D-printing is also helpful in preoperative discussion with parents, caretakers, and pediatric cardiologists. 3D-prints are strongly recommended in patients with complex double outlet right ventricle. Graphical Abstract

Introduction This study aimed to evaluate the predictive validity and discriminatory ability of clinical outcomes, inflammatory activity, oxidative and vascular damage, and metabolic mechanisms for detecting significant improve maximum heart rate after physical activity training in individuals with psychiatric disorders and obesity comorbid using a longitudinal design and transdiagnostic perspective. Methods Patients with major depressive disorder, bipolar disorder and, schizophrenia and with comorbid obesity (n = 29) were assigned to a 12-week structured physical exercise program. Peripheral blood biomarkers of inflammation, oxidative stress, vascular mechanisms, and metabolic activity, as well as neurocognitive and functional performance were assessed twice, before and after intervention. Maximum heart rate was considered a marker of effectiveness of physical activity. Mixed one-way analysis of variance and linear regression analyses were performed. Results Individuals with psychiatric disorders and comorbid obesity exhibited an improvement in cognition, mood symptoms and body mass index, increase anti-inflammatory activity together with enhancement of the oxidative and cardiovascular mechanisms after physical activity training (p<0.05 to 0.0001; d = 0.47 to 1.63). A better clinical outcomes along with regulation of inflammatory, oxidative, and cardiovascular mechanisms were critical for predicting significant maximum heart rate variation over time (χ² = 32.2 to 39.0, p < 0.0001). Conclusions The regulation of the anti-inflammatory mechanisms may be essential for maintained of healthy physical activity across psychiatric disorders and obesity. Likewise, inflammatory activity, oxidative stress, vascular and cardio-metabolic mechanisms may be a useful to identify individuals at greater risk of multi-comorbidity.

Mitochondrial function is modulated by its interaction with the endoplasmic reticulum (ER). Recent research indicates that these contacts are disrupted in familial models of amyotrophic lateral sclerosis (ALS). We report here that this impairment in the crosstalk between mitochondria and the ER impedes the use of glucose-derived pyruvate as mitochondrial fuel, causing a shift to fatty acids to sustain energy production. Over time, this deficiency alters mitochondrial electron flow and the active/dormant status of complex I in spinal cord tissues, but not in the brain. These findings suggest mitochondria-associated ER membranes (MAM domains) play a crucial role in regulating cellular glucose metabolism and that MAM dysfunction may underlie the bioenergetic deficits observed in ALS.

Human cancer cell lines are the mainstay of cancer research. Recent reports showed that highly mutated adult carcinoma cell lines (mainly HeLa and MCF-7) present striking diversity across laboratories and that long-term continuous culturing results in genomic/transcriptomic heterogeneity with strong phenotypical implications. Here, we hypothesize that oligomutated pediatric sarcoma cell lines mainly driven by a fusion transcription factor, such as Ewing sarcoma (EwS), are genetically and phenotypically more stable than the previously investigated adult carcinoma cell lines. A comprehensive molecular and phenotypic characterization of multiple EwS cell line strains, together with a simultaneous analysis during 12 months of continuous cell culture show that fusion-driven pediatric sarcoma cell line strains are genomically more stable than adult carcinoma strains, display remarkably stable and homogenous transcriptomes, and exhibit uniform and stable drug response. Additionally, the analysis of multiple EwS cell lines subjected to long-term continuous culture reveals that variable degrees of genomic/transcriptomic/phenotypic changes among fusion-driven cell lines, further exemplifying that the potential for reproducibility of in vitro scientific results may be rather understood as a spectrum, even within the same tumor entity.

Background Postoperative acute kidney injury (AKI) after major abdominal surgery leads to poor outcomes. The Hypotension Prediction Index (HPI) may aid in managing intraoperative hemodynamic instability. This study assessed if HPI-guided therapy reduces moderate-to-severe AKI incidence in moderate-to-high-risk elective abdominal surgery patients. Methods This multicenter randomized trial was conducted from October 2022 to February 2024 across 28 hospitals evaluating HPI-guided management compared to a wide range of real-world hemodynamic approaches. 917 patients (≥65 years or >18 years with ASA status >II) undergoing moderate-to-high-risk elective abdominal surgery were included in the intention-to-treat analysis. HPI-guided management triggered interventions when the HPI exceeded 80, using fluids and/or vasopressors/inotropes based on hemodynamic data. The primary outcome was the incidence of moderate-to-severe AKI within the first 7 days after surgery. Secondary outcomes included overall complications, the need for renal replacement therapy, duration of hospital stay, and 30-day mortality. Results Median age was 71 years (IQR, 65-77) in the HPI group and 70 years (IQR, 63-76) in standard care group. ASA status III/IV was 58.3% (268/459) in the HPI group and 57.9% (263/458) in standard care group. The incidence of moderate-to-severe AKI was 6.1% (28/459) in the HPI group and 7.0% (32/458) in the standard care group (RR 0.89, 95% 0.54-1.49; P =0.66). Overall complications occurred in 31.9% (146/459) of the HPI group and 29.7% (136/458) of the standard care group (RR 1.08, 95% CI 0.85-1.37; P = 0.52). The incidence of renal replacement therapy did not differ between groups. Median length of hospital stay was 6 days (IQR, 4-10) in both groups. The 30-day mortality was 1.1% (5/459) in the HPI group versus 0.9% (4/458) in standard care group (RR 1.35, 95% CI 0.36-5.10; P = 0.66). Conclusions HPI-guided hemodynamic therapy did not reduce the incidence of postoperative AKI or overall complications compared to standard care. ClinicalTrials.gov Identifier NCT05569265

Background: Anaphylaxis is a severe allergic reaction with increasing incidence in Europe. It is often caused by food, insect venom, and drugs. White, red, and green beans (Phaseolus vulgaris) are legumes of the Fabaceae family consumed worldwide. In Spain, beans are the third most consumed legume species after chickpeas and lentils. Allergy to different legumes is very frequent in children and represents the fifth cause of food allergy.Objective: Demonstrate a new phenotype in patients with green bean anaphylaxis.Material and Methods: We report a 20-year-old woman who experienced anaphylaxis after consuming cooked green beans and required emergency treatment. There were no associated cofactors such as medications, alcohol, or physical exercise. After the episode, she tolerated well nuts, garlic, chickpeas, peas, and soy. Prick-prick with raw and cooked green bean, ISAC, SDS-PAGE and IgE-Western blot were performed.Results: The prick+prick test with raw and cooked green beans was positive. The sodium dodecyl sulfate–polyacrylamide gel electrophoresis–immunoglobulin E (SDS-PAGE/IgE)– western blot analysis with white and red beans as well as cooked and raw green beans showed identification of several proteins with a molecular weight of 25–75 kDa in the extract of raw beans. Only one protein with a molecular weight of approximately 10 kDa was recognized in cooked beans.Conclusion: We present a case of anaphylaxis induced by green beans (Phaseolus vulgaris) because of a 10-kDa protein and tolerance to other legumes, which suggests a new phenotype