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Mycobacterium fortuitum osteomyelitis of the cuboid bone treated with CERAMENT G and V: a case report
(Copernicus GmbH, 2022-07-25) Fraga, Kilian; Maireles, Miriam; Jordan, Marc; Soldevila, Laura; Murillo, Oscar
We present the rare case of a 61-year-old female withMycobacterium fortuitum osteomyelitis of the cuboid bone following penetrating plantar trauma. Thepatient underwent a single-stage surgery for the condition, including lesion debridement andbone defect filling with absorbable, gentamicin-/vancomycin-loaded, calciumsulfate-hydroxyapatite biocomposites, that resolved favorably 5 monthsafter intervention.
Efficacy of midazolam in outpatient pediatric dentistry: A systematic review
(Wiley, 2025-10-21) Rabassa Blanco, Judit; Cahuana-Bartra, Pau; González Chópite, Yndira; Rocha Eiroa, Maria Dolores; Ramírez Rámiz, Albert; Mashala, Elias Isaack; Brunet i Llobet, Lluís; Miranda i Rius, Jaume
Aims: The aim of this systematic review was to analyze the efficacy, advantages and adverse effects of midazolam in outpatient pediatric dentistry. Methods: This review was carried out in accordance with the PRISMA criteria. A systematic electronic search was conducted through MEDLINE/PubMed, Scopus, and the Cochrane Library databases up to September 2024. An advanced and reproducible search strategy was used to identify relevant studies. Articles were excluded if they focused solely on midazolam as a premedication for general anesthesia or elective surgery, involving patients with special diseases. Inclusion criteria required participants aged 0-16 years, patients with behavioral and/or cooperation disorders and undergoing simple dental restorative procedures under local anesthesia, such as fillings, pulp therapies, stainless steel crowns, or basic extractions. Patients with specific medical conditions, as well as those who were not monitored for vital signs during sedation, were excluded from the study. The risk of bias assessment was analyzed using the criteria set out in the Cochrane Handbook for Systematic Reviews of Interventions, version 5.1.0. Results: A total of 28 studies were included in the analysis, which were conducted across 11 countries and involved a total of 4374 children aged between 2 and 14 years. Most studies demonstrated a low risk of bias. Many of the participants were ASA I or II status and were assessed using behavioral scales, primarily the Frankl scale. Twelve adjunct drugs were combined with midazolam, and various administration routes were explored, including oral, intranasal, and buccal. Dosing protocols varied, as did fasting guidelines prior to sedation. Outcome measures included vital sign monitoring and behavioral assessments, most commonly via the Houpt and MOAA/S scales. Midazolam generally proved effective in reducing anxiety and improving cooperation, with reported benefits extending to future dental visits. Adverse effects were infrequently noted and typically mild, including nausea, vomiting, and paradoxical reactions. Conclusions: Midazolam has been shown to be an effective and safe agent for moderate sedation in pediatric dental procedures when administered orally at a dose range of 0.3-0.5 mg/kg. The evidence suggests that it reliably reduces anxiety and improves cooperation. Supervision, preferably by an anesthesiologist, is recommended when combined with other drugs to ensure patient safety.
Endometrial cancer progression driven by PTEN-deficiency requires miR-424(322)~503
(Nature Publishing Group, 2025-10-06) Vidal Sabanés, Maria; Navaridas, Raúl; Egea, Joaquim; Encinas, Mario; Rodriguez Barrueco, Ruth; Silva, Jose M.; Matias-Guiu, Xavier, 1958-; Llobet Navas, David; Dolcet, Xavier; Bonifaci Cano, Núria
Endometrial cancer is the most frequent type of cancer in the female reproductive tract. Loss-of-function alterations in PTEN, leading to enhanced PI3K/AKT activation, are among the most frequent molecular alterations in endometrial cancer. Increased PI3K/AKT signaling resulting from PTEN loss promotes cellular proliferation and confers resistance to TGFβ-mediated apoptosis, a key regulator of endometrial homeostasis. In this study, we have analyzed the role of miRNAs in driving these altered cellular responses. A comprehensive transcriptomic analysis of miRNA expression revealed the upregulation of several miRNAs caused by PTEN deficiency and/or TGFβ stimulation. The miR-424(322)~503 cluster drew our attention due to its involvement in regulating apoptosis and proliferation. However, miR-424(322)~503 cluster has a paradoxical role in cancer, exhibiting either oncogenic and tumor suppressive functions depending on cell type or context. To ascertain the function of miR-424(322)~503 in endometrial carcinogenesis caused by PTEN deficiency, we generated a double Pten/miR-424(322)~503 knock-out mice. We demonstrate that loss of miR-424(322)~503 impairs proliferation of both wild type or Pten deficient endometrial organoids by interfering with growth factor and PI3K/AKT signaling. Furthermore, the absence of miR-424(322)~503 restores TGFβ-induced apoptosis, which is otherwise compromised by PTEN deficiency. In vivo, Pten/miR-424(322)~503 knock-out mice exhibit reduced endometrial cancer progression compared to Pten deficient mice through a cell-autonomous mechanism.
PREDICT validity for prognosis of breast cancer patients with pathogenic BRCA1/2 variants
(Springer Science and Business Media LLC, 2023-05-12) A. Muranen, Taru; Morra, Anna; Khan, Sofia; R. Barnes, Daniel; K. Bolla, Manjeet; Dennis, Joe; Keeman, Renske; Leslie, Goska; T. Parsons, Michael; Wang, Qin; U. Ahearn, Thomas; Aittomäki, Kristiina; L. Andrulis, Irene; K. Arun, Banu; Behrens, Sabine; Bialkowska, Katarzyna; E. Bojesen, Stig; J. Camp, Nicola; Chang-claude, Jenny; Czene, Kamila; Devilee, Peter; M. Domchek, Susan; M. Dunning, Alison; Engel, Christoph; Gareth Evans, D.; Gago-dominguez, Manuela; García-closas, Montserrat; Gerdes, Anne-marie; Glendon, Gord; Guénel, Pascal; Hahnen, Eric; Hamann, Ute; Hanson, Helen; J. Hooning, Maartje; Hoppe, Reiner; Izatt, Louise; Jakubowska, Anna; A. James, Paul; N. Kristensen, Vessela; Lalloo, Fiona; J. Lindeman, Geoffrey; Mannermaa, Arto; Margolin, Sara; L. Neuhausen, Susan; G. Newman, William; Peterlongo, Paolo; Phillips, Kelly-anne; Angel Pujana, Miquel; Rantala, Johanna; Rønlund, Karina; Saloustros, Emmanouil; K. Schmutzler, Rita; Schneeweiss, Andreas; F. Singer, Christian; Suvanto, Maija; Yen Tan, Yen; R. Teixeira, Manuel; Thomassen, Mads; Tischkowitz, Marc; Tripathi, Vishakha; Wappenschmidt, Barbara; Zhao, Emily; F. Easton, Douglas; C. Antoniou, Antonis; Chenevix-trench, Georgia; D. P. Pharoah, Paul; K. Schmidt, Marjanka; Blomqvist, Carl; Nevanlinna, Heli
We assessed the PREDICT v 2.2 for prognosis of breast cancer patients with pathogenic germline BRCA1 and BRCA2 variants, using follow-up data from 5453 BRCA1/2 carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC). PREDICT for estrogen receptor (ER)-negative breast cancer had modest discrimination for BRCA1 carrier patients overall (Gonen & Heller unbiased concordance 0.65 in CIMBA, 0.64 in BCAC), but it distinguished clearly the high-mortality group from lower risk categories. In an analysis of low to high risk categories by PREDICT score percentiles, the observed mortality was consistently lower than the expected mortality, but the confidence intervals always included the calibration slope. Altogether, our results encourage the use of the PREDICT ER-negative model in management of breast cancer patients with germline BRCA1 variants. For the PREDICT ER-positive model, the discrimination was slightly lower in BRCA2 variant carriers (concordance 0.60 in CIMBA, 0.65 in BCAC). Especially, inclusion of the tumor grade distorted the prognostic estimates. The breast cancer mortality of BRCA2 carriers was underestimated at the low end of the PREDICT score distribution, whereas at the high end, the mortality was overestimated. These data suggest that BRCA2 status should also be taken into consideration with tumor characteristics, when estimating the prognosis of ER-positive breast cancer patients.
Efficacy of a preoperative smoking cessation intervention in orthopedic and general and urological surgery patients: A study protocol for a randomized clinical trial
(European Publishing, 2025-10-17) Gavilan, Eva; Fernández, Esteve; Minguell, Joan; Trilla, Enrique; Sánchez, Josep M.; Espín-basany, Eloy; Zuriguel, Esperanza; Álvarez, Consuelo; Montllor, Irene; Ferré, Miquel; Aneas, Silvia; Gayubas, Agustín; Botana, Cesar; Colmenero, Marta; Pérez, Gemma; Rodríguez, Natalia; Gili, Nuria; Martínez, Cristina
Tobacco use is a major risk factor for any surgical intervention. Offering patients help with giving up smoking before surgery increases cessation rates and lowers the risk of complications. The aim of this clinical trial is to evaluate the efficacy of an intensive presurgical intervention for promoting smoking cessation in smokers undergoing either orthopedic surgery with implants or general/urological surgery. We will conduct a stratified randomized clinical trial [intervention group (IG) and control group (CG), 1:1 allocation] at the Vall d'Hebron University Hospital, Barcelona, Spain. The IG will receive intensive help to quit smoking (psychoeducational and behavioral support, nicotine replacement therapy with followup, and an information leaflet). The CG will receive brief advice and the same information leaflet in a single session. Sample size was calculated to include four equal groups (IG and CG in both types of surgery) with an estimated difference of 15 points in abstinence between IG and CG; assuming a loss to follow-up of 10%, a total of 232 subjects will be needed (58 per group). The primary dependent variables are self-reported and verified abstinence from tobacco consumption (expired CO) and surgical complications. We will conduct descriptive and bivariate statistical analysis for independent data. Logistic regression will be performed to assess the efficacy of the intervention. The relative risk of surgical complications will be calculated using Cox regression models. Patient recruitment began in May 2023. This trial will be the first to evaluate an intervention of this nature in Spain. If its efficacy is demonstrated, the results will support the design of a protocol for a smoking cessation program aimed at smokers who are scheduled for surgery.
Mammographic density and breast cancer pathological subtypes by menopausal status and body mass index
(Springer Science and Business Media LLC, 2025-10-24) Fernández-morata, Julia; Pollán, Marina; Fernández De Larrea-baza-baz, Nerea; Pachón-olmos, Vanessa; García-pérez, Javier; Castelló, Adela; Sierra, María Ángeles; Lucas, Pilar; Llobet, Rafael; Stradella, Agostina; Cantos, Blanca; Ramón Y Cajal, Teresa; Santisteban, Marta; Ángel Seguí, Miguel; Santaballa Bertrán, Ana; Granja, Mónica; Camps-herrero, Julia; Recalde, Sabela; Nuñez-garcía, Beatriz; Calvo Verges, Nuria; Pérez-gómez, Beatriz; Pastor-barriuso, Roberto; Lope, Virginia
Background Mammographic density (MD) is an established biomarker of breast cancer (BC) risk. However, its relationship to BC pathological subtypes remains unclear. This study aimed to investigate this association and assess whether it differs by body mass index (BMI) and menopausal status. Methods MD percentage was assessed in the diagnostic mammograms of the contralateral breast of 714 BC patients recruited from eight Spanish hospitals. Participants completed an epidemiological questionnaire, and hospital researchers collected clinical and pathological data. Standardized prevalences (SPs) and standardized prevalence ratios (SPRs) for each BC pathological subtype across MD categories were estimated based on multinomial logistic regression models, both overall and stratified by BMI and menopausal status. Results Mean MD was 26.1% (SD = 17.3). Although no statistically significant differences were detected, women with MD >= 50% had a 13% lower SP of hormone receptor positive tumors (SPR = 0.87; 95% CI 0.67-1.13), a 36% higher SP of human epidermal growth factor receptor 2 positive (HER2+) tumors (SPR = 1.36; 95% CI 0.72-2.58), and a 23% higher SP of triple negative (TN) tumors (SPR = 1.23; 95% CI 0.47-3.22), compared to those with MD < 10%. These patterns were mainly observed in pre/perimenopausal women and in those with BMI >= 25 kg/m(2). Conclusions High MD might be mainly associated with the development of more aggressive and non-hormone-dependent cancers, such as HER2+ and TN BC, especially among pre/perimenopausal an overweight women.
Can Vitamin D Reduce Glucocorticoid-Induced Adverse Effects in Patients with Giant Cell Arteritis? Results from 1568 Patients in the Spanish ARTESER Registry
(MDPI AG, 2025-10-20) A. Ghio, Gastón; Domínguez-Álvaro, Marta; Hernández Rodríguez, Iñigo; Fernández-fernández, Elisa; Silva-díaz, Maite; M. Belzunegui, Joaquín; Moriano, Clara; Sánchez Martín, Julio; Narváez, Javier; Galíndez Agirregoikoa, Eva; Riveros Frutos, Anne; Ortiz Sanjuán, Francisco; C. Salman Monte, Tarek; Vasques Rocha, Margarida; L. Iñiguez, Carlota; García Dorta, Alicia; Molina Almela, Clara; Alcalde Villar, María; L. Hernández, José; Castañeda, Santos; Blanco, Ricardo
Objective: To determine whether oral vitamin D supplementation reduces the risk of glucocorticoid (GC)-associated severe adverse events (SAEs) in patients with giant cell arteritis (GCA) included in the Spanish ARTESER registry. Methods: The ARTESER registry collected data from patients diagnosed with GCA across 26 Spanish public hospitals between June 2013 and March 2019. SAEs were defined as fatal, life-threatening, or requiring hospitalization. Patients were categorized according to the use or non-use of oral vitamin D supplements. Incidence rates (IRs) of SAEs were expressed per person-year with 95% confidence intervals (CIs). Cox proportional hazards models assessed vitamin D supplementation and its interaction with cumulative glucocorticoid dose. Results: Of 1568 patients (mean age 76.9 +/- 8.1 years; 70.1% women) receiving GC, 120 (7.6%) experienced SAEs (IR 0.039; 95% CI 0.033-0.047). Vitamin D supplementation was documented in 1186 (75.6%) compared with 382 (24.4%) non-supplemented patients. SAE incidence was similar in supplemented (n = 89; 7.5%; IR 0.038, 95% CI 0.030-0.046) and non-supplemented patients (n = 31; 8.1%; IR 0.045, 95% CI 0.031-0.064) (p = 0.387). Multivariable Cox regression showed a significant interaction between vitamin D supplementation and cumulative glucocorticoid dose (interaction term HR 0.90; p = 0.033), consistent with a dose-dependent protective effect. Conclusions: Vitamin D supplementation was not independently associated with a lower incidence of GC-related SAEs, likely due to residual confounding factors. However, the interaction with cumulative GC exposure suggests a modulatory effect. Prospective studies incorporating stratified baseline vitamin D assessments are warranted.
Lifestyle changes and postmenopausal breast cancer risk in women from the European Prospective Investigation into Cancer and Nutrition
(Springer Science and Business Media LLC, 2025-10-29) Vasson, Fanélie; Matta, Komodo; Biessy, Carine; S. Antoniussen, Christian; Fournier, Agnès; Marques, Chloé; Cadeau, Claire; Le Cornet, Charlotte; T. Fortner, Renée; B. Schulze, Matthias; Sieri, Sabina; Panico, Salvatore; Tumino, Rosario; Ricceri, Fulvio; Masala, Giovanna; E. Hiensch, Anouk; M. Monninkhof, Evelyn; Agudo, Antonio; Guevara, Marcela; M. Colorado-yohar, Sandra; Sánchez, Maria-josé; Llorente, Adrian; Tin Tin, Sandar; G. Jackson, Isobel; J. Gunter, Marc; Botteri, Edoardo; Ferrari, Pietro; Dossus, Laure
BackgroundThe risk of breast cancer has been associated with various lifestyle factors, yet the evidence regarding how lifestyle modifications affect this risk remains limited. This study examines the relationship between changes in the Healthy Lifestyle Index (HLI) and postmenopausal breast cancer risk in women participating in the European Prospective Investigation into Cancer (EPIC).MethodsHLI scores (ranging from 0 to 16) were computed based on smoking habits, alcohol consumption, body mass index (BMI), and physical activity levels, using data from baseline and follow-up questionnaires, which were separated by a median interval of 10 (IQR: 5.2-12.0) years. Among the 125,746 women included in the analyses, 2,175 developed breast cancer over a median follow-up period of nearly 4 (IQR: 2.9-8.4) years starting from the date of the second lifestyle questionnaire. Cox proportional hazards models were employed to estimate hazard ratios (HRs) and confidence intervals (CIs) for the relationship between changes in HLI and postmenopausal breast cancer risk, analysed both overall and by estrogen receptor (ER) status. Individual components of the HLI were also analysed, with sensitivity analyses addressing potential reverse causation by delaying the start of follow-up by 1 to 3 years.ResultsEach unit increase in the HLI-reflecting a healthier lifestyle-was not associated with the overall risk of postmenopausal breast cancer. Among individual components, only a one-unit increase in the BMI score, corresponding to a shift towards a healthier BMI, was inversely associated with overall (HR = 0.936; 95% CI 0.880-0.996) and ER-positive (HR = 0.930; 95% CI 0.865-1.000) postmenopausal breast cancer risks.ConclusionsLifestyle changes, as measured by the HLI, during mid-adulthood were not significantly associated with the risk of postmenopausal breast cancer. More specifically, the results of this study suggested that a shift towards a healthier BMI may contribute to breast cancer prevention. Further research involving diverse and larger study populations and lifestyle assessments at earlier life stages could provide deeper insights.
Addressing common biases in the evaluation of lifetime alcohol consumption patterns and dementia risk: the EPIC-Spain dementia cohort
(Frontiers Media SA, 2025-10-14) Huerta, José M.; Colorado-yohar, Sandra M.; Andreu-reinón, M. Encarnación; Mokoroa, Olatz; Tainta, Mikel; Guevara, Marcela; Gasque, Alba; Castilla, Jesús; Petrova, Dafina; Crous-bou, Marta; Zamora-ros, Raúl; Sánchez, María José; Chirlaque, María Dolores
Background: Alcohol consumption has been described to exhibit a J-shaped relationship with dementia risk, but previous observations may be partly biased due to sick-quitters and competing risks of death. Objective: To examine the association between baseline and lifetime alcohol consumption and the risk of dementia and subtypes in a large Mediterranean cohort, accounting for lifetime drinking patterns, potential confounding, and competing risks of death. Methods: Prospective study of 30,211 participants, 29-69 years at recruitment (1992-1996), from the EPIC-Spain dementia cohort. Alcohol intake was assessed using a validated dietary history and retrospective questionnaires covering ages 20, 30, and 40 years. Dementia cases (n = 1,114) were ascertained through linkage with healthcare and mortality databases and individual medical record review over a mean follow-up of 22.8 years. Multivariate competing risk models were used to estimate sub-hazard ratios (sHRs) for dementia by categories of baseline and lifetime alcohol consumption, using lifetime abstainers as the reference group. Results: Mean lifetime alcohol consumption was 41.9 and 4.4 g/d in men and women, respectively. No significant associations were found between baseline or lifetime alcohol consumption and risk of overall dementia (sHR(currentvs.never) = 0.96, 95% CI: 0.82, 1.13; sHR(evervs.never) = 0.96, 95% CI: 0.82, 1.11), Alzheimer's disease, or non-Alzheimer subtypes. These null findings remained consistent across strata of sex, BMI or smoking categories, and by beverage type. Sensitivity analyses excluding mis-reporters of energy intake or low-quality diagnoses yielded similar results. Conclusions: In this large prospective cohort with over 1,100 dementia cases and long-term follow-up, alcohol consumption was not significantly associated with dementia risk. These findings challenge the notion of a protective effect of moderate drinking and warrant continued investigation using methodologically rigorous approaches to clarify the role of alcohol dose, timing, and pattern on dementia risk.
Effects of omega-3 supplementation on gastrointestinal cancers and treatment-related complications: an umbrella review of meta-analyses
(Oxford University Press (OUP), 2025-11-02) Abbasi, Hamid; Kamali, Majid; Eftekhar, Alireza; Tejareh, Faezeh; Paydareh, Amin; Hassan Naji, Mohammad; Rangraz, Zahra; Mohamadiyan, Zahra; Bakhshimoghaddam, Farnush; Shamsi-goushki, Ali; Alhouei, Barbod; Doaei, Saeid; Ajami, Marjan; Gholamalizadeh, Maryam
Background Many meta-analyses and systematic reviews have explored the impact of omega-3 supplementation on clinical outcomes in individuals with gastrointestinal (GI) cancers. Thus, this study aimed to capture the effects of omega-3 supplementation on GI cancers and associated complications.Methods This umbrella study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A comprehensive advanced search was executed across Scopus, PubMed, and Web of Science until 25 January 2025. Data were pooled by using random-effects models based on heterogeneity. The entire statistical analysis was performed via RStudio and R. The statistical analysis results are presented as the mean difference (MD), standard mean difference (SMD), and relative risk (RR) in conjunction with their 95% confidence intervals (CIs).Results Eight meta-analysis papers were included in our umbrella review. Omega-3 fatty acid supplementation improved the serum concentrations of tumor necrosis factor alpha (TNF-alpha) (SMD: -0.34; 95% CI: -0.56, -0.11), interleukin-6 (IL-6) (SMD: -0.30; 95% CI: -0.49, -0.12; MD: -4.96; 95% CI: -6.62, -3.30), and C-reactive protein (CRP) (MD: -5.46; 95% CI: -10.06, -0.87). Omega-3 supplementation improved the CD4+/CD8+ ratio (SMD: 0.48; 95% CI: 0.26, 0.71) and reduced the length of hospitalization (MD: -2.45 d; 95% CI: -3.11, -1.80). Omega-3 supplementation was associated with a 24% significant reduction in the risk of overall complications (RR: 0.76; 95% CI: 0.67, 0.86).Conclusion Omega-3 supplementation may reduce the risk of overall complications and length of hospitalization in individuals suffering from GI cancers. Additionally, supplementation with omega-3 may alleviate the levels of pro-inflammatory cytokines such as TNF-alpha and IL-6, and acute-phase proteins such as CRP.
Novel RRAGD Variants in Autosomal Dominant Kidney Hypomagnesemia and Therapeutic Perspectives
(Elsevier BV, 2025-07-29) Adella, Anastasia; Jouret, François; Madariaga, Leire; Leermakers, Pieter A.; Arango, Pedro; Ariceta, Gema; B. Beck, Bodo; Bjerre, Anna; Bockenhauer, Detlef; Coccia, Paula; Dhamija, Radhika; De Frutos, Fernando; Garcia-castano, Alejandro; Van Katwijk, Sara B.; Lucas, Jesus; Möller, Thomas; Müller, Dominik; Pinto E Vairo, Filippo; Raki, Melinda; Rips, Jonathan; Peter Schlingmann, Karl; Venselaar, Hanka; Vernet Machado Bressan Wilke, Matheus; Nijenhuis, Tom; Hoenderop, Joost; De Baaij, Jeroen
Introduction: Variants in the Ras-related GTPase D (RRAGD) gene have been associated with autosomal dominant kidney hypomagnesemia (ADKH) characterized by hypokalemia, nephrocalcinosis, and dilated cardiomyopathy (DCM). RRAGD, which encodes for the RagD protein, is involved in the activation of the mechanistic target of rapamycin complex 1 (mTORC1). Owing to the limited characterization of patients' phenotypes, the understanding of RRAGD-associated ADKH (ADKH-RRAGD) remains incomplete. Consequently, available treatment strategies are primarily symptomatic and insufficient. Methods: In the present case series, 13 new patients and 3 novel RRAGD variants, that is, p.(Ser77Phe), p. (Thr91Ile), and p.(Ile100Arg), are described. To assess the pathogenicity of the novel variants, an in vitro assay of mTORC1 activity was performed. In addition, the clinical response to diuretics (furosemide and thiazide, n = 4) and Na+-glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin (n = 6) was evaluated in patients carrying the RRAGD p.(Thr97Pro) variant during routine. Results: The patients presented with kidney tubulopathies, including hypomagnesemia, hypercalciuria, and nephrocalcinosis. Five patients also exhibited DCM. In vitro assays demonstrated constitutive activation of noncanonical mTORC1 signaling caused by the p.(Ser77Phe) and p.(Ile100Arg) variants. Clinically, patients remained sensitive to diuretic challenges, whereas dapagliflozin treatment increased serum magnesium (Mg2+) levels by 0.04 mM but exacerbated hypokalemia. Conclusion: To date, 37 patients with ADKH-RRAGD have been identified. Kidney tubulopathy is the most prominent feature within the phenotypic spectrum of ADKH-RRAGD. Molecularly, constitutive activation of noncanonical mTORC1 is present in most RRAGD variants. From a therapeutic perspective, dapagliflozin may increase serum Mg2+ levels in patients with RRAGD variants. (c) 2025 International Society of Nephrology. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Multidisciplinary approach for patients with early and locally advanced non-small cell lung cancer (NSCLC): 2nd Spanish Lung Cancer Group (GECP) expert consensus statement
(AME Publishing Company, 2025-09-01) Ospina-serrano, Aylen Vanessa; González-larriba, Jose Luis; Nadal, Ernest; Hernando Trancho, Florentino; Bosch-barrera, Joaquim; Calvo, Virginia; Bolufer-nadal, Sergio; Campo-cañaveral De La Cruz, José Luis; Macía-vidueira, Ivan; Álvarez-kindelán, Antonio; Del Barco-morillo, Edel; Bernabé-caro, Reyes; Casal-rubio, Joaquin; Cilleruelo-ramos, Ángel; Cobo-dols, Manuel; Dómine-gómez, Manuel; Figueroa-almánzar, Santiago; Insa-mollá, Amelia; Jarabo-sarceda, José Ramón; Jiménez-maestre, Unai; López-castro, Rafael; Majem, Margarita; Martinez-marti, Alex; Martínez Téllez, Elisabeth; Sánchez-lorente, David; López-valcárcel, Marta; Couñago, Felipe; Garcia-campelo, Rosario; De Castro, Javier; Massutí-sureda, Bartomeu; Provencio, Mariano
Background: In light of the ongoing advancements in the treatment of patients with early- and locally advanced-stage non-small cell lung cancer (NSCLC), the members of the Spanish Lung Cancer Group (GECP) deemed it necessary to update its 2023 consensus suggestions for the management of these patients. Methods: From July to November 2024, a panel of experts, including thoracic surgeons, radiation oncologists, and medical oncologists, was convened. The consensus process was developed using a mixed approach that incorporated Delphi and nominal group techniques. The consensus coordination group reviewed the relevant scientific literature for the update and developed a questionnaire for the panel of experts to vote on. Two rounds of voting were conducted, followed by a final nominal group meeting to discuss clinical situations where consensus had not been reached and draw final conclusions. In instances where high-quality scientific data were not available or were the subject of controversy, final suggestions were based on the expertise of the participants. Results: Thirty experts from the multidisciplinary team participated in the voting and discussions. The document was updated to incorporate recent advancements in molecular diagnosis and biomarkers, the role of the multidisciplinary thoracic committee, criteria for neoadjuvant/perioperative treatment, approaches to inoperable/unresectable disease, and adjuvant treatment. Proposals that did not require updating were not voted on again and remain part of the document, maintaining their first version. Conclusions: Updated suggestions were developed for the most relevant situations in the treatment of patients with early-stage and locally advanced NSCLC. These suggestions will support clinical decisionmaking in daily practice. This paper presents the statements developed by the expert panel and summarizes the scientific evidence supporting them.
Pulmonary Hypertension Drives Prognosis in Idiopathic Pulmonary Fibrosis: Insights from the European IPF Registry
(MDPI AG, 2025-10-17) Guenther, Andreas; Tello, Silke; Carre Schoppe, Marc; Pons-kuehnemann, Joern; Seeger, Werner; Stiben, Johannes; Tello, Khodr; Molina Molina, Maria; Vancheri, Carlo; Crestani, Bruno; Krauss, Ekaterina
Background/Objectives: In patients with idiopathic pulmonary fibrosis (IPF), a progressive disease characterized by lung tissue scarring, the impact of comorbidities is only partially understood. In particular, the prognostic implications of pulmonary hypertension (PH) are yet to be fully disclosed. Methods: To identify distinct IPF phenotypes on the basis of comorbidities and functional data, we performed cluster mixed data retrospective analysis, as well as recursive partitioning analysis on a dataset of 324 patients from the European IPF Registry (eurIPFreg); all patients were classified as IPF on the basis of established guidelines. Diagnosis of PH was based on echocardiographic and right heart catheter criteria as indicated in the 2022 ESC/ERS guidelines. Results: Two distinct clinical clusters with significant survival differences were identified (p < 0.001). Cluster 1, with fewer comorbidities, had a median survival of 4.41 years, whereas Cluster 2, with higher rates of arterial hypertension, diabetes mellitus, cardiovascular disease, PH, and dyslipidemia, showed a shorter median survival of 2.85 years. Multivariate Cox regression analysis confirmed PH as a significant predictor of reduced survival (HR 2.03). Recursive partitioning (RP) revealed that FVC was the strongest prognostic indicator: FVC below 50% predicted poor survival, and among patients with a FVC above 50%, the presence of PH indicated a significantly worse outcome. Conclusions: In this real-world IPF cohort, comorbidity cluster and RP analysis identified PH as the most relevant comorbidity. The findings suggest that PH may be more prevalent and impactful in IPF than previously recognized, with implications for clinical management.
Efficient deep neural networks for cancer detection on histopathology combining attention and image downsampling
(Springer Science and Business Media LLC, 2025-10-22) Socolovsky, Miguel; López, Alberto; K. Greenson, Joel; Rennert, Gad; B. Gruber, Stephen; Moreno, Victor
Pathology diagnosis of colorectal cancer is time-consuming and requires a high level of expertise. However, it is an essential step towards establishing the adequate treatment. The need to analyse a large number of these histopathological images calls for automatic tools capable of aiding pathologists in this arduous task. Deep learning techniques, together with the wealth of data available nowadays, provide a promising candidate for such job. Adopting state-of-the-art artificial intelligence algorithms, we developed a model to accurately detect colorectal cancer in digitalised histopathological whole-slide images. Our end-to-end approach uses the principles of multiple-instance learning combined with deep convolutional neural networks in order to fully leverage the information contained within each image and make robust predictions at the patient's level. The model also allows to highlight the areas in the slide most likely to harbour tumour tissue. Given the finite computational resources available, working at maximum resolution can be detrimental. Therefore, we explored the impact of lowering the working image resolution. The algorithms were trained and validated on a subset of more than 1300 patients of the Molecular Epidemiology of Colorectal Cancer study with histopathology images available. These images gave rise to > 10(5) tiles of 256 x 256 pixels each. Once we identified the best-performing model we put it to the test on images from The Cancer Genome Atlas. We obtained the best outcomes working at 4 mu m/pix, achieving the following metrics on the test dataset: F1-Score of 0.96, a Matthews correlation coefficient of 0.92 and an area under the receiver operating characteristic curve of 0.99. These results are exceptional and prove that computational costs can be reduced while keeping the performance up to standard.
Salivary Characteristics and Other Risk Factors Associated with the Severity of Chemical and Mechanical Tooth Wear in At-Risk Groups: A Cross-Sectional Study
(MDPI AG, 2025-10-14) Rius-bonet, Ona; Willaert, Eva; Jiménez-murcia, Susana; Diego-esteve, Guillem; Artero, Cristina; Sánchez, Isabel; Baenas, Isabel; Del Carmen Peña-cala, María; Fernández-aranda, Fernando; Martinez-gomis, Jordi
Background/Objectives: Tooth wear (TW) is a prevalent multifactorial condition resulting from chemical erosion and mechanical forces, yet the contributions of risk-group status and salivary factors remain insufficiently characterized. This study aimed to investigate the relationship between salivary characteristics and the severity of chemical and mechanical TW in at-risk groups, including gastroesophageal reflux disease (GERD), sleep bruxism (SB), eating disorders (EDs) and gambling disorder (GD). Methods: This cross-sectional observational study enrolled adults categorized into the four mutually exclusive at-risk groups and an age and sex-matched healthy control group. Demographic information, medical history, oral hygiene, diet, stress, and parafunctional habits were obtained through questionnaires. TW was assessed by a single examiner using TWES 2.0. Maximum bilateral force and salivary pH, flow and buffer capacity was measured. Correlations, multivariate linear regression, and mediation models were used to explore the relationships between the different variables and TW. Results: In total, 147 participants, divided into five groups (34 with GERD, 28 with SB 20 with GD, 20 with ED, and 45 controls) were included. The lowest resting salivary pH was observed in the GERD and ED groups (GERD: 6.63 +/- 0.61; ED: 6.62 +/- 0.52). The GERD group also exhibited the highest chemical (1.51 +/- 0.58) and mechanical (1.08 +/- 0.58) TW. Chemical and mechanical wear were strongly correlated, and mechanical wear increased with age. Risk-group status and salivary pH explained 47% of chemical wear, while age and bite force explained 54% of mechanical wear. Conclusions: Chemical TW was strongly linked to risk-group status-particularly GERD/ED-and low salivary pH, while mechanical TW related to age and bite force. Further longitudinal studies with larger samples, employing standardized methodologies and criteria are needed.
VaRHC: an R package for semi-automation of variant classification in hereditary cancer genes according to ACMG/AMP and gene-specific ClinGen guidelines
(Oxford University Press (OUP), 2023-03-14) Munté, Elisabet; Feliubadaló, Lidia; Pineda, Marta; Tornero, Eva; Gonzalez, Maribel; Moreno-cabrera, José Marcos; Roca, Carla; Bales Rubio, Joan; Arnaldo, Laura; Capellá, Gabriel; Luis Mosquera, Jose; Lázaro, Conxi
Motivation: Germline variant classification allows accurate genetic diagnosis and risk assessment. However, it is a tedious iterative process integrating information from several sources and types of evidence. It should follow gene-specific (if available) or general updated international guidelines. Thus, it is the main burden of the incorporation of next-generation sequencing into the clinical setting.Results: We created the vaRiants in HC (vaRHC) R package to assist the process of variant classification in hereditary cancer by: (i) collecting information from diverse databases; (ii) assigning or denying different types of evidence according to updated American College of Molecular Genetics and Genomics/Association of Molecular Pathologist gene-specific criteria for ATM, CDH1, CHEK2, MLH1, MSH2, MSH6, PMS2, PTEN, and TP53 and general criteria for other genes; (iii) providing an automated classification of variants using a Bayesian metastructure and considering CanVIG-UK recommendations; and (iv) optionally printing the output to an .xlsx file. A validation using 659 classified variants demonstrated the robustness of vaRHC, presenting a better criteria assignment than Cancer SIGVAR, an available similar tool.Availability and implementation: The source code can be consulted in the GitHub repository () Additionally, it will be submitted to CRAN soon.
Serum KL-6 as a biomarker to predict progression at one year in interstitial lung disease
(Springer Science and Business Media LLC, 2025-10-09) Bonella, Francesco; C. Vegas Sanchez, M.; D’alessandro, M.; Millan-billi, P.; F. Santos, R.; Schröder, N.; N. Bastos, H.; Molina-molina, M.; Sánchez Pernaute, O.; Castillo Villegas, D.; Bargagli, E.
About one third of non-IPF ILD patients progresses over time. Serum KL-6, a lung epithelial mucin type 1, is an established marker to assess disease severity in ILD but its ability to predict progression needs to be further explored. To investigate whether serum KL-6 is of additional value to stratify the patients for the risk of developing clinical or functional progression at one year. ILD patients from 6 European centers were retrospectively enrolled. Disease progression was defined as relative decline >= 10% in FVC or >= 15% in DLco from baseline. Serum KL-6 was measured using a full-automated chemiluminescent immunoassay (Fujirebio). Comparative logistic regression was used to identify predictors of progression at one year. 303 patients were included. 37% developed progression after one year from KL-6 measurement. A stepwise selection was used to identify and include five predictors of progression in a risk score: age, gender, BMI, FVC, and KL-6. The final model was superior to KL-6 alone to predict progression at one year, with 55% sensitivity, 73% specificity and 67% accuracy at a cut-off of 5. Patients were stratified in low and high risk of progression at one year based on the cut-off of 5, with a similar accuracy for IIP 0.687 and CTD-ILD 0.720 but not for HP. Serum KL-6 levels, included in a risk score with other clinical and functional variables, may help to better stratify patients for the risk of disease progression at one year, compared to any individual predictor.
White adipose tissue undergoes pathological dysfunction in the TDP-43A315T mouse model of amyotrophic lateral sclerosis (ALS)
(Springer Science and Business Media LLC, 2025-10-09) Benito-casado, Cristina; Durán-mateos, Esther; Ferrer-donato, Águeda; Barroso García, Gemma; Domínguez-rubio, Raúl; Povedano, Mónica; M. Fernandez-martos, Carmen
White adipose tissue (WAT) has a crucial role in maintaining systemic energy homeostasis. Numerous biological pathway studies have highlighted the importance of adipokines in regulating metabolic pathways and contributing to metabolic dysfunction in animal models and patients with ALS. Despite these associations, the specific molecular mechanisms remain poorly understood. Moreover, the direct contribution of WAT to the energy metabolism abnormalities observed in ALS has yet to be clearly defined. The current study sought to identify perturbances in WAT, main source of leptin, during the clinical course of the disease in TDP-43A315T mice using histological, proteomic, and molecular biological techniques. We present the first evidence of a significant histological alteration in WAT prior to the symptomatic stage of the disease in TDP-43A315T mice, providing novel insights into pathological features earlier in the onset of symptoms, and showing WAT as a target organ for ALS. In human ALS cases, we found that circulating leptin levels at the time of diagnosis were lower in the plasma of men with ALS who were overweight or obese and had rapidly progressive ALS, emphasizing the importance of considering sex-specific approaches when analysing adipokines essential for body weight control.
Caspase-3 in Brain Death Donors Is Associated with Reduced Primary Graft Dysfunction After Heart Transplantation
(MDPI AG, 2025-09-26) Herrador, Lorena; González-costello, José; Niubo-bosch, Jordi; Calatayud-samper, Laura; Maestro-benedicto, Alba; Farrero-torres, Marta; Blasco-peiro, Teresa; Almenar-bonet, Luis; Blázquez-bermejo, Zorba; Garrido-bravo, Iris; Gran-ipiña, Ferran; Grande-trillo, Antonio; Manito, Nicolas; Moreno-gonzalez, Gabriel
Primary graft dysfunction (PGD) remains a major cause of early morbidity and mortality after a heart transplant (HTx). Understanding the donor-related mechanisms involved may help improve organ selection and post-HTx outcomes. This study aimed to explore the association between the donor serum biomarkers of cell death and inflammation and the incidence of PGD and rejection in HTx recipients. We conducted a retrospective, multicenter observational study of brain-dead (DBD) heart donors and corresponding recipients between 2013 and 2019. Donor blood samples were analyzed for inflammatory cytokines, cell death-related proteins, and mitochondrial (mtDNA) and genomic DNA (gDNA). A total of 39 donor-recipient pairs were included. Sixteen recipients developed severe PGD, and five experienced >= 2R cellular rejection. Donors whose recipients developed PGD had significantly lower serum Caspase-3 levels compared to those without PGD (391.6 [101.8-1003.3] vs. 65.3 [40.2-163.3] pg/mL; p = 0.04). A trend toward lower mtDNA/gDNA ratio was also observed in the same group (10.5 [5.4-24.6] vs. 6.5 [3.3-10.7]; p = 0.067). Lower Caspase-3 levels in donor serum were significantly associated with the development of severe PGD in recipients. This may suggest that the sublethal activation of apoptotic pathways in the donor could play a protective role, potentially conditioning the graft to tolerate ischemic injury.
Molecular epidemiology and antimicrobial resistance profiles of Pseudomonas aeruginosa causing bloodstream infections in neutropenic cancer patients
(Frontiers Media SA, 2025-09-30) Cadenas-jiménez, Irene; María Badía-tejero, Ana; López-causapé, Carla; Morosini, María-isabel; Portillo-calderón, Inés; Machado, Marina; Larrosa, Nieves; Martín Dávila, Piluca; Palacios-baena, Zaira; Puig-albasanz, Adaia; Tubau, Fe; Oliver, Antonio; Sastre, Enric; Martí, Sara; Gudiol, Carlota
Background: Bloodstream infections (BSI) in neutropenic cancer patients, particularly those caused by Pseudomonas aeruginosa (PA), are associated with high morbidity and mortality. The increasing prevalence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) PA strains complicates clinical management. This study aimed to characterise PA strains causing BSI in neutropenic cancer patients and assess the association between microbiological features and clinical outcomes. Methods: We analysed PA strains from 94 BSI episodes in neutropenic cancer patients across five Spanish hospitals (2006-2018). Antimicrobial resistance, alginate and pigment production were assessed. Whole-genome sequencing was performed to identify resistance mutations and virulence genes. Results: PA strains exhibited high genetic diversity, with ST175 as the most prevalent clone (28.7%). MDR non-XDR and XDR strains accounted for 10.3% and 18.1% of cases, respectively. The highest resistance rates were for ciprofloxacin (42.6%) and imipenem (36.2%). Resistance was primarily driven by chromosomal mutations. ExoU was present in 24.4% of strains, associated with serotype O11 and ST253. Seven-day and 30-day mortality were 21.3% and 31.9%, respectively. Mortality was not significantly influenced by resistance phenotypes or the presence of ExoU. Polymicrobial infection (p = 0.016), septic shock (p < 0.001), Intensive Care Unit admission (p = 0.002), and inadequate empirical antibiotic therapy (p = 0.002), were linked to increased 7-day mortality. Conclusion: ST175 was the dominant high-risk clone, associated with antimicrobial resistance, while virulence traits were more common in susceptible strains. Inadequate empirical antibiotic therapy and septic shock significantly impacted early 7-day mortality, underscoring the need for early diagnosis and optimised treatment strategies.

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