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Intrahepatic cholangiocarcinoma (iCCA) denotes a rare, highly malignant, and heterogeneous class of primary liver adenocarcinomas exhibiting phenotypic characteristics of cholangiocyte differentiation. Among the distinctive pathological features of iCCA, one that differentiates the most common macroscopic subtype (eg, mass-forming type) of this hepatic tumor from conventional hepatocellular carcinoma, is a prominent desmoplastic reaction manifested as a dense fibro-collagenous-enriched tumor stroma. Cancer-associated fibroblasts (CAFs) represent the most abundant mesenchymal cell type in the desmoplastic reaction. Although the protumor effects of CAFs in iCCA have been increasingly recognized, more recent cell lineage tracing studies, advanced single-cell RNA sequencing, and expanded biomarker analyses have provided new awareness into their ontogeny, as well as underscored their biological complexity as reflected by the presence of multiple subtypes. In addition, evidence has been described to support CAFs' potential to display cancer-restrictive roles, including immunosuppression. However, CAFs also play important roles in facilitating metastasis, as exemplified by lymph node metastasis and peritoneal carcinomatosis, which are common in iCCA. Herein, the authors provide a timely appraisal of the origins and phenotypic and functional complexity of CAFs in iCCA, together with providing mechanistic insights into lymphangiogenesis and peritoneal metastasis relevant to this lethal human cancer., Competing Interests: Disclosure Statement None disclosed., (Copyright © 2024. Published by Elsevier Inc.)

Biliary tract cancers (BTCs) are rare and aggressive malignancies with an increasing incidence and poor prognosis. The standard systemic treatment for BTCs has evolved to include immune checkpoint inhibitors associated with gemcitabine-cisplatin as first-line therapies. However, survival rates remain low, highlighting the critical need for personalized treatment strategies based on molecular profiling. Currently, significant advancements have been made in the molecular characterization of BTCs, where genetic alterations, such as IDH1 mutations and FGFR2 fusions, provide targets for therapy. Molecular profiling is crucial early in the management process to identify potential candidates for clinical trials and guide treatment strategy. The integration of these molecular insights into clinical practice has allowed for the development of targeted therapies, although many of them are still in the phase 2 trial stage without definitive survival benefits demonstrated in phase 3 trials. This integration of comprehensive molecular profile insights with traditional treatment approaches offers a new horizon in the personalized medicine landscape for BTCs, with the aim of significantly improving patient outcomes through precision oncology.

Objectives: Vestibular evoked myogenic potentials (VEMPs) are useful for studying the disturbances along nerve pathways implicated in the transmission of neurological information from otolithic organs related to vestibular function. This study aims to determine the differences in VEMPs in patients affected with benign paroxysmal positional vertigo (BPPV)., Methods: We recruited 36 patients, 9 diagnosed with recurrent BPPV (rBPPV), 9 with only one episode of vertigo (iBPPV), and 18 as a control group. We performed cervical and ocular VEMPs (cVEMPs and oVEMPs)., Results: We observed differences in asymmetry ratio, which was 41.82% in cVEMPs in iBPPV and 68.27% in oVEMPs in rBPPV, while no asymmetry was found in control cases. Also, there was a lack of both VEMP responses in 22.2% of cases and an absence of cVEMP in 11.1% in iBPPV; in rBPPV, 11.1 % presented no responses in cVEMPs or oVEMPs, 22.2% showed no oVEMP, and 11.1% showed no cVEMP. These values were normal in the control group., Conclusion: The value of VEMPs in BPPV demonstrates the implication of vestibular damage, mainly utricle damage. For better sensitivity in detecting otolith abnormalities, we should perform oVEMPs and cVEMPs in recurrent BPPV and early stages of BPPV., (Copyright © 2024 Sociedad Española de Otorrinolaringología y Cirugía de Cabeza y Cuello. Published by Elsevier España, S.L.U. All rights reserved.)

Study Objectives: to characterize possible differences in the function of the ANS in patients with chronic insomnia compared to a control group, using a wearable device, in order to determine whether those findings allow diagnosing this medical entity., Methods: Thirty-two patients with chronic insomnia and nineteen patients without any sleep disorder, as a control group, were recruited prospectively. Both groups of patients underwent an in-patient night with simultaneous polysomnography and wearable device recording Empatica E4 a diverse array of physiological signals, including electrodermal activity, temperature, accelerometry, and photoplethysmography, providing a comprehensive resource for in-depth sleep analysis., Results: In polysomnography, patients suffering from insomnia showed a significant decrease in sleep efficiency and total sleep time, prolonged sleep latency, and increased wakefulness after sleep onset. Accelerometry results were statistically significant differences in the three axis (x, y, z) just in stage N3, no differences were observed between both groups in REM sleep. The lowest temperature was reached in REM sleep in both groups. Peripheral temperature did not decrease during the different sleep phases compared to wakefulness in insomnia, unlike in the control group. Heart rate was higher in patients with insomnia than in controls during wakefulness and sleep stage. Heart rate variability was lower in stage N3 and higher in REM sleep compared to wakefulness in both groups. Sweating was significantly higher in patients with insomnia compared to the control group, as indicated by Skin Conductance Variability values and Sudomotor Nerve., Conclusions: Our study suggests that patients with insomnia have increased sympathetic activity during sleep, showing a higher heart rate. Temperature and sweating significantly influence the different sleep phases., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Rybel Wix has potential conflicts of interest with UCB Pharma, Exeltis, Bioprojet and Idorsia. All other authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background & Aims: Ductular reaction expansion is associated with poor prognosis in patients with advanced liver disease. However, the mechanisms promoting biliary cell proliferation are largely unknown. Here, we identify neutrophils as drivers of biliary cell proliferation and the defective wound-healing response., Methods: The intrahepatic localization of neutrophils was evaluated in patients with chronic liver disease. Neutrophil dynamics were analyzed by intravital microscopy and neutrophil-labeling assays in DDC-treated mice. Neutrophil depletion or inhibition of recruitment was achieved using a Ly6g antibody or a CXCR1/2 inhibitor, respectively. Mice deficient in PAD4 (peptidyl arginine deiminase 4) and ELANE/NE (neutrophil elastase) were used to investigate the mechanisms underlying ductular reaction expansion., Results: In this study we describe a population of ductular reaction-associated neutrophils (DRANs), which are in direct contact with biliary epithelial cells in chronic liver diseases and whose numbers increased in parallel with disease progression. We show that DRANs are immobilized at the site of ductular reaction for a prolonged period of time. In addition, liver neutrophils display a unique phenotypic and transcriptomic profile, showing a decreased phagocytic capacity and increased oxidative burst. Depletion of neutrophils or inhibition of their recruitment reduces DRANs and the expansion of ductular reaction, while mitigating liver fibrosis and angiogenesis. Mechanistically, neutrophils deficient in PAD4 and ELANE abrogate neutrophil-induced biliary cell proliferation, thus indicating the role of neutrophil extracellular traps and elastase release in ductular reaction expansion., Conclusions: Overall, our study reveals the accumulation of DRANs as a hallmark of advanced liver disease and a potential therapeutic target to mitigate ductular reaction and the maladaptive wound-healing response., Impact and Implications: Our results indicate that neutrophils are highly plastic and can have an extended lifespan. Moreover, we identify a new role of neutrophils as triggers of expansion of the biliary epithelium. Overall, the results of this study indicate that ductular reaction-associated neutrophils (or DRANs) are new players in the maladaptive tissue-healing response in chronic liver injury and may be a potential target for therapeutic interventions to reduce ductular reaction expansion and promote tissue repair in advanced liver disease., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objective: To study the respiratory patterns and the hemodynamic variations related to postural changes in inpatients with coronavirus disease (COVID-19)., Methods: This report is a prospective study in a cohort of inpatients admitted with COVID-19. We recruited 10 patients admitted to the hospital with moderate or severe COVID-19 who showed improvement in oxygen saturation with prone positioning. We performed cardiorespiratory polygraphy and hemodynamic evaluations by thoracic electrical bioimpedance., Results: We observed a median minimum oxygen saturation of 85.00% (IQR: 7.00) in the supine position versus 91.00% (IQR: 8.00) ( P = 0.173) in the prone position. The airflow restriction in the supine position was 2.70% (IQR: 6.55) versus 1.55% (IQR: 2.80) ( P = 0.383) in the prone position. A total of 36.4% of patients were classified as having a normo-hemodynamic state in the supine position, whereas 54.5% were classified in this group in the prone position ( P = 0.668). A decrease in vascular resistance was observed in the prone position (18.2% of vasoconstriction) compared to the supine position (36.4% of vasoconstriction) ( P = 0.871)., Conclusion: This brief report describes the effects of prone positioning on respiratory and hemodynamic variables in 10 patients with moderate or severe COVID-19.

Background & Aims: Loss of hepatocyte identity is associated with impaired liver function in alcohol-related hepatitis (AH). In this context, hepatocyte dedifferentiation gives rise to cells with a hepatobiliary (HB) phenotype expressing biliary and hepatocyte markers and showing immature features. However, the mechanisms and impact of hepatocyte dedifferentiation in liver disease are poorly understood., Methods: HB cells and ductular reaction (DR) cells were quantified and microdissected from liver biopsies from patients with alcohol-related liver disease (ArLD). Hepatocyte-specific overexpression or deletion of C-X-C motif chemokine receptor 4 (CXCR4), and CXCR4 pharmacological inhibition were assessed in mouse liver injury. Patient-derived and mouse organoids were generated to assess plasticity., Results: Here, we show that HB and DR cells are increased in patients with decompensated cirrhosis and AH, but only HB cells correlate with poor liver function and patients' outcome. Transcriptomic profiling of HB cells revealed the expression of biliary-specific genes and a mild reduction of hepatocyte metabolism. Functional analysis identified pathways involved in hepatocyte reprogramming, inflammation, stemness, and cancer gene programs. The CXCR4 pathway was highly enriched in HB cells and correlated with disease severity and hepatocyte dedifferentiation. In vitro, CXCR4 was associated with a biliary phenotype and loss of hepatocyte features. Liver overexpression of CXCR4 in chronic liver injury decreased the hepatocyte-specific gene expression profile and promoted liver injury. CXCR4 deletion or its pharmacological inhibition ameliorated hepatocyte dedifferentiation and reduced DR and fibrosis progression., Conclusions: This study shows the association of hepatocyte dedifferentiation with disease progression and poor outcome in AH. Moreover, the transcriptomic profiling of HB cells revealed CXCR4 as a new driver of hepatocyte-to-biliary reprogramming and as a potential therapeutic target to halt hepatocyte dedifferentiation in AH., Impact and Implications: Here, we show that hepatocyte dedifferentiation is associated with disease severity and a reduced synthetic capacity of the liver. Moreover, we identify the CXCR4 pathway as a driver of hepatocyte dedifferentiation and as a therapeutic target in alcohol-related hepatitis. Therefore, this study reveals the importance of preserving strict control over hepatocyte plasticity in order to preserve liver function and promote tissue repair., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Little is known about pollutant concentrations in marine remote areas such as the Porcupine Bank in the NE Atlantic Ocean. Remote locations are much less studied than the more readily accessible coastal areas, nevertheless, are of great importance both to unveil how far human influence has reached and, are more challenging, to infer background concentrations (BCs) of naturally occurring and/or anthropogenic pollutants. Knowledge of contaminant background levels are critical for establishing remediation and management strategies; in addition, background assessment is heavily emphasised in legislative monitoring requirements. Obtaining suitable sampling locations to assess background concentrations can be challenging, as samples should match characteristics to the target area and not be impacted by historical or current inputs of the chemical substances of study. Anthropogenic impacts generally deem local-based sampling to be unsuitable to infer background pollution values. Sampling in remote areas such as the Porcupine Bank better fulfils low impact and pressure requirements making them more suitable for the derivation of background concentration estimates for organic compounds and metals. The total concentrations of polycyclic aromatic hydrocarbons (PAHs) and metal(loid)s in deep sea sediments were evaluated and both an environmental status and a set of concentration data were adequate to derive BCs concentrations is presented. Concentration data indicated, in comparison with previous published data, trace level presence of PAHs and metal(loids) in sediments from the Porcupine Bank. These values will provide a valuable tool to identify the natural presence of organic and inorganic compounds and be the basis to perform a sound environmental assessment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Among patients affected by the virus COVID-19, physicians have observed ventilation disorders. It is relevant to assess neurological involvement, including the role of diaphragmatic function. Its possible impairment could be related to the systemic inflammatory response and disease progression that both typify COVID-19 infection. We distinguished two groups (severe group (SG) and mild group (MG)) according to the severity of respiratory symptomatology. We performed neurophysiological and sonography studies to evaluate the diaphragmatic function. Regarding the sonography variables, we identified statistically significant differences in the right mean diaphragmatic thickness along with the expiration, showing 1.56 mm (SEM: 0.11) in the SG vs 1.92 mm (SEM: 0.19) in the MG (p = 0.042). The contractibility of both hemidiaphragms was 15% lower in the severe group, though this difference is not statistically significant. In our examination of the neurophysiological variables, in the amplitude responses, we observed a greater difference between responses from both phrenic nerves as follows: the raw differences in amplitude were 0.40 μV (SEM: 0.14) in the SG vs 0.35 μV (SEM: 0.19) in the MG and the percentage difference was 25.92% (SEM: 7.22) in the SG vs 16.28% (SEM: 4.38%) in the MG. Although diaphragmatic dysfunction is difficult to detect, our combined functional and morphological approach with phrenic electroneurograms and chest ultrasounds could improve diagnostic sensitivity. We suggest that diaphragmatic dysfunction could play a relevant role in respiratory disturbance in hospitalised patients with severe COVID-19.

Deep brain stimulation of the subthalamic nucleus is efficient for the treatment of motor symptoms (i.e., tremors) in patients with Parkinson's disease. Gait disorders usually appear during advanced stages of idiopathic Parkinson's disease in up to 80% of patients and have an important impact on their quality of life. The effects of deep brain stimulation of the subthalamic nucleus on gait and balance are still controversial. For this reason, alternative targets have been considered, such as stimulation of the pedunculopontine nucleus and the pars reticulata of substantia nigra, involved in the integration of the functional connections for gait. Due to the proximity of the subthalamic nucleus to the substantia nigra, their combined stimulation is feasible and may lead to better outcomes, improving axial symptoms. Our objective was to prospectively compare simultaneous stimulation of both structures versus conventional subthalamic stimulation in improving gait disorders. In ten patients with advanced Parkinson's disease, deep brain stimulation leads (eight linear contacts) were implanted, and gait analysis was performed 6 months after surgery in off-stimulation and after 4 weeks of dual or single subthalamic stimulation. An improvement in gait parameters was confirmed with both stimulation conditions, with better results with combined substantia nigra and subthalamic stimulation compared with conventional subthalamic stimulation. Further studies are needed to determine if this effect remains after long-term dual-target stimulation.

Marine litter is an emerging environmental problem. In this study, micro and mesoplastics were determined for the first time in seawater in Ría de Vigo (Spain) identifying their concentration, annual cycle, size, shape and polymer composition. Besides, temporal variations at an annual scale were also established. The Ría de Vigo is well known for the important industry related to marine activities (fishing, mollusc culture, shipyards, and tourism). Three sampling stations were selected along the transverse axis of Ría and were monthly sampled for one year. Seawater samples were collected using a manta trawl and analyzed with ATR-FTIR, and Raman spectroscopy to determine plastic polymer type. The mesozooplankton community (0.2-20 mm) was also studied. The samples were collected with bongo nets in the same sampling stations as plastics. Manta trawl net (330 μm) was used to collect 32 samples (identifying 854 plastic particles; 677 microplastics and 177 mesoplastics). The mean concentration across all sites was 25.4 ± 13.4 items·km -2 . The microplastics abundance was greater than that of mesoplastics (79%, and 21%, respectively). Around 30% of plastics analyzed were Polyethylene (PE), 19% were acrylates, 18% were Polypropylene (PP) and 10% were Polystyrene (PS). The main shapes of both micro and mesoplastics were fibers followed by paint sheets being black the main colour in both cases. The results showed high seasonal variability by micro and mesoplastics but similar spatial distribution. This seasonal heterogeneity can have effects on a future monitoring program. Furthermore, it was demonstrated that pollution by mesoplastics cannot be estimated through the microplastics abundances. Regarding the values of microplastics-zooplankton, they present a great negative correlation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) are highly stable and bioaccumulative, and microplastics (MPs; plastics <5 mm) are ubiquitous in the marine environment. In this study we report the levels of a selection of pollutants in liver and muscle of juvenile gilthead seabream (Sparus aurata) exposed to virgin and weathered MP enriched diets during three months and followed by one month of MP depuration. In general, a major concentration of pollutants in liver was observed. According to OCPs, total DDTs was two or three times higher in liver. Levels in muscle suffer higher variability between treatments and sampling periods. The MP index was negatively correlated to HCB and positively to p,p'DDT in liver. Levels of pollutants are correlated to biological parameters such as total size and total weight. Our results suggest that the bioaccumulation is subjected to the molecular structure of the pollutants and that MPs are correlated with the detoxification system., (Copyright © 2021 Elsevier Ltd. All rights reserved.)