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- A novel deleterious variant and a founder effect in four new families of MBD4-Associated Neoplasia Syndrome recruited over a period of 20 YearsPublication . Querido, Inês; Pinto, Carla; Arinto, Patrícia; Brandão, Andreia; Santos, Catarina; Pinheiro, Manuela; Guerra, Joana; Silva, João; Peixoto, Ana; Teixeira, Manuel R.; Pinto, CarlaDNA glycosylases play a crucial role in DNA repair mediated by the base excision repair (BER) pathway, and alterations in these enzymes have been associated with hereditary cancer predisposition. Recently, germline biallelic loss-of-function variants in MBD4 were shown to be responsible for a novel autosomal recessive multi-tumor predisposition syndrome, provisionally denominated as MBD4-associated neoplasia syndrome and characterized by the association of adenomatous polyposis, colorectal cancer, and acute myeloid leukemia (AML). Here, we studied the MBD4 gene in five individuals from four families affected by adenomatous polyposis and AML, who had been referred for genetic counselling at a single institution over a period of approximately 20 years. All patients with this phenotype presented homozygous deleterious germline variants in MBD4, of which one is a founder variant recurrent in three of the families, and another variant has not been previously described in the literature. Our work allowed a molecular diagnosis for these families and significantly contributes to expanding the knowledge about this emerging syndrome caused by MBD4 constitutional deficiency.
- The impact of war on asthma, a systematic review and meta-analysis: An EAACI task force reportPublication . Rufo, João Cavaleiro; Paciência, Inês; Jutel, Marek; Moreira, André; Annesi-Maesano, Isabella; Suojalehto, Hille; Zemelka-Wiącek, Magdalena; Trikamjee, Thulja; Demir, Semra; Eguíluz-Gracia, Ibon; Carvalho, Daniela; Backland, Anaïs; Lawson, Josh; Cavaleiro Rufo, JoãoWartime events have been followed by an increase in asthma prevalence, which is believed to result from a combination of environmental hazards and psychological trauma. This systematic review and meta-analysis aimed to investigate this relationship by pooling available data on various wartime exposures, such as occupational, environmental, and psychological factors. MEDLINE, Scopus, and Cochrane databases were searched for articles that measure the effect of war-related exposures on asthma. Risk of bias was assessed using the Effective Public Health Practice Project tool. The retrieved effects were then used to fit meta-analytical models. A total of 48 studies, corresponding to 90 effect measures, were included. War-related post-traumatic stress disorder showed the strongest association with asthma outcomes (OR [95% CI]=2.25 [1.04, 4.89]), followed by experiencing at least one life-threatening event (1.96 [1.18, 3.26]) and depression (1.56 [1.02, 2.37]). Although environmental exposures were also associated with an increased asthma risk in subgroup analysis (1.64 [1.32, 2.04]), this effect was mitigated when psychological variables were included in the models. The study's results show that wartime events and conflicts may increase asthma prevalence and outcomes associated with asthma. The management of asthma symptoms, lung function, and mental health seems fundamental in individuals who have experienced psychological trauma in war zones.
- Assessment of fat mass and fat-free mass in Portuguese adults: calibration of single-frequency leg-to-leg bioelectrical impedance with dual-energy x-ray absorptiometryPublication . Farias, Fernanda; Severo, Milton; Ramos, Elisabete; Lopes, Carla; Nogueira, Luísa; Araújo, Joana; Nogueira, LuisaBioelectrical impedance analysis (BIA) is more commonly employed in outpatient evaluations and epidemiological studies as it is cheaper and less time-consuming. Therefore, we aimed to compare fat mass (FM) and fat-free mass (FFM) estimated by BIA and dual-energy x-ray absorptiometry (DXA) in Portuguese adults, and to calibrate BIA estimates. We analyzed data from two population-based cohorts: EPIPorto (n = 391; <65 y) and EPITeen (n = 973; 27 y). Both completed single-frequency leg-to-leg BIA (Tanita TBF-300) and DXA (QDR 4500A Hologic). Agreement between BIA and DXA (FM/FFM) was evaluated by Bland and Altman. To calibrate the BIA estimates, the coefficients were estimated by linear regression using univariate (FM or FFM, separately) and multivariate models (FM and FFM in the same model). The correlation between BIA and DXA was high for FFM and for FM (FFM: r = 0.946/r = 0.954; FM: r = 0.926/r = 0.921, for EPIPorto and EPITeen, respectively). However, BIA underestimated FM (19.4% EPIPorto; 24.3% EPITeen) and overestimated FFM (11.3% EPIPorto; 14.4% EPITeen). Using the multivariate constrained model to have an absolute equal intercept for FFM and FM, the following calibration equations for BIA measurements were obtained for EPIPorto: FFMcalibrated =-5.119 + 0.995 £ FFMBIA;FMcalibrated = +5.119 + 0.980 £ FMBIA; and for EPITeen: FFMcalibrated =-5.707 + 0.984 £ FFMBIA;FMcalibrated = +5.707 + 0.975 £ FMBIA. FM assessed by single-frequency leg-to-leg BIA was largely underestimated and FFM overestimated in comparison to DXA, suggesting the use of BIA model-specific calibration equations to calibrate FM and FFMestimates in clinical settings and research studies.
- Prevalence of high-grade endometrioid endometrial cancer of no specific molecular profile (NSMP): A systematic review and meta-analysisPublication . Casanova, João; Ramos, Ana Sofia; Costa, Ana Gomes da; Babiciu, Alexandru; Serra, Sofia Silvério; Moutinho, Filipa; Costa, Teresa; Tripepi, Marta; Abu-Rustum, Nadeem R.; Martins, João Paulo; Lima, Jorge; Oliveira Martins, João PauloEndometrial cancer of no specific molecular profile (NSMP) represents the most prevalent molecular subtype of endometrial cancer, comprising over 50 % of all diagnoses. Although studies have explored the prevalence of the NSMP subtype, to our knowledge, no systematic review or meta-analysis has specifically targeted grade 3 (G3, high-grade) tumors. We aimed to determine the prevalence of G3 endometrioid endometrial cancer of NSMP and assess regional variations in this prevalence. We also sought to synthesize available data concerning oncologic outcomes, including overall survival, progression-free survival, and disease-specific survival. We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (PROSPERO No: CRD42024544247). We searched the electronic databases: PubMed/Medline, Scopus, Web of Science, Cochrane Library, and EMBASE. To estimate the overall prevalence of the NSMP subtype, we performed a meta-analysis using the proportions method with the Freeman-Tukey (arcsine) transformation. For estimating oncologic outcomes, we conducted a meta-analysis using hazard ratios (HRs) when available. In the absence of HRs, we utilized Kaplan-Meier curves. All pooled estimates and their corresponding 95% confidence intervals (CIs) were calculated using a random-effects model with the inverse variance method and restricted maximum likelihood estimator. We analyzed 31 studies, encompassing 2,660 patients. The pooled prevalence of NSMP within G3 endometrioid endometrial cancer was 0.29 (95 %CI: 0.23–0.34, I 2 = 80.8 %). This prevalence was highest in North America (0.43, 95 %CI: 0.17–0.71) and lowest in Europe (0.23, 95 %CI: 0.19–0.28). The random-effects pooled estimate indicated that the NSMP subtype was associated with intermediate oncologic outcomes compared to other molecular subtypes.
- Prognostic role and clinicopathological features of SMAD4 gene mutation in pancreatic cancer: a systematic review and meta-analysisPublication . Rodrigues, Tânia; Martins, João Paulo; Albuquerque, Joana; Cardoso, Joana; Coelho, José Luís Passos; Oliveira Martins, João PauloThe prognostic value of SMAD4 in pancreatic cancer has been evaluated in several studies. However, the conclusions remain controversial. Therefore, we aimed to evaluate the prognostic value of the SMAD4 gene in pancreatic cancer to aid in the design of therapeutic strategies. This review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria and the proposed methodology was registered on PROSPERO. An electronic search was made in MEDLINE (via PubMed), Web of Science and Google Scholar to identify all relevant studies. Eligible studies were those written in English including patients with Pancreatic Ductal Adenocarcinoma (PDAC), who underwent pancreatic surgery with curative intent and provided data on SMAD4 gene status or SMAD4 protein expression and its association to prognosis, measured by overall survival (OS). The effect measure of interest was the hazard ratio (HR) for OS between PDAC with or without SMDA4 mutations. A total of 24 studies on SMAD4, with 4340 samples, were included in this systematic review and meta-analysis. Our pooled results demonstrated that patients with tumours with SMAD4 alteration had significantly worse prognosis for OS (HR= 1.43, 95% CI = 1.17–1.76, p-value = 0.002). This systematic review and meta-analysis support the use of driver mutations in the SMAD4 gene as a prognostic marker for pancreatic cancer.
- Understanding wearable health technology use in older adults through social and psychological factorsPublication . Félix, José; Moreira, Juliana; Pereira, Soraia; Guedes, Diana; Sá, Catarina; Santos, Rubim; Faria, Brígida; Kontio, Elina; Pinheiro, Ana Rita; Sousa, Andreia S. P.; Pinheiro de Sousa, Andreia Sofia; Faria, Brigida Monica; Rubim Silva Santos, Manuel; Sousa Félix, José Manuel; Santos Moreira, Juliana; C. Guedes, Diana; Pinheiro, Ana RitaAs populations age globally, wearable health technologies offer promising solutions to support autonomy and well-being among older adults. This study explored the adoption of smart wearable systems, such as wristbands and chest sensors, for remote health monitoring among 352 older adults (aged 60–99) in Northern Portugal. Results showed that 74.4% of participants expressed interest in using wearable systems, with safety (93.9%) cited as the main benefit. Prevention (11.4%) and improved health monitoring (6.1%) were reported less frequently and should be considered secondary factors. However, barriers included discomfort (62.7%), heaviness (31.1%), and device size (32.7%), particularly in smartwatches. Chest bands were preferred when soft, lightweight, and discreet. Technology use frequency, especially smartphone usage, emerged as a key predictor of interest, as confirmed by a decision tree machine learning model with an accuracy of 71.88%. Despite low educational levels, participants demonstrated high motivation to use features such as medication reminders (83.5%), healthy habit prompts (74.2%), and appointment alerts (70.2%). Although many respondents felt reassured by the potential of continuous monitoring, some reported concerns related to anxiety (54.9%) and over-surveillance. These findings underscore the importance of balancing technological functionality with emotional comfort. The study highlights the need for user-centered design, digital literacy initiatives, and co-creation with older users to improve adherence and usability. Tailored interventions and accessible technologies can enhance health outcomes and promote independent living among aging populations.
- Occupational exposure to solar ultraviolet radiation: A systematic review of protective measuresPublication . Rocha, Ricardo; Santos, Joana; Baptista, João Santos; Guedes, Joana; Carvalhais, Carlos; Alberto Alves Carvalhais, Carlos; Santos, JoanaSolar ultraviolet radiation (UVR) is classified as a Group 1 carcinogen and poses a significant occupational hazard to outdoor workers. Despite preventive guidelines, adherence to protective measures remains inconsistent. This systematic review identified the protective measures adopted by healthy outdoor workers and assessed their adherence to and the effectiveness of these measures. Following the PRISMA 2020 statement, the review searched Scopus, Web of Science, and PubMed for peer-reviewed studies published between 2015 and 2025. Eligible studies included at least 100 healthy participants and evaluated preventive or protective measures against solar UVR. Independent reviewers extracted data and assessed risk of bias using the McMaster Critical Review Form. From 17,756 records, 51 studies met the inclusion criteria after screening and a subsequent snowballing process. The identified protective strategies clustered into physical, behavioural, and organisational categories. Adherence ranged from low to moderate, with structured interventions and employer support improving compliance. Sunscreen use remained low due to perceived inconvenience and lack of provision. Overall, the evidence revealed substantial variability in implementation and effectiveness across occupations. Strengthened regulations and integrated interventions combining education, personal protective equipment, and organisational measures are essential. Future research should prioritise longitudinal designs and objective indicators such as biomarkers and dosimetry.
- Dose-dependent pharmacological mechanisms within the Neuroscience-based Nomenclature: a new concept to facilitate neuroscience-based prescribingPublication . Zemach, Sasson; Zohar, Joseph; Correll, Christoph U.; Stahl, Stephen M.; Drago, Filippo; Goodwin, Guy M.; Moller, Hans-Jurgen; Uchida, Hiroyuki; Siafis, Spyridon; Santos, Marlene; Blier, Pierre; Santos, MarleneIn this Personal View, we introduce the concept of different dosage different pharmacology (DDDP), which describes how certain psychotropic medications have distinct therapeutic effects at low and high doses due to differing neurobiological mechanisms. Using the Neuroscience-based Nomenclature (NbN) framework, which classifies drugs by pharmacology and modes of action, we identified ten agents demonstrating DDDP in a comprehensive expert-based consensus process: amisulpride, amitriptyline, aripiprazole, brexpiprazole, cariprazine, doxepin, mirtazapine, quetiapine, risperidone, and trazodone. These medications show clearly demarcated dose-dependent effects, with changes in pharmacological action. For example, some drugs show anxiolytic or hypnotic effects at low doses (via histamine H1 or noradrenergic α1 antagonism) and antidepressant effects at high doses (via reuptake inhibition of serotonin or norepinephrine). Understanding these differences supports more rational prescribing (eg, increasing dopamine partial agonist doses beyond the optimal range might reduce efficacy). DDDP, within the NbN framework, offers a neuroscience-based approach to more precise psychopharmacology.
- The impact of virtual reality-based forest therapy in psychiatric inpatient care: a pilot studyPublication . Martins, Rafael; Sousa, Sara de; Viana, João; Fortuna, Rita; Henriques, André; Silva, Alzira; Almeida, Raquel Simões de; Simões de Almeida, Raquel; de Sousa, SaraThis study evaluated the effectiveness of a Virtual Reality (VR)-based Forest Therapy program in reducing depressive symptoms, anxiety, stress, and physiological distress among psychiatric inpatients. A quasi-experimental study was conducted with 16 inpatients (mean age: 38) in a clinical setting. Participants engaged in four immersive VR sessions simulating forest environments. Psychometric assessments included the DASS-21 and WHO-5, administered pre- and post-intervention. Autonomic responses were monitored via Heart Rate Variability (HRV) and Electrodermal Activity (EDA). Following the intervention, participants showed statistically significant improvements in depression, anxiety, stress, and well-being scores (p < .001). While changes in physiological indicators (HRV and EDA) were not statistically significant, observed trends suggested increased autonomic stability and relaxation. The findings suggest that VR-based Forest Therapy appears to be a promising, accessible intervention for promoting well being in psychiatric settings with limited nature access. While the results are encouraging, the lack of a control group and follow-up data limits conclusions regarding long-term durability. Further research with larger samples is required to validate these findings.
- NMR-based urinary biomarkers in pediatric primary mitochondrial disorders and chronic kidney disease: shared mitochondrial dysfunction, diverging biosignaturesPublication . Coelho, Margarida Paiva; Rodrigues, João E.; Costa, Teresa; Dias, Aureliano; Graça, Inês C. R.; Rocha, Hugo; Vilarinho, Laura; Martins, Esmeralda; Gil, Ana M.; Carvalho de Azevedo Rocha, Hugo DanielRenal involvement is a recognized feature of primary mitochondrial disorders (PMD), either at presentation or during the disease course. Simultaneously, the metabolomic fingerprint of chronic kidney disease (CKD) is often associated with underlying mitochondrial dysfunction. This study aimed to characterize urinary metabolic signatures in genetically confirmed paediatric PMD without chronic kidney disease, comparing them to healthy controls, suspected (unconfirmed) mitochondrial disease (SMD), and non-mitochondrial CKD. We performed untargeted 1 H NMR metabolomic profiling of 76 urine samples from 51 paediatric patients and 10 healthy controls. PMD patients in acute decompensation or known CKD and statistical outlier samples were excluded. Final comparisons included genetically confirmed PMD without CKD (n=13), SMD (n=10), non-mitochondrial CKD (n=28; 17 at stages 1–2 and 9 at stages 3–5), and healthy controls (n=10). Spectral data were analyzed using multivariate statistical approaches—including principal component analysis (PCA) and partial least squares–discriminant analysis (PLS-DA)—as well as univariate methods with Mann-Whitney U for pairwise group metabolite comparison. Urinary metabolic profiles of PMD patients differed from healthy controls and CKD patients. Multivariate analysis revealed a strong discriminative ability between PMD and controls (Q² = 0.53) and advanced CKD (Q2=0.78). Compared to controls, PMD patients had increased levels of Krebs cycle intermediates (cis-aconitate, fumarate and succinate), creatine, tryptophan, homovanillate (HVA) and hypoxanthine, as well as decreased histidine. All, except fumarate and histidine, remained discriminative when comparing PMD to CKD. CKD patients showed a diverging metabolomic fingerprint with 1-methylnicotinamide (MNA) and 2-hydroxyisobutyrate emerging as potential CKD-specific biomarkers, effectively discriminating between CKD stage 3–5 from earlier stages and controls. A five-metabolite panel comprising cis-aconitate, fumarate, HVA, tryptophan and histidine achieved high diagnostic performance for identifying PMD, with an area under the curve (AUC) of 0.836 (PMD vs. controls) and AUC=0.783 across all groups. This biosignature integrates metabolites involved in distinct functional domains including energy metabolism, neurotransmitter turnover and amino acid metabolism and renal handling. Urinary metabolomic profiling by NMR revealed a distinct biosignature in pediatric PMD patients without renal involvement, characterized by elevated levels of tryptophan, HVA, and Krebs cycle intermediates, and diminished histidine. The divergent changes in tryptophan, histidine and HVA, suggest a mitochondria-specific metabolic phenotype in PMD. These findings support the use of urinary NMR metabolomics as a non-invasive tool for biomarker discovery in PMD and highlight the potential of integrated, multiparametric metabolic fingerprints for diagnostic refinement and patient stratification.