Psoriasis: A STAT3-centric view

Signal Transducer and Activator of Transcription (STAT)3 has recently emerged as a key player in the development and pathogenesis of psoriasis and psoriatic-like inflammatory conditions. Indeed, STAT3 hyperactivation has been reported in virtually every cell type involved in disease initiation and maintenance, and this factor mediates the signal of most cytokines that are involved in disease pathogenesis, including the central Interleukin (IL)-23/IL-17/IL-22 axis. Despite the recent availability of effective biological agents (monoclonal antibodies) against IL-17 and IL-23, which have radically changed the current standard of disease management, the possibility of targeting either STAT3 itself or, even better, the family of upstream activators Janus kinases (JAK1, 2, 3, and TYK2) offers additional therapeutic options. Due to the oral/topical administration modality of these small molecule drugs, their lower cost, and the reduced risk of eliciting adverse immune responses, these compounds are being actively scrutinized in clinical settings. Here, we summarize the main pathological features of psoriatic conditions that provide the rationale for targeting the JAK/STAT3 axis in disease treatment

Self-reported well-being score modelling and prediction: Proof-of-concept of an approach based on linear dynamic systems

Assessment and recognition of perceived well-being has wide applications in the development of assistive healthcare systems for people with physical and mental disorders. In practical data collection, these systems need to be less intrusive, and respect users' autonomy and willingness as much as possible. As a result, self-reported data are not necessarily available at all times. Conventional classifiers, which usually require feature vectors of a prefixed dimension, are not well suited for this problem. To address the issue of non-uniformly sampled measurements, in this study we propose a method for the modelling and prediction of self-reported well-being scores based on a linear dynamic system. Within the model, we formulate different features as observations, making predictions even in the presence of inconsistent and irregular data. We evaluate the proposed method with synthetic data, as well as real data from two patients diagnosed with cancer. In the latter, self-reported scores from three well-being-related scales were collected over a period of approximately 60 days. Prompted each day, the patients had the choice whether to respond or not. Results show that the proposed model is able to track and predict the patients' perceived well-being dynamics despite the irregularly sampled data

Effects of nonselective and selective cyclooxygenase inhibitors on the contractions of isolated bronchial smooth muscle in the horse

We evaluated the effects of nonselective cyclooxygenase (COX)-1/COX-2 inhibitors (acetylsalicylic acid, indomethacin, ibuprofen, flunixin meglumine, phenylbutazone), preferential COX-2 inhibitors (diclofenac, meloxicam, carprofen), selective COX-1 inhibitor (SC-560), and selective COX-2 inhibitors (celecoxib, firocoxib, parecoxib) on the contractions of isolated bronchi induced by electrical field stimulation (EFS). Bronchial rings, obtained from lungs of slaughtered horses, were put in isolated organ baths, and the mechanical activity was measured by means of isotonic transducers. Electrical Field Stimulation was applied to the preparations, and the effects of drugs on the amplitude of evoked contractions were measured. Nonselective COX inhibitors did not modify EFS-induced contractions to a relevant degree, except indomethacin which caused a concentration-dependent decrease of the contraction amplitude. Conversely, preferential COX-2 inhibitors enhanced the contractions in a concentration-related fashion, whilst the selective COX-1 inhibitor reduced them. Among selective COX-2 inhibitors, parecoxib increased EFS-evoked contractions whereas celecoxib and firocoxib were ineffective. These results suggest that the inhibition of prostanoid synthesis does not modify the electrical field-stimulated contractions of isolated horse bronchi. Since EFS-induced contractions of horse bronchi were previously shown to be of full cholinergic nature, the increase caused by diclofenac, meloxicam, carprofen, and parecoxib could be due to an inhibition of acetylcholinesterase; in accordance, these drugs potentiated exogenous acetylcholine-induced but not carbachol-induced bronchial contraction. Indomethacin and SC-560 might instead decrease bronchial contractions by inhibiting calcium currents. Clinical use of meloxicam and carprofen in horses with bronchial hyper-responsiveness requires caution for a potential risk of causing adverse effects due to bronchoconstriction

DAX-1 Expression in Pediatric Rhabdomyosarcomas: Another Immunohistochemical Marker Useful in the Diagnosis of Translocation Positive Alveolar Rhabdomyosarcoma

OBJECTIVES: The aim of this study was to investigate the expression of DAX-1 in a series of pediatric rhabdomyosarcomas (RMS) with known translocation and compare it to Ap2\u3b2, known to be selectively expressed in ARMS. DESIGN: We revised a series of 71 alveolar rhabdomyosarcomas (ARMS), enrolled in the Italian Protocols RMS 79 and 96, and 23 embryonal rhabdomyosarcomas (ERMS) as controls. Before investigating Ap2\u3b2 and DAX-1, ARMS were reviewed and reclassified as 48 ARMS and 23 non-ARMS. RESULTS: Translocation positive ARMS showed a characteristic Ap2\u3b2/DAX-1+ staining pattern in 78% of cases, while 76% of classic ERMS were negative for both. Ap2\u3b2 alone was positive in 3.9% of RMS lacking translocation, whereas DAX-1 alone was positive in 25.4%. Conversely, 9% and 6% of translocation positive ARMS were positive only for DAX-1 or Ap2\u3b2, respectively. The 23 non-ARMS shared the same phenotype as ERMS but had a higher frequency of DAX-1 expression. CONCLUSIONS: DAX-1 is less specific than Ap2\u3b2, however it is a sensitive marker for translocation positive ARMS and can be helpful in their diagnosis if used in combination with Ap2\u3b2

Role of Portion Size in the Context of a Healthy, Balanced Diet: A Case Study of European Countries

Over the past decades, a generalised increase in food portion sizes has probably contributed to the growing global obesity epidemic. Increasing awareness of appropriate portion sizes could contribute to reversing this trend through better control of calorie intake. In this study, a comparison of standard portion sizes in European countries for various food categories shows a wide variability of their importance for food, nutrient, and energy consumption according to government and institutional websites. On the other hand, the overall averages appear to be largely in line with the values indicated by the Italian Society of Human Nutrition, which is the most comprehensive and detailed document among those evaluated. The exceptions are milk and yoghurt, for which the reference portions in Europe are generally higher, and vegetables and legumes, for which portions are smaller than those reported in the Italian document. Moreover, the portion sizes of staple foods (e.g., pasta and potatoes) vary according to different food traditions. It is reasonable to consider that the creation of harmonised standard reference portions common to the European countries, based on international guidelines and scientific evidence, would significantly contribute to consumers' nutritional education and ability to make informed choices for a healthy diet

LDL-cholesterol control in the primary prevention of cardiovascular diseases. An expert opinion for clinicians and health professionals

Aims: Although adequate clinical management of patients with hypercholesterolemia without a history of known cardiovascular disease is essential for prevention, these subjects are often disregarded. Furthermore, the scientific literature on primary cardiovascular prevention is not as rich as that on secondary prevention; finally, physicians often lack adequate tools for the effective management of subjects in primary prevention and have to face some unsolved relevant issues. This document aims to discuss and review the evidence available on this topic and provide practical guidance. Data synthesis: Available algorithms and risk charts represent the main tool for the assessment of cardiovascular risk in patients in primary prevention. The accuracy of such an estimate can be substantially improved considering the potential contribution of some additional risk factors (C-reactive protein, lipoprotein(a), family history of cardiovascular disease) and conditions (environmental pollution, sleep quality, socioeconomic status, educational level) whose impact on the cardiovascular risk has been better understood in recent years. The availability of non-invasive procedures to evaluate subclinical atherosclerosis may help to identify subjects needing an earlier intervention. Unveiling the presence of these conditions will improve cardiovascular risk estimation, granting a more appropriate intervention. Conclusions: The accurate assessment of cardiovascular risk in subjects in primary prevention with the use of algorithms and risk charts together with the evaluation of additional factors will allow physicians to approach each patient with personalized strategies, which should translate into an increased adherence to therapy and, as a consequence, a reduced cardiovascular risk

A protocol for a multicentre, parallel-group, pragmatic randomised controlled trial to evaluate the NEVERMIND system in preventing and treating depression in patients with severe somatic conditions

Background Depressive symptoms are common in individuals suffering from severe somatic conditions. There is a lack of interventions and evidence-based interventions aiming to reduce depressive symptoms in patients with severe somatic conditions. The aim of the NEVERMIND project is to address these issues and provide evidence by testing the NEVERMIND system, designed to reduce and prevent depressive symptoms in comparison to treatment as usual. Methods The NEVERMIND study is a parallel-groups, pragmatic randomised controlled trial to assess the effectiveness of the NEVERMIND system in reducing depressive symptoms among individuals with severe somatic conditions. The NEVERMIND system comprises a smart shirt and a user interface, in the form of a mobile application. The system is a real-time decision support system, aiming to predict the severity and onset of depressive symptoms by modelling the well-being condition of patients based on physiological data, body movement, and the recurrence of social interactions. The study includes 330 patients who have a diagnosis of myocardial infarction, breast cancer, prostate cancer, kidney failure, or lower limb amputation. Participants are randomised in blocks of ten to either the NEVERMIND intervention or treatment as usual as the control group. Clinical interviews and structured questionnaires are administered at baseline, at 12 weeks, and 24 weeks to assess whether the NEVERMIND system is superior to treatment as usual. The endpoint of primary interest is Beck Depression Inventory II (BDI-II) at 12 weeks defined as (i) the severity of depressive symptoms as measured by the BDI-II. Secondary outcomes include prevention of the onset of depressive symptoms, changes in quality of life, perceived stigma, and self-efficacy. Discussion There is a lack of evidence-based interventions aiming to reduce and prevent depressive symptoms in patients with severe somatic conditions. If the NEVERMIND system is effective, it will provide healthcare systems with a novel and innovative method to attend to depressive symptoms in patients with severe somatic conditions. Trial registration DRKS00013391. Registered 23 November 2017

The NEVERMIND e-health system in the treatment of depressive symptoms among patients with severe somatic conditions: A multicentre, pragmatic randomised controlled trial

Background This study assessed the effectiveness of the NEVERMIND e-health system, consisting of a smart shirt and a mobile application with lifestyle behavioural advice, mindfulness-based therapy, and cognitive behavioural therapy, in reducing depressive symptoms among patients diagnosed with severe somatic conditions. Our hypothesis was that the system would significantly decrease the level of depressive symptoms in the intervention group compared to the control group. Methods This pragmatic, randomised controlled trial included 425 patients diagnosed with myocardial infarction, breast cancer, prostate cancer, kidney failure, or lower limb amputation. Participants were recruited from hospitals in Turin and Pisa (Italy), and Lisbon (Portugal), and were randomly assigned to either the NEVERMIND intervention or to the control group. Clinical interviews and structured questionnaires were administered at baseline, 12 weeks, and 24 weeks. The primary outcome was depressive symptoms at 12 weeks measured by the Beck Depression Inventory II (BDI-II). Intention-to-treat analyses included 425 participants, while the per-protocol analyses included 333 participants. This trial is registered in the German Clinical Trials Register, DRKS00013391. Findings Patients were recruited between Dec 4, 2017, and Dec 31, 2019, with 213 assigned to the intervention and 212 to the control group. The sample had a mean age of 59·41 years (SD=10·70), with 44·24% women. Those who used the NEVERMIND system had statistically significant lower depressive symptoms at the 12-week follow-up (mean difference=-3·03, p<0·001; 95% CI -4·45 to -1·62) compared with controls, with a clinically relevant effect size (Cohen's d=0·39). Interpretation The results of this study show that the NEVERMIND system is superior to standard care in reducing and preventing depressive symptoms among patients with the studied somatic conditions. Funding The NEVERMIND project received funding from the European Union's Horizon 2020 Research and Innovation Programme under grant agreement No. 689691

Prevalence of hepatic steatosis in patients with type 2 diabetes and response to glucose-lowering treatments. A multicenter retrospective study in Italian specialist care

Type 2 diabetes (T2D) is a risk factor for metabolic dysfunction-associated fatty liver disease (MAFLD), which is becoming the commonest cause of chronic liver disease worldwide. We estimated MAFLD prevalence among patients with T2D using the hepatic steatosis index (HSI) and validated it against liver ultrasound. We also examined whether glucose-lowering medications (GLM) beneficially affected HSI

Similar effectiveness of dapagliflozin and GLP-1 receptor agonists concerning combined endpoints in routine clinical practice: A multicentre retrospective study

Aims According to cardiovascular outcome trials, some sodium-glucose contransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) are recommended for secondary cardiovascular prevention in type 2 diabetes (T2D). In this real-world study, we compared the simultaneous reductions in HbA1c, body weight and systolic blood pressure after initiation of dapagliflozin or GLP-1RA as second or a more advanced line of therapy. Materials and methods DARWIN-T2D was a retrospective multi-centre study conducted at diabetes specialist clinics in Italy that compared T2D patients who initiated dapagliflozin or GLP-1RA (exenatide once weekly or liraglutide). Data were collected at baseline and at the first follow-up visit after 3 to 12 months. The primary endpoint was the proportion of patients achieving a simultaneous reduction in HbA1c, body weight and systolic blood pressure. To reduce confounding, we used multivariable adjustment (MVA) or propensity score matching (PSM). Results Totals of 473 patients initiating dapagliflozin and 336 patients initiating GLP-1RA were included. The two groups differed in age, diabetes duration, HbA1c, weight and concomitant medications. The median follow-up was 6 months in both groups. Using MVA or PSM, the primary endpoint was observed in 30% to 32% of patients, with no difference between groups. Simultaneous reduction of HbA1c, BP and SBP by specific threshold, as well as achievement of final goals, did not differ between groups. GLP-1RA reduced HbA1c by 0.3% more than the reduction achieved with dapagliflozin. Conclusion In routine specialist care, initiation of dapagliflozin can be as effective as initiation of a GLP-1RA for attainment of combined risk factor goals