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Background and objectives: Fibrosis contributes to 45% of deaths in industrialized nations and is characterized by an abnormal accumulation of extracellular matrix (ECM). There are no specific anti-fibrotic treatments for liver fibrosis, and previous unsuccessful attempts at drug development have focused on preventing ECM deposition. Because liver fibrosis is largely acknowledged to be reversible, regulating fibrosis resolution could offer novel therapeutical options. However, little is known about the mechanisms controlling ECM remodeling during resolution. Changes in proteolytic activity are essential for ECM homeostasis and macrophages are an important source of proteases. Herein, in this study we evaluate the role of macrophage-derived cathepsin D (CtsD) during liver fibrosis. Methods: CtsD expression and associated pathways were characterized in single-cell RNA sequencing and transcriptomic datasets in human cirrhosis. Liver fibrosis progression, reversion and functional characterization were assessed in novel myeloid-CtsD and hepatocyte-CtsD knock-out mice. Results: Analysis of single-cell RNA sequencing datasets demonstrated CtsD was expressed in macrophages and hepatocytes in human cirrhosis. Liver fibrosis progression, reversion and functional characterization were assessed in novel myeloid-CtsD (CtsDΔMyel) and hepatocyte-CtsD knock-out mice. CtsD deletion in macrophages, but not in hepatocytes, resulted in enhanced liver fibrosis. Both inflammatory and matrisome proteomic signatures were enriched in fibrotic CtsDΔMyel livers. Besides, CtsDΔMyel liver macrophages displayed functional, phenotypical and secretomic changes, which resulted in a degradomic phenotypical shift, responsible for the defective proteolytic processing of collagen I in vitro and impaired collagen remodeling during fibrosis resolution in vivo. Finally, CtsD-expressing mononuclear phagocytes of cirrhotic human livers were enriched in lysosomal and ECM degradative signaling pathways. Conclusions: Our work describes for the first-time CtsD-driven lysosomal activity as a central hub for restorative macrophage function during fibrosis resolution and opens new avenues to explore their degradome landscape to inform drug development.

Surface Electromyography (sEMG) signals are widely used as input to control robotic devices, prosthetic limbs, exoskeletons, among other devices, and provide information about someone’s intention to perform a particular movement. However, the redundant action of 32 muscles in the forearm and hand means that the neuromotor system can select different combinations of muscular activities to perform the same grasp, and these combinations could differ among subjects, and even among the trials done by the same subject. In this work, 22 healthy subjects performed seven representative grasp types (the most commonly used). sEMG signals were recorded from seven representative forearm spots identified in a previous work. Intra- and intersubject variability are presented by using four sEMG characteristics: muscle activity, zero crossing, enhanced wavelength and enhanced mean absolute value. The results confirmed the presence of both intra- and intersubject variability, which evidences the existence of distinct, yet limited, muscle patterns while executing the same grasp. This work underscores the importance of utilizing diverse combinations of sEMG features or characteristics of various natures, such as time-domain or frequency-domain, and it is the first work to observe the effect of considering different muscular patterns during grasps execution. This approach is applicable for fine-tuning the control settings of current sEMG devices.

Surface-electromyography (sEMG) allows investigators to detect differences in muscle activation due to hand pathologies. However, its use as a functional indicator and the challenges related to the required normalization have not been fully addressed. This study aimed to use forearm muscle sEMG signals to distinguish between healthy individuals and patients with hand osteoarthritis (HOA). sEMG data were collected from seven sensors on the forearms of twenty-one healthy women and twenty women with HOA during the Sollerman test. Amplitude-based parameters (median and range) were normalized using three methods: maximum signals during Sollerman tasks (MAX), during maximum voluntary contraction tasks (MVC), and during maximum effort grasping (GRASP). Waveform parameters (new-zero-crossing and enhanced-wavelength) were also considered. MVC and GRASP resulted in higher values in patients. Discriminant analysis showed the worst success rates in predicting HOA for amplitude-based parameters, requiring extra tasks for normalization (MVC or GRASP), while when using both amplitude (MAX) and waveform parameters and only Sollerman tasks, the success rate reached 90.2% Results show the importance of normalization methods, highlight the potential of waveform parameters as reliable pathology indicators, and suggest sEMG as a diagnostic tool. Additionally, the comparison of sEMG parameters allows the functional impact of suffering from HOA to be inferred.

Abstract This work presents a dataset of human hand kinematics and forearm muscle activation collected during the performance of a wide variety of activities of daily living (ADLs), with tagged characteristics of products and tasks. A total of 26 participants performed 161 ADLs selected to be representative of common elementary tasks, grasp types, product orientations and performance heights. 105 products were used, being varied regarding shape, dimensions, weight and type (common products and assistive devices). The data were recorded using CyberGlove instrumented gloves on both hands measuring 18 degrees of freedom on each and seven surface EMG sensors per arm recording muscle activity. Data of more than 4100 ADLs is presented in this dataset as MATLAB structures with full continuous recordings, which may be used in applications such as machine learning or to characterize healthy human hand behaviour. The dataset is accompanied with a custom data visualization application (ERGOMOVMUS) as a tool for ergonomics applications, allowing visualization and calculation of aggregated data from specific task, product and/or participants’ characteristics.

Abstract Background Hand kinematics during hand function tests based on the performance of activities of daily living (ADLs) can provide objective data to determine patients’ functional loss. However, they are rarely used during clinical assessments because of their long duration. Starting with the 20 Sollerman Hand Function Test (SHFT) tasks, we propose identifying a reduced set of ADLs that provides similar kinematic information to the original full set in terms of synergies, ranges of motion and velocities. Methods We followed an iterative method with the kinematics of 16 hand joints while performing the 20 ADLs of the SHFT. For each subject, ADLs were ordered according to their influence on the synergies obtained by means of a principal component analysis, the minimum number of ADLs that represented the original kinematic synergies (maximum angle of 30° between synergies), and the maintained ranges of joint movements (85% of the original ones) were selected for each subject. The set of the most frequently selected ADLs was verified to be representative of the SHFT ADLs in terms of motion strategies, ranges of motion and joint velocities when considering healthy subjects and Hand Osteoarthritis patients. Results A set of 10 tasks, the BE-UJI activity set, was identified by ensuring a certain (minimum) similarity in synergy (maximum mean angle between synergies of 25.5°), functional joint ranges (maximum differences of 10°) and joint velocities (maximum differences of 15°/s). The obtained tasks were: pick up coins from purses, lift wooden cubes, pick up nuts and turn them, write with a pen, cut with a knife, lift a telephone, unscrew jar lids and pour water from a cup, a jar and a Pure-Pak. These activities guarantee using the seven commonest handgrips in ADLs. Conclusion The BE-UJI activity set for the hand function assessment can be used to obtain quantitative data in clinics as an alternative to the SHFT. It reduces the test time and allows clinicians to obtain objective kinematic data of the motor strategies, ranges of motion and joint velocities used by patients.

Abstract This work aims to: (1) Provide maximal hand force data on six different grasp types for healthy subjects; (2) detect grasp types with maximal force significantly affected by hand osteoarthritis (HOA) in women; (3) look for predictors to detect HOA from the maximal forces using discriminant analyses. Thirty-three healthy subjects (37 ± 17 years, 17 women, 16 men) and 30 HOA patients (72 ± 9 years, all women) participated in the experiment. Participants were asked to exert their maximal force while performing six different grasp types 3 times. Two MANOVAs were conducted to detect if force depended on gender in healthy participants and if force significantly diminished in women with HOA. Finally, a linear discriminant analysis for detecting HOA was performed using forces of the grasp types that were significantly affected by HOA. Gender-disaggregated statistics are provided for healthy participants. Significant differences are obtained for all grasp types per gender. The women with HOA exerted significantly lower force values (p

In the current article the aims for a constructive way forward in Drug-Induced Liver Injury (DILI) are to highlight the most important priorities in research and clinical science, therefore supporting a more informed, focused, and better funded future for European DILI research. This Roadmap aims to identify key challenges, define a shared vision across all stakeholders for the opportunities to overcome these challenges and propose a high-quality research program to achieve progress on the prediction, prevention, diagnosis and management of this condition and impact on healthcare practice in the field of DILI. This will involve 1. Creation of a database encompassing optimised case report form for prospectively identified DILI cases with well-characterised controls with competing diagnoses, biological samples, and imaging data; 2. Establishing of preclinical models to improve the assessment and prediction of hepatotoxicity in humans to guide future drug safety testing; 3. Emphasis on implementation science and 4. Enhanced collaboration between drug-developers, clinicians and regulatory scientists. This proposed operational framework will advance DILI research and may bring together basic, applied, translational and clinical research in DILI.

Background & Aims: Current therapies for the treatment of alcohol-related liver disease (ALD) have proven largely ineffective. Patients relapse and the disease progresses even after liver transplantation. Altered epigenetic mechanisms are characteristic of alcohol metabolism given excessive acetate and NAD depletion and play an important role in liver injury. In this regard, novel therapeutic approaches based on epigenetic modulators are increasingly proposed. MicroRNAs, epigenetic modulators acting at the post-transcriptional level, appear to be promising new targets for the treatment of ALD. Methods: MiR-873-5p levels were measured in 23 liver tissue from Patients with ALD, and GNMT levels during ALD were confirmed using expression databases (transcriptome n = 62, proteome n = 68). High-resolution proteomics and metabolomics in mice following the Gao-binge model were used to investigate miR-873-5p expression in ALD. Hepatocytes exposed to 50 mM alcohol for 12 h were used to study toxicity. The effect of anti-miR-873-5p in the treatment outcomes of ALD was investigated. Results: The analysis of human and preclinical ALD samples revealed increased expression of miR-873-5p in the liver. Interestingly, there was an inverse correlation with NNMT, suggesting a novel mechanism for NAD depletion and aberrant acetylation during ALD progression. High-resolution proteomics and metabolomics identified miR-873-5p as a key regulator of NAD metabolism and SIRT1 deacetylase activity. Anti-miR-873-5p reduced NNMT activity, fuelled the NAD salvage pathway, restored the acetylome, and modulated the levels of NF-κB and FXR, two known SIRT1 substrates, thereby protecting the liver from apoptotic and inflammatory processes, and improving bile acid homeostasis. Conclusions: These data indicate that targeting miR-873-5p, a repressor of GNMT previously associated with NAFLD and acetaminophen-induced liver failure. is a novel and attractive approach to treating alcohol-induced hepatoxicity. Impact and implications: The role of miR-873-5p has not been explicitly examined in the progression of ALD, a pathology with no therapeutic options. In this study, inhibiting miR-873-5p exerted hepatoprotective effects against ALD through rescued SIRT1 activity and consequently restored bile acid homeostasis and attenuated the inflammatory response. Targeting hepatic miR-873-5p may represent a novel therapeutic approach for the treatment of ALD.

Background & aimsWe recently showed that alcoholic hepatitis (AH) is characterized by dedifferentiation of hepatocytes and loss of mature functions. Glucose metabolism is tightly regulated in healthy hepatocytes. We hypothesize that AH may lead to metabolic reprogramming of the liver, including dysregulation of glucose metabolism.MethodsWe performed integrated metabolomic and transcriptomic analyses of liver tissue from patients with AH or alcoholic cirrhosis or normal liver tissue from hepatic resection. Focused analyses of chromatin immunoprecipitation coupled to DNA sequencing was performed. Functional in vitro studies were performed in primary rat and human hepatocytes and HepG2 cells.ResultsPatients with AH exhibited specific changes in the levels of intermediates of glycolysis/gluconeogenesis, the tricarboxylic acid cycle, and monosaccharide and disaccharide metabolism. Integrated analysis of the transcriptome and metabolome showed the used of alternate energetic pathways, metabolite sinks and bottlenecks, and dysregulated glucose storage in patients with AH. Among genes involved in glucose metabolism, hexokinase domain containing 1 (HKDC1) was identified as the most up-regulated kinase in patients with AH. Histone active promoter and enhancer markers were increased in the HKDC1 genomic region. High HKDC1 levels were associated with the development of acute kidney injury and decreased survival. Increased HKDC1 activity contributed to the accumulation of glucose-6-P and glycogen in primary rat hepatocytes.ConclusionsAltered metabolite levels and messenger RNA expression of metabolic enzymes suggest the existence of extensive reprogramming of glucose metabolism in AH. Increased HKDC1 expression may contribute to dysregulated glucose metabolism and represents a novel biomarker and therapeutic target for AH.

The specific role of forearm muscles in the development of activities of daily living (ADL) remains unknown. Consequently, studying forearm muscle activity during the most commonly used grasps in ADL would yield valuable insights for hand function evaluation, rehabilitation, and advancements in prosthetic control. In this study, forearm muscle activity was analyzed in 22 healthy subjects, examining seven representative forearm areas during the performance of seven types of grasps at 50% of maximum effort. A Scheirer–Ray–Hare test revealed significant differences for grasp, spot, and their interaction (α < 0.05), but not for repetition (and its interactions). Specific significant differences between grasps were found in specific spots by means of Bonferroni post hoc analyses, ensuring the possibility to discriminate between grasps, which is key to identifying the person’s intention to perform a particular grasp. The median values ranged from 4.4% to 32.8%, depending on the spot and grasp, with small 95% confidence intervals (0.5% to 5.5%). Cylindrical grasp requires the highest muscle activity among all spots, while lateral pinch demands the least. The findings elucidate the contribution, coordination, and function of each muscle in relation to each grasp, with implications for rehabilitation, prosthetics, and telerobotic and teleoperation systems.

Background & Aims: : The accumulation of adipose tissue macrophages (ATMs) in obesity has been associated with hepatic injury. However, the contribution of ATMs to hepatic fibrosis in non-alcoholic fatty liver disease (NAFLD) remains to be elucidated. Herein, we investigate the relationship between ATMs and liver fibrosis in patients with patients with NAFLD and evaluate the impact of modulation of ATMs over hepatic fibrosis in an experimental non-alcoholic steatohepatitis (NASH) model. Methods: Adipose tissue and liver biopsies from 42 patients with NAFLD with different fibrosis stages were collected. ATMs were characterised by immunohistochemistry and flow cytometry and the correlation between ATMs and liver fibrosis stages was assessed. Selective modulation of the ATM phenotype was achieved by i.p. administration of dextran coupled with dexamethasone in diet-induced obesity and NASH murine models. Chronic administration effects were evaluated by histology and gene expression analysis in adipose tissue and liver samples. In vitro crosstalk between human ATMs and hepatic stellate cells (HSCs) and liver spheroids was performed. Results: Patients with NAFLD presented an increased accumulation of pro-inflammatory ATMs that correlated with hepatic fibrosis. Long-term modulation of ATMs significantly reduced pro-inflammatory phenotype and ameliorated adipose tissue inflammation. Moreover, ATMs modulation was associated with an improvement in steatosis and hepatic inflammation and significantly reduced fibrosis progression in an experimental NASH model. In vitro, the reduction of the pro-inflammatory phenotype of human ATMs with dextran–dexamethasone treatment reduced the secretion of inflammatory chemokines and directly attenuated the pro-fibrogenic response in HSCs and liver spheroids. Conclusions: Pro-inflammatory ATMs increase in parallel with fibrosis degree in patients with NAFLD and their modulation in an experimental NASH model improves liver fibrosis, uncovering the potential of ATMs as a therapeutic target to mitigate liver fibrosis in NAFLD. Impact and implications: We report that human adipose tissue pro-inflammatory macrophages correlate with hepatic fibrosis in non-alcoholic fatty liver disease (NAFLD). Furthermore, the modulation of adipose tissue macrophages (ATMs) by dextran-nanocarrier conjugated with dexamethasone shifts the pro-inflammatory phenotype of ATMs to an anti-inflammatory phenotype in an experimental murine model of non-alcoholic steatohepatitis. This shift ameliorates adipose tissue inflammation, hepatic inflammation, and fibrosis. Our results highlight the relevance of adipose tissue in NAFLD pathophysiology and unveil ATMs as a potential target for NAFLD.

The recording of hand kinematics during product manipulation is challenging, and certain degrees of freedom such as distal interphalangeal (DIP) joints are difficult to record owing to limitations of the motion capture systems used. DIP joint kinematics could be estimated by taking advantage of its kinematic linkage with proximal interphalangeal (PIP) and metacarpophalangeal joints. This work analyses this linkage both in free motion conditions and during the performance of 26 activities of daily living. We have studied the appropriateness of different types of linear regressions (several combinations of independent variables and constant coefficients) and sets of data (free motion and manipulation data) to obtain equations to estimate DIP joints kinematics both in free motion and manipulation conditions. Errors that arise when estimating DIP joint angles assuming linear relationships using the equations obtained both from free motion data and from manipulation data are compared for each activity of daily living performed. Estimation using manipulation condition equations implies a lower mean absolute error per task (from 5.87° to 13.67°) than using the free motion ones (from 9° to 17.87°), but it fails to provide accurate estimations when passive extension of DIP joints occurs while PIP is flexed. This work provides evidence showing that estimating DIP joint angles is only recommended when studying free motion or grasps where both joints are highly flexed and when using linear relationships that consider only PIP joint angles.

When studying hand kinematics, it is key to differentiate between free motion and manipulation. This differentiation can be achieved using pressure sensors or through visual analysis in the absence of sensors. Certain data gloves, such as the CyberGlove II, allow recording hand kinematics with good accuracy when properly calibrated. Other gloves, such as the Virtual Motion Glove 30 (VMG30), are also equipped with pressure sensors to detect object contact. The aim of this study is to perform a technical validation to evaluate the feasibility of using virtual reality gloves with pressure sensors such as the VMG30 for hand kinematics characterization during product manipulation, testing its accuracy for motion recording when compared with CyberGlove as well as its ability to differentiate between free motion and manipulation using its pressure sensors in comparison to visual analysis. Firstly, both data gloves were calibrated using a specific protocol developed by the research group. Then, the active ranges of motion of 16 hand joints angles were recorded in three participants using both gloves and compared using repeated measures ANOVAs. The detection capability of pressure sensors was compared to visual analysis in two participants while performing six tasks involving product manipulation. The results revealed that kinematic data recordings from the VMG30 were less accurate than those from the CyberGlove. Furthermore, the pressure sensors did not provide additional precision with respect to the visual analysis technique. In fact, several pressure sensors were rarely activated, and the distribution of pressure sensors within the glove was questioned. Current available gloves such as the VMG30 would require design improvements to fit the requirements for kinematics characterization during product manipulation. The pressure sensors should have higher sensitivity, the pressure sensor’s location should comprise the palm, glove fit should be improved, and its overall stiffness should be reduced.

In-shoe models are required to extend the clinical application of current multisegment kinetic models of the bare foot to study the effect of foot orthoses. Work to date has only addressed marker placement for reliable kinematic analyses. The purpose of this study is to address the difficulties of recording contact forces with available sensors. Ten participants walked 5 times wearing two different types of footwear by stepping on a pressure platform (ground contact forces) while wearing in-shoe pressure sensors (foot sole contact forces). Pressure data were segmented by considering contact cells’ anteroposterior location, and were used to compute 3D moments at foot joints. The mean values and 95% confidence intervals were plotted for each device per shoe condition. The peak values and times of forces and moments were computed per participant and trial under each condition, and were compared using mixed-effect tests. Test–retest reliability was analyzed by means of intraclass correlation coefficients. The curve profiles from both devices were similar, with higher joint moments for the instrumented insoles at the metatarsophalangeal joint (~26%), which were lower at the ankle (~8%) and midtarsal (~15%) joints, although the differences were nonsignificant. Not considering frictional forces resulted in ~20% lower peaks at the ankle moments compared to previous studies, which employed force plates. The device affected both shoe conditions in the same way, which suggests the interchangeability of measuring joint moments with one or the other device. This hypothesis was reinforced by the intraclass correlation coefficients, which were higher for the peak values, although only moderate-to-good. In short, both considered alternatives have drawbacks. Only the instrumented in-soles provided direct information about foot contact forces, but it was incomplete (evidenced by the difference in ankle moments between devices). However, recording ground reaction forces offers the advantage of enabling the consideration of contact friction forces (using force plates in series, or combining a pressure platform and a force plate to estimate friction forces and torque), which are less invasive than instrumented insoles (which may affect subjects’ gait).

Intrahepatic neutrophil infiltration has been implicated in severe alcoholic hepatitis (SAH) pathogenesis; however, the mechanism underlying neutrophil-induced injury in SAH remains obscure. This translational study aims to describe the patterns of intrahepatic neutrophil infiltration and its involvement in SAH pathogenesis. Immunohistochemistry analyses of explanted livers identified two SAH phenotypes despite a similar clinical presentation, one with high intrahepatic neutrophils (Neuhi), but low levels of CD8+ T cells, and vice versa. RNA-Seq analyses demonstrated that neutrophil cytosolic factor 1 (NCF1), a key factor in controlling neutrophilic ROS production, was upregulated and correlated with hepatic inflammation and disease progression. To study specifically the mechanisms related to Neuhi in AH patients and liver injury, we used the mouse model of chronic-plus-binge ethanol feeding and found that myeloid-specific deletion of the Ncf1 gene abolished ethanol-induced hepatic inflammation and steatosis. RNA-Seq analysis and the data from experimental models revealed that neutrophilic NCF1-dependent ROS promoted alcoholic hepatitis (AH) by inhibiting AMP-activated protein kinase (a key regulator of lipid metabolism) and microRNA-223 (a key antiinflammatory and antifibrotic microRNA). In conclusion, two distinct histopathological phenotypes based on liver immune phenotyping are observed in SAH patients, suggesting a separate mechanism driving liver injury and/or failure in these patients.

Background & Aims: The molecular mechanisms driving the progression from early-chronic liver disease (CLD) to cirrhosis and, finally, acute-on-chronic liver failure (ACLF) are largely unknown. Our aim was to develop a protein network-based approach to investigate molecular pathways driving progression from early-CLD to ACLF. Methods: Transcriptome analysis was performed on liver biopsies from patients at different liver disease stages, including fibrosis, compensated cirrhosis, decompensated cirrhosis and ACLF, and control healthy livers. We created 9 liver-specific disease-related protein-protein interaction networks capturing key pathophysiological processes potentially related to CLD. We used these networks as a framework and performed gene set-enrichment analysis (GSEA) to identify dynamic gene profiles of disease progression. Results: Principal component analyses revealed that samples clustered according to the disease stage. GSEA of the defined processes showed an upregulation of inflammation, fibrosis and apoptosis networks throughout disease progression. Interestingly, we did not find significant gene expression differences between compensated and decompensated cirrhosis, while ACLF showed acute expression changes in all the defined liver disease-related networks. The analyses of disease progression patterns identified ascending and descending expression profiles associated with ACLF onset. Functional analyses showed that ascending profiles were associated with inflammation, fibrosis, apoptosis, senescence and carcinogenesis networks, while descending profiles were mainly related to oxidative stress and genetic factors. We confirmed by qPCR the upregulation of genes of the ascending profile and validated our findings in an independent patient cohort. Conclusion: ACLF is characterized by a specific hepatic gene expression pattern related to inflammation, fibrosis, apoptosis, senescence and carcinogenesis. Moreover, the observed profile is significantly different from that of compensated and decompensated cirrhosis, supporting the hypothesis that ACLF should be considered a distinct entity. Lay summary: By using transjugular biopsies obtained from patients at different stages of chronic liver disease, we unveil the molecular pathogenic mechanisms implicated in the progression of chronic liver disease to cirrhosis and acute-on-chronic liver failure. The most relevant finding in this study is that patients with acute-on-chronic liver failure present a specific hepatic gene expression pattern distinct from that of patients at earlier disease stages. This gene expression pattern is mostly related to inflammation, fibrosis, angiogenesis, and senescence and apoptosis pathways in the liver.

Alcoholic hepatitis (AH) is the most severe form of alcoholic liver disease for which there are no effective therapies. Patients with AH show impaired hepatocyte proliferation, expansion of inefficient ductular cells and high lipopolysaccharide (LPS) levels. It is unknown whether LPS mediates ductular cell expansion. We performed transcriptome studies and identified keratin 23 (KRT23) as a new ductular cell marker. KRT23 expression correlated with mortality and LPS serum levels. LPS-TLR4 pathway role in ductular cell expansion was assessed in human and mouse progenitor cells, liver slices and liver injured TLR4 KO mice. In AH patients, ductular cell expansion correlated with portal hypertension and collagen expression. Functional studies in ductular cells showed that KRT23 regulates collagen expression. These results support a role for LPS-TLR4 pathway in promoting ductular reaction in AH. Maneuvers aimed at decreasing LPS serum levels in AH patients could have beneficial effects by preventing ductular reaction development.

The early and objective detection of hand pathologies is a field that still requires more research. One of the main signs of hand osteoarthritis (HOA) is joint degeneration, which causes loss of strength, among other symptoms. HOA is usually diagnosed with imaging and radiography, but the disease is in an advanced stage when HOA is observable by these methods. Some authors suggest that muscle tissue changes seem to occur before joint degeneration. We propose recording muscular activity to look for indicators of these changes that might help in early diagnosis. Muscular activity is often measured using electromyography (EMG), which consists of recording electrical muscle activity. The aim of this study is to study whether different EMG characteristics (zero crossing, wavelength, mean absolute value, muscle activity) via collection of forearm and hand EMG signals are feasible alternatives to the existing methods of detecting HOA patients’ hand function. We used surface EMG to measure the electrical activity of the dominant hand’s forearm muscles with 22 healthy subjects and 20 HOA patients performing maximum force during six representative grasp types (the most commonly used in ADLs). The EMG characteristics were used to identify discriminant functions to detect HOA. The results show that forearm muscles are significantly affected by HOA in EMG terms, with very high success rates (between 93.3% and 100%) in the discriminant analyses, which suggest that EMG can be used as a preliminary step towards confirmation with current HOA diagnostic techniques. Digit flexors during cylindrical grasp, thumb muscles during oblique palmar grasp, and wrist extensors and radial deviators during the intermediate power–precision grasp are good candidates to help detect HOA.

Alcoholic hepatitis, a common cause of liver failure, lacks effective treatment. Here, the authors show altered hepatic HNF4a isoform expression and hypermethylation of its target genes in patients. HNF4a dysregulation is improved in vitro by TGFb or PPARg modulation suggesting potential therapeutic avenues.

Background: Chronic hepatic inflammation leads to liver fibrosis, which may progress to cirrhosis, a condition with high morbidity. Our aim was to assess the as yet unknown role of innate immunity protein CD5L in liver fibrosis. Methods: CD5L was measured by ELISA in plasma samples from cirrhotic (n = 63) and hepatitis (n = 39) patients, and healthy controls (n = 7), by immunohistochemistry in cirrhotic tissue (n = 12), and by quantitative RT-PCR in mouse liver cell subsets isolated by cell sorting. Recombinant CD5L (rCD5L) was administered into a murine model of CCl4-induced fibrosis, and damage, fibrosis and hepatic immune cell infiltration, including the LyC6hi (pro-fibrotic)-LyC6low (pro-resolutive) monocyte ratio were determined. Moreover, rCD5L was added into primary human hepatic stellate cells to study transforming growth factor β (TGFβ) activation responses. Findings: Cirrhotic patients showed elevated plasma CD5L concentrations as compared to patients with hepatitis and healthy controls (Mann-Whitney test p

Introduction and aims. Alcoholic hepatitis is the most severe manifestation of alcoholic liver disease. Unfortunately, there are still some unresolved issues in the diagnosis and management of this disease, such as the need of histological diagnosis, an accurate prognostic stratification, and the development of novel targeted therapies. The present study aimed at addressing these issues by means of metabolomics, a novel high-throughput approach useful in other liver diseases.Material and methods. 64 patients with biopsy-proven alcoholic hepatitis were included and compared with 26 patients with decompensated alcoholic cirrhosis without superimposed alcoholic hepatitis, which was ruled out by liver biopsy.Results. The comparison of the metabolic profiles of patients with alcoholic hepatitis and decompensated cirrhosis showed marked differences between both groups. Importantly, metabolic differences were found among alcoholic hepatitis patients when subjects were stratified according to 90-day survival. Based on these findings, two non-invasive signatures were developed. The first one allowed an accurate non-invasive diagnosis of alcoholic hepatitis (AUROC 0.932; 95% CI 0.901-0.963). The second signature showed a good performance in the prognostic stratification of patients with alcoholic hepatitis (AUROC 0.963; 95% CI 0.895-1.000).Conclusions. Signatures based on metabolomics allowed an accurate non-invasive diagnosis and prognostic stratification of alcoholic hepatitis. The differences observed in the metabolic profile of the patients according to the presence and severity of alcoholic hepatitis are related with different mechanisms involved in the pathophysiology of alcoholic hepatitis such as peroxisomal activity, synthesis of inflammatory mediators or oxidation. This information could be useful for the development of novel targeted therapies.

Background & Aims: MicroRNAs (miRNAs) circulate in several body fluids and can be useful biomarkers. The aim of this study was to identify blood-circulating miRNAs associated with cirrhosis progression and acute-on-chronic liver failure (ACLF). Methods: Using high-throughput screening of 754 miRNAs, serum samples from 45 patients with compensated cirrhosis, decompensated cirrhosis, or ACLF were compared with those from healthy individuals (n = 15). miRNA levels were correlated with clinical parameters, organ failure, and disease progression and outcome. Dysregulated miRNAs were evaluated in portal and hepatic vein samples (n = 33), liver tissues (n = 17), and peripheral blood mononuclear cells (PBMCs) (n = 16). Results: miRNA screening analysis revealed that circulating miRNAs are dysregulated in cirrhosis progression, with 51 miRNAs being differentially expressed among all groups of patients. Unsupervised clustering and principal component analysis indicated that the main differences in miRNA expression occurred at decompensation, showing similar levels in patients with decompensated cirrhosis and those with ACLF. Of 43 selected miRNAs examined for differences among groups, 10 were differentially expressed according to disease progression. Moreover, 20 circulating miRNAs were correlated with model for end-stage liver disease and Child-Pugh scores. Notably, 11 dysregulated miRNAs were associated with kidney or liver failure, encephalopathy, bacterial infection, and poor outcomes. The most severely dysregulated miRNAs (i.e. miR-146a-5p, miR-26a-5p, and miR-191-5p) were further evaluated in portal and hepatic vein blood and liver tissue, but showed no differences. However, PBMCs from patients with cirrhosis showed significant downregulation of miR-26 and miR-146a, suggesting a extrahepatic origin of some circulating miRNAs. Conclusions: This study is a repository of circulating miRNA data following cirrhosis progression and ACLF. Circulating miRNAs were profoundly dysregulated during the progression of chronic liver disease, were associated with failure of several organs and could have prognostic utility. Lay summary: Circulating miRNAs are small molecules in the blood that can be used to identify or predict a clinical condition. Our study aimed to identify miRNAs for use as biomarkers in patients with cirrhosis or acute-on-chronic liver failure. Several miRNAs were found to be dysregulated during the progression of disease, and some were also related to organ failure and disease-related outcomes.

Hepatocellular death contributes to progression of alcohol–associated (ALD-associated) and non–alcohol-associated (NAFL/NASH) liver diseases. However, receptor-interaction protein kinase 3 (RIP3), an intermediate in necroptotic cell death, contributes to injury in murine models of ALD but not NAFL/NASH. We show here that a differential role for mixed-lineage kinase domain–like protein (MLKL), the downstream effector of RIP3, in murine models of ALD versus NAFL/NASH and that RIP1-RIP3-MLKL can be used as biomarkers to distinguish alcohol-associated hepatitis (AH) from NASH. Phospho-MLKL was higher in livers of patients with NASH compared with AH or healthy controls (HCs). MLKL expression, phosphorylation, oligomerization, and translocation to plasma membrane were induced in WT mice fed diets high in fat, fructose, and cholesterol but not in response to Gao-binge (acute on chronic) ethanol exposure. Mlkl–/– mice were not protected from ethanol-induced hepatocellular injury, which was associated with increased expression of chemokines and neutrophil recruitment. Circulating concentrations of RIP1 and RIP3, but not MLKL, distinguished patients with AH from HCs or patients with NASH. Taken together, these data indicate that MLKL is differentially activated in ALD/AH compared with NAFL/NASH in both murine models and patients. Furthermore, plasma RIP1 and RIP3 may be promising biomarkers for distinguishing AH and NASH.

Data gloves with strain gauges are a widely used technology to record hand kinematics. Several researchers have experienced problems when using data glove models to record distal interphalangeal (DIP) joints, mainly in relation to bad glove fitting. The aim of this work is to report the problems that arise when using one of these gloves (CyberGlove) and to determine an appropriate hand size to avoid these problems. First, static controlled postures of DIP joints and dynamic recordings while closing/opening the fist were taken using the data gloves on participants with different hand sizes, in order to establish the minimum hand length that does not pose recording problems. The minimum obtained hand length that allowed proper recording was 184 mm. Then, validation was performed, which consisted of recording the functional range of motion of the DIP joints in a sample of eight healthy participants with hand lengths longer than the minimum obtained one. These results were then compared to the results found in the literature. Although the glove fit properly, some problems remained: difficulty to record small flexion angles or a diminished touch sensitivity. Its usability would improve if two or three different glove sizes were commercially available.

Abstract Background A deeper knowledge of the activity of the forearm muscles during activities of daily living (ADL) could help to better understand the role of those muscles and allow clinicians to treat motor dysfunctions more effectively and thus improve patients’ ability to perform activities of daily living. Methods In this work, we recorded sEMG activity from 30 spots distributed over the skin of the whole forearm of six subjects during the performance of 21 representative simulated ADL from the Sollerman Hand Function Test. Functional principal component analysis and hierarchical cluster analysis (HCA) were used to identify forearm spots with similar muscle activation patterns. Results The best classification of spots with similar activity in simulated ADL consisted in seven muscular-anatomically coherent groups: (1) wrist flexion and ulnar deviation; (2) wrist flexion and radial deviation; (3) digit flexion; (4) thumb extension and abduction/adduction; (5) finger extension; (6) wrist extension and ulnar deviation; and (7) wrist extension and radial deviation. Conclusion The number of sEMG sensors could be reduced from 30 to 7 without losing any relevant information, using them as representative spots of the muscular activity of the forearm in simulated ADL. This may help to assess muscle function in rehabilitation while also simplifying the complexity of prosthesis control.

Sensorized gloves allow the measurement of all hand kinematics that are essential for daily functionality. However, they are scarcely used by clinicians, mainly because of the difficulty of analyzing all joint angles simultaneously. This study aims to render this analysis easier in order to enable the applicability of the early detection of hand osteoarthritis (HOA) and the identification of indicators of dysfunction. Dimensional reduction was used to compare kinematics (16 angles) of HOA patients and healthy subjects while performing the tasks of the Sollerman hand function test (SHFT). Five synergies were identified by using principal component (PC) analyses, patients using less fingers arch, higher palm arching, and a more independent thumb abduction. The healthy PCs, explaining 70% of patients’ data variance, were used to transform the set of angles of both samples into five reduced variables (RVs): fingers arch, hand closure, thumb-index pinch, forced thumb opposition, and palmar arching. Significant differences between samples were identified in the ranges of movement of most of the RVs and in the median values of hand closure and thumb opposition. A discriminant function for the detection of HOA, based in RVs, is provided, with a success rate of detection higher than that of the SHFT. The temporal profiles of the RVs in two tasks were also compared, showing their potentiality as dysfunction indicators. Finally, reducing the number of sensors to only one sensor per synergy was explored through a linear regression, resulting in a mean error of 7.0°.

Abstract Fatty-acid-binding proteins (FABPs) are small intracellular proteins that coordinate lipid-mediated processes by targeting metabolic and immune response pathways. The aim of the study was to investigate plasma FABPs levels and their relationship with clinical outcomes in cirrhosis. Plasma levels of L-FABP1(liver and kidney), I-FABP2(intestine), and A-FABP4(adipocyte and macrophages) were measured in 274 patients with decompensated cirrhosis. Hepatic gene expression of FABPs was assessed in liver biopsies from patients with decompensated cirrhosis and in liver cell types from mice with cirrhosis. Immunohistochemistry of A-FABP4 in human liver biopsy was also performed. Plasma levels of FABPs were increased in patients with decompensated cirrhosis compared to those of healthy subjects (L-FABP1: 25 (17–39) vs 10 (9–17) ng/mL p = 0.001, I-FABP2: 1.1 (0.5–2.1) vs 0.6 (0.4–1) ng/mL p = 0.04 and A-FABP4: 37 (20–68) vs 16 (11–33) ng/mL p = 0.002), respectively. Increased A-FABP4 levels were associated with complications of cirrhosis, acute-on-chronic liver failure and poor survival. Hepatic A-FABP4 gene expression was upregulated in decompensated cirrhosis. Macrophages were the main liver cell that over-expressed A-FABP4 in experimental cirrhosis and increased A-FABP4 was found in macrophages of human biopsies by immunohistochemistry. A-FABP4 levels are increased in decompensated cirrhosis and correlate with poor outcomes. Liver macrophages appear to be the main source of A-FABP4 in decompensated cirrhosis.

Assistive devices (ADs) are products intended to overcome the difficulties produced by the reduction in mobility and grip strength entailed by ageing and different pathologies. Nevertheless, there is little information about the effect that the use of these devices produces on hand kinematics. Thus, the aim of this work is to quantify this effect through the comparison of kinematic parameters (mean posture, ROM, median velocity and peak velocity) while performing activities of daily living (ADL) using normal products and ADs. Twelve healthy right-handed subjects performed 11 ADL with normal products and with 17 ADs wearing an instrumented glove on their right hand, 16 joint angles being recorded. ADs significantly affected hand kinematics, although the joints affected differed according to the AD. Furthermore, some pattern effects were identified depending on the characteristics of the handle of the ADs, namely, handle thickening, addition of a handle to products that initially did not have one, extension of existing handles or addition of handles to apply higher torques. An overview of the effects of these design characteristics on hand kinematics is presented as a basis for the selection of the most suitable AD depending on the patient’s impairments.

Thumb opposition is essential for grasping, and involves the flexion and abduction of the carpometacarpal and metacarpophalangeal joints of the thumb. The high number of degrees of freedom of the thumb in a fairly small space makes the in vivo recording of its kinematics a challenging task. For this reason, along with the very limited independence of the abduction movement of the metacarpophalangeal joint, many devices do not implement sensors to measure such movement, which may lead to important implications in terms of the accuracy of thumb models. The aims of this work are to examine the correlation between thumb joints and to obtain an equation that allows thumb metacarpophalangeal abduction/adduction movement to be estimated from the other joint motions of the thumb, during the commonest grasps used during activities of daily living and in free movement. The correlation analysis shows that metacarpophalangeal abduction/adduction movement can be expressed mainly from carpometacarpal joint movements. The model thus obtained presents a low estimation error (6.29°), with no significant differences between grasps. The results could benefit most fields that do not typically include this joint movement, such as virtual reality, teleoperation, 3D modeling, prostheses, and exoskeletons.

The role of the hand is crucial for the performance of activities of daily living, thereby ensuring a full and autonomous life. Its motion is controlled by a complex musculoskeletal system of approximately 38 muscles. Therefore, measuring and interpreting the muscle activation signals that drive hand motion is of great importance in many scientific domains, such as neuroscience, rehabilitation, physiotherapy, robotics, prosthetics, and biomechanics. Electromyography (EMG) can be used to carry out the neuromuscular characterization, but it is cumbersome because of the complexity of the musculoskeletal system of the forearm and hand. This paper reviews the main studies in which EMG has been applied to characterize the muscle activity of the forearm and hand during activities of daily living, with special attention to muscle synergies, which are thought to be used by the nervous system to simplify the control of the numerous muscles by actuating them in task-relevant subgroups. The state of the art of the current results are presented, which may help to guide and foster progress in many scientific domains. Furthermore, the most important challenges and open issues are identified in order to achieve a better understanding of human hand behavior, improve rehabilitation protocols, more intuitive control of prostheses, and more realistic biomechanical models.

Simultaneous measurement of the kinematics of all hand segments is cumbersome due to sensor placement constraints, occlusions, and environmental disturbances. The aim of this study is to reduce the number of sensors required by using kinematic synergies, which are considered the basic building blocks underlying hand motions. Synergies were identified from the public KIN-MUS UJI database (22 subjects, 26 representative daily activities). Ten synergies per subject were extracted as the principal components explaining at least 95% of the total variance of the angles recorded across all tasks. The 220 resulting synergies were clustered, and candidate angles for estimating the remaining angles were obtained from these groups. Different combinations of candidates were tested and the one providing the lowest error was selected, its goodness being evaluated against kinematic data from another dataset (KINE-ADL BE-UJI). Consequently, the original 16 joint angles were reduced to eight: carpometacarpal flexion and abduction of thumb, metacarpophalangeal and interphalangeal flexion of thumb, proximal interphalangeal flexion of index and ring fingers, metacarpophalangeal flexion of ring finger, and palmar arch. Average estimation errors across joints were below 10% of the range of motion of each joint angle for all the activities. Across activities, errors ranged between 3.1% and 16.8%.