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The radionuclide thorium-229 features an isomer with an exceptionally low excitation energy that enables direct laser manipulation of nuclear states. It constitutes one of the leading candidates for use in next-generation optical clocks1-3. This nuclear clock will be a unique tool for precise tests of fundamental physics4-9. Whereas indirect experimental evidence for the existence of such an extraordinary nuclear state is substantially older10, the proof of existence has been delivered only recently by observing the isomer's electron conversion decay11. The isomer's excitation energy, nuclear spin and electromagnetic moments, the electron conversion lifetime and a refined energy of the isomer have been measured12-16. In spite of recent progress, the isomer's radiative decay, a key ingredient for the development of a nuclear clock, remained unobserved. Here, we report the detection of the radiative decay of this low-energy isomer in thorium-229 (229mTh). By performing vacuum-ultraviolet spectroscopy of 229mTh incorporated into large-bandgap CaF2 and MgF2 crystals at the ISOLDE facility at CERN, photons of 8.338(24) eV are measured, in agreement with recent measurements14-16 and the uncertainty is decreased by a factor of seven. The half-life of 229mTh embedded in MgF2 is determined to be 670(102) s. The observation of the radiative decay in a large-bandgap crystal has important consequences for the design of a future nuclear clock and the improved uncertainty of the energy eases the search for direct laser excitation of the atomic nucleus.
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Arsenic is highly toxic and a significant threat to human health, but certain bacteria have developed defense mechanisms initiated by AsIII binding to AsIII-sensing proteins of the ArsR family. The transcriptional regulator AfArsR responds to AsIII and SbIII by coordinating the metalloids with three cysteines, located in a short sequence of the same monomer chain. Here, we characterize the binding of AsIII and HgII to a model peptide encompassing this fragment of the protein via solution equilibrium and spectroscopic/spectrometric techniques (pH potentiometry, UV, CD, NMR, PAC, EXAFS, and ESI-MS) combined with DFT calculations and MD simulations. Coordination of AsIII changes the peptide structure from a random-coil to a well-defined structure of the complex. A trigonal pyramidal AsS3 binding site is formed with almost exactly the same structure as observed in the crystal structure of the native protein, implying that the peptide possesses all of the features required to mimic the AsIII recognition and response selectivity of AfArsR. Contrary to this, binding of HgII to the peptide does not lead to a well-defined structure of the peptide, and the atoms near the metal binding site are displaced and reoriented in the HgII model. Our model study suggests that structural organization of the metal site by the inducer ion is a key element in the mechanism of the metalloid-selective recognition of this protein.
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Arsênio , Arsênio/química , Arsênio/metabolismo , Sítios de Ligação , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Metaloides/química , Metaloides/metabolismo , Teoria da Densidade Funcional , Simulação de Dinâmica Molecular , Ligação ProteicaRESUMO
Technetium-99m (99mTc) remains the cornerstone of nuclear medicine for single photon emission computed tomography (SPECT) due to its widespread availability and chemical and physical features. Its multiple oxidation states allow for the design and production of radiopharmaceuticals with versatile properties, namely in terms of pharmacokinetic profile. 99mTc(V) is the most common oxidation state, but 99mTc(I) gained traction after the pioneering work of Alberto and colleagues, which resulted in the introduction of the organometallic core fac-[99mTc(CO)3(H2O)3]+. This core is readily available from [99mTcO4]- and displays three labile water molecules that can be easily swapped for ligands with different denticity and/or donor atoms in aqueous environment. This makes it possible to radiolabel small molecules as well as high molecular weight molecules, such as antibodies or other proteins, while assuring biological activity. Direct radiolabelling of those proteins with fac-[99mTc(CO)3]+ under mild conditions is accomplished through incorporation of a polyhistidine tag (His-tag), a commonly used tag for purification of recombinant proteins. This review aims to address the direct radiolabelling of His-tagged macromolecules with fac-[99mTc(CO)3]+ for development of molecular imaging agents and the impact of this technology in the discovery and development of imaging and/or therapeutic agents towards clinical application.
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[This corrects the article DOI: 10.1371/journal.ppat.1010321.].
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Cryptococcosis is a potentially lethal fungal infection of humans caused by organisms within the Cryptococcus neoformans/gattii species complex. Whilst C. neoformans is a relatively common pathogen of immunocompromised individuals, C. gattii is capable of acting as a primary pathogen of immunocompetent individuals. Within the host, both species undergo morphogenesis to form titan cells: exceptionally large cells that are critical for disease establishment. To date, the induction, defining attributes, and underlying mechanism of titanisation have been mainly characterized in C. neoformans. Here, we report the serendipitous discovery of a simple and robust protocol for in vitro induction of titan cells in C. gattii. Using this in vitro approach, we reveal a remarkably high capacity for titanisation within C. gattii, especially in strains associated with the Pacific Northwest Outbreak, and characterise strain-specific differences within the clade. In particular, this approach demonstrates for the first time that cell size changes, DNA amplification, and budding are not always synchronous during titanisation. Interestingly, however, exhibition of these cell cycle phenotypes was correlated with genes associated with cell cycle progression including CDC11, CLN1, BUB2, and MCM6. Finally, our findings reveal exogenous p-Aminobenzoic acid to be a key inducer of titanisation in this organism. Consequently, this approach offers significant opportunities for future exploration of the underlying mechanism of titanisation in this genus.
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Cryptococcus gattii , Cryptococcus neoformans , Proteínas Fúngicas , Humanos , Hospedeiro Imunocomprometido , Componente 6 do Complexo de Manutenção de MinicromossomoRESUMO
BACKGROUND AND AIMS: Current guidelines recommend bowel preparation before small-bowel capsule endoscopy (SBCE). However, the optimal protocol is yet to be defined. To determine the best timing for preparation in SBCE, we compared small-bowel visualization quality (SBVQ), diagnostic yield (DY), and patient-reported outcomes across four purgative regimens. METHODS: In this prospective, randomized (1:1:1:1), multicentric study, patients with suspected small bowel bleeding were randomized into four arms: G1 (1L of polyethylene-glycol + ascorbic acid [Moviprep®] the night before SBCE), G2 (1L in the morning, up to 2 hours before SBCE), G3 (0.5L up to 2 hours before + 0.5L after the capsule reached the duodenum), and G4 (1L after reaching the duodenum). To assess DY, lesions were categorized as having high (P2) or low (P0 or P1) bleeding potential. Small-bowel visualization quality (SBVQ) was assessed using the Brotz score. Transit times (TT) were measured, and patient tolerability was scored from 0 to 5 with higher scores indicating better tolerability. RESULTS: A total of 387 patients were included; 59% female with a median age of 73 years (IQR 23). The exam completion rate was lower in G1 (90%, p<0.001). Small bowel TT was shorter for patients receiving purgative during SBCE (G3 and G4, p=0.001). SBVQ was better in patients receiving purgative after reaching the SB (p<0.001): median of 7 for G1, 8 for G2, and 9 for G3 and G4. The overall DY of patients receiving intra-procedure purgatives (G3 + G4) was superior (42.7 vs 31.3%, p=0.02); significant differences were found in the second and third terciles. Likewise, G3 and G4 had higher angioectasia detection (p=0.04). Patients' satisfaction was significantly superior for G4 (median 4 points, IQR 1). CONCLUSIONS: The group that received the bowel preparation the night before SBCE had poorer outcomes. Intra-procedure purgative regimens reduced SBTT, enhanced visualization, improved DY, and increased angioectasia detection. G4 was the best-tolerated regimen.
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BACKGROUND: Housing is considered a social determinant of health. In Catalonia and Spain, ensuring affordable housing is challenging and cooperative housing under a grant-of-use emerges as an alternative, challenging traditional housing models. This study aims to quantify its impact on health before and after moving to the cooperative house. METHODS: A longitudinal study of individuals in cooperative housing projects in Catalonia (July 2018-April 2023) was conducted. Data, including sociodemographic, housing information, and health-related details, were collected through baseline and follow-up surveys. RESULTS: Seventy participants (42 women, 28 men) showed positive changes in housing conditions during follow-up. Improved perceptions of health, mental health, and social support were observed. Despite limitations in sample size and short follow-up, initial findings suggest improvements in health. CONCLUSIONS: Cooperative housing under a grant-of-use in Catalonia appears promising for improving health and living conditions. Further research is warranted to explore its full potential as an alternative amid housing challenges in the region.
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Habitação , Humanos , Espanha , Feminino , Masculino , Estudos Longitudinais , Adulto , Pessoa de Meia-Idade , Habitação/estatística & dados numéricos , Habitação/economia , Nível de Saúde , Apoio Social , Saúde MentalRESUMO
Despite the recognized potential of nanoparticles, only a few formulations have progressed to clinical trials, and an even smaller number have been approved by the regulatory authorities and marketed. Virus-like particles (VLPs) have emerged as promising alternatives to conventional nanoparticles due to their safety, biocompatibility, immunogenicity, structural stability, scalability, and versatility. Furthermore, VLPs can be surface-functionalized with small molecules to improve circulation half-life and target specificity. Through the functionalization and coating of VLPs, it is possible to optimize the response properties to a given stimulus, such as heat, pH, an alternating magnetic field, or even enzymes. Surface functionalization can also modulate other properties, such as biocompatibility, stability, and specificity, deeming VLPs as potential vaccine candidates or delivery systems. This review aims to address the different types of surface functionalization of VLPs, highlighting the more recent cutting-edge technologies that have been explored for the design of tailored VLPs, their importance, and their consequent applicability in the medical field.
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Vacinas de Partículas Semelhantes a Vírus , Humanos , Vacinas de Partículas Semelhantes a Vírus/imunologia , Nanopartículas/química , Animais , Vírion/química , Sistemas de Liberação de Medicamentos/métodosRESUMO
A 66-year-old man was admitted to the emergency department due to malaise, fatigue and anorexia for the last 2 weeks. He presented no fever, no respiratory or gastrointestinal symptoms. The patient had been previously diagnosed with Crohn's Disease (CD) (A2L1L4B1 of Montreal Classification) 10 years before, when he presented complaints of watery diarrhea and unexplained weight loss. Despite refusing to start treatment, in the last staging exams performed 5 years before the admission (colonoscopy and magnetic resonance imaging) the patient was in deep remission. Nevertheless, he frequently missed his medical appointments and his disease had not been monitored since then. He denied previous use of corticosteroids, past abdominal surgery or previous CD related hospital admissions. He also denied smoking habits or chronic lung disease.
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BACKGROUND: Biofilms are the leading cause of nosocomial infections and are hard to eradicate due to their inherent antimicrobial resistance. Candida albicans is the leading cause of nosocomial fungal infections and is frequently co-isolated with the bacterium Pseudomonas aeruginosa from biofilms in the cystic fibrosis lung and severe burn wounds. The presence of C. albicans in multispecies biofilms is associated with enhanced antibacterial resistance, which is largely mediated through fungal extracellular carbohydrates sequestering the antibiotics. However, significantly less is known regarding the impact of polymicrobial biofilms on antifungal resistance. RESULTS: Here we show that, in dual-species biofilms, P. aeruginosa enhances the susceptibility of C. albicans to amphotericin B, an effect that was biofilm specific. Transcriptional analysis combined with gene ontology enrichment analysis identified several C. albicans processes associated with oxidative stress to be differentially regulated in dual-species biofilms, suggesting that P. aeruginosa exerts oxidative stress on C. albicans, likely through the secretion of phenazines. However, the mitochondrial superoxide dismutase SOD2 was significantly down-regulated in the presence of P. aeruginosa. Monospecies biofilms of the sod2Δ mutant were more susceptible to amphotericin B, and the susceptibility of these biofilms was further enhanced by exogenous phenazines. CONCLUSIONS: We propose that in dual-species biofilms, P. aeruginosa simultaneously induces mitochondrial oxidative stress, while down-regulating key detoxification enzymes, which prevents C. albicans mounting an appropriate oxidative stress response to amphotericin B, leading to fungal cell death. This work highlights the importance of understanding the impact of polymicrobial interactions on antimicrobial susceptibility.
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Anfotericina B , Candida albicans , Anfotericina B/farmacologia , Pseudomonas aeruginosa , Biofilmes , Antibacterianos/farmacologia , Fenazinas , Antifúngicos/farmacologiaRESUMO
Human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorder (HAND) remains an important neurological manifestation in HIV-1-infected (HIV+) patients. Furthermore, detection of the HIV-1 matrix protein p17 (p17) in the central nervous system (CNS) and its ability to form toxic assemblies in the brain have been recently confirmed. Here, we show for the first time, using both an in vitro blood-brain barrier (BBB) model and in vivo biodistribution studies in healthy mice, that p17 can cross the BBB. There is rapid brain uptake with 0.35% ± 0.19% of injected activity per gram of tissue (IA/g) 2 min after administration, followed by brain accumulation with 0.28% ± 0.09% IA/g after 1 h. The interaction of p17 with chemokine receptor 2 (CXCR2) at the surface of brain endothelial cells triggers transcytosis. The present study supports the hypothesis of a direct role of free p17 in neuronal dysfunction in HAND by demonstrating its intrinsic ability to reach the CNS. IMPORTANCE The percentage of patients affected by HIV-1-associated neurocognitive disorder (HAND) ranges from 30% to 50% of HIV-infected (HIV+) patients. The mechanisms leading to HAND development need to be elucidated, but the roles of secreted viral proteins, chemokines, and proinflammatory molecules appear to be clear. In particular, the blood-brain barrier (BBB) represents a route for entry into the central nervous system (CNS) and thus plays an important role in HAND. Several findings suggest a key role for the HIV-1 matrix protein p17 (p17) as a microenvironmental factor capable of inducing neurocognitive disorders. Here, we show the ability of the p17 to cross the BBB and to reach the CNS, thus playing a crucial role in neuronal dysfunction in HAND.
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Barreira Hematoencefálica/metabolismo , Antígenos HIV/metabolismo , Infecções por HIV/metabolismo , Infecções por HIV/virologia , HIV-1/fisiologia , Interações Hospedeiro-Patógeno , Produtos do Gene gag do Vírus da Imunodeficiência Humana/metabolismo , Animais , Autofagia , Linhagem Celular , Células Cultivadas , Suscetibilidade a Doenças , Endossomos/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/virologia , Humanos , Camundongos , Ligação Proteica , Transporte Proteico , Receptores de Interleucina-8B/metabolismoRESUMO
Exposure of human sperm to progesterone (P4) activates cation channel of sperm (CatSper) channels, inducing an intracellular Ca2+ concentration ([Ca2+]i) transient followed by repetitive [Ca2+]i activity (oscillations), which are believed to be functionally important. We investigated the potential significance of store-operated Ca2+-entry in these oscillations using the inhibitor SKF96365 (30 µM; SKF). Following pre-treatment of human sperm with 3 µM P4, exposure to SKF doubled the proportion of oscillating cells (P = 0.00004). In non-pre-treated cells, SKF had an effect similar to P4, inducing a [Ca2+]i transient in >80% of cells which was followed by oscillations in ≈50% of cells. The CatSper blocker RU1968 (11 µM) inhibited the SKF-induced [Ca2+]i increase and reversibly arrested [Ca2+]i oscillations. Using whole-cell patch clamp, we observed that SKF enhanced CatSper currents by 100% within 30 s, but amplitude then decayed to levels below control over the next minute. When cells were stimulated with P4, CatSper currents were stably increased (by 200%). Application of SKF then returned current amplitude to control level or less. When sperm were prepared in medium lacking bovine serum albumin (BSA), both P4 and SKF induced a [Ca2+]i transient in >95% of cells but the ability of SKF to induce oscillations was greatly reduced (P = 0.0009). We conclude that SKF, similar to a range of small organic molecules, activates CatSper channels, but that a secondary blocking action also occurs, which was detected only during patch-clamp recording. The failure of SKF to induce oscillations when cells were prepared without BSA emphasizes that the drug does not fully mimic the actions of P4.
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Canais de Cálcio , Sinalização do Cálcio , Humanos , Masculino , Canais de Cálcio/metabolismo , Cálcio/metabolismo , Sêmen/metabolismo , Motilidade dos Espermatozoides , Espermatozoides/metabolismoRESUMO
OBJECTIVES: To evaluate the prevalence, magnitude, and potential determinants of work productivity impairment in patients with Behçet's Syndrome (BS), focusing on the role of irreversible organ damage. METHODS: A post-hoc analysis of the BS overall damage index (BODI) prospective validation study was performed. Demographics and clinical features were recorded in all patients. The Work Productivity and Activity Impairment: General Health (WPAI: GH) questionnaire was administered to assess the work limitation and the BODI to measure organ damage. The independent effect of BS features on WPAI: GH outcomes was evaluated by regression analysis. RESULTS: Out of 148 patients, 34.5% were unemployed, with age (OR 1.035) and BODI score (OR 1.313 for 1-unit increase) as the only factors significantly (p< 0.05) associated with the unemployment state. An overall work impairment was reported in about 64.2% of the employed patients. Indeed, 22.7% reported missing work h due to their health (absenteeism), with a mean time loss of 34.4%; whereas 60.2% declared a reduced performance at work because of their health (presenteeism), with a mean productivity impairment of 45.4%. Ocular damage was associated with absenteeism (ß 0.225); female sex (ß 0.260), physician global assessment of disease activity (ß 0.502) and an increased BODI score (ß 0.166 for 1-point increase) with presenteeism; fibromyalgia (ß 0.246), physician global assessment (ß 0.469), and musculoskeletal damage (ß 0.325) with overall work impairment. CONCLUSIONS: Disease activity and organ damage accrual remarkably affect work productivity in BS patients. Achieving remission and preventing damage accrual are crucial and complementary objectives.
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Septorhinoplasty (SRP) is one of the most commonly performed procedures worldwide. There is a recognized debate about the impact of nasal surgery on olfactory function (OF). The study's objective was to assess the effect of SRP on late postoperative OF. A comprehensive review and meta-analysis were employed to assess OF after SRP. All the integrated studies used objective instruments to quantify OF before and after surgery. A literature search was conducted, and the selected works were evaluated, computed, and finally included in a meta-analysis. The risk of bias was assessed using the NIH Guidance for Evaluating the Quality of Before-After (Pre-Post) Studies with No Control Group. Only the latest follow-up OF measurements provided by each research were considered in the analysis. The 95% confidence interval of the effect magnitude for each study was calculated to elucidate effect sizes. Eleven studies were included in the analysis. Five studies reported late OF improvement (45.5%), five reported no alteration in OF (45.5%), and only one study reported OF impairment after SRP (9%). Some works described a transitory decline in OF shortly following surgery, followed by postoperative improvement. A pooled meta-analysis showed that OF was not significantly altered after SRP (p = 0.10) in the late follow-up. SRP surgery seems to constitute a safe procedure concerning OF in the long term. According to research, OF may deteriorate temporarily after surgery with later improvement, sometimes to higher values than baseline. The anticipated evolution of OF after intervention could be discussed during the preoperative consultation for SRP.
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Rinoplastia , Olfato , Humanos , Rinoplastia/efeitos adversos , Rinoplastia/métodosRESUMO
A 55-year-old woman with cirrhosis was admitted for acute decompensation caused by portal vein thrombosis. Ten days later, the patient presented melena. Esophagogastroscopy revealed two gastric polyps, both with bleeding stigmata. One of the polyps was removed with a diathermic loop, after adrenalin injection, while in the other the "ligate and let go" technique was applied, after biopsy. A "metallic tulip-bundle" technique, combining through the scope and over-the-scope clips, was applied for hemostasis. This case underlines how the combination of various endoscopic techniques may be useful to manage upper gastrointestinal bleeding, especially in patients with important comorbidities.
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Hemostáticos , Feminino , Humanos , Pessoa de Meia-Idade , Hemorragia Gastrointestinal/etiologia , Hemostasia , Melena , Cirrose Hepática/complicações , Cirrose Hepática/patologiaRESUMO
The authors report a case of a 62-year-old male presenting to the emergency department with hematochezia. Urgent colonoscopy revealed numerous diverticula in the sigmoid colon, two of them inverted. Oozing bleeding from a visible vessel was identified on the top of the most distal inverted diverticulum. An over-the-scope clip was released after suction into the transparent cap and successful hemostasis was achieved.
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Divertículo do Colo , Divertículo , Masculino , Humanos , Pessoa de Meia-Idade , Divertículo do Colo/complicações , Divertículo do Colo/diagnóstico por imagem , Divertículo do Colo/cirurgia , Colo , Divertículo/complicações , Divertículo/diagnóstico por imagem , Divertículo/cirurgia , Colonoscopia , Hemorragia Gastrointestinal/diagnóstico por imagem , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/terapia , HemostasiaRESUMO
This case demonstrates the utility of the "purse string" to close large defects and shows that optical diagnosis may have pitfalls in evaluating the invasion of neoplastic lesions, particularly large ones.
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Ressecção Endoscópica de Mucosa , Humanos , Reto/cirurgiaRESUMO
Over the past few decades, there has been an exponential increase in the utilization of endoscopic procedures. Accurately predicting the demand is crucial for effective capacity planning and resource allocation in the endoscopic unit. However, predictive models are not integrated into current endoscopy software. To overcome this limitation, our group used data on the demand in our tertiary unit from 2015 to 2021 (83 months) to develop forecast models using exponential smoothing techniques adjusted for trend and seasonality (derivation phase). These models were recently published at the Revista Española de Enfermedades Digestivas.
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We report the successful removal of a giant esophageal leiomyoma using submucosal tunneling endoscopic resection in a 37-year-old woman with significant dysphagia.
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Ressecção Endoscópica de Mucosa , Neoplasias Esofágicas , Leiomioma , Neoplasias Gástricas , Feminino , Humanos , Adulto , Neoplasias Esofágicas/diagnóstico por imagem , Neoplasias Esofágicas/cirurgia , Leiomioma/diagnóstico por imagem , Leiomioma/cirurgia , Estudos Retrospectivos , Resultado do Tratamento , Neoplasias Gástricas/cirurgiaRESUMO
BACKGROUND: Sarcopenia, frailty and malnutrition are associated with adverse outcomes in liver cirrhosis. Studies assessing the prognostic value of these conditions in ambulatory patients with cirrhosis are scarce. METHODS: A prospective cohort study was conducted, with consecutive inclusion of all patients with cirrhosis observed in the Hepatology outpatient clinic of a Portuguese tertiary centre. At study enrolment, evaluation of muscle mass (ultrasound quadriceps femoris thickness), muscle strength (handgrip dynamometry) and nutritional status (Patient-Generated Subjective Global Assessment Short Form) was held. Follow-up ended upon the occurrence of a composite endpoint, comprising liver decompensation events and liver-related death, or last medical appointment/non-liver related death before the end of the study. The prognostic value of anthropometrical parameters and nutritional status in the composite endpoint was assessed using a multivariate Cox regression analysis, adjusted for several confounders. RESULTS: Ninety patients were enrolled (80% male), with a mean age of 63.5±10.5 years. The median follow-up was 30 (interquartile range 38) weeks, during which 12 patients reached the composite endpoint. These patients presented a lower mean handgrip strength [23.1±6.41 vs 30.3±10.4 Kg, p=0.04], compared to patients who did not reach the composite endpoint. On Cox regression multivariate analysis, however, no independent predictors of the composite endpoint were found, apart from previous decompensation episodes. CONCLUSION: In this study, muscle strength was lower in the group of patients with cirrhosis who presented a liver-related event. Handgrip strength might be a promising tool in the ambulatory setting to identify patients at risk of liver decompensation and liver-related death in the short term.