Tumor-Infiltrating Lymphocyte Recognition in Primary Melanoma by Deep Learning Convolutional Neural Network.

The presence of tumor-infiltrating lymphocytes (TILs) is associated with a favorable prognosis of primary melanoma (PM). Recently, artificial intelligence (AI)-based approach in digital pathology was proposed for the standardized assessment of TILs on hematoxylin and eosin-stained whole slide images (WSIs). Herein, the study applied a new convolution neural network (CNN) analysis of PM WSIs to automatically assess the infiltration of TILs and extract a TIL score. A CNN was trained and validated in a retrospective cohort of 307 PMs including a training set (237 WSIs, 57,758 patches) and an independent testing set (70 WSIs, 29,533 patches). An AI-based TIL density index (AI-TIL) was identified after the classification of tumor patches by the presence or absence of TILs. The proposed CNN showed high performance in recognizing TILs in PM WSIs, showing 100% specificity and sensitivity on the testing set. The AI-based TIL index correlated with conventional TIL evaluation and clinical outcome. The AI-TIL index was an independent prognostic marker associated directly with a favorable prognosis. A fully automated and standardized AI-TIL appeared to be superior to conventional methods at differentiating the PM clinical outcome. Further studies are required to develop an easy-to-use tool to assist pathologists to assess TILs in the clinical evaluation of solid tumors.

Histological features of immune cell infiltrate in lesional skin correlate with therapeutic response to dupilumab.

In the last decade, dupilumab, a monoclonal human antibody inhibiting IL-4/IL-13 signaling, has revolutionized the therapeutic management of moderate-to-severe atopic dermatitis (AD), permitting a long-term control of its signs and symptoms. The aim of this study was to identify histologic predictors of dupilumab efficacy after 16 weeks of treatment in a cohort of forty adult patients with moderate to severe AD who had undergone a skin biopsy for diagnostic purposes prior to treatment initiation. We found that EASI 75 and EASI 90 responses at week 16 were significantly associated with perivascular localization (OR=17.6, p=0.038) and lichenoid distribution (OR=31.8, p=0.025) of the immune infiltrate. Moreover, for each unit increase in the number (cells/m2) of CD4+ cells, the likelihood to achieve EASI75 response decreased by 1% (OR=0.99, p=0.037). In conclusion our study suggested a few pre-treatments qualitative and quantitative immunohistochemical features as promising markers predicting dupilumab response in AD patients.

Hyaluronic Acid Injections to Correct Lips Deformity Following Surgical Removal of Permanent Implant.

One of the most attractive areas of the face are the lips, they are crucial for emotion and communication, both during animation and at rest. Throughout the years, several techniques to obtain permanent lip enhancement have been introduced, such as the use of nonresorbable fillers. The main problem related to permanent fillers is that undesirable results could not always be repaired; although lip sequelae can be addressed surgically, some surgeons will not perform this type of procedure due to its complexity and the lack of guidelines.In this paper, the authors present a case of a labial incompetence developed after lips implant removal performed elsewhere; after clinical examination the patient was planned for surgery, although during preoperative instrumental examination (chest X-ray) a solitary pulmonary nodule was noted; further investigation performed with needle biopsy revealed a lung cancer. For this reason, the surgical procedure planned for lip restoration was not performed; however, the patient asked for a minimally invasive procedure, thus to improve, although temporarily, her lips appearance.For the aforementioned reasons, the patient was treated just with hyaluronic acid injections achieving a pleasant result, solving also the labial incompetence at rest.To the best of the author's knowledge, this paper represents the first one describing the use of hyaluronic acid injections to restore lip competence following surgical removal of permanent implant.

Debris of carbon-fibers originated from a CFRP (pEEK) wrist-plate triggered a destruent synovitis in human.

Application of carbon-fiber-reinforced-polymer (CFRP) artifacts in humans has been promoted in Orthopedic and Trauma Surgery. Literature documents the biocompatibility of materials used, namely carbon fibers (CF) and poly-ether thermoplastics, like poly-ether-ether-ketone (PEEK). A properly designed and accurately implanted composite artifact should not expose its fibers during or after surgery: however this may happen. A white Caucasian woman came to our attention 11 months after surgery for a wrist fracture. She had a severe impairment, being unable to flex the thumb; index finger and distal phalanx of third finger. We retrieved a correctly positioned plate and documented an aggressive erosive flexor tendons synovitis with eroded stumps of flexor tendons. The plate and soft tissues were analyzed by Visible Light and Scanning Electron Microscopy. Histopathology showed granulomatous fibrogenic process with CF engulfed inside multinucleated giant cells. Fibers were unmasked and disrupted inside the holes where screws were tightened and corrugation of the polymer coating led to further unmasking. The mechanism of foreign-body reaction to CF has not been studied in depth yet, particularly at the ultrastructural level and in Humans. This case documents a damage occurred in a clinical application and which was theoretically possible. Our opinion is that a proper way to promote the use of CRFP in the Clinic in the short term is to direct Research towards finding a better way to prevent CF debris to be exposed and released. In the longer term, the biological response to CF deserves a deeper understanding.

Subjective hypnotic efficacy of Trazodone and Mirtazapine in patients with chronic insomnia: a retrospective, comparative study.

OBJECTIVE: To compare the efficacy of two sedating antidepressants, trazodone and mirtazapine, for the treatment of chronic insomnia. DESIGN: Retrospective cross-sectional study. Patients received trazodone or mirtazapine for at least three months at the dosage that was effective in the titration period. MATERIAL AND METHODS: 150 patients with chronic insomnia, referred to the Sleep Disorder Center of Bari, diagnosed as chronic insomniacs according to ICSD-3 diagnostic criteria, with or without dysthymic disorder according to DSM V diagnostic criteria, and treated with trazodone or mirtazapine were retrospectively chart-reviewed. 79 patients satisfying inclusion criteria were enrolled: 33 had been treated with trazodone (12 males and 21 females aged 36 to 77 years, mean age 63.57+10.38 years; 18 with psychophysiological insomnia and 15 with insomnia associated with dysthymic disorder) and 46 with mirtazapine (26 males and 20 females aged 25 to 86 years, mean age 60.04+16.67 years; 25 with psychophysiological insomnia and 21 with insomnia comorbid with dysthymic disorder). The patients were considered responsive to the treatment when they no longer met the criteria for insomnia at the end of the maintenance period. RESULTS: Both drugs were efficacious in more than 60% without any difference in the proportion of responders between the two medication groups (87.87% in the trazodone group versus 86.95% in the mirtazapine group; p=0.26 and regardless of sex, age and possible association of insomnia with depression). The minimum dosages used for both drugs (25 mg for trazodone and 7.5 mg for mirtazapine) corresponded to the highest percentage of responders in the groups treated successfully with either trazodone (37.93%) or mirtazapine (52.5%). For each medication group, subgroup analysis revealed higher statistically significant rates of responders in patients with lower final dosage (25 to 75 mg for trazodone and 7.5 to 15 mg for mirtazapine) than in those with higher final dosage (100 to 150 mg for trazodone and 15 to 30 mg for mirtazapine) (100% versus 42.85%; p<0.001 in the trazodone group and 100% versus 53.84%; p<0.001 in mirtazapine group) Conclusion. On a long term basis trazodone administration appeared as effective and well tolerated as mirtazapine in the treatment of chronic insomnia regardless of its association with dysthymia. Both medications resulted efficacious at very low doses and had a sustained efficacy, likely without problems of tolerance.

Impaired cognitive executive dysfunction in adult treated hypertensives with a confirmed diagnosis of poorly controlled blood pressure.

BACKGROUND: High blood pressure (BP) poses a major risk for cognitive decline. Aim of the study was to highlight the relationship between cognitive assessment scores and an effective therapeutic BP control. METHODS: By medical visit and ambulatory BP monitoring (ABPM), we studied 302 treated hypertensives, subdivided according to office/daytime BP values into 120 with good (GC) and 98 poor (PC) BP control, 40 with "white coat hypertension" (WCH) and 44 a "masked-hypertension" phenomenon (MH). Patients underwent neuropsychological assessment to evaluate global cognitive scores at the Mini Mental State Examination (MMSE) and Frontal Assessment Battery (FAB) and attention/executive functions (Delayed Recall, Digit Span Forwards, Digit Span Backwards, Selective Attention, Verbal Fluency, Stroop Test and Clock Drawing). Carotid intima-media thickness (IMT) served as the index of vascular damage. RESULTS: There were no differences among the groups in terms of gender, age, education, metabolic assessment, clinical history and hypertension treatment. GC presented lower office and ambulatory BP values and IMT. PC performed worse than GC on global executive and attention functions, especially executive functions. In PC, office systolic BP (SBP) was significantly associated to the MMSE and FAB scores and, in particular, to Verbal Fluency, Stroop Errors and Clock Drawing tests. Office diastolic BP (DBP) was associated to Selective attention, nocturnal SBP to Digit Span backwards and Verbal Fluency. Worse cognitive assessment scores were obtained in WCH than GC. CONCLUSIONS: The findings showed that in adult treated hypertensives, a poor BP control, as both doctor's office and daytime scores, is associated to impaired global cognitive and especially executive/attention functions.

Clinical and functional effects of beta-blocker therapy discontinuation in patients with biventricular heart failure.

BACKGROUND: Nearly two-thirds of patients with heart failure with reduced ejection fraction (HFrEF) have right ventricular dysfunction, previously identified as an independent predictor of reduced functional capacity and poor prognosis. Beta-blocker therapy (ß-BT) reduces mortality and hospitalizations in patients with HFrEF and is approved as first-line therapy regardless of concomitant right ventricular function. However, the exact role of sympathetic nervous system activation in right ventricular dysfunction and the potential usefulness (or harmfulness) of ß-BT in these patients are still unclear. OBJECTIVES: The aim of the study is to evaluate the medium-term effect of ß-BT discontinuation on functional capacity and right ventricular remodelling based on cardiopulmonary exercise testing (CPET), echocardiography and serum biomarkers in patients with clinically stable biventricular dysfunction. METHODS: In this single-centre, open-label, prospective trial, 16 patients were enrolled using the following criteria: patients were clinically stable without signs of peripheral congestion; NYHA II-III while on optimal medical therapy (including ß-BT); LVEF 40% or less; echocardiographic criteria of right ventricular dysfunction. Patients were randomized 1 : 1 either to withdraw (group 0) or continue (group 1) ß-BT. In group 0, optimal heart rate was obtained with alternative rate-control drugs. Echo and serum biomarkers were performed at baseline, after 3 and 6 months; CPET was performed at baseline and 6 months. Mann--Whitney U test was adopted to determine the relationships between ß-BT discontinuation and effects on right ventricular dysfunction. RESULTS: At 6 months' follow up, S' DTI improved (ΔS': 1.01 vs. -0.92 cm/s; P = 0.03), while estimated PAPs (ΔPAPs: 0.8 vs. -7.5 mmHg; P = 0.04) and echo left ventricular-remodelling (ΔEDVi: 19.55 vs. -0.96 ml/mq; P = 0.03) worsened in group 0. In absolute terms, the only variables significantly affected by ß-BT withdrawal were left ventricular EDV and ESV, appearing worse in group 0 (mean EDVi 115 vs. 84 ml/mq; mean ESVi 79 vs. 53.9 ml/mq, P = 0.03). No significant changes in terms of functional capacity were observed after ß-BT withdrawal. CONCLUSION: In HFrEF patients with concomitant right ventricular dysfunction, ß-BT discontinuation did not produce any beneficial effects. In addition, despite maintenance of optimal heart rate control, ß-BT discontinuation induced worsening of left ventricular remodelling. Our study corroborates the hypothesis that improvement in left ventricular function may likewise be a major determinant for improvement in right ventricular function, reducing pulmonary wedge pressure and right ventricular afterload, with only a marginal action of its negative inotropic effect. In conclusion, ß-BT appears beneficial also in heart failure patients with biventricular dysfunction.

Case report: Vitiligo-like toxicity due to ribociclib during first-line treatment of metastatic breast cancer: two cases of premature interruption of therapy and exceptional response.

Cancer treatment-related adverse events (AEs) are sometimes associated with outcomes for cancer patients, especially with the newest therapies such as target therapy and immunotherapy. A few years ago, the first-line therapy for hormone-receptor-positive metastatic breast cancer (mBC) patients has been deeply changed by the introduction of cyclin-dependent kinase (CDK) 4/6 inhibitors, and now, we are improving our knowledge about their AEs and significance in clinical practice. Here, we report our experience with two cases of vitiligo-like lesions that occur early during treatment with ribociclib. We tried to change the CDK4/6 inhibitor for one patient, but the skin reaction persisted. Both patients retained only the endocrine therapy alone and had an unexpected durable progression-free survival (PFS). Some data on skin toxicities, including vitiligo-like lesions by CDK4/6 inhibitors, have recently been reported in the literature, but for the first time, we highlight a possible correlation with improved survival outcomes of patients. Uncovering the etiology of this toxicity, verifying the involvement of the immune system, and demonstrating a possible positive impact in survival represent an intriguing research objective for the near future.

Melanocytic Lesions with Peripheral Globules: Proposal of an Integrated Management Algorithm.

INTRODUCTION: A peripheral rim of globules represents a marker of the horizontal growth phase in nevi and is a common feature in children and adolescents. The observation of melanocytic lesions with peripheral globules (MLPGs) in adulthood deserves more attention, since melanoma may exhibit this feature, albeit rarely. Risk-stratified management recommendations considering a global clinical approach are still missing. OBJECTIVES: To analyze current knowledge on MLPGs and propose an integrated management algorithm stratified for age groups. METHODS: We conducted a narrative review of current published data on MLPGs, analyzing clinical dermoscopic and confocal distinguishing features of melanoma from benign nevi. RESULTS: The risk of finding a melanoma when removing an MLPG increases with age, especially in people >55 years old, and is significantly higher in the extremities, head/neck and in case of a single asymmetrical lesion, ≥6 mm in diameter. Dermoscopic features associated with melanoma diagnosis include atypical peripheral globules, asymmetrical distribution, multiple rims as well as the reappearance of globules after prior loss. In addition, wide blue-grey regression areas, atypical networks, eccentric blotches, tan structureless peripheral areas and vascularization are atypical dermoscopic features. Confocal worrisome findings are represented by pagetoid cells within the epidermis, architectural disarrangement and atypical cells of the dermo-epidermal junction with irregular peripheral nests. CONCLUSION: We proposed a multi-step age-stratified management algorithm integrating clinical, dermoscopic and confocal findings that may increase the early recognition of melanoma and avoid surgical excision of benign nevi.

"Skin rashes" and immunotherapy in melanoma: distinct dermatologic adverse events and implications for therapeutic management.

Immune checkpoint inhibitors have shown efficacy in the treatment of different cancers by stimulating the antitumoral activity of the patient's immune system, representing a major breakthrough in the field of cancer therapy. Monoclonal antibodies including anti-cytotoxic T-lymphocyte-associated protein 4, anti-programmed cell death protein 1 and its ligand inhibitors have been approved for advanced melanoma among other solid cancers. Although immunotherapy demonstrated a good safety profile, a new spectrum of multisystemic immune-related adverse events has been recently reported due to their use. Cutaneous reactions represent one of the leading adverse events, often reported in literature as "skin rash", and rarely further characterized in distinct dermatologic entities. Herein we describe the distinctive cutaneous rashes occurring during immunotherapies for advanced melanoma, discussing implications in the treatment management.

Advanced cardiac imaging in the spectrum of COVID-19 related cardiovascular involvement.

Cardiovascular involvement is a common complication of COVID-19 infection and is associated to increased risk of unfavorable outcome. Advanced imaging modalities (coronary CT angiography and Cardiac Magnetic Resonance) play a crucial role in the diagnosis, follow-up and risk stratification of patients affected by COVID-19 pneumonia with suspected cardiovascular involvement. In the present manuscript we firstly review current knowledge on the mechanisms by which SARS-CoV-2 can trigger endothelial and myocardial damage. Secondly, the implications of the cardiovascular damage on patient's prognosis are presented. Finally, we provide an overview of the main findings at advanced cardiac imaging characterizing COVID-19 in the acute setting, in the post-acute syndrome, and after vaccination, emphasizing the potentiality of CT and CMR, the indication and their clinical implications.

Transcatheter Aortic Bioprosthesis Durability: A Single-Center Experience.

BACKGROUND: Transcatheter aortic valve implant (TAVI) is gaining momentum in the treatment of severe, symptomatic aortic valve stenosis, and its indication is expanding to lower surgical risk individuals, who are generally younger and have a long life expectancy. Therefore, transcatheter bioprostheses durability appears of critical importance. Aim of the present study is to evaluate mid-term outcomes of TAVI in a high-volume single center cohort. METHODS: We analyzed all consecutive patients (n = 408) who underwent transfemoral TAVI at a single, high-volume center, between 2007 and 2014. Study objectives were all-cause death and bioprosthetic valve failure (BVF) at long term follow-up. Structural valve deterioration (SVD), BVF and valve-related death were defined according to current international standards. Follow-up was performed by in person visit and transthoracic echocardiography, which was obtained only in a minority of patients, or phone call as per patient preference. RESULTS: At a median follow-up of 1821 days, overall mortality was 64.5%, with cardiovascular disease accounting for roughly half of total deaths. Valve-related deaths occurred in 10 patients. Seventeen patients were diagnosed with BVF, and 15 required repeat intervention. Moderate and severe SVD were observed in 10 and 7 patients, respectively. In the subgroup of patients with echocardiographic mid-term follow-up (n = 76), no significant increase of transprosthetic gradients nor increase of significant regurgitation was detected. CONCLUSION: In the present unselected, all-comers cohort, TAVI bioprostheses appeared to have excellent durability at long-term follow-up.

Maxillo-facial reconstruction following cancer ablation during COVID-19 pandemic in southern Italy.

In COVID-19 pandemic era, one major concern is related to ensure optimal management to oncologic patients, even though a context of radical uncertainty. The aim of our effort is to guarantee high-quality and timely care, minimizing COVID-19 infection risk, according to our head and neck (HN) reconstructive mission, still more challenging because of the criticality of the period. Thus, our reconstructive decision algorithm is changed. Microvascular free flaps, reported to be the gold standard for surgical reconstruction, represent extremely specialized procedures necessitating an extended resource allocation not affordable in the adversities of the period. Therefore, we are obliged to define a paradigm shift in our approach, based on free-style reconstructive surgery principles of propeller flap concept. According to our experience, we believe that this viable and feasible surgical technique could represent a reconstructive landmark in this pandemic era, since any guideline is missing, besides HN reconstructive surgery is most likely heading towards a new reconstructive approach.

Inclusion of Synovial Tissue-Derived Characteristics in a Nomogram for the Prediction of Treatment Response in Treatment-Naive Rheumatoid Arthritis Patients.

OBJECTIVE: This study applied a synovitis score obtained during routine care from ultrasound (US)-guided biopsies of synovial tissue (ST) in patients with rheumatoid arthritis (RA) and patients with other inflammatory and noninflammatory joint diseases to identify pretreatment synovial biomarkers associated with disease characteristics, and to integrate the findings into a multiparameter nomogram for use in baseline prediction of diagnosis and treatment response in treatment-naive rheumatoid arthritis (RA) patients. METHODS: The study enrolled a total of 1,015 patients with various autoimmune diseases (545 patients with RA, 167 patients with psoriatic arthritis [PsA], 199 patients with undifferentiated peripheral inflammatory arthritis [UPIA], 18 patients with crystal-induced arthritis, 26 patients with connective tissue diseases, and 60 patients with osteoarthritis [OA] [as part of the SYNGem cohort]). All patients underwent a US-guided ST biopsy at baseline, and patients were then stratified according to disease phase. The KSS, along with disease characteristics and clinical outcomes, were incorporated into a nomogram for prediction of achievement of clinical remission in RA patients who were previously naive to treatment. In patients in whom a treat-to-target strategy was applied, remission was defined as change in the Disease Activity Score in 28 joints (DAS28) at 6 months after treatment initiation. RESULTS: The KSS significantly differed among RA patients, as well as PsA patients and UPIA patients, when compared to OA patients. In RA, the KSS directly correlated with the DAS28 and was related to autoantibody positivity in treatment-naive RA patients. Moreover, at baseline, treatment-naive RA patients achieving 6-month remission according to DAS28 had a lower KSS, shorter duration of symptoms (very early RA [VERA]), and lower disease activity than treatment-naive RA patients not achieving remission according to DAS28. Results of logistic regression analysis identified the following synergistic predictive factors of achievement of DAS28-based disease remission at 6 months: having a short disease duration (VERA), not having high disease activity, and having a KSS of <5 at baseline. A nomogram integrating these baseline clinical and histologic characteristics in treatment-naive RA patients yielded an up to 81.7% probability of achieving 6-month remission according to the DAS28. CONCLUSION: The KSS is a reliable tool for synovitis assessment on US-guided ST biopsy, contingent on the phase of the disease and the autoimmune profile of each patient. This tool could be integrated within a therapeutic response-predictive nomogram for the prediction of treatment response in RA patients who were previously naive to treatment.

The Safety of Radiotherapy in the Treatment of Primary Cutaneous B-Cell Lymphoma: A Multidisciplinary Systematic Review.

Primary cutaneous B-cell lymphomas (PCBCL) are rare types of extranodal non-Hodgkin's lymphoma. The choice of treatment usually depends on the variant of PCBCL, number, size, and location of the lesions, involved body surface area as well as patient's age and health condition. The efficacy of radiotherapy (RT) in the treatment of PCBCL has been widely reported conversely, data about the acute and late skin toxicity, patient's treatment satisfaction and quality of life are scarce. A systematic search using PubMed, Scopus, and Cochrane library was performed to identify full original articles analyzing the safety of RT in patients with PCBCL with the primary outcome to assess the acute and late skin toxicity. Secondary outcomes were complete remission, disease free survival, and overall survival. The literature search resulted in 276 articles including eight studies assessing the safety of RT for the treatment of PCBCL. Most patients (median 73%, range 11.9-99.9%) were recorded as having acute skin toxicity of grade 1-2, while acute grade 3-4 toxicity occurred in a median of 8% (range 4-23%) of patients. A median of 20% (range 4-54%) of patients had late skin toxicity of grade 1-2. No late grade 3-4 toxicity was reported. Only one study evaluated patient's satisfaction showing that the 97% of patients were satisfied with radiation therapy. This systematic review confirms the safety of RT in the treatment of PCBCL. Patients with a PCBCL should be managed in highly specialized centers in the context of a multidisciplinary team including dermatologist, hematologist, pathologist, and radiation oncologist.

SKIN-COBRA (Consortium for Brachytherapy data Analysis) ontology: The first step towards interdisciplinary standardized data collection for personalized oncology in skin cancer.

PURPOSE: The primary objective of the SKIN-COBRA (Consortium for Brachytherapy data Analysis) ontology is to define a specific terminological system to standardize data collection for non-melanoma skin cancer patients treated with brachytherapy (BT, interventional radiotherapy). Through ontological characterization of information, it is possible to find, isolate, organize, and integrate its meaning. MATERIAL AND METHODS: SKIN-COBRA is a standardized data collection consortium for non-melanoma skin patients treated with BT, including 8 cancer centers. Its ontology was firstly defined by a multicentric and multidisciplinary working group and evaluated by the consortium, followed by a multi-professional technical commission involving a mathematician, an engineer, a physician with experience in data storage, a programmer, and a software expert. RESULTS: Two hundred and ninety variables were defined in 10 input forms. There are 3 levels, with each offering a specific type of analysis: 1. Registry level (epidemiology analysis); 2. Procedures level (standard oncology analysis); 3. Research level (radiomics analysis). The ontology was approved by the technical commission and consortium, and an ad-hoc software system was defined to be implemented in the SKIN-COBRA consortium. CONCLUSIONS: Large databases are natural extension of traditional statistical approaches, a valuable and increasingly necessary tool for modern healthcare system. Future analysis of the collected multinational and multicenter data will show whether the use of the system can produce high-quality evidence to support multidisciplinary management of non-melanoma skin cancer and utilizing this information for personalized treatment decisions.

Vive la Difference! The Effects of Natural and Conventional Wines on Blood Alcohol Concentrations: A Randomized, Triple-Blind, Controlled Study.

Different alcoholic beverages can have different effects on blood alcohol concentration (BAC) and neurotoxicity, even when equalized for alcohol content by volume. Anecdotal evidence suggested that natural wine is metabolized differently from conventional wines. This triple-blind study compared the BAC of 55 healthy male subjects after consuming the equivalent of 2 units of alcohol of a natural or conventional wine over 3 min in two separate sessions, one week apart. BAC was measured using a professional breathalyzer every 20 min after consumption for 2 h. The BAC curves in response to the two wines diverged significantly at twenty minutes (interval T20) and forty minutes (interval T40), and also at their maximum concentrations (peaks), with the natural wine inducing a lower BAC than the conventional wine [T20 = 0.40 versus 0.46 (p < 0.0002); T40 = 0.49 versus 0.53 (p < 0.0015); peak = 0.52 versus 0.56 (p < 0.0002)]. These differences are likely related to the development of different amino acids and antioxidants in the two wines during their production. This may in turn affect the kinetics of alcohol absorption and metabolism. Other contributing factors could include pesticide residues, differences in dry extract content, and the use of indigenous or selected yeasts. The study shows that with the same quantity and conditions of intake, natural wine has lower pharmacokinetic and metabolic effects than conventional wine, which can be assumed due to the different agronomic and oenological practices with which they are produced. It can therefore be hypothesized that the consumption of natural wine may have a different impact on human health from that of conventional wine.

Differential synovial tissue biomarkers among psoriatic arthritis and rheumatoid factor/anti-citrulline antibody-negative rheumatoid arthritis.

BACKGROUND: Differential diagnosis among psoriatic arthritis (PsA) and seronegative rheumatoid arthritis (Abneg RA) can be challenging particularly in the clinical setting of peripheral phenotype and autoantibodies seronegativity. The aim of the study was to identify synovial tissue (ST) biomarkers differentially expressed in PsA and Abneg RA and test their predictive value of therapeutic response. METHODS: Thirty-four PsA patients [12 DMARD naive and 22 non-responder to methotrexate (MTX-IR)] with peripheral joint involvement and 55 Abneg RA (27 DMARD naive and 28 MTX-IR) underwent US-guided ST biopsy and immunohistochemistry (IHC) for CD68+, CD3+, CD20+, CD21+, CD117+, and CD138+ cells. After study entry, each DMARD-naive patient started MTX therapy and was followed in an outpatient setting for at least 6 months to define the achievement of Minimal Disease Activity (PsA) and DAS remission (Abneg RA) status respectively. Each IR-MTX patient was treated according to EULAR recommendations. RESULTS: At study entry, IHC analysis revealed that PsA patients had comparable levels of lining and sublining CD68+ and sublining CD21+, CD20+, and CD3+ cells than Abneg RA, despite the therapeutic regimen. Moreover, regardless of the therapeutic scheme, PsA patients showed higher IHC score of CD117+ cells (p = 0.0004 and p = 0.0005 for naive and MTX-IR patients respectively) compared to Abneg RA patients. Conversely, Abneg RA patients showed higher IHC score of CD138+ cells, irrespective to the therapeutic scheme (p = 0.04 and p = 0.002 for naive and MTX-IR patients respectively). Analyzing the response rate to the therapeutic scheme, naive PsA patients reaching MDA status at 6 months follow-up, showed, at the study entry, lower IHC score of CD3+ cells compared to PsA patients not reaching this outcome (p = 0.02); conversely, naive Abneg RA patients reaching DAS remission status at 6 months follow-up, showed, at the study entry, lower IHC score of sublining CD68+ cells compared to Abneg RA patients not reaching this outcome (p < 0.001). CONCLUSIONS: CD117+ and CD138+ cells are differentially distributed among PsA and Abneg RA. Histological analysis of ST may help to solve the clinical overlap between the two diseases and provides prognostic data about the therapy success.