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Testicular large B-cell lymphoma is genetically similar to PCNSL and distinct from nodal DLBCL
(Wolters Kluwer, 2024-10-07) Karube, Kennosuke; Salaverria Frigola, Itziar; Enjuanes, Anna; Wiemann, Stefan; Heppner, Frank L.; Siebert, Reiner; Climent, Fina; Campo Güerri, Elias; Giné Soca, Eva; López Guillermo, Armando; Tapia, Gustavo; Beà Bobet, Sílvia M.; Luizaga Velasco, Luis; Bárcena, Cristina; Kelleher, Nicholas; Villamor i Casas, Neus; Baumann, Tycho; Muntañola, Ana; Sancho, Juan Manuel; García Sancho, Alejandro Martín; González Barca, Eva; Rivas Delgado, Alfredo; López González, Cristina; Clot Razquin, Guillem; Nadeu Prat, Ferran; Grau, Marta; Frigola G; Bosch Schips, Jan; Radke, Josefine; Ishaque, Naveed; Alcoceba, Miguel; Matutes, Estella; Brito, Jordi A.
Testicular large B-cell lymphoma (TLBCL) is an infrequent and aggressive lymphoma arising in an immune-privileged site and has recently been recognized as a distinct entity from diffuse large B-cell lymphoma (DLBCL). We describe the genetic features of TLBCL and compare them with published series of nodal DLBCL and primary large B-cell lymphomas of the CNS (PCNSL). We collected 61 patients with TLBCL. We performed targeted next-generation sequencing, copy number arrays, and fluorescent in situ hybridization to assess chromosomal rearrangements in 40 cases with available material. Seventy percent of the cases showed localized stages. BCL6 rearrangements were detected in 36% of cases, and no concomitant BCL2 and MYC rearrangements were found. TLBCL had fewer copy number alterations (p < 0.04) but more somatic variants (p < 0.02) than nodal DLBCL and had more frequent 18q21.32-q23 (BCL2) gains and 6q and 9p21.3 (CDKN2A/B) deletions. PIM1, MYD88L265P, CD79B, TBL1XR1, MEF2B, CIITA, EP300, and ETV6 mutations were more frequent in TLBCL, and BCL10 mutations in nodal DLBCL. There were no major genetic differences between TLBCL and PCNSL. Localized or disseminated TLBCL displayed similar genomic profiles. Using LymphGen, the majority of cases were classified as MCD. However, we observed a subgroup of patients classified as BN2, both in localized and disseminated TLBCL, suggesting a degree of genetic heterogeneity in the TLBCL genetic profile. TLBCL has a distinctive genetic profile similar to PCNSL, supporting its recognition as a separate entity from DLBCL and might provide information to devise targeted therapeutic approaches.
Dynamic biomarkers in hormone receptor-positive/HER2-negative breast cancer trials: a new hope for precision oncology
(Springer Nature, 2026-01-28) Grazia, Giuseppe Di; Schettini, Francesco; Sánchez Bayona, Rodrigo; Casals Pascual, Climent; Pascual, Tomás; Generali, Daniele; Gennari, Alessandra; Vigneri, Paolo; Harbeck, Nadia; Cortés, Javier; Prat Aparicio, Aleix
Hormone receptor-positive/HER2-negative breast cancer evolves in response to therapy, demanding smarter, adaptive biomarker-based treatment strategies. We review emerging dynamic biomarkers to guide therapeutic decision-making, spanning tissue and liquid biopsies, metabolic imaging, and microbiome profiling, that capture tumor or host-related changes over time. By contrasting Academic and Industry approaches, we advocate for a cultural shift in clinical trial design and implementation, aiming to move from reactive to proactive Oncology.
Case Report: Personalized management of HER2-positive breast cancer with advanced nodal disease during pregnancy: a clinical case and review
(Frontiers Media, 2026-01-19) Gullotta, Gullotta; Walbaum, Benjamin; Seguí, Elia; López Rojano, Marta; Mension Coll, Eduard; Cebrecos, Isaac; Mollà, Meritxell; Oses, Gabriela; Bargallo, Xavier; Ganau, Sergi; Sanfeliu Torres, Esther ; Brasó-Maristany, Fara; Muñoz Mateu, Montserrat; Prat Aparicio, Aleix; Vidal Losada, Maria Jesús; Adamo, Barbara
Background: Pregnancy-associated breast cancer (PrBC) poses complex challenges in diagnosis and treatment, particularly when associated with biologically aggressive subtypes and extensive nodal involvement. Management must be individualized, integrating oncologic urgency, fetal safety, and limited validated evidence in this unique setting.Case Summary: We present the case of a 36-year-old woman diagnosed during the second trimester of pregnancy with HER2-positive (HER2+), node-positive (cT2[m]N3a) breast cancer (BC). After a multidisciplinary team discussion, patient initiated anthracycline- and taxane-based neoadjuvant chemotherapy during gestation. Given its contraindication during pregnancy, anti-HER2 therapy was added postpartum, and surgery included nipple-sparing mastectomy with targeted axillary dissection (TAD) of clipped nodes. Pathology revealed minimal residual invasive disease in the breast and a complete axillary response, allowing omission of axillary lymph node dissection (ALND). Genomic profiling with HER2DX supported high-risk disease and informed systemic therapy with delayed anti HER2 therapy, and conservative axillary management (TAD without ALND) in cT2N3 PrBC, without compromising fetal outcome. The patient subsequently received adjuvant chest wall and nodal region radiotherapy plus trastuzumab-emtansine (T-DM1).Conclusion: This case underscores the value of personalized, multidisciplinary management in PrBC, particularly in patients with high-risk biologic features and advanced nodal disease. Integrating clinical judgment, genomic tools, and adaptive strategies, while accounting for gestational limitations, can optimize oncologic outcomes without compromising fetal safety
Design and validation of a diagnostic suspicion checklist to differentiate epileptic from psychogenic nonepileptic seizures (PNES-DSC)
(Elsevier B.V., 2024-05-01) Sobregrau Sangrà, Pau; Bailles, Eva; Radua, Joaquim; Carreño, Mar; Donaire Pedraza, Antonio Jesús; Setoain Perego, Xavier; Bargalló Alabart, Núria; Rumià, Jordi; Sánchez-Vives, María Victoria; Pintor Pérez, Luis
Objective Psychogenic non-epileptic seizures (PNES) are complex clinical manifestations and misdiagnosis as status epilepticus remains high, entailing deleterious consequences for patients. Video-electroencephalography (vEEG) remains the gold-standard method for diagnosing PNES. However, time and economic constraints limit access to vEEG, and clinicians lack fast and reliable screening tools to assist in the differential diagnosis with epileptic seizures (ES). This study aimed to design and validate the PNES-DSC, a clinically based PNES diagnostic suspicion checklist with adequate sensitivity (Se) and specificity (Sp) to discriminate PNES from ES. Methods A cross-sectional study with 125 patients (n = 104 drug-resistant epilepsy; n = 21 PNES) admitted for a vEEG protocolised study of seizures. A preliminary PNES-DSC (16-item) was designed and used by expert raters blinded to the definitive diagnosis to evaluate the seizure video recordings for each patient. Cohen's kappa coefficient, leave-one-out cross-validation (LOOCV) and balance accuracy (BAC) comprised the main validation analysis. Results The final PNES-DSC is a 6-item checklist that requires only two to be present to confirm the suspicion of PNES. The LOOCV showed 71.4% BAC (Se = 45.2%; Sp = 97.6%) when the expert rater watched one seizure video recording and 83.4% BAC (Se = 69.6%; Sp = 97.2%) when the expert rater watched two seizure video recordings. Conclusion The PNES-DSC is a straightforward checklist with adequate psychometric properties. With an integrative approach and appropriate patient history, the PNES-DSC can assist clinicians in expediting the final diagnosis of PNES when vEEG is limited. The PNES-DSC can also be used in the absence of patients, allowing clinicians to assess seizure recordings from smartphones.
Whole-exome sequencing of vulvar squamous cell carcinomas reveals an impaired prognosis in patients with TP53 mutations and concurrent CCND1 gains
(Nature Publishing Group, 2024-10-01) Ordi, Oriol ; Saco, Adela; Peñuelas, Núria; Blanco Irazuegui, Odei; Pino Saladrigues, Marta del; Carreras Dieguez, Núria ; Marimon, Lorena; Rodrigo Calvo, María Teresa; Morató, Alba; Sisuashvili, Lia; Bustamante Pineda, Mariona; Cruells, Adrià; Darecka, Katarzyna; Vega, Naiara; Alos, Silvia; Trias Puigsureda, Isabel; Fusté, Pere; Parra, Genís; Gut, Marta; Munmany, Meritxell; Torné Bladé, Aureli; Jares Gerboles, Pedro; Rakislova, Natalia
Very little information is available on the mutational landscape of vulvar squamous cell carcinoma (VSCC), a disease that mainly affects older women. Studies focusing on the mutational patterns of the currently recognized etiopathogenic types of this tumor (human papillomavirus [HPV]-associated [HPV-A], HPV-independent [HPV-I] with TP53 mutation [HPV-I/TP53mut], and HPV-I with wild-type TP53 [HPV-I/TP53wt]) are particularly rare, and there is almost no information on the prognostic implications of these abnormalities.Whole-exome DNA sequencing of 60 VSCC and matched normal tissues from each patient was performed. HPV detection, immunohistochemistry (IHC) for p16, p53, and mismatch repair proteins were also performed. Ten tumors (16.7%) were classified as HPV-A, 37 (61.7%) as HPV-I/TP53mut, and 13 (21.6%) as HPV-I/TP53wt. TP53 was the most frequently mutated gene (66.7%), followed by FAT1 (28.3%), CDKN2A (25.0%), RNF213 (23.3%), NFE2L2 (20%) and PIK3CA (20%). All the 60 tumors (100%) were DNA mismatch repair proficient. Seventeen tumors (28.3%) showed CCND1 gain. Bivariate analysis, adjusted for International Federation of Gynecology and Obstetrics stage, revealed that TP53 mutation, CCND1 gain, and the combination of the 2 alterations were strongly associated with impaired recurrence-free survival (hazard ratio, 4.4; P < .001) and disease-specific survival (hazard ratio, 6.1; P = .002). Similar results were obtained when p53 IHC status was used instead of TP53 status and when considering only HPV-I VSCC. However, in the latter category, p53 IHC maintained its prognostic impact only in combination with CCND1 gains. All tumors carried at least one potentially actionable genomic alteration. In conclusion, VSCCs with CCND1 gain represent a prognostically adverse category among HPV-I/TP53mut tumors. All patients with VSCCs are potential candidates for targeted therapy.
Endocervical Brush Cytology After Cervical Conization as a Predictor of Treatment Failure: A Prospective Cohort Study
(Lippincott, Williams & Wilkins. Wolters Kluwer Health, 2025-01-01) Carreras Dieguez, Núria ; Torras, Ines; Martí Delgado, Cristina; Matas, Isabel; Glickman, Ariel; Fusté, Pere; Mula, Cristina; Alos, Silvia; Hoya, Sandra; Rakislova, Natalia; Saco, Adela; Marimon, Lorena; Ordi i Majà, Jaume; Torné Bladé, Aureli; Pino Saladrigues, Marta del
Objective Endocervical curettage (ECC) is the gold standard for predicting the persistence of high-grade squamous intraepithelial lesions (HSIL) after cervical conization. However, ECC has a high rate of unsatisfactory samples and may be uncomfortable for women. Endocervical sampling with brush (ECB) has been proposed as an alternative to ECC, which, in addition to the cytological evaluation, allows performing HPV testing using the same sample. The authors compared ECC and ECB performed immediately after conization to identify women with persistent HSIL. Materials and Methods This is a prospective single-center study, including 518 patients who underwent conization over a 10-year period (2012–2021). Immediately after treatment conization, the authors performed ECB sampling followed by ECC to all patients. They evaluated the accuracy of the 2 techniques for diagnosing persistent HSIL during follow-up. Results Persistent HSIL was identified in 8.9% of women. Eighteen percent of the ECC samples and only 7% of ECB cytology were unsatisfactory (p < .001). The accuracy of detecting persistent HSIL was similar for ECB and ECC (89.0%, 95% CI = 85.9–91.5 vs 90.8%, 95% CI = 87.7–93.2; p = .797). Adding HPV testing to ECB cytological evaluation increased the accuracy to 91.5% (95% CI = 88.8–93.6). Conclusions ECB can be reliably used to identify women with persistent HSIL after conization, as its accuracy is similar to ECC, with a lower rate of unsatisfactory results. The technique allows adding HPV testing to cytological evaluation, improving the accuracy of the test.
White matter diffusion estimates in obsessive-compulsive disorder across 1653 individuals: machine learning findings from the ENIGMA OCD Working Group.
(Nature Publishing Group, 2024-02-07) Kim, Bo-Gyeom; Kim, Gakyung; Abe, Yoshinari; Alonso Ortega, María del Pino; Ameis, Stephanie H.; Anticevic, Alan; Arnold, Paul D.; Balachander, Srinivas; Banaj, Nerisa; Bargalló Alabart, Núria; Batistuzzo, Marcelo C.; Benedetti, Francesco; Bertolín Triquell, Sara; Beucke, Jan C.; Bollettini, Irene; Brem, Silvia; Brennan, Brian P.; Buitelaar, Jan K.; Calvo Escalona, Rosa; Castelo-Branco, Miguel; Cheng, Yuqi; Chhatkuli, Ritu Bhusal; Ciullo, Valentina; Coelho, Anna; Couto, Beatriz; Dallaspezia, Sara; Ely, Benjamin A.; Ferreira, Sónia; Fontaine, Martine; Fouche, Jean Paul; Grazioplene, Rachael G.; Gruner, Patricia; Hagen, Kristen; Hansen, Bjarne; Hanna, Gregory L.; Hirano, Yoshiyuki; Höxter, Marcelo Q.; Hough, Morgan; Hu, Hao; Huyser, Chaim; Ikuta, Toshikazu; Jahanshad, Neda; James, Anthony; Jaspers-Fayer, Fern; Kasprzak, Selina; Kathmann, Norbert; Kaufmann, Christian; Kim, Minah; Koch, Katharina; Kvale, Gerd; Kwon, Jun Soo; Lázaro García, Luisa; Lee, Junhee; Lochner, Christine; Lu, Jin; Rodriguez Manrique, Daniela; Martínez Zalacaín, Ignacio; Masuda, Yoshitada; Matsumoto, Koji; Maziero, Maria Paula; Menchón Magriñá, José Manuel; Minuzzi, Luciano; Moreira, Pedro Silva; Morgado, Pedro; Narayanaswamy, Janardhanan C.; Narumoto, Jin; Ortiz García, Ana Encarnación; Ota, Junko; Pariente, Jose Carlos; Perriello, Chris; Picó Pérez, Maria; Pittenger, Christopher; Poletti, Sara; Real, Eva; Reddy, Y. C. Janardhan; Rooij, Daan van; Sakai, Yuki; Sato, João R; Segalàs Cosi, Cinto; Shavitt, Roseli G.; Shen, Zonglin; Shimizu, Eiji; Shivakumar, Venkataram; Soriano Mas, Carles; Sousa, Nuno; Sousa, Mafalda Machado de; Spalletta, Gianfranco; Stern, Emily R.; Stewart, S. Evelyn; Szeszko, Philip R.; Thomas, Rajat; Thomopoulos, Sophia I.; Vecchio, Daniela; Venkatasubramanian, Ganesan; Vriend, Chris; Walitza, Susanne; Wang, Zhen; Watanabe, Anri; Wolters, Lidewij H.; Xu, Jian; Yamada, Kei; Yun, Je-Yeon; Zarei, Mojtaba; Zhao, Qin; Zhu, Xi; ENIGMA-OCD working group; Thompson, Paul M.; Bruin, Willem B.; Wingen, Guido van; Piras, Federica; Piras, Fabrizio; Stein, Dan J., 1962-; Heuvel, Odile A. van den; Simpson, Helen Blair; Marsh, Rachel; Cha, Jiook
White matter pathways, typically studied with diffusion tensor imaging (DTI), have been implicated in the neurobiology of obsessive-compulsive disorder (OCD). However, due to limited sample sizes and the predominance of single-site studies, the generalizability of OCD classification based on diffusion white matter estimates remains unclear. Here, we tested classification accuracy using the largest OCD DTI dataset to date, involving 1336 adult participants (690 OCD patients and 646 healthy controls) and 317 pediatric participants (175 OCD patients and 142 healthy controls) from 18 international sites within the ENIGMA OCD Working Group. We used an automatic machine learning pipeline (with feature engineering and selection, and model optimization) and examined the cross-site generalizability of the OCD classification models using leave-one-site-out cross-validation. Our models showed low-to-moderate accuracy in classifying (1) “OCD vs. healthy controls” (Adults, receiver operator characteristic-area under the curve = 57.19 ± 3.47 in the replication set; Children, 59.8 ± 7.39), (2) “unmedicated OCD vs. healthy controls” (Adults, 62.67 ± 3.84; Children, 48.51 ± 10.14), and (3) “medicated OCD vs. unmedicated OCD” (Adults, 76.72 ± 3.97; Children, 72.45 ± 8.87). There was significant site variability in model performance (cross-validated ROC AUC ranges 51.6–79.1 in adults; 35.9–63.2 in children). Machine learning interpretation showed that diffusivity measures of the corpus callosum, internal capsule, and posterior thalamic radiation contributed to the classification of OCD from HC. The classification performance appeared greater than the model trained on grey matter morphometry in the prior ENIGMA OCD study (our study includes subsamples from the morphometry study). Taken together, this study points to the meaningful multivariate patterns of white matter features relevant to the neurobiology of OCD, but with low-to-moderate classification accuracy. The OCD classification performance may be constrained by site variability and medication effects on the white matter integrity, indicating room for improvement for future research.
Murine typhus as the leading cause of non-focalized fever in the Canary Islands
(Springer Verlag, 2024-11-29) Vélez-Tobarias, Mónica; Torres-Vega, Ana María; Carmelo Pascual, Emma; Morais-Martín, Julio; Pérez, José Antonio; Gonzalo-Hernández. C.; Clot Razquin, Guillem; Ascaso Terrén, Carlos
Purpose and methods: This prospective study aims to diagnose the etiology of non-focalized fever lasting between 5 and 28 days in the islands of La Palma and El Hierro (Canary Islands, Spain) during 2021, using serology and PCR. Results: The etiological profile described in this study aligns with that of fever of intermediate duration (FID), with zoonoses being the primary cause. Murine typhus (MT) is identified as the leading cause, followed by Q fever (QF). The incidence of MT is the highest reported nationally and comparable to the highest in Europe, with 39.6 cases per 100,000 inhabitants in La Palma and 79.7 cases per 100,000 inhabitants in El Hierro. Q fever, known to be endemic to the Canary Islands, presents incidences of 26.5 cases per 100,000 inhabitants in La Palma and 15.6 cases per 100,000 inhabitants in El Hierro. MT shows no gender differences and has a homogeneous geographical distribution. In contrast, QF is more prevalent in men and has a heterogeneous geographical distribution. Conclusions: The high incidence of MT found in both urban and peri-urban areas is particularly noteworthy. Its potential connection with climate change and/or the growth of the reservoir population in the Canary Islands remains unknown. MT's similarity to QF in terms of clinical signs and treatment, coupled with the absence of a specific protocol for early diagnosis, may have contributed to its underdiagnosis. MT can lead to significant health concerns, including risk of hospitalization, complications, and even death. Therefore, the registration of cases for epidemiological control is deemed essential.
Massive parallel sequencing of head and neck conventional squamous cell carcinomas: A comprehensive review
(Springer Verlag, 2024-11-29) Nadal Serra, Alfons; Cardesa García, Antonio; Agaimy, Abbas; Almangush, Alhadi; Franchi, Alessandro; Hellquist, Henrik; Leivo, Ilmo; Zidar, Nina; Ferlito, Alfio
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and is a cause of significant mortality and morbidity. The epidemiology of this cancer varies worldwide due to either genetic differences in populations or differences in carcinogen exposure. The application of massive parallel sequencing-based techniques in HNSCC should provide a helpful understanding of the genetic alterations that eventually lead to HNSCC development and progression, and ideally, could be used for personalized therapy. In this review, the reader will find an overview of the mutational profile of conventional HNSCC according to published results on massive parallel sequencing data that confirm the pivotal role of TP53 and the frequent involvement of CDKN2A and PIK3CA. The reader will also find a more detailed description of the genes, such as NOTCH1 and FBXW7, that were not identified in HNSCCs before the development of these techniques, the differences that can be site-specific, such as the different mutational signatures that indicate specific carcinogens for various subsites of the head and neck, and finally, the actionability of these findings that should allow more personalized therapy for patients.
The contribution of minimally invasive tissue sampling compared to antemortem-derived cause of death determination among inpatient child deaths: the minimally invasive tissue sampling in Malawi study.
(International Society of Global Health, 2025-08-04) Voskuijl, Wieger P.; Chasweka, Dennis; Lawrence, Sarah; Brals, Daniella; Kamiza, Steve; Bandsma, Robert; Berkley, James A.; Mbale, Emmie; Attipa, Charalampos; Eneya, Chisomo; Huwa, Cornelius; Khoswe, Stanley; Moxon, Christopher; Potani, Isabel; Waller, Jessica L.; Diaz, Maureen H.; Walson, Judd; Ordi i Majà, Jaume; Denno, Donna M.
Improved causes of death (CoD) understanding in low- and middle-income countries is needed to reduce child mortality. Compared to full autopsy, minimally invasive tissue sampling (MITS), using transcutaneous needle sampling, is a feasible, socially acceptable, and validated method. We aimed to quantify the additional contribution of MITS to CoD attribution based on clinical records and inpatient research data with intensive patient characterisation. Methods We enrolled children aged seven days to 59 months who died while on admission for acute illness and/or severe malnutrition to Queen Elizabeth Central Hospital in Blantyre, Malawi. Standard MITS procedures included histologic, immunohistochemical, and microbiologic testing. Phase 1 CoD determination was based on medical records alone, Phase 2 also included research data, and Phase 3 included all data, including from MITS. Results We enrolled 29 children. Based on clinical notes alone (Phase 1), we identified 60 causal and 39 contributing conditions. Of the 45 (45%) infectious conditions, pathogens were identified in 15 (33%). Only one patient’s (3%) CoD was unchanged compared to including all data (Phase 3). Further, we identified 69 new (n = 43) or adjusted (n = 26) diagnoses among 28 cases (97%); the majority were undernutrition-related (n = 22, 32%) or infectious (n = 41, 59%) conditions. Overall, the majority of final Phase 3 conditions were also undernutrition-related (n = 46, 32%) or infectious (n = 61, 43%) and a pathogen was identified in 54 (89%) of the infectious conditions. Klebsiella pneumoniae was the most prevalent aetiology in both pneumonia and sepsis. Conclusions The addition of MITS to clinical and inpatient research data led to almost all (97%) of cases receiving new and/or refined diagnoses, including microbe identification in infectious conditions. Pathogens not specifically addressed by current clinical guidelines, such as Klebisiella pneumoniae, were commonly identified. Our findings support the utility of MITS to understand CoD even after thorough clinical characterisation of children during hospitalisation.
Association of astrocyte-specific gene expression in the dorsolateral prefrontal cortex with clozapine treatment in schizophrenia.
(Nature Publishing Group, 2025-10-31) Prohens Coll, Llucia; Rodríguez Ferret, Natalia ; Gonzalez Segura, Àlex; Martínez Pinteño, Albert; Olivares Berjaga, David; Martínez Martín, Irene; Mezquida Mateos, Gisela; Santas Martín, Jon A.; Morentín, Benito; Meana, J. Javier; Callado, Luis F.; Gassó Astorga, Patricia; Rivero Calera, Guadalupe; Mas Herrero, Sergi
Gene expression profiling studies could be a valuable tool in identifying the specific genes and pathways involved in the mechanism of action of clozapine, leading to a better understanding of the molecular biology underlying treatment-resistant schizophrenia (TRS). We aimed to identify the co-expressed modules that reflect the genetic differences between clozapine-treated and non-clozapine-treated patients with schizophrenia as a proxy of TRS. Gene expression of DLPFC samples from 26 subjects with schizophrenia (13 clozapine treated and 13 non-clozapine treated) were analyzed using Clariom S Human Array. Weighted gene coexpression network analysis (WGCNA) was applied to identify modules of co-expressed genes and to test its association with clozapine treatment. As a result of our analysis of the gene co-expression architecture in the DLPFC, among the 13 modules identified, one module (green) was significantly associated with clozapine treatment (p = 3.7 × 10−2). This module was significantly enriched in astrocyte markers (5.7 × 10−29) and genes involved in the polygenic architecture of TRS (1.6 × 10−2). This finding provides cell type-specific associations that could help in the interpretation of the neurobiological basis of TRS. A better understanding of the specific DLPFC cell types involved in clozapine treatment will contribute to the study of potential pathways and ultimately help improve psychiatric classification tools in personalized medicine.
Anticancer drugs are the first cause of drug-induced liver injury in a reference hospital.
(John Wiley & Sons, 2024-02) Pocurull Aparicio, Anna; Moreta, Maria José; Heitman, David; Olivas Alberch, Ignasi; Collazos Clemente, Cristina; Canga, Elia; Sáez Peñataro, Joaquín; Andrade, Raúl J.; Lucena, M. Isabel; Mariño Méndez, Zoe; Diaz Lorca, Maria Alba; Lens García, Sabela; Londoño, María Carlota; Forns, Xavier
Drug-induced liver injury (DILI) is a challenging liver disorder for hepatologists. We aimed to assess the pattern and causes of DILI in a tertiary hospital. We registered prospectively all patients referred with suspicion of DILI from 2018 to 2023. A total of 106 patients fulfilled the diagnostic criteria (30 caused by paracetamol were excluded; total number 76). The pattern of liver injury was hepatocellular in 55 (72%). Drugs causing DILI were antineoplastic (26%), antibiotics (24%), analgesics (12%), and recreational drugs (9%). Regarding clinical outcomes, 39 (51%) required hospitalization and 7 (9%) underwent a liver transplantation or died from acute liver injury. We identified 126 additional patients with DILI due to immune check-point inhibitors who were not referred to a liver disease specialist. Antineoplastic drugs have become the first cause of DILI in hospitals. A multidisciplinary approach and specific educational tools to increase DILI awareness are needed among different specialists.
Neuroanatomical substrate of visuospatial and visuoperceptual impairment in Parkinson's disease.
(Wiley, 2009-06-15) Pereira, Joana B.; Junqué i Plaja, Carme, 1955-; Martí Domènech, Ma. Josep; Ramírez Ruiz, Blanca; Bargalló Alabart, Núria; Tolosa, Eduardo
To determine magnetic resonance imaging patterns of gray matter (GM) atrophy underlying visuospatial and visuoperceptual impairment in Parkinson's disease (PD), we applied voxel-based morphometry to 36 nondemented PD patients and correlated their whole brain GM density with performance on three visuospatial and visuoperceptual tests. In addition, group comparisons between patients and 20 healthy controls were also performed. Correlations between visuospatial performance and GM density were found in the superior parietal lobules and the superior occipital gyrus of PD patients. Poor performance on visuoperceptual tests was also found to be significantly associated with GM decreases in the fusiform, the parahippocampus, and the middle occipital gyrus. Finally, group comparisons between controls and patients showed widespread GM cortical reductions in PD, involving posterior temporal and parietal regions. Taken together, these findings suggest that visuospatial and visuoperceptual dysfunctions reflect structural GM changes in temporo-parietal cortical regions of PD patients
Polygenic risk score of glycemic homeostasis, Type 2 Diabetes Mellitus and glycemic components in first episode psychosis
(Elsevier B.V., 2025-11-01) Segura, Alex G.; Verdolini, Norma; Valli, Isabel; García Rizo, Clemente; Diaz-Caneja, Covadonga M.; Vieta i Pascual, Eduard, 1963-; Mezquida Mateos, Gisela; Lobo, Antonio; González-Pinto, Ana; Andreu-Bernabeu, Álvaro; Roldán, Alexandra; Martínez-Arán, Anabel, 1971-; Baeza, Inmaculada, 1970-; Mane, Anna; Labad, Javier; Müller, Daniel J.; Guasch-Capella, Nora; Bernardo Arroyo, Miquel; Mas Herrero, Sergi; Bioque Alcázar, Miquel; González, Jairo; Andrés, Pablo; Cavone, Vito; Corripio, Iluminada; Duque, Alejandra; Mar Barrutia, Lorea; Marin, Julen; De-la-Camara, Concepción; Vaquero-Puyuelo, David; Rivero, Olga; Escartí Fabra, María José; Trabsa, Amira; Legido, Teresa; Forte, Maria Florencia; Serra Navarro, Maria; de la Serna, Helena; Castro-Fornielles, J.; Contreras, Fernando; García-Portilla González, María Paz, 1962-; González-Blanco, Leticia; Segarra Echevarría, Rafael; Zabala Rabadán, Arantzazu; Rodríguez-Jiménez, Roberto; Martínez-Gras, Isabel; Usall i Rodié, Judith; Barajas, Ana; Sarró, Salvador; Pomarol-Clotet, Edith; Ibáñez Cuadrado, Ángela; Cuesta, Manuel J.
Objective: First episode of psychosis (FEP) is associated with glucose homeostasis abnormalities even before pharmacological intervention. Given inconclusive GWAS results regarding a direct genetic link between schizophrenia and type 2 diabetes mellitus (T2DM), we hypothesized that FEP patients may exhibit altered genetic risk for glycemic traits. We compared polygenic risk scores (PRS) for T2DM (PRST2DM), fasting glucose (PRSFG), and glycated hemoglobin (HbA1c) (PRSHbA1c) between FEP patients and controls, examining their associations with glycemic measures over 24 months. Methods: We analyzed data from 242 FEP patients and 119 controls, assessing fasting serum glucose and HbA1c at baseline and 24 months. We examined cross-sectional and longitudinal associations between PRS and glycemic measures within each group. Results: FEP patients and controls did not differ significantly in PRS. Significant associations were observed for PRSFG with baseline serum glucose in controls (p = 0.008), PRSFG during follow-up (p = 0.034), PRSHbA1c at 24 months (p = 0.018), and HbA1c longitudinally (p = 0.025). After multiple testing corrections, only the association between PRSFG and baseline serum glucose in controls remained significant (p_adj = 0.023). No associations were found for PRST2DM. Conclusions: Despite the link between FEP and glycemic disturbances, PRST2DM did not differ between FEP patients and controls. However, PRS for glycemic traits showed associations with glycemic measures in both groups before multiple testing correction, suggesting that genetic predisposition may influence glucose homeostasis in early psychosis. The absence of a direct association between common genetic variants underlying T2DM and early glycemic dysregulation in FEP underscores the importance of considering environmental factors and epigenetic mechanisms.
Diagnostic accuracy of a simplified minimally invasive tissue sampling protocol for stillbirths in low-resource settings
(BMJ Publishing Group, 2025-10-28) Peñuelas, Núria; Saco, Adela; Hurtado, Juan Carlos; Marimon, Lorena; Varo, Rosauro; Mandomando, Inácio; Navero-Castillejos, Jessica; Carrilho, Carla; Fernandes, Fabiola; Guisseve, Assucena; Ismail, Mamudo R.; Morató, Alba; Lorenzoni, Cesaltina; Tivane, Aida; Diez-Ahijado, Laia; Lopez-Diaz, Jesus; Darecka, Katarzyna; Nhampossa, Tacilta; Bassat Orellana, Quique; Martinez, Mikel; Menéndez, Clara; Gonzalez, Raquel; Ordi i Majà, Jaume; Rakislova, Natalia
Background: Stillbirth rates remain unacceptably high in low- and middle-income countries (LMICs). Understanding the causes of death (CoD) is mandatory to develop effective strategies to reduce this high mortality. Minimally invasive tissue sampling (MITS) is a promising alternative to conventional autopsy (CA) but its validation in stillbirths remains limited. Existing evidence indicates that most samples of conventional MITS (c-MITS) lack diagnostic relevance in stillbirths. This study aimed to validate c-MITS against CA in stillbirths and design and assess a cost-efficient, simplified MITS (s-MITS) protocol. Methods: The study comprised two subsets of stillbirths occurring at Maputo Central Hospital, Mozambique. The CaDMIA-Plus cohort (Cause of Death investigation using Minimally Invasive Autopsy, n=90; 2017-2018), in which both c-MITS and CA were performed, was used to validate c-MITS against the gold standard and to determine the diagnostic value of each sample and design a s-MITS. The MIBio cohort (Mortality Identification Biomarkers, n=98; 2021-2022), which included only s-MITS, was used to evaluate the performance and cost of the s-MITS in comparison to c-MITS in an independent cohort. Results: Almost perfect overall agreement (Kappa=0.82) was observed between the c-MITS and CA-attributed CoD. Lung and placenta samples were identified as the most informative in c-MITS. When using only lung and placenta results to model an s-MITS, substantial agreement (Kappa=0.79) was found between the s-MITS-derived CoD and those attributed by CA. Similar CoD distributions were observed when applying the s-MITS to the MIBio cohort, while costs were reduced by 55.7%. The leading CoDs were primarily related to maternal conditions and pregnancy complications (70.0-72.4%) and infectious diseases (25.6-27.6%). Conclusions: c-MITS is a simpler and cost-effective alternative to CA for determining CoD in stillbirths. s-MITS has a diagnostic accuracy similar to that of c-MITS, while significantly reducing costs, making it adequate for implementation in routine clinical practice in LMICs.
Confusing Histopathological Features and HPV Testing Results in Vulvar Squamous Cell Carcinoma Arising in a Young Woman: A Case Solved Using Next-Generation Sequencing.
(Lippincott, Williams & Wilkins, 2025-03-01) Sisuashvili, Lia; Saco, Adela; Carreras Dieguez, Núria ; Celada Castro, Cristina; Marimon, Lorena; Montironi, Carla; Ordi i Majà, Jaume; Rakislova, Natalia
Vulvar squamous cell carcinoma (VSCC) can be classified according to human papillomavirus (HPV) status as HPV-associated (HPV-A) and HPV-independent (HPV-I). However, a small subset of tumors may show overlapping features and become a serious diagnostic challenge for pathologists. We report an unusual case of VSCC arising in a 21-year-old patient with type 1 diabetes mellitus. The tumor had keratinizing histologic features, was associated with a premalignant lesion with features of a high-grade squamous intraepithelial lesion (HSIL), and showed consistent p53 immunohistochemical (IHC) overexpression, but variable results in the HPV testing and p16 IHC staining. Molecular analysis revealed mutation of TP53 and overexpression of cell cycle-regulating genes (including CCND1) and collagen-coding genes (such as COL6A1). These molecular findings in genes, previously reported as upregulated in HPV-I VSCC, supported an etiological origin independent of HPV for the tumor. In conclusion, molecular analysis may help to correctly classify challenging VSCC, showing puzzling clinical, morphologic, and IHC characteristics.
Clinical and brain volumetric correlates of decreased DTI-ALPS, suggestive of local glymphatic dysfunction, in iRBD
(Springer Nature, 2025-04-23) Roura, Ignacio; Pardo, Jèssica; Martín Barceló, Cristina; Falcón Falcón, Carles Maria; Oltra González, Javier; Campabadal Delgado, Anna; Bargalló Alabart, Núria; Serradell, Mónica; Mayà Casalprim, Gerard; Montini, Angelica; Pont Sunyer. Claustre; Gaig Ventura, Carles; Buongiorno, Maria Teresa; Junqué i Plaja, Carme, 1955-; Iranzo, Alex; Segura i Fàbregas, Bàrbara
Glymphatic alterations may underlie neurodegeneration in alpha-synucleinopathies. Reduced Diffusion-Tensor Imaging ALong the Perivascular Space (DTI-ALPS), a proxy of perivascular glymphatic activity, has been scarcely studied in isolated REM sleep behaviour disorder (iRBD), a prodromal synucleinopathy stage. Furthermore, its associations with clinical symptoms and brain structural abnormalities remain unexplored. We assessed the DTI-ALPS in sixty-two patients with iRBD and twenty-three healthy controls (HC), exploring its associations with clinical symptoms, cortical thickness and brain volumetric data. iRBD patients exhibited a lower DTI-ALPS and poorer odor identification, semantic fluency and processing speed relative to HC. The DTI-ALPS positively correlated with cognitive performance, olfactory function and amygdalar, hippocampal, brainstem and diencephalic volumes, and negatively with age in iRBD. Perivascular glymphatic activity is compromised in iRBD and is associated with brain atrophy and clinical risk factors of progression to alpha-synucleinopathies, supporting the potential of the DTI-ALPS index as an early imaging neurodegeneration marker.
Tract-specific fractional anisotropy predicts cognitive outcome in a community sample of middle-aged participants with white matter lesions
(International Society for Cerebral Blood Flow and Metabolism, 2014-05) Soriano Raya, Juan José; Miralbell Blanch, Júlia; López Cancio, Elena; Bargalló Alabart, Núria; Arenillas, Juan Francisco; Barrios Cerrejón, M. Teresa; Cáceres, Cynthia; Toran, Pere; Alzamora, María Teresa; Dávalos, Antoni; Mataró Serrat, Maria
Cerebral white matter lesions (WMLs) have been consistently related to cognitive dysfunction but the role of white matter (WM) damage in cognitive impairment is not fully determined. Diffusion tensor imaging is a promising tool to explain impaired cognition related to WMLs. We investigated the separate association of high-grade periventricular hyperintensities (PVHs) and deep white matter hyperintensities (DWMHs) with fractional anisotropy (FA) in middle-aged individuals. We also assessed the predictive value to cognition of FA within specific WM tracts associated with high-grade WMLs. One hundred participants from the Barcelona-AsIA Neuropsychology Study were divided into groups based on low- and high-grade WMLs. Voxel-by-voxel FA were compared between groups, with separate analyses for high-grade PVHs and DWMHs. The mean FA within areas showing differences between groups was extracted in each tract for linear regression analyses. Participants with high-grade PVHs and participants with high-grade DWMHs showed lower FA in different areas of specific tracts. Areas showing decreased FA in high-grade DWMHs predicted lower cognition, whereas areas with decreased FA in high-grade PVHs did not. The predictive value to cognition of specific WM tracts supports the involvement of cortico-subcortical circuits in cognitive deficits only in DWMHs.
Interpretable surface-based detection of focal cortical dysplasias: a Multi-centre Epilepsy Lesion Detection study
(Oxford University Press, 2022-11-21) Spitzer, Hannah; Ripart, Mathilde; Whitaker, Kirstie; D'Arco, Felice; Mankad, Kshitij; Chen, Andrew A.; Napolitano, Antonio; De Palma, Luca; De Benedictis, Alessandro; Foldes, Stephen; Humphreys, Zachary; Zhang, Kai; Hu, Wenhan; Mo, Jiajie; Likeman, Marcus; Davies, Shirin; Güttler, Christopher; Lenge, Matteo; Cohen, Nathan T.; Tang, Yingying; Wang, Shan; Chari, Aswin; Tisdall, Martin; Bargalló Alabart, Núria; Conde Blanco, Estefanía; Pariente, Jose Carlos; Pascual-Diaz, Saül; Delgado-Martínez, Ignacio; Pérez-Enríquez, Carmen; Lagorio, Ilaria; Abela, Eugenio; Mullatti, Nandini; O'Muircheartaigh, Jonathan; Vecchiato, Katy; Liu, Yawu; Caligiuri, Maria Eugenia; Sinclair, Ben; Vivash, Lucy; Willard, Anna; Kandasamy, Jothy; McLellan, Ailsa; Sokol, Drahoslav; Semmelroch, Mira; Kloster AG; Opheim, Giske; Ribeiro, Letícia; Yasuda, Clarissa; Rossi-Espagnet, Camilla; Hamandi, Khalid; Tietze, Anna; Barba, Carmen; Guerrini, Renzo; Gaillard, William Davis; You, Xiaozhen; Wang, Irene; González Ortiz, Sofía; Severino, Mariasavina; Striano, Pasquale; Tortora, Domenico; Kälviäinen, Reetta; Gambardella, Antonio; Labate, Angelo; Desmond, Patricia; Lui. Elaine; O'Brien, Terence; Shetty, Jay; Jackson, Graeme; Duncan, John S.; Winston, Gavin P.; Pinborg, Lars H.; Cendes, Fernando; Theis, Fabian J.; Shinohara, Russell T.; Cross, Judith Helen; Baldeweg, Torsten; Adler, Sophie; Wagstyl, Konrad
One outstanding challenge for machine learning in diagnostic biomedical imaging is algorithm interpretability. A key application is the identification of subtle epileptogenic focal cortical dysplasias (FCDs) from structural MRI. FCDs are difficult to visualize on structural MRI but are often amenable to surgical resection. We aimed to develop an open-source, interpretable, surface-based machine-learning algorithm to automatically identify FCDs on heterogeneous structural MRI data from epilepsy surgery centres worldwide. The Multi-centre Epilepsy Lesion Detection (MELD) Project collated and harmonized a retrospective MRI cohort of 1015 participants, 618 patients with focal FCD-related epilepsy and 397 controls, from 22 epilepsy centres worldwide. We created a neural network for FCD detection based on 33 surface-based features. The network was trained and cross-validated on 50% of the total cohort and tested on the remaining 50% as well as on 2 independent test sites. Multidimensional feature analysis and integrated gradient saliencies were used to interrogate network performance. Our pipeline outputs individual patient reports, which identify the location of predicted lesions, alongside their imaging features and relative saliency to the classifier. On a restricted 'gold-standard' subcohort of seizure-free patients with FCD type IIB who had T1 and fluid-attenuated inversion recovery MRI data, the MELD FCD surface-based algorithm had a sensitivity of 85%. Across the entire withheld test cohort the sensitivity was 59% and specificity was 54%. After including a border zone around lesions, to account for uncertainty around the borders of manually delineated lesion masks, the sensitivity was 67%. This multicentre, multinational study with open access protocols and code has developed a robust and interpretable machine-learning algorithm for automated detection of focal cortical dysplasias, giving physicians greater confidence in the identification of subtle MRI lesions in individuals with epilepsy.
Deep versus periventricular white matter lesions and cognitive function in a community sample of middle-aged participants
(Cambridge University Press (CUP), 2012) Soriano Raya, Juan José; Miralbell Blanch, Júlia; López Cancio, Elena; Bargalló Alabart, Núria; Arenillas, Juan Francisco; Barrios Cerrejón, M. Teresa; Cáceres, Cynthia; Toran, Pere; Alzamora, María Teresa; Dávalos, Antoni; Mataró Serrat, Maria
The association of cerebral white matter lesions (WMLs) with cognitive status is not well understood in middle-aged individuals. Our aim was to determine the specific contribution of periventricular hyperintensities (PVHs) and deep white matter hyperintensities (DWMHs) to cognitive function in a community sample of asymptomatic participants aged 50 to 65 years. One hundred stroke- and dementia-free adults completed a comprehensive neuropsychological battery and brain MRI protocol. Participants were classified according to PVH and DWMH scores (Fazekas scale). We dichotomized our sample into low grade WMLs (participants without or with mild lesions) and high grade WMLs (participants with moderate or severe lesions). Analyses were performed separately in PVH and DWMH groups. High grade DWMHs were associated with significantly lower scores in executive functioning (−0.45 standard deviations [SD]), attention (−0.42 SD), verbal fluency (−0.68 SD), visual memory (−0.52 SD), visuospatial skills (−0.79 SD), and psychomotor speed (−0.46 SD). Further analyses revealed that high grade DWMHs were also associated with a three- to fourfold increased risk of impaired scores (i.e.,<1.5 SD) in executive functioning, verbal fluency, visuospatial skills, and psychomotor speed. Our findings suggest that only DWMHs, not PVHs, are related to diminished cognitive function in middle-aged individuals. (JINS, 2012, 18, 1–12)

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