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The success of an atrioventricular septal defect repair depends largely on the function of the left atrioventricular valve. Given the exposure of this valve to systemic pressures, postoperative haemodynamic management has been of interest, though practices are variable. A single-centre, retrospective study of infants less than 1 year of age admitted to the paediatric cardiac ICU following atrioventricular septal defect repair between January 2022 and May 2025 was conducted. Utilising high-fidelity physiologic data, the primary aim of this study was to characterise haemodynamics in the first 48 h of progression of left atrioventricular valve regurgitation after complete repair. Regurgitation data was collected from echocardiograms. Generalised estimation equation modelling was done to help further isolate the association of worsening left atrioventricular valve regurgitation with haemodynamic variables. Among twenty-eight patients, nine (32%) exhibited worsening left atrioventricular valve regurgitation. Haemodynamic parameters significantly correlated with worse left atrioventricular valve regurgitation were increased mean arterial blood pressure, increased blood pressure variability, and decreased cerebral and renal near-infrared spectroscopy. Of note, blood pressure variability had a greater association with worsening left atrioventricular valve regurgitation when compared to absolute mean arterial blood pressure. In infants recovering from atrioventricular septal defect repair, early postoperative haemodynamic alterations, in particular mean arterial blood pressure variability, are associated with worse left atrioventricular valve function. A high cardiac output, low systemic vascular resistance state with minimal blood pressure variability appears optimal to decrease impact on the left atrioventricular valve.

Nevus-associated melanoma (NAM) is histologically defined by coexisting nevus and melanoma components, yet the nevus component is frequently not visible on dermoscopy. We performed a retrospective, single-centre observational study including histologically diagnosed NAMs (2011-2024). Dermoscopic images were assessed independently by two readers. Histopathology was systematically revised to quantify nevus proportion, size, and depth. Univariate and multivariable logistic regression evaluated associations with (a) invasive vs. in situ NAM and (b) dermoscopically visible vs. non-visible nevus component. Among 340 NAMs, 36.8% were in situ and 63.2% invasive. A dermoscopic nevus was visible in 45.6%. In multivariable analysis, nevus visibility under dermoscopy was independently associated with histopathologic features such as larger nevus size, particularly 2.1-4 mm (OR 2.5, 95% CI 1.3-4.6), 4.1-10 mm (OR 3.7, 95% CI 2.0-7.0), and > 10 mm (OR 5.3, 95% CI 1.4-20.0), whereas deep nevus location (OR 0.3, 95% CI 0.2-0.5) and ulceration (OR 0.2, 95% CI 0.1-0.6) reduced visibility. Invasive NAM was independently associated with a visible nevus component under dermoscopy (OR 2.5, 95% CI 1.7-3.7), shiny white structures (OR 5.0, 95% CI 2.6-9.4), negative pigment network (OR 1.9, 95% CI 1.2-3.2), and blue-white veil (OR 8.3, 95% CI 4.5-15.4), whereas atypical pigment network and melanoma pigmentation were inversely associated with invasion. Dermoscopic nevus visibility in NAM is mainly determined by nevus size and depth, while melanoma-related changes, particularly ulceration, can obscure the nevus component. Dermoscopic markers of invasiveness should prompt timely management even when an associated nevus is suspected.

Enterococcus faecium, a member of the human gut microbiota and the second most abundant enterococcal species after E. faecalis, is an important agent of healthcare-associated infection. Its high capacity to acquire antimicrobial resistance genes (ARGs) makes infections difficult to treat. This study investigated ready-to-eat (RTE) meat products, typical of central Italy, as potential vectors of antibiotic-resistant enterococci, focusing on E. faecium. A total of 148 enterococcal strains, 36 of which were identified as E. faecium, were isolated. Among 22 distinct clones, eight were resistant to tetracycline (TET), two also to linezolid (LZD), and one showed a multidrug-resistance phenotype. Antibiotic susceptibility was determined by minimum inhibitory concentration testing, supported by whole-genome sequence analysis. Both LZD-resistant strains harbored LZD resistance genes (optrA or a combination of optrA and poxtA), while only one isolate demonstrated horizontal gene transfer via conjugation. The isolates were further characterized for virulence factors and biofilm formation capacity, both under basal conditions and following exposure to simulated upper gastrointestinal transit. All eight TET resistant strains presented genotypic virulence traits. Following exposure to simulated upper gastrointestinal transit, these isolates demonstrated high survival rates, maintaining both their antibiotic resistance phenotypes and biofilm-forming capacity. These findings highlight the potential role of the analyzed RTE meat products as vehicles for virulent and antibiotic-resistant E. faecium strains capable of surviving upper gastrointestinal exposure. The study underscores the need to implement enterococci surveillance in the food sector to improve monitoring of resistant E. faecium and to limit its possible dissemination and association in clinical risks.

Fertility-sparing treatment is an established option for reproductive-age women with early-stage endometrioid endometrial cancer or atypical endometrial hyperplasia. Despite high initial response rates with progestin-based therapy, predicting treatment response and recurrence remains challenging. This narrative review summarizes current evidence on prognostic and predictive biomarkers for conservative management. Progesterone receptor positivity is the most consistent favorable predictor of response, while POLE ultra-mutated tumors show excellent remission and low recurrence. Mismatch repair deficiency and p53 abnormalities are strong negative predictors, associated with poor response and higher relapse risk. PTEN loss and PIK3CA mutations may contribute to hormonal resistance, especially in combination. Ki-67 and L1 neuronal cell adhesion molecule provide additional prognostic value for recurrence risk. Elevated serum human epididymis protein 4 levels predict poor response to progestin-based therapy and represent the most promising non-invasive biomarker for patient selection and monitoring. Urine metabolomics is emerging as a complementary non-invasive tool. Magnetic resonance imaging-based radiomics and apparent diffusion coefficient histogram analysis show promise in predicting complete response and identifying resistance patterns before treatment. However, no single biomarker is sufficient for clinical decision-making. Future progress requires multi-modal strategies integrating molecular, serum, and imaging data, validated in prospective multi-center studies.

In the SELECT-GCA trial, upadacitinib 15 mg/d was associated with higher rates of disease remission and reduced glucocorticoid exposure vs placebo in patients with giant cell arteritis (GCA) through 1 year. This study evaluated the clinical impact of upadacitinib continuation vs withdrawal through 2 years. In period 1 of SELECT-GCA, patients aged ≥50 years were randomised 2:1:1 to oral upadacitinib 15 mg or 7.5 mg with a 26-week glucocorticoid taper or placebo with a 52-week taper. In period 2 (52-week re-randomised, blinded extension), patients achieving ≥24 weeks of consecutive remission by week 52 were re-randomised 2:1 to continue upadacitinib or switch to placebo. Efficacy endpoints were assessed from weeks 52 to 104, and safety was evaluated over 2 years. All P values are nominal. Among 103 patients receiving upadacitinib 15 mg who achieved ≥24 weeks sustained remission and were re-randomised in period 2, 68 continued treatment and 35 switched to placebo at week 52. From weeks 52 to 104, patients continuing upadacitinib 15 mg vs switching to placebo experienced fewer disease flares (7.4% vs 59.5%; P ≤ .0001), greater maintenance of glucocorticoid-free remission (71.7% vs 31.4%; P ≤ .0001), and lower glucocorticoid exposure (median exposure: 0 mg vs 1048 mg; P ≤ .0001). Safety was generally similar between upadacitinib and placebo groups. No new clinically significant safety risks were identified with upadacitinib through 2 years, and safety remained consistent with the established profile. These data further support a favourable benefit-risk profile for extended use of upadacitinib 15 mg for treatment of GCA.

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The clinical significance of persistently positive antiphospholipid antibodies (aPLs) remains incompletely defined. To describe the clinical and laboratory characteristics of patients with confirmed aPL positivity enrolled in the nationwide START2 Antiphospholipid Registry. Adult patients were included if all three laboratory tests-Lupus Anticoagulant (LA), anticardiolipin antibodies (aCL), and anti-β2-glycoprotein I antibodies (aβ2GPI)-were performed and confirmed after ≥12 weeks. Patients were categorized as Antiphospholipis Syndrome (APS) or aPL carriers. Clinical manifestations, non-criteria features, laboratory profiles, associated risk factors, and antithrombotic treatments were analyzed descriptively. Among 500 enrolled patients, 341 were classified as APS and 159 as carriers. Women were overrepresented among carriers (76% vs 62%, p = 0.002). APS patients displayed a higher prevalence of non-criteria manifestations, largely driven by renal involvement in those with SLE. Laboratory profiles were similarly distributed across APS and carriers: triple positivity (43% vs 44%), double positivity (13% vs 12%), and isolated LA positivity (23% vs 30%). Venous thromboembolism (VTE) occurred more frequently in APS patients LA-positive only (67%, p = 0.004), while arterial thrombosis was more evenly distributed across profiles. After a first VTE, most APS patients received warfarin (62%), whereas arterial APS was treated with either warfarin (51%) or aspirin (37%). Among carriers, aspirin was the preferred prophylactic strategy (45%). Triple, double, and LA positive only represent the most common laboratory patterns. LA positivity omly shows a disproportionately high rate of VTE. Non-criteria manifestations remain more common in APS. Substantial variability persists in antithrombotic management, underscoring the need for prospective treatment trials.

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The Sicilian Black pig is a well-adapted autochthonous breed, yet its susceptibility to respiratory disease remains poorly defined due to limited data on pathogen circulation and lesion patterns in extensive production systems. This study characterised the pathological features of Porcine Respiratory Disease Complex (PRDC) in this breed by examining lungs and tracheobronchial lymph nodes from 59 animals through pathological assessment, molecular detection of major respiratory pathogens, and evaluation of crystalline particulates using scanning electron microscopy coupled with energy-dispersive X-ray analysis to characterise infectious and environmental contributors. Gross examination revealed multifocal cranioventral bronchopneumonia in 35/59 pigs (59.32%) and diffuse interstitial pneumonia in 18/59 pigs (30.51%). Molecular testing identified Mycoplasma hyopneumoniae (M. hyopneumoniae) as the most frequent pathogen (17/47; 36.17%), followed by porcine circovirus type 2 (PCV2; 10/47; 21.28%) and Pasteurella multocida (6/47; 12.77%), with co-infections consistently involving M. hyopneumoniae. The presence of pathogen DNA was correlated with increased severity of lesions as well as the presence of fibrosis and hyperplasia of the BALT. Histological evidence of Metastrongylus spp. lungworms was identified in 7/35 pigs (20%) with bronchopneumonia. Silicate crystals consistent with pulmonary silicosis were detected in 10/59 lungs (17.0%), indicating substantial exposure to silicate-rich dust in outdoor environments. However, silicosis was not related to the presence of specific respiratory pathogens. Overall, these findings demonstrate that respiratory disease in Sicilian Black pigs is multifactorial, arising from the combined influence of bacterial, viral, parasitic, and environmental components. The concurrent detection of M. hyopneumoniae, PCV2, secondary bacterial agents, lungworm infestation, and silicate particulates supports an integrated PRDC model in this native breed. These results highlight the need for a multifaceted control strategy, including improved diagnostics, targeted management, immunoprophylaxis, helminth control, and mitigation of silicate-rich dust to reduce the impact of PRDC in extensive production systems.

AIM: Chronic subdural hematoma (cSDH) is a common neurosurgical condition in elderly patients, frequently associated with trauma, anticoagulant use, and chronic comorbidities. While surgical evacuation and now middle meningeal artery embolization remain the predominant treatment options, endoscopic-assisted techniques have been increasingly used as a surgical adjunct. We evaluated the safety, clinical outcomes, and recent advancements in endoscopic-assisted evacuation of cSDH through both a retrospective case series and an updated review of the current literature. MATERIAL and METHODS: A retrospective analysis of 39 patients undergoing 44 endoscopic-assisted evacuations of subdural hematomas between October 2021 and May 2025 was performed. Patient demographics, imaging, operative details, complications, and recurrence were analyzed. A systematic review of 15 studies published between 2022 and 2025 was added to a prior review performed by our group to assess outcomes associated with endoscopic approaches to cSDH. RESULTS: Of the 39 patients (67% male, ages 20 to 73), four experienced recurrence, three prior to middle meningeal artery (MMA) embolization and one after. All patients received postoperative subdural drains, and no intraoperative complications related to the endoscope occurred. The literature review included an additional 16 recent studies (n=1060 patients) in addition to 13 studies from a previous systematic review, reporting recurrence rates of 0% to 16.7%. Endoscopic evacuation was associated with reduced recurrence, shorter hospital stays, and improved hematoma clearance compared to traditional techniques. CONCLUSION: Endoscopic-assisted evacuation of cSDH appears to be a safe and effective adjunct to conventional surgical methods through improved visualization, potential coagulation of distal meningeal artery territories, and reduced recurrence. While results are promising, larger prospective studies are needed to confirm long-term benefits and refine patient selection.

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Long-range correlations (LRCs) in DNA sequences have been reported for decades, but their interpretation has been limited by incomplete representation of repetitive and structurally complex regions in earlier human genome assemblies. Here, we use the complete telomere-to-telomere (T2T) human reference genome to systematically map LRC structure across all human chromosomes. Most chromosomes exhibited persistent long-range dependence (LRD), with chromosome-specific scaling intervals spanning kilobase to megabase scales and wavelet Hurst exponents consistently above the uncorrelated expectation of 0.5. Spatially resolved Hurst landscapes revealed that this signal is not uniformly distributed along chromosomes, but instead reflects a heterogeneous genomic mosaic. For the purine-pyrimidine encoding, chromosomes 9, 15, X, and Y showed complex fluctuation profiles not adequately summarized by a single scaling exponent; multifractal detrended fluctuation analysis (MF-DFA) confirmed broad, q-dependent multiscaling consistent with multifractal behavior in these chromosomes, consistent with heterogeneous contributions from satellite-rich and structurally distinct sequence compartments. Surrogate analyses further showed that the observed correlations exceed expectations from base composition alone and are not fully explained by local sequence structure preserved in block-shuffled controls. However, short-memory Autoregressive Moving-Average (ARMA) surrogates reproduced the observed H range in a subset of chromosomes, indicating that the strength of evidence for LRD is chromosome-dependent. Together, these results demonstrate that LRC is a widespread but spatially heterogeneous property of the complete human genome. The T2T assembly reveals that previously unresolved repetitive and satellite-rich regions are strongly associated with chromosome-scale and local scaling variation, providing a framework for future studies of genome evolution, chromatin structure, recombination, structural variation, and genomic instability.

Primary lateral sclerosis (PLS) is a rare upper motor neuron neurodegenerative disorder whose cognitive profile, particularly at early stages, remains incompletely defined. We aimed to characterize cognitive and behavioral features of PLS at diagnosis and compare them with predominant upper motor neuron amyotrophic lateral sclerosis (PUMN-ALS) and healthy controls (HCs). Patients diagnosed with PLS between 2007 and 2021 were identified from the population-based Piemonte and Valle d'Aosta ALS Register. Diagnoses were established according to consensus criteria, including early, probable, and definite PLS. All patients underwent comprehensive neuropsychological and behavioral assessment within 3 months of their first ALS center visit. Cognitive-behavioral status was classified using ALS-frontotemporal dementia (FTD) consensus criteria. Thirty-two PLS patients were included (mean disease duration, 25 months). Cognitive and/or behavioral impairment was identified in 29.3% of patients, most commonly affecting executive function, memory, and social cognition, including 21.1% early PLS. Compared with HCs, PLS patients showed poorer performance across several cognitive domains and higher anxiety and depression scores. Compared with matched PUMN-ALS patients, PLS patients demonstrated slightly worse executive performance, while the overall frequency of cognitive-behavioral impairment was similar. Behavioral profiles differed qualitatively, with apathy more frequent in PUMN-ALS. No PLS patient met criteria for frontotemporal dementia. Cognitive and behavioral impairments are already detectable at the time of diagnosis in a substantial proportion of patients with PLS, including early PLS, supporting the view of PLS as a multidimensional neurodegenerative disorder with early extramotor involvement.

Reconstruction of chest wall defects after oncologic resection requires techniques that minimize wound morbidity and preserve timely access to adjuvant therapy. The Kiss Latissimus Dorsi (LD) flap offers robust, well-vascularized tissue with reliable healing, while extended thoracoabdominal hatchet flaps provide a muscle-sparing alternative based on local perforators. Comparative data between these approaches remain limited. A retrospective cohort study was conducted including female patients who underwent chest wall reconstruction between 2015 and 2023 using either a Kiss LD flap (n&#x2009;=&#x2009;11) or an extended thoracoabdominal hatchet flap (n&#x2009;=&#x2009;12). Groups were comparable in demographic and clinical characteristics. The primary endpoint was time to complete wound healing. Secondary endpoints included wound complications, delayed healing (>&#x2009;30 days), need for reintervention, and timing of adjuvant therapy. Healing occurred significantly earlier in the Kiss LD group compared with the hatchet group (21.7&#x2009;&#xb1;&#x2009;5.2 vs. 34.5&#x2009;&#xb1;&#x2009;8.7 days; p&#x2009;<&#x2009;0.001). Delayed healing was less frequent in the Kiss LD flap group (9.1% vs. 50.0%; p&#x2009;=&#x2009;0.02). Overall wound complications were lower in the Kiss LD cohort (18.2% vs. 41.7%; p&#x2009;=&#x2009;0.048), and no reinterventions were required, whereas one patient in the hatchet group required debridement. Patients in the Kiss LD group initiated adjuvant therapy earlier than those in the hatchet group (33.4&#x2009;&#xb1;&#x2009;6.5 vs. 47.8&#x2009;&#xb1;&#x2009;9.9 days; p&#x2009;<&#x2009;0.001). The Kiss Latissimus Dorsi flap was associated with faster and more reliable healing than the extended thoracoabdominal hatchet flap, alongside earlier initiation of adjuvant therapy. The Kiss LD flap may represent a reliable reconstructive strategy for oncologic patients when treatment sequencing is essential.

[This corrects the article DOI: 10.3389/fpubh.2026.1847349.].

Targeting oxidative phosphorylation (OXPHOS) represents an attractive therapeutic strategy in acute myeloid leukemia, which exhibits exceptional dependence on mitochondrial respiration compared to normal hematopoietic cells. However, clinical attempts to exploit this vulnerability have been limited by on-target toxicity to healthy tissue. Here, we comprehensively compare the cellular consequences of inhibiting distinct nodes of the electron transport chain in AML. We demonstrate that selective inhibition of the F1 subunit of ATP synthase with EB2023 (ammocidin A) delivers an energetic stress to AML cells without the profound redox stress that characterizes complex I inhibition, preventing NAD+/NADH imbalance and allowing continued TCA cycling. Further, the duration of OXPHOS inhibition is transient in nature in vivo, a finding revealed through pharmacokinetic and serial pharmacodynamic monitoring of AMPK phosphorylation accompanied by OPA1-mediated mitochondrial structural remodeling that primes AML cells for BCL2 inhibitor synergy. EB2023 in combination with venetoclax demonstrates potent anti-AML activity across cell lines and patient-derived xenograft models at doses that spare normal hematopoietic progenitors and avoid the neuropathy and sustained detrimental systemic metabolic rewiring in healthy tissues associated with prior efforts to target OXPHOS. These findings establish F1-selective ATP synthase inhibition as a clinically actionable therapeutic strategy in AML and establish the duration of OXPHOS inhibition as a critical and previously underappreciated determinant of therapeutic index.

The mTOR inhibitor everolimus improved progression-free survival in patients with hormone receptor-positive breast cancer resistant to hormone therapy. Despite initial success, everolimus has not yet realized its full therapeutic potential due to its associated toxicities and the development of resistance. Here, we exploited biocompatible lignin nanoparticles to enhance everolimus delivery and the mechanism of action in hormone receptor-positive breast cancer cells. Everolimus was released from the lignin nanoparticles in a concentration-dependent manner, following a Fickian diffusion-like model. The nanoparticles protected the drug from potential pH-induced degradation. Confocal microscopy confirmed the diffusion and cytoplasmic localization of lignin nanoparticles, as well as the efficient release of the drug. Everolimus release effectively inhibits the proliferation in breast cancer MCF7 cells. EVE/LNPs showed an improved in vitro antitumor effect compared to EVE against the MCF7 cell line (63 vs 81% survival rate at 10 nM). Under acidic pH conditions, the lignin nanoparticles underwent partial degradation, probably generating oligomers with potential modulating effects on mTOR and FOXM1. Molecular docking simulations showed that lignin oligomers could selectively interact with the ATP-binding cavity of mTOR. The affinity of these interactions was modulated by the redox state of the lignin oligomers, with the strongest bond being observed for quinone derivatives. This dual-action mechanism, which combines drug delivery and modulation of cellular signaling, offers a promising "on/off" switch approach to enhance everolimus-based cancer therapies. Further in vivo studies are warranted to validate these findings.

Understanding how exposure-based trauma treatment modifies neural representations of trauma memory may lead to optimized and targeted interventions for posttraumatic stress disorder. Although exposure therapies reliably reduce symptoms, the neural mechanisms through which repeated trauma memory retrieval and processing reshape representational structure, and whether such changes can be bolstered through pharmacological agents shown to enhance extinction learning, remain poorly understood. Women with PTSD related to interpersonal violence (N=80) completed two days of repeated exposure to an individualized trauma and neutral narrative during fMRI. Immediately after Day 1 exposures, participants were randomized to placebo (n=37) or 100mg Levodopa (L-DOPA; n=43), targeting dopaminergic enhancement of memory consolidation. Support vector machines characterized multivariate neural representations of distinct aversive cognitive states: painful stimulus delivery, trauma memory recall, self-reported anxiety during memory recall. To test generalization of representational changes across contexts, the Day 2 narratives were presented in either the same or different sensory context compared to Day 1. Across participants, medial prefrontal cortex (mPFC) network representations for each aversive state reduced from Day 1 to Day 2. There was no impact of L-DOPA on self-reported anxiety to the trauma memory or on neural representations of trauma memory recall or painful stimulus delivery. L-DOPA was associated with attenuated anxiety representations in the mPFC under a changed context, potentially consistent with enhanced generalization of representational updating. These findings highlight that trauma memory representations in the mPFC are malleable with repeated exposure. The augmenting effect of L-DOPA was mostly null, except for decreased mPFC representations for anxiety in a changed context.

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