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Real-world data on the long-term effectiveness of the anti-IL17 agent secukinumab in treating moderate-to-severe Hidradenitis suppurativa (HS) are lacking. In this study, 24 patients with moderate-severe HS received five weekly subcutaneous injections followed by maintenance doses every 4 weeks. Primary outcomes included HiSCR, IHS4 reduction, and DLQI measures assessed at 12-week intervals. The median secukinumab drug survival was 16.0 months (range 3-51), with a 56.5% maximal response rate at 6 months and dropout exceeding 40% at 1 year. Baseline disease burden emerged as a key predictor of treatment response, overshadowing factors like sex or BMI. Prior systemic steroid use negatively impacts drug survival. The study underscores the critical 6-month window for assessing treatment efficacy, emphasizing the importance of initial induction dosing. Additionally, the newly developed scoring system, IHS4-55, showed analogies to the older HiSCR score in capturing treatment response. In this real-life scenario, challenges persist in HS management, necessitating innovative therapeutic approaches and predictive markers., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Over the past decade, significant advancements in the field of melanoma have included the introduction of a new staging system and the development of immunotherapy and targeted therapies, leading to changes in substage classification and impacting patient prognosis. Despite these strides, early detection remains paramount. The quest for dependable prognostic biomarkers is ongoing, given melanoma's unpredictable nature, especially in identifying patients at risk of relapse. Reliable biomarkers are critical for informed treatment decisions., Areas Covered: This review offers a comprehensive review of prognostic biomarkers in the context of clinical trials for immunotherapy and targeted therapy. It explores different clinical scenarios, including adjuvant, metastatic, and neo-adjuvant settings. Key findings suggest that tumor mutational burden, PD-L1 expression, IFN-γ signature, and immune-related factors are promising biomarkers associated with improved treatment responses., Expert Opinion: Identifying practical prognostic factors for melanoma therapy is challenging due to the tumor's heterogeneity. Promising biomarkers include tumor mutational burden (TMB), circulating tumor DNA, and those characterizing the tumor microenvironment, especially the immune component. Future research should prioritize large-scale, prospective studies to validate and standardize these biomarkers, emphasizing clinical relevance and real-world applicability. Easily accessible biomarkers have the potential to enhance the precision and effectiveness of melanoma management.

Background: Infective endocarditis (IE) is still a severe disease with elevated morbidity and mortality. Nevertheless, the last European guidelines (GL) date back to 2015, and a recent survey described a diffuse suboptimal adherence to their recommendations. Here, we described a real-life scenario about adherence to IE treatment GL., Methods: This was a retrospective, multicentric, case-control study. All the cases of IE admitted to our wards from 2016 to 2020 were enrolled. Patients were divided into two groups, according to the non-adherence (group A, cases) or adherence (group B, controls) to 2015 ESC guidelines. Only targeted treatments were considered. Groups were compared for demographic, clinical, microbiological, and laboratory data and outcome. As a post hoc analysis, we analysed the characteristics of deviations from the guidelines and how these deviations affected mortality., Results: A total of 246 patients were enrolled, with 128 (52%) in group A and 118 (48%) in group B. Groups were homogeneous except for aetiologies: staphylococcal and blood-culture-negative IE were more frequent in group A, while streptococcal and enterococcal IE were more frequent in group B ( p < 0.001). In-hospital mortality was comparable in the two groups. The most frequent causes of deviations from the guidelines were use of daptomycin, in addition to standard treatments and the missing administration of rifampin or gentamycin., Conclusions: Adherence to 2015 ESC guidelines was limited but it did not affect mortality.

Objectives: To investigate the relationship between Mediterranean diet (MedDiet) adherence and response to an exercise and health education program to prevent hospitalization-associated disability (HAD) in acutely hospitalized older adults., Design: Randomized controlled trial., Setting and Participants: Secondary analysis of a subset of 109 participants from AGECAR-PLUS study with available data on MedDiet adherence (mean age 87, and range 75-98)., Intervention: Participants were randomized into the control group (n = 46, usual care) or the intervention group (n = 63, supervised exercise and health education) at admission., Measurements: MedDiet adherence was measured with MEDAS and through urinary total polyphenols (UTP). Functional status was assessed with the Barthel Index., Results: At discharge, patients in the intervention group who had low levels of MedDiet or UTP showed an increase in functional status [adjusted mean (95% CI) = 77.8 (70.8-84.8) points, p = 0.005, and adjusted mean (95% CI) = 78.0 (68.3-87.7) points, p = 0.020, respectively]., Conclusion: Older individuals over age 75 with low MedDiet adherence were likely to benefit more from a physical exercise and health education intervention., Competing Interests: All authors have completed the ICMJE uniform disclosure form and declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Objective: Synovial fibrosis contributes to osteoarthritis (OA) pathology, but the underlying mechanisms remain unknown. We have observed increased microRNA-27b-3p (miR-27b-3p) levels in synovial fluid of patients with late-stage radiographic knee OA. Here, we investigated the contribution of miR-27b-3p to synovial fibrosis in patients with severe knee OA and in a mouse model of knee OA., Methods: We stained synovium sections obtained from patients with radiographic knee OA scored according to the Kellgren/Lawrence scale and mice that underwent destabilization of the medial meniscus (DMM) for miR-27b-3p using in situ hybridization. We examined the effects of intraarticular injection of miR-27b-3p mimic into naive mouse knee joints and intraarticular injection of a miR-27b-3p inhibitor into mouse knee joints after DMM. We performed transfection with miR-27b-3p mimic and miR-27b-3p inhibitor in human OA fibroblast-like synoviocytes (FLS) using reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) array, RNA sequencing, RT-qPCR, Western blotting, immunofluorescence, and migration assays., Results: We observed increased miR-27b-3p expression in the synovium from patients with knee OA and in mice with DMM-induced arthritis. Injection of the miR-27b-3p mimic in mouse knee joints induced a synovial fibrosis-like phenotype, increased synovitis scores, and increased COL1A1 and α-smooth muscle actin (α-SMA) expression. In the mouse model of DMM-induced arthritis, injection of the miR-27b-3p inhibitor decreased α-SMA but did not change COL1A1 expression levels or synovitis scores. Transfection with the miR-27b-3p mimic in human OA FLS induced profibrotic responses, including increased migration and expression of key extracellular matrix (ECM) genes, but transfection with the miR-27b-3p inhibitor had the opposite effects. RNA sequencing identified a PPARG/ADAMTS8 signaling axis regulated by miR-27b-3p in OA FLS. Human OA FLS transfected with miR-27b-3p mimic and then treated with the PPARG agonist rosiglitazone or with ADAMTS8 small interfering RNA exhibited altered expression of select ECM genes., Conclusion: Our findings demonstrate that miR-27b-3p has a key role in ECM regulation associated with synovial fibrosis during OA., (© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Background: The management of Latent Tuberculosis Infection is crucial in fighting Tuberculosis worldwide, and particularly in low incidence European Countries. While guidelines for the management of Tuberculosis in newly arrived immigrants have been issued by the European Center for Disease Control and Prevention and by the National Health Authorities in Italy, these are not widely implemented yet at local level., Study Design: We report our program for the screening of Latent Tuberculosis Infection and active Tuberculosis in asylum seekers, jointly implemented by Public Health Authorities and the Infectious Diseases Department of a tertiary care, teaching hospital in Northern Italy., Methods: We reviewed records of the asylum seekers who were screened at our center via Tuberculin Skin Test and/or Interferon Gamma Release Assay plus chest X-ray and either treated with Isoniazid Preventive Treatment or for active Tuberculosis Disease in case of positive results., Results: We screened 726 migrants, mostly males (97.3%) and from Sub-Saharan Africa (82.2%) and found a high adherence rate for both screening (98.2%) and Isoniazid Preventive Treatment (90.1%). In addition, we found seven cases of active Tuberculosis., Conclusions: Latent Tuberculosis Infection screening and treatment proved feasible in our program, which should be systematically implemented in asylum seekers reaching Europe.

Background: Predictive biomarkers of response to chemotherapy plus antiangiogenic for metastatic colorectal cancer (mCRC) are lacking. The objective of this study was to test the prognostic role of splenomegaly on baseline CT scan., Methods: This study is a sub-study of PRODIGE-9 study, which included 488 mCRC patients treated by 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) and bevacizumab in first line. The association between splenic volume, and PFS and OS was evaluated by univariate and multivariable Cox analyses. The relation between circulating monocytic Myeloid derived suppressor cells (mMDSC) and splenomegaly was also determined., Results: Baseline splenic volume > 180 mL was associated with poor PFS (median PFS = 9.2 versus 11.1 months; log-rank p = 0.0125), but was not statistically associated with OS (median OS = 22.6 versus 28.5 months; log-rank p = 0.1643). The increase in splenic volume at 3 months had no impact on PFS (HR 0.928; log-rank p = 0.56) or on OS (HR 0.843; log-rank p = 0.21). Baseline splenic volume was positively correlated with the level of baseline circulating mMDSC ( r = 0.48, p -value = 0.031)., Conclusion: Baseline splenomegaly is a prognostic biomarker in patients with mCRC treated with FOLFIRI and bevacizumab, and a surrogate marker of MDSC accumulation.

Community-acquired pneumonia (CAP) is the leading cause of death among infectious diseases and an important health problem, having considerable implications for healthcare systems worldwide. Despite important advances in prevention through vaccines, new rapid diagnostic tests and antibiotics, CAP management still has significant drawbacks. Mortality remains very high in severely ill patients presenting with respiratory failure or shock but is also high in the elderly. Even after a CAP episode, higher risk of death remains during a long period, a risk mainly driven by inflammation and patient-related co-morbidities. CAP microbiology has been altered by new molecular diagnostic tests that have turned viruses into the most identified pathogens, notwithstanding uncertainties about the specific role of each virus in CAP pathogenesis. Pneumococcal vaccines also impacted CAP etiology and thus had changed Streptococcus pneumoniae circulating serotypes. Pathogens from specific regions should also be kept in mind when treating CAP. New antibiotics for CAP treatment were not tested in severely ill patients and focused on multidrug-resistant pathogens that are unrelated to CAP, limiting their general use and indications for intensive care unit (ICU) patients. Similarly, CAP management could be personalized through the use of adjunctive therapies that showed outcome improvements in particular patient groups. Although pneumococcal vaccination was only convincingly shown to reduce invasive pneumococcal disease, with a less significant effect in pneumococcal CAP, it remains the best therapeutic intervention to prevent bacterial CAP. Further research in CAP is needed to reduce its population impact and improve individual outcomes.

A global cross-sectional survey was performed to gather data on the current treatment of infections caused by multidrug-resistant (MDR) bacteria among hematological patients admitted to ICUs worldwide. The survey was performed in April 2019 using an electronic platform (SurveyMonkey®) being distributed among 83 physicians and completed by 48 (57.8%) responders. ESBL Enterobacteriaceae, carbapenem-resistant K. pneumoniae and carbapenem-resistant P. aeruginosa were the main concerns. Previous MDR infection (34% of responders), MDR colonization (20%) and previous antibiotic exposure within the last 3 months (20.5%) were considered the most relevant risk factors of bloodstream infection (BSI) due to MDR bacteria. In 48.8% of the ICUs, there was no antimicrobial stewardship (AMS) team focused on hematological patients. Updates on local epidemiology of MDR pathogens were provided in 98% of the centers, using phone or verbal communications (56.1% and 53.7%, respectively). In presence of febrile neutropenia, initial therapy consisted of anti-Gram-negative plus anti-Gram-positive antibiotics for 41% of participants. Antibiotic de-escalation and/or discontinuation of therapy were considered as a promising strategy for the prevention of MDR development (32.4%). Factors associated with antibiotic de-escalation were clinical improvement (43.6%) and neutrophil count recovery (12.8%). Infectious Disease consultation and AMS interventions were not determining factors for de-escalation decisions (more than 50% of responders). Infection control and educational programs were valued as necessary measures for implementation by ICU practitioners. These findings should guide future efforts on collaborative team working, improving compliance with adequate treatment protocols, implementing antimicrobial stewardship programs in critically ill hematological patients, and educational activities.

Purpose of Review: Overview of influenza infection, focusing on outcome and complications in critically ill patients. We also discuss relevant elements in immunopathogenesis and their role as predictors of severity., Recent Findings: Pandemic influenza A (H1N1) virus circulates seasonally and remains the predominant subtype among intensive care patients. Mortality in acute respiratory failure (ARF) is around 20%, independent of influenza subtypes. During severe infection, the imbalance between pro-inflammatory and anti-inflammatory molecules, such as Th1 and Th17 cytokines, is associated with complicated infections and mortality. Primary viral pneumonia presents in more than 70% of ICU influenza patients and more than 50% develop acute respiratory distress syndrome. Bacterial secondary infection occurs in 20% of severe cases and Streptococcus pneumoniae and Staphylococcus aureus remain the prevalent pathogens. Myocarditis and late-onset cardiovascular complications are associated with mortality. Antiviral therapy within 48 h after onset, avoidance of corticosteroids and rescue therapies for ARF or myocarditis, such as extracorporeal membrane oxygenation, improve survival., Summary: The present review summarizes current knowledge on pathogenesis and clinical manifestations of severe influenza. Immunological dysfunction during viral infection correlates with severity and mortality among ICU patients. A theranostics strategy should be implemented to improve outcomes.

Introduction : Treatment of ventilator-associated pneumonia (VAP) is a major challenge. The increase in multi-drug resistant bacteria has not been accompanied by the validation of new drugs, or by any new antimicrobial strategies to exploit the available agents. VAP due to Gram-negative bacteria has increased mortality, both due to the resistant pathogens themselves and due to inappropriate treatment. Local epidemiology, patients' characteristics and clinical responses provide the most important information for therapeutic decision-making. Moreover, data on VAP therapy due to resistant bacteria are lacking, and the choice of treatment is often based on clinical practice and individual experience. Areas covered : This review summarizes the strategies available for treating the three most prevalent resistant Gram-negative organisms causing VAP: Pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacteriaceae. The review covers the results of a Pubmed search, clinical practice guidelines and reviews, and the authors' experience. Expert opinion : The existing evidence focuses on bloodstream infections or other sites rather than pneumonia and there are no recommendations for the treatment of VAP by multi-drug resistant Gram-negative bacteria, especially for combination regimens. The approval of new drugs is needed to provide effective and safe alternatives for treating carbapenemase-producing strains. Precision medicine and personalized approach are also fundamental in future research.

Introduction: Data are lacking with regard to curative resection of metastasis from small bowel adenocarcinoma (SBA). This study evaluated outcomes and prognostic factors in patients with curatively resected metastatic SBA., Methods: A series of 34 patients undergoing resection of metastatic SBA from January 2009 to November 2014 at French centers were included into this cohort study. The primary endpoint was overall survival (OS). Secondary endpoints were recurrence-free survival (RFS) and prognostic factors. Univariate analyses were performed to determine prognostic risk factors., Results: The sites of SBA metastases were peritoneal (29.4%), liver (26.5%), lymph nodes (11.8%), lung (2.9%), multiple (14.7%), and other (14.7%). Thirty (88.2%) patients received adjuvant or perioperative chemotherapy, mainly was oxaliplatin-based (76.5%). The median OS was 28.6 months and RFS was 18.7 months. Fourteen (41.2%) patients survived for more than 36 months. In univariate analysis, poor differentiation (P = 0.006), invaded margins (P = 0.003), and lymphatic invasion in the primary tumor (P = 0.039) were associated with decreased OS., Conclusion: Overall survival of patients after resection of metastatic SBA remains poor, but long-term survivors are observed. Resection of metastatic SBA should be consider if patients are expected to be operated on with curative intent and have moderately or well-differentiated tumors., (Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

HIV/HCV coinfection is associated with accelerated progressive liver disease. Understanding the pathogenesis of liver fibrosis remains crucial to improving the global management of this patient population. This review will mainly focus on the mechanisms involved in the faster progression of liver fibrosis seen in HIV/HCV coinfection, which is caused by a multiplicity of complex factors including virus features, the immune system, interactions between viruses and the immune response, the direct effects of HIV on hepatocytes, fibrinogenetic/inflammatory mediators, microbial translocation, and metabolic abnormalities. The direct role of viruses as well as chronic inflammation, deterioration of immune status, and the harmful effect of antiretroviral agents may all concur to produce dyslipidemia and insulin resistance. Metabolic abnormalities play an important role in the genesis of hepatic steatosis, which is closely linked to liver fibrosis progression. There is also a link between immunologic and metabolic abnormalities: increased expression of leptin and reduced expression of adiponectin seems to be associated with advanced hepatic injury. New antifibrotic strategies are outlined. Ultimately, sustained virological response to hepatitis C therapy is associated with liver fibrosis regression in patients with HIV/HCV coinfection.

Objectives: Sézary syndrome (SS) is characterized by erythroderma, generalized lymphadenopathy, and the presence of circulating atypical lymphocytes, which are difficult to identify by morphologic data., Methods: We revised our series of 107 patients in an attempt to better define the phenotypic aberrancies in blood at diagnosis and the immunophenotypic stability over time detected by flow cytometry. Polymerase chain reaction assay was also used to study CD26/dipeptidyl peptidase IV (DPPIV) gene methylation., Results: The most common aberrancies were represented by the lack of CD26 (96/107) or CD38 (101/107) expression and the presence of a "dim" CD3, CD4, or CD2 population. There was a high variability in CD7 expression. In total, 31% of the patients had phenotypical heterogeneity in CD26 and CD7 expression at diagnosis. The phenotype was stable over time in 73 of 95 patients with available follow-up data, while 22 of 95 patients developed changes in CD26, CD7, or CD2 expression. CD4+CD26- SS showed hypermethylation of the CpG islands for the promoter region of CD26/DPPIV. Multivariate analysis showed that CD26 expression is a favorable prognostic factor (hazard ratio, 2.94; P = .045)., Conclusions: We confirm the relevance of CD26 negativity in SS diagnosis and monitoring. Nevertheless, the presence of rare CD26+ cases suggests that a multiparameter flow cytometry approach should be used. Changes in methylation profile could account for phenotypical heterogeneity., (Copyright© by the American Society for Clinical Pathology.)

Analysis of p34cdc2 kinase in higher eukaryotes has demonstrated that p34cdc2 function is conserved in all eukaryotic cells. The p34cdc2 kinase (the product of the cdc2 gene) is required during the G1 cell cycle phase at the initiation of DNA replication and also in G2-M phases for entry into mitosis. In this paper we report the isolation and characterization of a cdc2 Petunia hybrida PCR fragment (cdc2Pet). Using a DNA probe based on this fragment and a p34cdc2-specific antibody, cdc2Pet transcript and p34 protein levels were found to be constant both in 2C nuclei of highly proliferating mesophyll 2C cells derived from protoplasts and in 2C nuclei isolated directly from expanded petunia leaves. Both the cdc2Pet transcript and p34cdc2 protein levels were found to be higher in nuclei at 4C than in those at 2C, even when these 4C nuclei were from non-proliferating tissue. Thus cdc2Pet mRNA and protein levels measured in different tissues should not be interpreted to reflect exclusively the proliferative state of the tissue but also the frequency of G2 cells including those in the differentiated state.