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1.
Cancers (Basel) ; 13(19)2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34638467

RESUMO

The microRNA 21 (miR-21) is upregulated in almost all known human cancers and is considered a highly potent oncogene and potential therapeutic target for cancer treatment. In the liver, miR-21 was reported to promote hepatic steatosis and inflammation, but whether miR-21 also drives hepatocarcinogenesis remains poorly investigated in vivo. Here we show using both carcinogen (Diethylnitrosamine, DEN) or genetically (PTEN deficiency)-induced mouse models of hepatocellular carcinoma (HCC), total or hepatocyte-specific genetic deletion of this microRNA fosters HCC development-contrasting the expected oncogenic role of miR-21. Gene and protein expression analyses of mouse liver tissues further indicate that total or hepatocyte-specific miR-21 deficiency is associated with an increased expression of oncogenes such as Cdc25a, subtle deregulations of the MAPK, HiPPO, and STAT3 signaling pathways, as well as alterations of the inflammatory/immune anti-tumoral responses in the liver. Together, our data show that miR-21 deficiency promotes a pro-tumoral microenvironment, which over time fosters HCC development via pleiotropic and complex mechanisms. These results question the current dogma of miR-21 being a potent oncomiR in the liver and call for cautiousness when considering miR-21 inhibition for therapeutic purposes in HCC.

2.
PeerJ ; 9: e11895, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34595063

RESUMO

Background: The cost and complexity of the polymerase chain reaction (PCR) test are barriers to diagnosis and treatment of hepatitis C virus (HCV) infection. We investigated the cost-effectiveness of testing strategies using antigen instead of PCR testing. Methods: We developed a mathematical model for HCV to estimate the number of diagnoses and cases of liver disease. We compared the following testing strategies: antibody test followed by PCR in case of positive antibody (baseline strategy); antibody test followed by HCV-antigen test (antibody-antigen); antigen test alone; PCR test alone. We conducted cost-effectiveness analyses considering either the costs of HCV testing of infected and uninfected individuals alone (A1), HCV testing and liver-related complications (A2), or all costs including HCV treatment (A3). The model was parameterized for the country of Georgia. We conducted several sensitivity analyses. Results: The baseline scenario could detect 89% of infected individuals. Antibody-antigen detected 86% and antigen alone 88% of infected individuals. PCR testing alone detected 91% of the infected individuals: the remaining 9% either died or spontaneously recovered before testing. In analysis A1, the baseline strategy was not essentially more expensive than antibody-antigen. In analysis A2, strategies using PCR became cheaper than antigen-based strategies. In analysis A3, antibody-antigen was again the cheapest strategy, followed by the baseline strategy, and PCR testing alone. Conclusions: Antigen testing, either following a positive antibody test or alone, performed almost as well as the current practice of HCV testing. The cost-effectiveness of these strategies depends on the inclusion of treatment costs.

3.
Eur J Appl Physiol ; 2021 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-34677625

RESUMO

PURPOSE: Muscle-tendon length can influence central and peripheral motor unit (MU) characteristics, but their interplay is unknown. This study aims to explain the effect of muscle length on MU firing and contractile properties by applying deconvolution of high-density surface EMG (HDEMG), and torque signals on the same MUs followed at different lengths during voluntary contractions. METHODS: Fourteen participants performed isometric ankle dorsiflexion at 10% and 20% of the maximal voluntary torque (MVC) at short, optimal, and long muscle lengths (90°, 110°, and 130° ankle angles, respectively). HDEMG signals were recorded from the tibialis anterior, and MUs were tracked by cross-correlation of MU action potentials across ankle angles and torques. Torque twitch profiles were estimated using model-based deconvolution of the torque signal based on composite MU spike trains. RESULTS: Mean discharge rate of matched motor units was similar across all muscle lengths (P = 0.975). Interestingly, the increase in mean discharge rate of MUs matched from 10 to 20% MVC force levels at the same ankle angle was smaller at 110° compared with the other two ankle positions (P = 0.003), and the phenomenon was explained by a greater increase in twitch torque at 110° compared to the shortened and lengthened positions (P = 0.002). This result was confirmed by the deconvolution of electrically evoked contractions at different stimulation frequencies and muscle-tendon lengths. CONCLUSION: Higher variations in MU twitch torque at optimal muscle lengths likely explain the greater force-generation capacity of muscles in this position.

4.
J Physiol ; 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34505294

RESUMO

Ageing is a natural process causing alterations in the neuromuscular system, which contributes to reduced quality of life. Motor unit (MU) contributes to weakness, but the mechanisms underlying reduced firing rates are unclear. Persistent inward currents (PICs) are crucial for initiation, gain control and maintenance of motoneuron firing, and are directly proportional to the level of monoaminergic input. Since concentrations of monoamines (i.e. serotonin and noradrenaline) are reduced with age, we sought to determine if estimates of PICs are reduced in older (>60 years old) compared to younger adults (<35 years old). We decomposed MU spike trains from high-density surface electromyography over the biceps and triceps brachii during isometric ramp contractions to 20% of maximum. Estimates of PICs (ΔFrequency; or simply ΔF) were computed using the paired MU analysis technique. Regardless of the muscle, peak firing rates of older adults were reduced by ∼1.6 pulses per second (pps) (P = 0.0292), and ΔF was reduced by ∼1.9 pps (P < 0.0001), compared to younger adults. We further found that age predicted ΔF in older adults (P = 0.0261), resulting in a reduction of ∼1 pps per decade, but there was no relationship in younger adults (P = 0.9637). These findings suggest that PICs are reduced in the upper limbs of older adults during submaximal isometric contractions. Reduced PIC magnitude represents one plausible mechanism for reduced firing rates and function in older individuals, but further work is required to understand the implications in other muscles and during a variety of motor tasks. KEY POINTS: Persistent inward currents play an important role in the neural control of human movement and are influenced by neuromodulation via monoamines originating in the brainstem. During ageing, motor unit firing rates are reduced, and there is deterioration of brainstem nuclei, which may reduce persistent inward currents in alpha motoneurons. Here we show that estimates of persistent inward currents (ΔF) of both elbow flexor and extensor motor units are reduced in older adults. Estimates of persistent inward currents have a negative relationship with age in the older adults, but not in the young. This novel mechanism may play a role in the alteration of motor firing rates that occurs with ageing, which may have consequences for motor control.

5.
J Appl Physiol (1985) ; 131(4): 1260-1271, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34473572

RESUMO

At high forces, the discharge rates of lower- and higher-threshold motor units (MU) are influenced in a different way by muscle pain. These differential effects may be particularly important for performing contractions at different speeds since the proportion of lower- and higher-threshold MUs recruited varies with contraction velocity. We investigated whether MU discharge and recruitment strategies are differentially affected by pain depending on their recruitment threshold (RT), across a range of contraction speeds. Participants performed ankle dorsiflexion sinusoidal-isometric contractions at two frequencies (0.25 and 1 Hz) and two modulation amplitudes [5% and 10% of the maximum voluntary contraction (MVC)] with a mean target torque of 20%MVC. High-density surface electromyography recordings from the tibialis anterior muscle were decomposed and the same MUs were tracked across painful (hypertonic saline injection) and nonpainful conditions. Torque variability, mean discharge rate (MDR), DR variability (DRvar), RT, and the delay between the cumulative spike train and the resultant torque output (neuromechanical delay, NMD) were assessed. The average RT was greater at faster contraction velocities (P = 0.01) but was not affected by pain. At the fastest contraction speed, torque variability and DRvar were reduced (P < 0.05) and MDR was maintained. Conversely, MDR decreased and DRvar and NMD increased significantly during pain at slow contraction speeds (P < 0.05). These results show that reductions in contraction amplitude and increased recruitment of higher-threshold MUs at fast contraction speeds appear to compensate for the inhibitory effect of nociceptive inputs on lower-threshold MUs, allowing the exertion of fast submaximal contractions during pain.NEW & NOTEWORTHY Pain induces changes in motor performance, motor unit recruitment, and rate coding behavior that varies across different contraction speeds. Here we show that that pain reduces motor unit discharge rate and prolongs the neuromechanical delay at slow contraction speeds only. This new evidence suggests that there are differential nociceptive inhibitory effects across the motor unit pool, which allows fast submaximal contractions to be exerted despite the presence of pain.

6.
JHEP Rep ; 3(3): 100279, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34522875

RESUMO

Background & Aims: Patients hospitalised because of mental illness often have risk factors for contracting HCV. Scaling-up HCV screening for all psychiatric inpatients as a case-detection strategy for viral elimination is underexplored. This study aimed to evaluate the cost-effectiveness of scaling-up HCV screening and treatment for psychiatry hospital admissions in Switzerland vs. the current standard-of-care risk-based approach, where only those with a history of substance misuse disorder are offered testing. Methods: HCV prevalence by history of substance misuse disorder was analysed in medical records from inpatient admissions to a Swiss psychiatry department. Cost-effectiveness was analysed from a healthcare provider perspective through a decision-tree screening model, using these HCV prevalence data. Model and parameter uncertainty were assessed using deterministic and probabilistic sensitivity analyses. Results: Prevalence of HCV in psychiatry inpatients with a history of substance misuse disorder (n = 1,013) was 25.7%, compared with 3.5% among the remaining inpatients (n = 3,535). Scaling up HCV screening and treatment for all psychiatry admissions was cost-effective vs. the risk-based approach, with an incremental cost-effectiveness ratio of US$9,188 per quality-adjusted life-year gained. The incremental cost-effectiveness ratio remained cost-effective considering a HCV prevalence as low as 0.07%. The population-level net monetary benefit of the generalised screening approach was US$435,156,348, with 917 additional patients per year detected and treated at a cost of US$3,294 per person (vs. US$2,122 under risk-based screening). Conclusions: Scaling up HCV screening and treatment at diagnosis with all-oral, interferon-free regimens as a generalised approach for psychiatric admissions was cost-effective and could support reaching World Health Organization targets for HCV elimination by 2030. Lay summary: Patients hospitalised because of mental illness often have risk factors for HCV. We found that testing all psychiatry patients in hospital for HCV was cost-effective compared with testing only patients who have a history of substance misuse. Scaling up HCV testing and treatment could help to wipe out HCV.

8.
Rev Med Suisse ; 17(748): 1453-1456, 2021 Sep 01.
Artigo em Francês | MEDLINE | ID: mdl-34468096

RESUMO

Treatment of hepatitis C has known major progress thanks to direct-acting antivirals resulting in the healing, defined by a viral clearance (sustained virological response [SVR]), in the vast majority of patients. However, there is a residual risk of progressive liver damage in a minority of patients, potentially leading to complications such as liver decompensation, hepatocellular carcinoma and/or death. This article discusses the current knowledge of residual liver disease after treatment, the impact of comorbidities and the factors potentially predicting patients at risk of complications and warranting surveillance.


Assuntos
Carcinoma Hepatocelular , Hepatite C Crônica , Hepatite C , Neoplasias Hepáticas , Antivirais/uso terapêutico , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/etiologia , Hepacivirus , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Hepatite C/epidemiologia , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/epidemiologia , Humanos , Cirrose Hepática/tratamento farmacológico , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/etiologia
10.
Int J Sports Med ; 2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34282592

RESUMO

The purpose of the study was to evaluate the influence of changes in ankle- and knee-joint angles on force steadiness and the discharge characteristics of motor units (MU) in soleus when the plantar flexors performed steady isometric contractions. Submaximal contractions (5, 10, 20, and 40% of maximum) were performed at two ankle angles (75° and 105°) and two knee angles (120° and 180°) by 14 young adults. The coefficient of variation of force decreased as the target force increased from 5 to 20% of maximal force, then remained unaltered at 40%. Independently of knee angle, the coefficient of variation for force at the ankle angle of 75° (long length) was always less (p<0.05) than that at 105° (shorter length). Mean discharge rate, discharge variability, and variability in neural activation of soleus motor units were less (p<0.05) at the 75° angle than at 105°. It was not possible to record MUs from medial gastrocnemius at the knee angle of 120° due to its minimal activation. The changes in knee-joint angle did not influence any of the outcome measures. The findings underscore the dominant role of the soleus muscle in the control of submaximal forces produced by the plantar flexor muscles.

12.
Health Sci Rep ; 4(2): e290, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34136654

RESUMO

Hepatitis C virus (HCV) affects over 70 million people globally, with an estimated 399 000 HCV-related deaths in 2016. The World Health Organization (WHO) has set a goal to eliminate HCV by 2030. Despite the availability of direct-acting antivirals-highly effective and well-tolerated therapies for HCV-many patients infected with HCV in Germany have not initiated treatment, including a majority of those who are aware of their positive diagnosis. Barriers to screening, diagnosis, and treatment are major factors taking many countries off track for HCV elimination by 2030. Identifying country-specific barriers and challenges, particularly in at-risk populations such as people who inject drugs or men who have sex with men, has the potential to create tailored programs and strategies to increase access to screening or treatment and engage at-risk populations. This review aims to report the current steps toward HCV elimination in Germany, the country-specific barriers and challenges that will potentially prevent reaching the 2030 HCV elimination goal and describe good practice examples to overcome these barriers.

14.
Infect Dis Ther ; 2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34125405

RESUMO

INTRODUCTION: Glecaprevir/pibrentasvir is approved for treating chronic hepatitis C virus (HCV) genotypes (GT) 1-6. We evaluated real-world effectiveness, safety, and patient-reported outcomes of glecaprevir/pibrentasvir in underserved patient populations, focusing on persons who use drugs infected with HCV. METHODS: Data were pooled from nine countries (13 November 2017-31 January 2020). Patients had HCV GT1-6, with or without compensated cirrhosis, with or without prior HCV treatment and received glecaprevir/pibrentasvir consistent with local label at their physician's discretion. Patients with prior direct-acting antiviral exposure were excluded from efficacy and quality-of-life analyses. The percentage of patients achieving sustained virologic response at post-treatment week 12 (SVR12) was assessed. Mean changes from baseline to SVR12 visit in 36-Item Short-Form Health Survey mental and physical component summary scores were reported. Safety was assessed in patients receiving at least one dose of glecaprevir/pibrentasvir. RESULTS: Of 2036 patients, 1701 (83.5%) received 8-week glecaprevir/pibrentasvir. In 1684 patients with sufficient follow-up, SVR12 rates were 98.0% (1651/1684) overall, 98.1% (1432/1459) in 8-week treated patients, 97.0% (519/535) in persons who use drugs, and greater than 95% across subgroups. Mean changes from baseline in mental and physical component summary scores were 3.7 and 2.4, respectively. One glecaprevir/pibrentasvir-related serious adverse event was reported; six glecaprevir/pibrentasvir-related adverse events led to discontinuation. CONCLUSIONS: Glecaprevir/pibrentasvir was highly effective, well tolerated, and improved quality of life in HCV-infected persons who use drugs and other underserved patients. TRIAL REGISTRATION: These multinational post-marketing observational studies are registered with ClinicalTrials.gov, number NCT03303599.

15.
J Neurophysiol ; 126(1): 213-226, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34107220

RESUMO

The pectoralis major critically enables arm movement in several directions. However, its neural control remains unknown. High-density electromyography (HD-sEMG) was acquired from the pectoralis major in two sets of experiments in healthy young adults. Participants performed ramp-and-hold isometric contractions in: adduction, internal rotation, flexion, and horizontal adduction at three force levels: 15%, 25%, and 50% scaled to task-specific maximal voluntary force (MVF). HD-sEMG signals were decomposed into motor unit spike trains using a convolutive blind source separation algorithm and matched across force levels using a motor unit matching algorithm. The mean discharge rate and coefficient of variation were quantified across the hold and compared between 15% and 25% MVF across all tasks, whereas comparisons between 25% and 50% MVF were made where available. Mean motor unit discharge rate was not significantly different between 15% and 25% MVF (all P > 0.05) across all tasks or between 25% and 50% MVF in horizontal adduction (P = 0.11), indicating an apparent saturation across force levels and the absence of rate coding. These findings suggest that the pectoralis major likely relies on motor unit recruitment to increase force, providing first-line evidence of motor unit recruitment in this muscle and paving the way for more deliberate investigations of the pectoralis major involvement in shoulder function.NEW & NOTEWORTHY This work is the first to investigate the relative contribution of rate coding and motor unit recruitment in the pectoralis major muscle in several functionally relevant tasks and across varying force levels in healthy adults. Our results demonstrate the absence of motor unit rate coding with an increase in EMG amplitude with increases in force level in all tasks examined, indicating that the pectoralis major relies on motor unit recruitment to increase force.

16.
J Neurophysiol ; 126(1): 264-274, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34133235

RESUMO

Persistent inward currents (PICs) play an essential role in setting motor neuron gain and shaping motor unit firing patterns. Estimates of PICs in humans can be made using the paired motor unit analysis technique, which quantifies the difference in discharge rate of a lower threshold motor unit at the recruitment onset and offset of a higher threshold motor unit (ΔF). Because PICs are highly dependent on the level of neuromodulatory drive, ΔF represents an estimate of level of neuromodulation at the level of the spinal cord. Most of the estimates of ΔF are performed under constrained, isometric, seated conditions. In the present study, we used high-density surface EMG arrays to discriminate motor unit firing patterns during isometric seated conditions with torque or EMG visual feedback and during unconstrained standing anterior-to-posterior movements with root mean square EMG visual feedback. We were able to apply the paired motor unit analysis technique to the decomposed motor units in each of the three conditions. We hypothesized that ΔF would be higher during unconstrained standing anterior-to-posterior movements compared with the seated conditions, reflecting an increase in the synaptic input to motoneurons drive while standing. In agreement with previous work, we found that there was no evidence of a difference in ΔF between the seated and standing postures, although slight differences in the initial and peak discharge rates were observed. Taken together, our results suggest that both the standing and seated postures are likely not sufficiently different, both being "upright" postures, to result in large changes in neuromodulatory drive.NEW & NOTEWORTHY In the present study, we show that the discharge rate of a lower threshold motor unit at the recruitment onset and offset of a higher threshold motor unit (ΔF) is similar between standing and seated conditions in human tibialis anterior motor units, suggesting that at least for these two upright postures neuromodulatory drive is similar. We also highlight a proposed technological development in using high-density EMG arrays for real-time muscle activity feedback to accomplish standing ramped contraction tasks and demonstrate the validity of the paired motor unit analysis technique during these conditions.

17.
J Appl Physiol (1985) ; 130(6): 1798-1813, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33955258

RESUMO

Modulation of movement velocity is necessary during daily life tasks, work, and sports activities. However, assessing motor unit behavior during muscle shortening and lengthening at different velocities is challenging. High-density surface electromyography (HD-sEMG) is an established method to identify and track motor unit behavior in isometric contractions. Therefore, we used this methodology to unravel the behavior of the same motor units in dynamic contractions at low contraction velocities. Velocity-related changes in tibialis anterior motor unit behavior during concentric and eccentric contractions at 10% and 25% maximum voluntary isometric contraction were assessed by decomposing HD-sEMG signals recorded from the tibialis anterior muscle of eleven healthy participants at 5°/s, 10°/s, and 20°/s. Motor units extracted from the dynamic contractions were tracked across different velocities at the same load levels. On average, 14 motor units/participant were matched across different velocities, showing specific changes in discharge rate modulation. Specifically, increased velocity led to an increased rate of change in discharge rate (e.g., discharge rate slope, P = 0.025), recruitment and derecruitment discharge rates (P = 0.003 and P = 0.001), and decreased recruitment angles (P = 0.0001). Surprisingly, the application of the motor unit extraction filters calculated from 20°/s onto the recordings at 5°/s and 10°/s revealed that >92% of motor units recruited at the highest velocity were active on both lower velocities, indicating no additional recruitment of motor units. Our results suggest that motor unit rate coding rather than recruitment is responsible for controlling muscle shortening and lengthening contractions at increasing velocities against a constant load.NEW & NOTEWORTHY The control of movement velocity is accomplished by the modulation of the neural drive to muscle and its variation over time. In this study, we tracked motor units decomposed from HD-sEMG across shortening and lengthening contractions at increasing velocities in two submaximal load levels. We demonstrate that concentric and eccentric contractions of the tibialis anterior muscle at slow velocities are achieved by specific motor unit rate coding strategies rather than distinct recruitment schemes.


Assuntos
Neurônios Motores , Contração Muscular , Eletromiografia , Humanos , Contração Isométrica , Músculo Esquelético , Recrutamento Neurofisiológico
18.
J Neural Eng ; 18(4)2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-34036939

RESUMO

Objective. Coactivation of gamma and alpha motor neuron activity ensures that muscle spindle responsiveness is maintained during muscle contractions. However, some evidence suggests that the activity of gamma motor neurons is phase-advanced with respect to that of alpha motor neurons during manual control tasks. We hypothesized that this might be a deliberate control strategy to maximize movement accuracy.Approach. Using a computational model of the neural activation of a muscle and its type Ia sensory feedback to the motor neurons, we systematically investigated the impact of the phase difference between oscillatory descending input to alpha and dynamic gamma motor neurons. Specifically, the amplification of the alpha motor neuron drive to the muscle was investigated as a function of the frequency of the synaptic input (1-9 Hz individually or superimposed) and the alpha-gamma phase difference (0-2π).Main results. Simulation results showed that when the phase advance of the dynamic gamma drive resulted in delays between muscle velocity and type Ia afferent feedback similar to those previously observed experimentally, low-frequency components (1 and 2 Hz) of the motor neuron synaptic input were amplified (gain up to 1.7). On the other hand, synaptic input at higher frequencies was unaffected.Significance. This finding suggests that by imposing a phase advance of the input to dynamic gamma motor neurons, components of the neural drive usually associated with voluntary control are amplified. In this way, our study suggests that this neural strategy increases the control-to-neural-noise ratio of the motor output during movement.


Assuntos
Neurônios Motores gama , Músculo Esquelético , Neurônios Motores , Contração Muscular , Fusos Musculares
19.
Viruses ; 13(5)2021 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-33924806

RESUMO

Hepatitis Delta virus (HDV) lies in between satellite viruses and viroids, as its unique molecular characteristics and life cycle cannot categorize it according to the standard taxonomy norms for viruses. Being a satellite virus of hepatitis B virus (HBV), HDV requires HBV envelope glycoproteins for its infection cycle and its transmission. HDV pathogenesis varies and depends on the mode of HDV and HBV infection; a simultaneous HDV and HBV infection will lead to an acute hepatitis that will resolve spontaneously in the majority of patients, whereas an HDV super-infection of a chronic HBV carrier will mainly result in the establishment of a chronic HDV infection that may progress towards cirrhosis, liver decompensation, and hepatocellular carcinoma (HCC). With this review, we aim to unravel Ariadne's thread into the labyrinth of acute and chronic HDV infection pathogenesis and will provide insights into the complexity of this exciting topic by detailing the different players and mechanisms that shape the clinical outcome.

20.
JHEP Rep ; 3(2): 100231, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33748726

RESUMO

Background & Aims: There are conflicting data regarding the epidemiology of hepatocellular carcinoma (HCC) arising in the context of non-alcoholic and metabolic-associated fatty liver disease (NAFLD and MAFLD). We aimed to examine the changing contribution of NAFLD and MAFLD, stratified by sex, in a well-defined geographical area and highly characterised HCC population between 1990 and 2014. Methods: We identified all patients with HCC resident in the canton of Geneva, Switzerland, diagnosed between 1990 and 2014 from the prospective Geneva Cancer Registry and assessed aetiology-specific age-standardised incidence. NAFLD-HCC was diagnosed when other causes of liver disease were excluded in cases with type 2 diabetes, metabolic syndrome, or obesity. Criteria for MAFLD included one or more of the following criteria: overweight/obesity, presence of type 2 diabetes mellitus, or evidence of metabolic dysregulation. Results: A total of 76/920 (8.3%) of patients were diagnosed with NAFLD-HCC in the canton of Geneva between 1990 and 2014. Between the time periods 1990-1994 and 2010-2014, there was a significant increase in HCC incidence in women (standardised incidence ratio [SIR] 1.83, 95% CI 1.08-3.13, p = 0.026) but not in men (SIR 1.10, 95% CI 0.85-1.43, p = 0.468). In the same timeframe, the proportion of NAFLD-HCC increased more in women (0-29%, p = 0.037) than in men (2-12%, p = 0.010) while the proportion of MAFLD increased from 21% to 68% in both sexes and from 7% to 67% in women (p <0.001). From 2000-2004 to 2010-2014, the SIR of NAFLD-HCC increased to 1.92 (95% CI 0.77-5.08) for men and 12.7 (95% CI 1.63-545) in women, whereas it decreased or remained stable for other major aetiologies of HCC. Conclusions: In a populational cohort spanning 25 years, the burden of NAFLD and MAFLD associated HCCs increased significantly, driving an increase in HCC incidence, particularly in women. Lay summary: Hepatocellular carcinoma (HCC) is the most common type of liver cancer, increasingly arising in patients with liver disease caused by metabolic syndrome, termed non-alcoholic fatty liver disease (NAFLD) or metabolic-associated fatty liver disease (MAFLD). We assessed all patients with HCC between 1990 and 2014 in the canton of Geneva (western Switzerland) and found an increase in all HCC cases in this timeframe, particularly in women. In addition, we found that HCC caused by NAFLD or MAFLD significantly increased over the years, particularly in women, possibly driving the increase in overall HCC cases.

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