Hospital Universitario Puerta de Hierro Majadahonda

Attention deficit/hyperactivity disorder (ADHD) is the most prevalent neurodevelopmental disorder worldwide, affecting approximately 5%-7% of school-aged children and 2%-5% of adults worldwide. However, there is still no reliable diagnostic tool for it. The lack of specific biomarkers further complicates the accurate diagnosis of ADHD. The SINCRONIA study seeks to develop and optimize an electroencephalogram (EEG)-based ADHD diagnostic classification algorithm by identifying biomarkers that provide optimal diagnostic performance. This protocol introduces a single-center, case-control study involving at least 165 participants, aged between 7 and 12 years, that is being conducted at the Puerta de Hierro University Hospital in Madrid, Spain. Participants will be allocated to 3 groups, including ADHD predominantly inattentive, ADHD predominantly combined or hyperactive/impulsive, and a control group, according to the best estimated diagnosis based on clinical interviews and a neuropsychological assessment that includes the Conners Continuous Performance Test. In addition, an EEG recording will be conducted separately, and functional connectivity metrics will be used to characterize brain networks associated with inhibitory control. The index test is expected to match or improve the clinical diagnosis of ADHD in children aged between 7 and 12 years and provide a set of eventual biomarkers that maximize diagnostic performance and provide pathophysiological clues. The SINCRONIA study began screening and recruitment in March 2023. Recruitment ended on December 11, 2024. A total of 165 eligible participants were enrolled. The SINCRONIA project is a high-quality, large-scale, unicenter study devoted to improving the objective diagnosis of ADHD by using EEG biomarkers. The EEG-based ADHD diagnosis is expected to have greater sensitivity and specificity than the Conners Continuous Performance Test.

The tumor suppressor p53 orchestrates critical cellular responses to stress, including cell cycle arrest, DNA repair, senescence, and apoptosis. While extensive research has elucidated many aspects of p53 function, the isoform-specific mechanisms governing cell fate decisions remain incompletely understood. Here, we leverage the simplified p53 gene architecture in Drosophila to systematically dissect the apoptotic and tumorigenic potential of individual p53 isoforms, uncovering fundamental differences in their function. Our findings indicate that whereas p53-A and p53-E pro-apoptotic activity strictly depends on the proliferative state of the cell, the full-length p53-B isoform -structurally analogous to vertebrate p53- induces apoptosis independently of cell cycle status. Furthermore, p53-B triggers apoptosis via transcription-independent mechanisms involving direct activation of the initiator caspase Dronc. We also show that all isoforms promote tumorigenesis by inducing the JNK pathway and the formation of senescent cells through distinct mechanisms in cells that are unable to complete the apoptosis program. Importantly, some of these findings are largely recapitulated by human versions of p53 when ectopically expressed in Drosophila cells. Together our data, reveal that p53 isoforms govern apoptosis and senescence-associated tumorigenesis through distinct molecular mechanisms, providing new insights into the complexity of p53-mediated cell fate determination.

This article explores the ethical and legal challenges posed by the regulation of assisted reproductive technologies (ART) in Spain, using a human rights-based framework. While the Spanish legal system provides relatively broad access to ART, including for single women and lesbian couples, it fails to adequately address key normative tensions between competing rights (such as bodily autonomy, the right to identity, protection from exploitation, and the best interests of the child). The analysis reveals how the existing legal model is shaped by an individualistic and liberal conception of reproductive rights, which overlooks the structural, interdependent, and relational dimensions of assisted reproduction. Building on feminist bioethics and reproductive justice theories, we propose a relational justice approach that foregrounds the ethical responsibilities and vulnerabilities shared by all actors involved (parents, donors, children, professionals, and the state). This framework allows for a more nuanced deliberation of rights in conflict, and calls for regulatory reforms that prioritize ethical consistency, reproductive equity, and care-based practices. The article concludes that strengthening ART regulation in Spain requires not only guaranteeing access, but also ensuring the conditions for ethically sustainable and socially just reproductive experiences.

Glioblastoma is the most prevalent and aggressive primary tumor of the nervous system. The condition manifests with a high rate of recurrence, predominantly in a localized pattern. The impact of distant recurrence on survival and the associated factors are a controversial subject. This study aims to determine whether the pattern of distant recurrence exerts any influence on progression-free survival, survival after first progression, and overall survival in patients with de novo glioblastoma and low residual tumor volume (RTV) < 5 cc. It also aims to identify which factors predict distant recurrence. A retrospective single-center cohort study included patients aged 18 years or over with de novo glioblastoma and RTV < 5 cc after histological diagnosis, who were treated between 2017 and 2023 in our center. Kaplan-Meier curves were utilized for time-to-event analyses. Risk factors were assessed by univariable analysis and logistic regression. The analysis encompassed 102 patients with a median survival period of 12.9 months. Distant recurrence was associated with a more extended progression-free survival (11.9 months; p = 0.003) and overall survival (21.5 months; p = 0.021) compared with the remaining patterns (6.1 and 12.7 months, respectively), with no significant impact on survival after the first progression. Epidermal growth factor receptor (EGFR) amplification (odds ratio [OR] = 3.42, 95% confidence interval [CI]: 1.14-10.60; p = 0.029) and Ki-67 < 30% (OR = 6.15, 95% CI: 1.12-33.67; p = 0.036) were identified as independent risk factors for distant recurrence. Distant recurrence in glioblastomas with low tumor burden after diagnosis is associated with superior progression-free survival and overall survival compared with other recurrence patterns. The EGFR amplification and Ki-67 < 30% were identified as independent risk factors for distant progression. The study underscores the significance of incorporating molecular profiling into decision-making processes for patients with glioblastoma. Furthermore, stratification by recurrence patterns has the potential to enhance the efficacy of future clinical trials.

ABSTRACT BACKGROUND Peak oxygen uptake (pVO 2 ) is a strong, independent predictor of adverse cardiovascular outcomes, supporting cardiopulmonary exercise testing as a primary end point assessing efficacy of novel drug therapies in obstructive hypertrophic cardiomyopathy (oHCM) clinical trials. However, characterizing changes in pVO 2 that patients perceive as beneficial or meaningful (ie, minimal important difference [MID]) has not been determined. METHODS Data from patients with symptomatic oHCM enrolled in SEQUOIA-HCM and MAPLE-HCM were pooled. A total of 282 patients were randomized 1:1 to aficamten (5–20 mg daily) or matching placebo in SEQUOIA-HCM, and 175 patients were randomized 1:1 to aficamten (5-20mg daily) or to metoprolol (50–200 mg) in MAPLE-HCM; follow-up in both trials was 24 weeks. Primary outcome was change from baseline to week 24 (Δ) in pVO 2 using Patient Global Impression of Change with anchor-based analysis to define MID. RESULTS At week 24, ΔpVO 2 (mL/kg/min) that corresponded to no change, one-category improvement, and one-category worsening were –0.05 (95% CI, –0.58 to 0.48), +0.35 (95% CI, –0.22 to 0.91), and –0.61 (95% CI, –1.36 to 0.13), respectively. Similarly, minute ventilation to carbon dioxide production ratio (VE/VCO 2 ) slope that corresponded to no change, one-category improvement, and one-category worsening were 0.16 (95% CI, –0.59 to 0.90), –1.15 (95% CI, – 1.89 to –0.42), and 0.88 (95% CI, –0.42 to 2.19), respectively. In a responder analysis using this new threshold for pVO 2 , 60% of patients receiving aficamten achieved a ΔpVO 2 ≥0.35 versus 31% of patients on placebo or metoprolol (odds ratio, 3.4 [95% CI, 2.3–4.9], P &lt;0.001). Consistent findings were seen with VE/VCO 2 responder analysis. CONCLUSIONS Changes in pVO 2 of +0.35 and –0.61 mL/kg/min were associated with a small but perceptible clinical improvement and worsening, respectively, in patients with oHCM. Applying this newly defined threshold resulted in excellent differentiation of treatment effect in a clinical trial. These novel data provide a measure of clarity to patients and clinicians regarding the interpretation of changes in pVO 2 following therapeutic interventions, with potential impact on HCM management strategies and future clinical trials. Clinical Trial Registration SEQUOIA-HCM ( NCT05186818 ; https://clinicaltrials.gov/study/NCT05186818?term=sequoia-hcm&amp;rank=1 ); MAPLE-HCM ( NCT05767346 ; https://clinicaltrials.gov/study/NCT05767346?term=maple-hcm&amp;rank=1 ) Clinical Perspective What Is New? Using pooled data from over 440 patients with symptomatic obstructive hypertrophic cardiomyopathy enrolled in two phase 3 clinical trials, we define, for the first time, the minimally important difference for peak oxygen uptake (pVO 2 ) and ventilatory efficiency (VE/VCO 2 ) using patient-anchored and distribution-based methodologies. A change in pVO 2 of +0.35 mL/kg/min and a change in VE/VCO 2 of –1.15 represent the minimal thresholds associated with patient-perceived clinical improvement. Responder analyses using these thresholds demonstrated robust differentiation between aficamten and placebo/metoprolol, with an odds ratio exceeding 3 for achieving a meaningful improvement in pVO 2 . What Are the Clinical Implications? These newly defined thresholds bridge the gap between statistically significant changes in cardiopulmonary exercise testing measures and clinically meaningful benefit as perceived by patients with obstructive hypertrophic cardiomyopathy. Clinicians can use these benchmarks to contextualize individual patient responses to medical therapy, informing shared decision-making regarding treatment continuation or modification. These data provide a standardized, patient-centered framework for designing and interpreting primary end points in future hypertrophic cardiomyopathy clinical trials.

There is a paucity of data to guide the management of posttransplant secondary antibody deficiency (SAD). We aimed to evaluate the role of IVIG in solid organ recipients with SAD. A phase 2, randomized, multicenter, open-label study of solid organ recipients with severe infection and SAD defined as serum IgG <600 mg/dL. The study evaluated the efficacy of adding a fixed protocol of IVIG early after detection of SAD to standard of care (SOC) for the prevention of infection occurring on-study and the treatment of infections, versus SOC. We also assessed reconstitution of humoral immunity in a substudy. Forty-four transplant recipients were randomized in 6 transplant centers in Spain. The IVIG protocol comprised 2 doses of 15 g (interval 7-15 d) followed by 3 doses of 20 g (interval 15-30 d). The primary endpoint was infection occurring on-study defined as a new severe infection after randomization. Forty-two patients were included in the intention-to-treat analysis (IVIG arm, n = 21 versus non-IVIG arm, n = 21). The rate of infection occurring on-study was lower in patients randomized to receive IVIG versus SOC (23.8% versus 66.7%, Fisher exact test, P = 0.012). The median number of infections occurring on-study was lower in the IVIG group. The median total number of new admissions considered to be related to an infection occurring on-study was significantly lower in IVIG-treated patients. A significant increase in specific anti-cytomegalovirus IgG, anti-varicella zoster IgG, anti-Clostridium difficile toxins A and B IgG, and anti-tetanus toxoid IgG and IgG1 was demonstrated in the IVIG arm. In solid organ recipients with severe infection and SAD, IVIG may reduce infection occurring on-study occurrence versus SOC.