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Systemic sclerosis (SSc) is a connective tissue disorder characterized by microvascular injury, extracellular matrix deposition, autoimmunity, inflammation, and fibrosis. The clinical complexity and high heterogeneity of the disease make the discovery of potential therapeutic targets difficult. However, the recent progress in the comprehension of its pathogenesis is encouraging. Growth Arrest-Specific 6 (Gas6) and Tyro3, Axl, and MerTK (TAM) receptors are involved in multiple biological processes, including modulation of the immune response, phagocytosis, apoptosis, fibrosis, inflammation, cancer development, and autoimmune disorders. In the present manuscript, we review the current evidence regarding SSc pathogenesis and the role of the Gas6/TAM system in several human diseases, suggesting its likely contribution in SSc and highlighting areas where further research is necessary to fully comprehend the role of TAM receptors in this condition. Indeed, understanding the involvement of TAM receptors in SSc, which is currently unknown, could provide valuable insights for novel potential therapeutic targets.

Hepatitis C virus (HCV) infection is a significant risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). Traditionally, the primary prevention strategy for HCV-associated HCC has focused on removing infection through antiviral regimes. Currently, highly effective direct-acting antivirals (DAAs) offer extraordinary success across all patient categories, including cirrhotics. Despite these advancements, recent studies have reported that even after sustained virologic response (SVR), individuals with advanced liver disease/cirrhosis at the time of DAA treatment may still face risks of HCC occurrence or recurrence. Based on this premise, this review tries to shed light on the multiple mechanisms that establish a tumorigenic environment, first, during chronic HCV infection and then, after eventual viral eradication by DAAs. Furthermore, it reviews evidence reported by recent observational studies stating that the use of DAAs is not associated with an increased risk of HCC development but rather, with a significantly lower chance of liver cancer compared with DAA-untreated patients. In addition, it seeks to provide some practical guidance for clinicians, helping them to manage HCC surveillance of patients who have achieved SVR with DAAs.

BackgroundA sex-based evaluation of prognosis in heart failure (HF) is lacking.Methods and resultsWe analyzed the Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score registry, which includes HF with reduced ejection fraction (HFrEF) patients. A cross-validation procedure was performed to estimate weights separately for men and women of all MECKI score parameters: left ventricular ejection fraction (LVEF), hemoglobin, kidney function assessed by Modification of Diet in Renal Disease, blood sodium level, ventilation vs. carbon dioxide production slope, and peak oxygen consumption (peakVO2). The primary outcomes were the composite of all-cause mortality, urgent heart transplant, and implant of a left ventricle assist device. The difference in predictive ability between the native and sex recalibrated MECKI (S-MECKI) was calculated using a receiver operating characteristic (ROC) curve at 2 years and a calibration plot. We retrospectively analyzed 7,900 HFrEF patients included in the MECKI score registry (mean age 61 ± 13 years, 6,456 men/1,444 women, mean LVEF 33% ± 10%, mean peakVO2 56.2% ± 17.6% of predicted) with a median follow-up of 4.05 years (range 1.72–7.47). Our results revealed an unadjusted risk of events that was doubled in men compared to women (9.7 vs. 4.1) and a significant difference in weight between the sexes of most of the parameters included in the MECKI score. S-MECKI showed improved risk classification and accuracy (area under the ROC curve: 0.7893 vs. 0.7799, p = 0.02) due to prognostication improvement in the high-risk settings in both sexes (MECKI score >10 in men and >5 in women).ConclusionsS-MECKI, i.e., the recalibrated MECKI according to sex-specific differences, constitutes a further step in the prognostic assessment of patients with severe HFrEF.

Context: Sport-related dystonia is a rare form of activity-specific dystonia that can severely impair an athlete's ability to perform. Due to a lack of data on the condition, it is difficult to diagnose and often overlooked, and no gold standard treatment has yet been defined. Case Presentation: We present a rare and challenging case of sport-related dystonia that affected a 24-year-old male professional soccer player. The patient presented with severe rigidity and dystonia of the right lower-extremity, particularly the ankle and foot. The symptoms set on >1 year prior to the presentation to our outpatient clinic. He began to complain of stiffness and difficulty moving his lower limbs, especially his right leg, initially when playing soccer, but then also when walking normally. On presentation, he was unable to run and walked with difficulty, supporting his body weight only on the outside of his right foot. He also reported a motor trick and reverse motor trick involving the oral musculature in order to move his lower limb more freely. Management and Outcomes: An integrated rehabilitation approach based on postural rehabilitation, neuromuscular rehabilitation, and dental intervention was used to successfully treat this condition. The approach included: (1) postural rehabilitation with the Mézières-Bertelè method to reduce muscular stiffness, (2) neuromuscular re-education with Tai Chi exercises and electromyography-guided biofeedback, and (3) dental intervention and swallowing rehabilitation to limit impaired oral habits (due to the relationship between his impaired lower limb movements and motor tricks of the oral musculature). After 7 months of integrated rehabilitation, the patient returned to professional soccer. Conclusions: This case report highlights the potential efficacy of an integrative rehabilitation approach for sports dystonia, particularly in cases where traditional treatments may not be effective. Such an approach could be considered a valuable option in the management of this rare, but debilitating, condition in athletes. Further research is needed to assess the effectiveness of this approach in larger populations. [ABSTRACT FROM AUTHOR]

IntroductionThe protein growth arrest-specific 6 (Gas6) and its tyrosine kinase receptors Tyro-3, Axl, and Mer (TAM) are ubiquitous proteins involved in regulating inflammation and apoptotic body clearance. Multiple sclerosis (MS) is the most common inflammatory demyelinating disease of the central nervous system leading to progressive and irreversible disability if not diagnosed and treated promptly. Gas6 and TAM receptors have been associated with neuronal remyelination and stimulation of oligodendrocyte survival. However, few data are available regarding clinical correlation in MS patients. We aimed to evaluate soluble levels of these molecules in the cerebrospinal fluid (CSF) and serum at MS diagnosis and correlate them with short-term disease severity.MethodsIn a prospective cohort study, we enrolled 64 patients with a diagnosis of clinical isolated syndrome (CIS), radiological isolated syndrome (RIS) and relapsing–remitting (RR) MS according to the McDonald 2017 Criteria. Before any treatment initiation, we sampled the serum and CSF, and collected clinical data: disease course, presence of gadolinium-enhancing lesions, and expanded disability status score (EDSS). At the last clinical follow-up, we assessed EDSS and calculated MS severity score (MSSS) and age-related MS severity (ARMSS). Gas6 and TAM receptors were determined using an ELISA kit (R&D Systems) and compared to neurofilament (NFLs) levels evaluated with SimplePlex™ fluorescence-based immunoassay.ResultsAt diagnosis, serum sAxl was higher in patients receiving none or low-efficacy disease-modifying treatments (DMTs) versus patients with high-efficacy DMTs (p = 0.04). Higher CSF Gas6 and serum sAXL were associated with an EDSS

Metabolic dysfunction-associated steatohepatitis (MASH) is the replacement term for what used to be called nonalcoholic steatohepatitis (NASH). It is characterized by inflammation and injury of the liver in the presence of cardiometabolic risk factors and may eventually result in the development of hepatocellular carcinoma (HCC), the most common form of primary liver cancer. Several pathogenic mechanisms are involved in the transition from MASH to HCC, encompassing metabolic injury, inflammation, immune dysregulation and fibrosis. In this context, Gas6 (Growth Arrest-Specific 6) and TAM (Tyro3, Axl, and MerTK) receptors may play important roles. The Gas6/TAM family is involved in the modulation of inflammation, lipid metabolism, fibrosis, tumor progression and metastasis, processes which play an important role in the pathophysiology of acute and chronic liver diseases. In this review, we discuss MASH-associated HCC and the potential involvement of the Gas6/TAM system in disease development and progression. In addition, since therapeutic strategies for MASH and HCC are limited, we also speculate regarding possible future treatments involving the targeting of Gas6 or TAM receptors.

BackgroundA large number of workers attend work despite being ill. Attending work during sickness can have a number of consequences for the worker (e.g., worsening of physical and mental condition), for co-workers, and for the company, and for service users.ObjectivesThe aim of this study was to assess the factors influencing presenteeism and mental health of workers during the COVID-19 pandemic.MethodsA systematic review following the PRISMA format was conducted in the PubMed, Scopus, Web of Science (WoS), Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycInfo, and ScienceDirect electronic databases in January 2023, using the following key words: Presenteeism, Mental Health, and COVID-19. The eligibility criteria applied were original articles published in English, Spanish, French, German, and Portuguese, workers during the COVID-19 pandemic (data collection date: January 01, 2020 – January 01, 2023), and articles assessing at least one measure of presenteeism and mental health status. Methodological quality was assessed using the critical appraisal tools of the Joanna Briggs Institute. The followed protocol is listed in the International Prospective Register of Systematic Reviews (PROSPERO) with code CRD42023391409.ResultsA total of 25 studies were included in this review recruiting a total of 164,274 participants. A number of factors influencing mental health and sickness presenteeism were identified: (1) mental health-related factors (burnout [in 4 studies], stress [in 9 studies], depression [in 1 study], fear of COVID-19 [in 1 study], no well-being [in 2 studies], etc.); (2) individual factors (health status [in 1 study], being young [in 1 study], workers who experienced interrupted medical care [in 2 studies], having a chronic disease [in 1 study], etc.); (3) factors related to the situation caused by COVID-19 (confinement, symptoms, loss of contract, risk of bankruptcy, etc. [in 1 study each one]); and (4) factors derived from working conditions (organisational support [in 1 study], patient care [in 1 study], work functioning or task performance impairment [in 4 studies], work fatigue [in 2 studies], safety climate [in 1 study], workload [in 1 study], etc.).ConclusionIdentifying the key determinants of presenteeism and understanding the phenomena and origins of sickness presenteeism will help to create a safe working environment and optimal organisational systems to protect vulnerable workers in a pandemic context.Systematic review registrationThe unique identifier is CRD42023391409.

Hepatitis C virus (HCV) infection is a significant risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). Traditionally, the primary prevention strategy for HCV-associated HCC has focused on removing infection through antiviral regimes. Currently, highly effective direct-acting antivirals (DAAs) offer extraordinary success across all patient categories, including cirrhotics. Despite these advancements, recent studies have reported that even after sustained virologic response (SVR), individuals with advanced liver disease/cirrhosis at the time of DAA treatment may still face risks of HCC occurrence or recurrence. Based on this premise, this review tries to shed light on the multiple mechanisms that establish a tumorigenic environment, first, during chronic HCV infection and then, after eventual viral eradication by DAAs. Furthermore, it reviews evidence reported by recent observational studies stating that the use of DAAs is not associated with an increased risk of HCC development but rather, with a significantly lower chance of liver cancer compared with DAA-untreated patients. In addition, it seeks to provide some practical guidance for clinicians, helping them to manage HCC surveillance of patients who have achieved SVR with DAAs. [ABSTRACT FROM AUTHOR]

Maddalena Illario,1– 3 Vincenzo De Luca,1 Gabrielle Onorato,2 Giovanni Tramontano,2,3 Ana Maria Carriazo,2,4 Regina Elisabeth Roller-Wirnsberger,5 Joao Apostolo,6 Patrik Eklund,7 Nandu Goswami,8 Guido Iaccarino,9 Maria Triassi,1 John Farrell,2 Jean Bousquet2,10 1Dipartimento di Sanità Pubblica, Università degli Studi di Napoli Federico II, Naples, Italy; 2Executive Board, EIP on AHA Reference Sites Collaborative Network, Brussels, Belgium; 3Research & Development Unit, Azienda Ospedaliera Universitaria Federico II, Naples, Italy; 4Deputy Regional Ministry, Regional Ministry of Health and Families of Andalusia, Seville, Spain; 5Department of Internal Medicine, Medical University of Graz, Graz, Austria; 6Health and Care Sciences Research Unit, Escola Superior de Enfermagem de Coimbra, Coimbra, Portugal; 7Department of Computing Science, Umeå University, Umeå, Sweden; 8Division of Physiology, Medical University of Graz, Graz, Austria; 9Dipartimento di Scienze Biomediche Avanzate, Università degli Studi di Napoli Federico II, Naples, Italy; 10MACVIA-France, Fondation partenariale FMC VIA-LR, Montpellier, FranceCorrespondence: Maddalena Illario, Dipartimento di Sanità Pubblica, Università degli Studi di Napoli Federico II, Via Sergio Pansini n.5, Naples, 80131, Italy, Tel +39 0817464211, Fax +39 0817464212, Email illario@unina.it Nandu Goswami, Division of Physiology, Medical University of Graz, Neue Stiftingtalstraße 6, Graz, 8010, Austria, Tel +43 31638573852, Fax +43 31638579005, Email nandu.goswami@medunigraz.atAbstract: The article describes some of the achievements of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA), after eight years in operation. These results were achieved thanks to the collaborative work of the action groups (AGs) and reference sites (RSs). RS regional ecosystems include key organisations committed to investing in innovation to foster active and healthy ageing. The AGs are groups of professionals committed to sharing their knowledge and skills in active and healthy ageing. This article reports on the approach used by the EIP on AHA to bring together experts and regions in identifying and addressing these challenges. Synergies between AGs offered substantial support to RSs, allowing regional health and care priorities and challenges to be identified and pursued through AG commitments. Building upon the experiences of the EIP on AHA, the Reference Sites Collaborative Network has set up a number of thematic action groups that bring together multidisciplinary experts from across Europe to address the main health and social care challenges at regional, national and European level.Keywords: active and healthy ageing, digital health, health policy, health innovation

RationaleFactors associated with long-term sequelae emerging after the acute phase of COVID-19 (so called “long COVID”) are unclear. Here, we aimed to identify risk factors for the development of COVID-19 sequelae in a prospective cohort of subjects hospitalized for SARS-CoV-2 infection and followed up one year after discharge.MethodsA total of 324 subjects underwent a comprehensive and multidisciplinary evaluation one year after hospital discharge for COVID-19. A subgroup of 247/324 who consented to donate a blood sample were tested for a panel of circulating cytokines.ResultsIn 122 patients (37.8%) there was evidence of at least one persisting physical symptom. After correcting for comorbidities and COVID-19 severity, the risk of developing long COVID was lower in the 109 subjects admitted to the hospital in the third wave of the pandemic than in the 215 admitted during the first wave, (OR 0.69, 95%CI 0.51-0.93, p=0.01). Univariable analysis revealed female sex, diffusing capacity of the lungs for carbon monoxide (DLCO) value, body mass index, anxiety and depressive symptoms to be positively associated with COVID-19 sequelae at 1 year. Following logistic regression analysis, DLCO was the only independent predictor of residual symptoms (OR 0.98 CI 95% (0.96-0.99), p=0.01). In the subgroup of subjects with normal DLCO (> 80%), for whom residual lung damage was an unlikely explanation for long COVID, the presence of anxiety and depressive symptoms was significantly associated to persistent symptoms, together with increased levels of a set of pro-inflammatory cytokines: interferon-gamma, tumor necrosis factor-alpha, interleukin (IL)-2, IL-12, IL-1β, IL-17. In logistic regression analysis, depressive symptoms (p=0.02, OR 4.57 [1.21-17.21]) and IL-12 levels (p=0.03, OR 1.06 [1.00-1.11]) 1-year after hospital discharge were independently associated with persistence of symptoms.ConclusionsLong COVID appears mainly related to respiratory sequelae, prevalently observed during the first pandemic wave. Among patients with little or no residual lung damage, a cytokine pattern consistent with systemic inflammation is in place.

The tyrosine kinase receptors of the TAM family—Tyro3, Axl and Mer—and their main ligand Gas6 (growth arrest-specific 6) have been implicated in several human diseases, having a particularly important role in the regulation of innate immunity and inflammatory response. The Gas6/TAM system is involved in the recognition of apoptotic debris by immune cells and this mechanism has been exploited by viruses for cell entry and infection. Coronavirus disease 2019 (COVID-19) is a multi-systemic disease, but the lungs are particularly affected during the acute phase and some patients may suffer persistent lung damage. Among the manifestations of the disease, fibrotic abnormalities have been observed among the survivors of COVID-19. The mechanisms of COVID-related fibrosis remain elusive, even though some parallels may be drawn with other fibrotic diseases, such as idiopathic pulmonary fibrosis. Due to the still limited number of scientific studies addressing this question, in this review we aimed to integrate the current knowledge of the Gas6/TAM axis with the pathophysiological mechanisms underlying COVID-19, with emphasis on the development of a fibrotic phenotype.

Abstract Aims Ventilation vs. carbon dioxide production (VE/VCO2) is among the strongest cardiopulmonary exercise testing prognostic parameters in heart failure (HF). It is usually reported as an absolute value. The current definition of normal VE/VCO2 slope values is inadequate, since it was built from small groups of subjects with a particularly limited number of women and elderly. We aimed to define VE/VCO2 slope prediction formulas in a sizable population and to test whether the prognostic power of VE/VCO2 slope in HF was different if expressed as a percentage of the predicted value or as an absolute value. Methods and results We calculated the linear regressions between age and VE/VCO2 slope in 1136 healthy subjects (68% male, age 44.9 ± 14.5, range 13–83 years). We then applied age‐adjusted and sex‐adjusted formulas to predict VE/VCO2 slope to HF patients included in the metabolic exercise test data combined with cardiac and kidney indexes score database, which counts 6112 patients (82% male, age 61.4 ± 12.8, left ventricular ejection fraction 33.2 ± 10.5%, peakVO2 14.8 ± 4.9, mL/min/kg, VE/VCO2 slope 32.7 ± 7.7) from 24 HF centres. Finally, we evaluated whether the use of absolute values vs. percentages of predicted VE/VCO2 affected HF prognosis prediction (composite of cardiovascular mortality + urgent transplant or left ventricular assist device). We did so in the entire cardiac and kidney indexes score population and separately in HF patients with severe (peakVO2 < 14 mL/min/kg, n = 2919, 61.1 events/1000 pts/year) or moderate (peakVO2 ≥ 14 mL/min/kg, n = 3183, 19.9 events/1000 pts/year) HF. In the healthy population, we obtained the following equations: female, VE/VCO2 = 0.052 × Age + 23.808 (r = 0.192); male, VE/VCO2 = 0.095 × Age + 20.227 (r = 0.371) (P = 0.007). We applied these formulas to calculate the percentages of predicted VE/VCO2 values. The 2‐year survival prognostic power of VE/VCO2 slope was strong, and it was similar if expressed as absolute value or as a percentage of predicted value (AUCs 0.686 and 0.690, respectively). In contrast, in severe HF patients, AUCs significantly differed between absolute values (0.637) and percentages of predicted values (0.650, P = 0.0026). Moreover, VE/VCO2 slope expressed as a percentage of predicted value allowed to reclassify 6.6% of peakVO2 < 14 mL/min/kg patients (net reclassification improvement = 0.066, P = 0.0015). Conclusions The percentage of predicted VE/VCO2 slope value strengthens the prognostic power of VE/VCO2 in severe HF patients, and it should be preferred over the absolute value for HF prognostication. Furthermore, the widespread use of VE/VCO2 slope expressed as percentage of predicted value can improve our ability to identify HF patients at high risk, which is a goal of utmost clinical relevance.