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Background: Chronic obstructive pulmonary disease (COPD) represents an important health challenge, despite being preventable and manageable thanks to up-to-date recommendations. In Italy, the pharmaceutical care of COPD patients is still ill-timed and inaccurate. This study aimed to describe the treatment of COPD patients in Italy and possible switches following an exacerbation., Methods: This observational retrospective analysis of Italian administrative healthcare data from the Fondazione Ricerca e Salute (ReS) database identified patients aged ≥ 45 years with COPD in 2019 and 2020. At least 6 years of look-back period and absence of concomitant asthma were required. COPD patients were categorized by treatment (SI-single/MI-multiple inhalers, TT-triple therapy, DT-dual therapy, other respiratory treatments, untreated) at index date (first dispensation during accrual period). Occurrence of moderate/severe exacerbation during one-year preceding index date and treatments during one-year preceding the exacerbation (possible switch) were evaluated., Results: From ~ 4.7 million beneficiaries of the Italian National Health Service in 2019 and 2020, respectively, 105,828 and 103,729 (43 and 41 × 1,000 inhabitants aged ≥ 45 years) were identified as having COPD. Of 2019/2020 patients: 3.4%/5.2% received SI-TT, 20.7%/17.5% MI-TT, 35.9%/38.1% DT, 33.0%/33.1% other treatments, and 7.0%/6.0% were untreated. Males were prevalent and median age was > 73 years for all groups. Of 2019/2020 cohorts, heart failure and coronary artery disease affected 24/20%, 18/17%, and 11%/16% patients with SI-TT, MI-TT, DT, and other treatments, respectively. A previous moderate/severe exacerbation (2019/2020 patients) occurred to 60.5%/56.6%, 39.9%/37.4%, 30.8%/29.2% and 31.9%/29.7% patients treated with SI-TT, MI-TT, DT, and other treatments, respectively. Of 2019/2020 patients experiencing moderate/severe exacerbation: 6.0%/7.0% receiving DT, 5.1%/7.0% receiving other treatments and 4.5%/10.0% untreated, switched to SI-TT; 23.7%/16.9% receiving DT, 21.4%/17.7% receiving other treatments and 15.4%/12.0% untreated, switched to MI-TT., Conclusions: COPD patients receiving TT were older and had more comorbidities, especially cardiovascular diseases, than patients receiving DT or other treatments. The limited number of patients switching after exacerbation suggests that many COPD patients may be inappropriately treated. Ensuring early and adequate treatment, combination of in-hospital and outpatient management, and integration of specialist and primary care is pivotal for the appropriate clinical management of COPD patients., (© 2024. The Author(s).)

The optimal management of bone tumors requires a multidisciplinary strategy to guarantee high-quality care. At specialized centers, the medical team responsible for managing patients with bone cancer comprises oncologists, surgeons, radiologists, pathologists, and rehabilitation specialists. The goal of treatment is to achieve long-term survival with minimal disability and pain. Postoperative rehabilitation is a fundamental therapeutic approach to enhance functionality and sustain the utmost quality of life following a limb-sparing surgery. Currently, megaprostheses are used for reconstructing bone defects after tumor resection, but in the literature, only a few studies have investigated rehabilitation outcomes in terms of functionality and impact on daily activities. This narrative review explores the functional and quality of life outcomes after the implantation of MUTARS ® prostheses in patients with lower extremity bone tumors. A comprehensive search was conducted on PubMed and Scopus using the following MESH terms: "MUTARS", "Megaprosthesis", "bone", "tumors", "metastasis", "lower limb", "rehabilitation", "outcome", and "quality of life", and 10 studies were included. The most frequent oncological pathology was found to be primitive bone tumors treated with modular prostheses. The outcome measures used were the Henderson et al. classification, Harris Hip Scale, Musculoskeletal Tumor Society score, Visual Analog Scale, Range Of Motion, Karnofsky Performance Scale, and quality of life questionnaire. MUTARS ® is a well-established treatment option after bone tumor resection, although it involves extensive and complex post-resection reconstruction that exposes joints and tissues to substantial mechanical stress. Proper rehabilitation after MUTARS ® surgery is a fundamental therapeutic step, although there is still insufficient evidence in the literature focusing on functional and rehabilitative outcomes. Therefore, more studies and guidelines are needed to define standardized rehabilitation protocols for clinical practice after orthopedic oncologic surgery.

Introduction: The diffuse large B-cell lymphoma (Dlbcl) is the most common non-Hodgkin lymphoma and at highest incidence among the elderly. Despite the improved outcomes of patients treated with the first-line (1L) standard of care until the end of 2022, composed by rituximab and polychemotherapy (R-Chop), during the last 20 years, the rate of relapsed and refractory Dlbcl (rrDlbcl) remains elevated. This study has identified and analyzed patients newly diagnosed with Dlbcl and treated with 1L, from the perspective of the Italian National Health Service (Ssn)., Methods: From the administrative database of Fondazione Ricerca e Salute (ReS) including ~5.5 million inhabitants/year in Italy, adults with a new in-hospital Dlbcl diagnosis (index date) and treated with 1L in 2018, 2019, 2020 and 2021 were identified and characterized in terms of demographics and comorbidities during a period (from 4 to 8 years) preceding index date. From 1 to 4 years following index date (follow-up), overall survival (Kaplan-Meier curves), percentage distribution of patients by line of therapy including dispensation/administration of chemo-immunotherapy, hemopoietic stem cell transplantation (Hsct), and direct healthcare costs charge to the Ssn, were evaluated., Results: Overall, from the ReS database, 206 patients newly diagnosed with Dlbcl and treated with 1L from 2018 to 2021 in Italy (incidence from 0.9 to 1.7 x100,000 adult inhabitants) were identified. They were mainly older (median age 68 [56; 75] years), males (56%) and affected by ≥2 comorbidities (52%), mostly cardiometabolic. During 4 years of follow-up, 56% of cases in 2018 survived. During the first follow-up year: 73%, 80%, 100% and 35% of cases in 2018, 2019, 2020 and 2021, respectively, received a 2L; 42% and 64% of cases in 2018 and 2020, respectively, received a 3L. At least one Hsct was found as a 2L among cases in 2018, 2020 and 2021. On average, each patient newly diagnosed with Dlbcl and treated with 1L from 2018 to 2021 caused a total expenditure directly charged to the Ssn ranging from € 20,000 to € 30,000 during the first follow-up year (chemo-immunotherapy accounted for 40-53%), which reduced with time in favor of other drugs and Hsct., Conclusions: This analysis confirms the high rate of rrDlbcl and the high economic impact charged to the SSN to support first the chemo-immunotherapy, then the chronic care and the absence of standardized further lines of therapy for patients with rrDlbcl.

Introduction: Exacerbations of chronic obstructive pulmonary disease (COPD) can increase the risk of severe cardiovascular events., Objective: Assess the crude incidence rates (IR) of cardiovascular events and the impact of exacerbations on the risk of cardiovascular events within different time periods following an exacerbation., Methods: COPD patients aged ≥45 years between 01/01/2015 and 12/31/2018 were identified from the Fondazione Ricerca e Salute administrative database. IRs of severe non-fatal and fatal cardiovascular events were obtained for post-exacerbation time periods (1-7, 8-14, 15-30, 31-180, 181-365 days). Time-dependent Cox proportional hazard models compared cardiovascular risks between periods with and without exacerbations., Results: Of 216,864 COPD patients, >55 % were male, mean age was 74 years, frequent comorbidities were cardiovascular, metabolic and psychiatric. During an average 34-month follow-up, 69,620 (32 %) patients had ≥1 exacerbation and 46,214 (21 %) experienced ≥1 cardiovascular event. During follow-up, 55,470 patients died; 4,661 were in-hospital cardiovascular-related deaths. Among 10,269 patients experiencing cardiovascular events within 365 days post-exacerbation, the IR was 15.8 per 100 person-years (95 %CI 15.5-16.1). Estimated hazard ratios (HR) for the cardiovascular event risk associated with periods post-exacerbation were highest within 7 days (HR: 34.3, 95 %CI: 33.1-35.6), especially for heart failure (HR 50.6; 95 %CI 48.6-52.7) and remained elevated throughout 365 days (HR 1.1, 95 %CI 1.02-1.13)., Conclusions: COPD patients in Italy are at high risk of severe cardiovascular events following exacerbations, suggesting the need to prevent exacerbations and possible subsequent cardiovascular events through early interventions and treatment optimization., Competing Interests: Declaration of competing interest APM received personal fees for the participation in clinical studies supported by Bayer, Novartis, Sanofi and Astra Zeneca, outside the present work. PR participated as a lecturer and advisor in scientific meetings and courses under the sponsorship of Almirall, AstraZeneca, Biofutura, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Menarini Group, Mundipharma, and Novartis, and her department was funded by Almirall, Boehringer Ingelheim, Chiesi Farmaceutici Novartis, and Zambon. FD received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events from Alfa Wassermann, Alfasigma, AstraZeneca, Bayer, Boehringer, BMS/Pfizer, Daiichi Sankyo, IL, GSK, Menarini, Novartis, Sandoz, Sanofi, Tillots Pharma AG. CN is an AstraZeneca employee and declares that her collaboration to this manuscript reflects only personal opinions. KR is an AstraZeneca employee and shareholder and declares that her collaboration to this manuscript reflects only personal opinions. The other authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: The role of rehabilitation during and after the COVID-19 pandemia was influenced by the progressive acquisition of knowledge on the pathology with the adaptation of the rehabilitative instruments to the heterogeneous impairments of the patients. The aim of this systematic review is to describe the effects of the rehabilitation tools applied in the last three years in the different phases of the COVID-19 disease., Evidence Acquisition: A literature search of MEDLINE (PubMed), Scopus and Physiotherapy Evidence Database (PEDro) was conducted. 2994 participants were included in this systematic review: 1225 patients for acute-COVID, 1331 patients for post-COVID, 438 patients for long-COVID., Evidence Synthesis: Of the initial 907 hits only 45 randomized controlled trials were included. The Cochrane library assessment tool was used to evaluate the risk of bias. The trials selected studied the effects of respiratory rehabilitation alone or in association with exercises, tele-rehabilitation, endurance training, virtual reality, electrostimulations in different settings and phases of the infection with the evaluation of clinical, quality of life and impairment outcome measures., Conclusions: All the rehabilitations tool were used based on the experts' opinion and on the rules of good clinical practice, during and after the pandemic period. Despite the heterogeneity of the studies, the different outcome measures and the small sample sizes, pulmonary rehabilitation, tele-rehabilitation and low/moderate intensity aerobic and endurance exercises seemed to improve clinical and quality of life outcomes at short (8 weeks) and mean time (2 months) after treatments in all phases of the infection.

The global cases of knee osteoarthritis (KOA) are projected to increase by 74.9% by 2050. Currently, over half of patients remain dissatisfied with their pain relief. This review addresses unmet needs for moderate-to-severe KOA pain; it offers evidence and insights for improved management. Italian experts from the fields of rheumatology, physical medicine and rehabilitation, orthopedics, primary care, and pain therapy have identified several key issues. They emphasized the need for standardized care protocols to address inconsistencies in patient management across different specialties. Early diagnosis is crucial, as cartilage responds better to early protective and structural therapies. Faster access to physiatrist evaluation and reimbursement for physical, rehabilitative, and pharmacological treatments, including intra-articular (IA) therapy, could reduce access disparities. Concerns surround the adverse effects of oral pharmacological treatments, highlighting the need for safer alternatives. Patient satisfaction with corticosteroids and hyaluronic acid-based IA therapies reduces over time and there is no consensus on the optimal IA therapy protocol. Surgery should be reserved for severe symptoms and radiographic KOA evidence, as chronic pain post-surgery poses significant societal and economic burdens. The experts advocate for a multidisciplinary approach, promoting interaction and collaboration between specialists and general practitioners, to enhance KOA care and treatment consistency in Italy.

Background: Atopic dermatitis (AD) is a heterogeneous disease, associated with comorbidities, and high healthcare consumptions and costs. This study assessed the burden before and after treatment with dupilumab in adults with severe AD from 2018 to 2020, from the perspective of the Italian National Health Service (SSN)., Methods: From Fondazione Ricerca e Salute's administrative healthcare database (~5 million inhabitants/year), adults treated with dupilumab from 09/01/2018 to 31/12/2020 (index date) and a five-year lookback were identified. Age, sex and comorbidities at baseline, concomitant drugs, overnight hospitalizations, outpatient specialist services and direct costs charged to the SSN one year before/after index date were assessed., Results: Of 337 adults treated with dupilumab (5.8x100,000 adult inhabitants/2019; 8.0x100,000/2020; 55% males; mean age 43±19), 68% (228/337) had ≥12-month follow-up available. Asthma was a common comorbidity (23% patients). Rates of patients treated with nearly all concomitant AD-related therapies reduced from 12 months before to 12 months after dupilumab treatment: antibacterials (from 59% to 50%), systemic corticosteroids (55% to 29%), antihistamines (54% to 38%) and cyclosporine (52% to 7%). A similar trend was observed among patients with asthma as comorbidity. Within 12 months before/after dupilumab, patients hospitalized halved from 14% to 7%, and patients receiving outpatient specialist care reduced from 72% to 65%. Annual mean direct total costs per patient treated with dupilumab charged to the SSN, net of dupilumab cost, were €1384 and €773, before and after dupilumab dispensation, respectively., Conclusions: Before dupilumab, observed patients had higher healthcare resource consumptions and direct SSN costs than after dupilumab.

Background. Patients with chronic kidney disease (CKD) can be successfully treated with sodium-glucose cotransporter-2 inhibitors (SGLT2-Is), regardless of diabetes. Fondazione Ricerca e Salute's (ReSD) administrative and Health Search's (HSD) primary care databases were combined in the Database Consortium ReS-HS to quantify and describe patients with CKD potentially eligible for SGLT2-Is and assess costs charged to the Italian National Health Service (SSN). Methods. Patients aged ≥18 with CKD and estimated glomerular filtration rate (eGFR) <60 ml/min in 2018, without dialysis and/or renal transplantation, were included. HSD was used to develop and validate algorithms for estimating eGFR, based on covariates, within the ReSD. Comorbidities, dispensed drugs, and direct healthcare costs were assessed. Results. In 2018, 66,297 (5.0% of HSD population) and 211,494 (4.4% of ReSD population) patients with CKD potentially eligible for SGLT2-Is were identified (females ≥58%). Prevalence increased with age with a peak at 75-84 years. Within HSD and ReSD cohorts, respectively: 31.0% and 41.5% had diabetes; in the observation periods, >82% and >96% received ≥1 pharmacological treatment, of which ≥50% and ≥25% received cardiovascular/blood agents and antidiabetics, respectively. From ReSD, mean per capita direct SSN cost was € 3,825 (CI 95%, € 3,655-€ 4,000): 50.1% due to hospitalizations, and 40.2% to pharmaceuticals (31.6% to cardiovascular drugs and 10.1% to antidiabetics). Conclusion. The Database Consortium ReS-HS methodology found 5% of adult SSN beneficiaries with CKD potentially eligible for SGLT2-Is bringing with them a high cardio-metabolic burden which increases the risk of CKD progression., (Copyright by Società Italiana di Nefrologia SIN, Rome,Italy.)

Background: Knee osteoarthritis is a degenerative and inflammatory disease causing pain and worsening patients' quality of life. Various conservative treatment options exist, but a gap between scientific evidence and clinical practice is still present. The aim of this prospective multicenter observational study is to describe the real outpatient territorial management of patients with knee osteoarthritis and to analyze the correlation between the anthropometric and clinical characteristics of the population of patients suffering from symptomatic knee osteoarthritis who were screened in the national survey. Methods: The educational national project was divided into three modules: the first and the last through webinars; and the second held in daily practice. The participants had to register structured observations, which were then stored in a national database and analyzed in order to identify correlations. The subgroups were stratified by body composition, radiological severity of knee osteoarthritis, pain, and functional ability. Results: The project has been joined by 155 physicians, and 2.656 observations about real-world outpatients being treated for knee osteoarthritis in Italy were collected. Data relating to real-world pharmacological and rehabilitation therapies in correlation with body composition, the radiological severity of knee osteoarthritis, pain, and functional ability were reported. Conclusions: Currently, there are no standardized protocols using effective combinations of therapeutic exercises, physical agents, and medications to control the progression of knee osteoarthritis. This real-word national survey proved to be useful for describing the current state of the art of therapeutic management of knee osteoarthritis and for emphasizing the need to fill the gap between scientific evidence and clinical practice., Competing Interests: The authors declare no conflicts of interest.

Objectives: Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease with significant impact on morbidity, mortality, and quality of life. This study aimed to evaluate epidemiology, healthcare needs and related costs of pSS patients from the Italian National Health Service perspective., Methods: From the Fondazione Ricerca e Salute's database (∼5 million inhabitants/year), pSS prevalence in 2018 was calculated. Demographics, mean healthcare consumptions and direct costs at one year following index date (first in-hospital diagnosis/disease waiver claim) were analysed through an individual direct matched pair case-control analysis (age, sex, residency)., Results: In Italy, 3.8/10,000 inhabitants were identified as affected by pSS (1,746 case: 1,746 controls) in 2018. In the year following index date, 53.7% of cases and 42.7% of controls received ≥1 drug (p<0.001); mean per capita cost was €501 and €161, respectively (p<0.01). At least one hospitalization occurred to 7.8% of cases and 3.9% of controls (p<0.001) with mean per capita costs of €416 and €129, respectively (p = 0.46). At least one outpatient specialist service was performed in 49.8% of cases and 30.6% of controls (p<0.001); mean per capita costs were €200 and €75, respectively (p<0.01). Overall, mean annual costs were €1,171 per case and €372 per control (p < 0.01)., Conclusion: According to results of this population-based study, the prevalence of pSS in Italy appears to be consistent with the definition of rare disease. Patients with pSS have higher pharmacological, in-hospital and outpatient specialist care needs, leading to three-times higher overall cost for the INHS, compared to the general population., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Over the last few decades, the use of neo/adjuvant therapies has significantly increased the number of breast cancer survivors who experience chemotherapy-induced peripheral neuropathy (CIPN). To date, few, low-efficacy, pharmacological remedies exist to manage this side effect. For this reason, alternative treatments are increasingly being investigated as possible strategies to prevent or promote faster recovery from CIPN. In this review we aimed to provide an overview of the literature evidence regarding all the non-pharmacological and rehabilitative interventions for patients affected by CIPN secondary to breast cancer care., Evidence Acquisition: A comprehensive literature search was conducted on PubMed, Scopus and Web of Science and included a total of 1895 patients (1528 with breast cancer) with a wide range of CIPN (motor, sensory and autonomic neuropathies) and chemotherapy treatments (e.g., Taxanes, Platins, Vinca alkaloids or monoclonal antibody drugs)., Evidence Synthesis: Of the initial 1108 hits, only 25 studies - describing different treatment modalities for peripheral neuropathies - were finally included in the qualitative synthesis. Most studies focused on acupuncture, physiotherapy, cryotherapy, and yoga., Conclusions: There is still controversial evidence on conservative non-pharmacological interventions for the management of CIPN symptoms. We believe however that moderate exercise, as well as all types of stress reducing activities like sport, yoga and mindfulness, should be encouraged in cancer patients for their positive effect on global physical and psychological health. Further studies of higher methodological quality are needed to determine the best conservative approach to CIPN.

Pain represents a common symptom of several diseases and is often associated with a reduction in rehabilitation outcomes and recovery. The effectiveness of pain alleviation by botulinum toxin has been recently demonstrated. We searched in PubMed the papers about this topic published in the last ten years, and we selected clinical trials, guidelines, meta-analyses, reviews, and systematic reviews. We used different approaches: multiperspective presentation, lexical evaluation, and systematic review. The systematic review was only performed for the randomized controlled trials. We predominantly found reviews and trials about the rehabilitation of stroke/brain injury and epicondylitis. The most common outcome measures were pain, function, and spasticity. Among the common words, pain was the most frequent and the terms were grouped into different families, especially concerning the outcomes. Rehabilitation showed a relatively low frequency. Finally, the systematic review showed moderate-low levels of bias which confirms the effectiveness of botulinum toxin for pain treatment. The current literature about botulinum toxin is wide and globally diffuse but with some limitations in study strategies and clearness in the formal presentation. The evidence justifies the use of botulinum toxin in treating pain in different diseases.

Musculoskeletal pain is a common symptom of Parkinson's disease (PD) that is not adequately treated with current dopaminergic drugs. This pilot study sought to investigate the effect of focal muscle vibration (fMV) on a group of Parkinson's disease patients suffering from chronic cervical pain. In addition to conventional physiotherapy, twenty-two patients with idiopathic Parkinson's disease (Hoehn and Yahr stages II-III) received three weeks of bilateral focal musclevibration to the trapezius muscles. The Visual Analogue Scale (VAS), the Short-form McGill, and the Present PainIntensity scales were used to assess pain at baseline (T0), after three weeks of treatment (T1), one week after the last treatment session (T2), and three weeks after T2 (T3). Pain intensity decreased significantly from baseline to T1 across all pain scales (p < 0.0001). Furthermore, the beneficial effect of fMV on cervical pain lasted up to one month after treatment. Our findings show that fMV, in combination with conventional physiotherapy, is effective at reducing pain intensity in PD patients, with results visible even after a month of follow-up.

Parkinson's disease (PD) is defined by progressive worsening of gait, posture, and balance, as well as disability in daily life activities, and improvement in chronic musculoskeletal pain, particularly neck pain associated with worsening of balance. The study's goal is to look into the relationship between scoliosis, balance, and cervical pain in Parkinson's disease patients. Cross-sectional, pilot study. The study included 16 Parkinson's patients. Neck cervical pain was measured using the pain visual analogue scale and the short form McGill pain questionnaire, while dynamic balance was assessed using static balance, Tinetti, Berg Balance, and the Short Physical Performance Battery scales (SPPB). Cobb angles are measured on a whole-spine standard X-ray to assess spinal scoliosis.An observational statistical analysis was performed with patients subdivided into two groups: non-scoliosis (NS) and true scoliosis (TS) based on whether they presented a Cobb's angle below or ≥10°. Neck pain was reported by 37% (n=3) of participants in the NS group versus 50% (n=4) in the TS group. Neck pain was more prevalent in patients with a disease duration of less than 48 months (n=6; 75.0% vs n=1; 12.5%; p-value < 0.05). Scoliosis, cervical pain, and postural imbalance are all significant but often overlooked Parkinson's disease complaints.

Megaprostheses are well-known, reliable, and effective reconstruction prostheses used in oncologic surgery for limb salvage in patients affected by primary or metastatic bone tumors. Rehabilitation plays a major role after MUTARS replacement, with the aim of improving function after surgery and maintaining the highest possible quality of life. Only a few studies have been published about the use of megaprostheses for the upper limb. The aim of this narrative review is to describe the results of functional and rehabilitative outcomes of patients affected by bone primary or metastatic bone cancer of the upper limb and surgically treated with MUTARS prostheses. A comprehensive search was conducted on PubMed and Scopus using the following MESH terms: "Mutars", "Megaprosthesis", "bone", "tumors", "metastasis", "upper limb", "rehabilitation", "outcome", "quality of life", and 10 studies were included. The most frequent oncological pathology was found to be metastases of the proximal humerus treated with modular endoprosthesis or modular reverse implants. Outcome measures used were ROM, MSTS, ASES, DASH, Constant-Murley score, Enneking score, VAS, MEP, TESS, and WOSI. Reconstruction of the proximal humerus with the MUTARS system seemed to be a valid treatment option after bone tumor resection. Rehabilitation after MUTARS surgery is very relevant, but currently, functional and rehabilitative outcomes are inadequately represented in the literature. Hence, further studies are needed to define standardized rehabilitation protocols after oncological orthopedic surgery that can be applied routinely in clinical practice.

Mast cells (MCs) are derived from hematopoietic progenitors, mature in vascularized tissues, and participate in innate and acquired immunity. Neuroinflammation is a highly debated topic in the biomedical literature; however, the impact of tumor necrosis factor (TNF) and IL-33 on MCs in the brain has not been widely addressed. MCs can be activated by IgE binding to FcεRI, as well as by different antigens. After activation, MCs mediate various immunological and inflammatory responses through TNF and IL-33. TNF has two receptors: TNFR1, a p55 molecule, and TNFR2, a p75 molecule. This cytokine is the only one of its kind to be stored in the granules of MCs and can also be generated by de novo synthesis via mRNA. In the central nervous system (CNS), TNF is produced almost exclusively by microglial cells, neurons, astrocytes, and, minimally, by endothelial cells. After its release into brain tissue, TNF rapidly induces the adhesion molecules endothelial leukocyte adhesion molecule 1 (ELAM-1), intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) in endothelial cells. TNF causes the chemoattraction of neutrophils by inducing several molecules, including CXC chemokines (IL-8). Both MCs and microglial cells act as a primary barrier against foreign molecules in the CNS, producing pro-inflammatory cytokines such as IL-33. IL-33 belongs to the IL-1 family, is activated through the ST2L/IL1-RAcP receptor complex, and mediates both the innate and adaptive immune response. IL-33 is a nuclear transcription factor expressed in the brain, where it induces pro-inflammatory cytokines (TNF and IL-1) and chemokines (CCL2, CCL3, CCL5, and CXCL10). Therefore, MCs and microglia in the CNS are a source of pro-inflammatory cytokines, including TNF and IL-33, that mediate many brain diseases. The inhibition of TNF and IL-33 may represent a new therapeutic approach that could complement existing neuroinflammatory therapies.

According to the latest statistics of the American Cancer Society 2022, breast cancer is a leading cause of morbidity and death among women worldwide. As a result of oncological procedures, breast cancer survivors often complain of pain and disability to the ipsilateral arm and shoulder. Objective: we aimed to analyze the latest literature regarding the efficacy of different rehabilitation treatments in patients affected by shoulder impairment secondary to breast cancer care. A comprehensive literature search was conducted on PubMed, PEDRO and Scopus databases. All English studies, published in the last decade up to March 2023, reporting shoulder problems in adult women treated for breast cancer with partial or total mastectomy ± breast reconstruction, lymphadenectomy, radio-, chemo-, hormonal or biologic therapy were assessed for eligibility. The methodological quality of the included trials was evaluated using the Cochrane bias tool. Of 159 articles identified, 26 were included in qualitative synthesis. Data from 1974 participants with a wide heterogeneity of breast cancer treatments were analyzed in this review. The methodological quality for most included studies was moderate. Several physiotherapy and interventional protocols showed some evidence of efficacy in shoulder range of motion (ROM), upper limb function, strength, pain and quality of life recovery after breast cancer treatment. Both physiotherapy alone or in combination with other techniques significantly improves shoulder disability, pain, and quality of life of patients undergoing breast cancer treatment regardless of their baseline characteristics or the time passed from surgery. The optimal treatment protocol and dosage remain unclear, and more homogeneous studies are needed in order to perform a meta-analysis of the literature., (© 2023. The Author(s).)

Background: Chronic kidney disease-associated pruritus (CKD-aP) affects patients on hemodialysis. This study identified hemodialysis patients presumably affected or not affected by CKD-aP and integrated healthcare costs, from the perspective of the Italian administrative healthcare data., Methods: Through cross-linkage of Italian administrative healthcare data collected between 2015 and 2017 (accrual period) in the database of Fondazione ReS (Ricerca e Salute), patients undergoing in-hospital/outpatient hemodialysis were selected. Cohorts with and without CKD-aP were created based on the presence/absence of CKD-aP-related treatment (according to common clinical practice and guidelines) supplies and assessed in terms of CKD-aP-related treatments and mean healthcare costs per capita paid by the Italian National Health Service (INHS)., Results: Of 1,239 people on hemodialysis for ≥2 years, CKD-aP affected 218 patients. Patients with CKD-aP were older and with more comorbidities. During the follow-up year, on average, the INHS spent €37,065 per case, €31,286 per control and € 35,988 per non-CKD-aP subject. High-efficiency dialytic therapies performed to people on hemodialysis with CKD-aP largely weighed on the overall mean annual cost., Conclusions: This real-world study identified patients on chronic hemodialysis potentially treated for CKD-aP. Interestingly, high-efficiency dialysis seems the most frequent and expensive choice for the treatment of CKD-aP. The discovery of appropriate and effective treatments for this condition might offer cost offsets., (© 2024 The Authors.)

Background: Tactile stimulation manoeuvres stimulate spontaneous breathing in preterm newborns. The aim of this study is to evaluate the effect of early respiratory physiotherapy on the need for mechanical ventilation during the first week of life in preterm infants with respiratory failure., Methods: This is a monocentric, randomised controlled trial. Preterm infants (gestational age ≤ 30 weeks) not intubated in the delivery room and requiring non-invasive respiratory support at birth were eligible for the study. The intervention group received early respiratory physiotherapy, while the control group received only a daily physiotherapy program (i.e., modifying the infant's posture in accordance with the patient's needs)., Results: between October 2019 and March 2021, 133 preterm infants were studied, 68 infants in the study group and 65 in routine care. The study group showed a reduction in the need for mechanical ventilation (not statistically significant) and a statistically significant reduction in hemodynamically significant patent ductus arteriosus with respect to the control group (19/68 (28%) vs. 35/65 (54%), respectively, p = 0.03)., Conclusions: early respiratory physiotherapy in preterm infants requiring non-invasive respiratory support at birth is safe and has proven to be protective against haemodynamically significant PDA.

Intra-articular (IA) ultrasound-guided hip injections are currently considered a cornerstone of the conservative management of symptomatic hip osteoarthritis (HOA), although their effect on clinical outcomes has not been fully elucidated.The purpose of this study is to investigate the effectiveness of ultrasound-guided IA hip injections of hyaluronic acid (HA) with or without corticosteroids (CS) on pain relief and functional improvement in patients with HOA. In total, 167 patients with HOA were assessed at baseline (T0) and 12 months after injection (T1) using the VAS and GLFS scores. The sample consisted mainly of female subjects (58.1%), presenting an average age of 70.6 ± 12.2 years and grade 3 HOA (63.9%) according to the Kellgren-Lawrence classification. Most of the patients (76.2%) underwent unilateral hip injection with a combination of medium-high molecular weight HA (1500-2000 kDa) and CS. At T1, lower use of anti-inflammatory drugs, an increase in the consumption of chondroprotectors, and an overall reduction of instrumental physical therapies and therapeutic exercise were recorded. In addition, a statistically significant intragroup and between-group decrease observed at T1 for both the VAS and GLFS. Study results suggested that intra-articular hip injections with HA alone and with CS could represent a useful therapeutic tool for pain reduction and functional improvement for patients with hip osteoarthritis.

Objective: To identify newly diagnosed patients with acute myeloid leukemia in 2017 treated with intensive chemotherapy or unfit for intensive chemotherapy, and to assess their probability of receiving allogeneic stem cell transplantation and survival, from the Italian National Health Service perspective., Patients and Methods: From the Ricerca e Salute database, adults with an in-hospital diagnosis of acute myeloid leukemia (International Classification of Disease-9th version-Clinical Modification code 205.0x) in 2017 (index date), without any identifying acute myeloid leukemia criteria within the preceding year, were selected. Among them, subjects treated with intensive chemotherapy (chemotherapy during an overnight hospitalization) within one year after index date were identified. The remaining were considered unfit for intensive chemotherapy. Gender, age and comorbidities were described. Within the follow-up period, probabilities of in-hospital allogeneic stem cell transplantation and overall survival were assessed through Kaplan Meier analyses., Results: From 4,840,063 beneficiaries of the Italian National Health Service, 368 newly acute myeloid leukemia diagnosed adults (9.0 *100,000) were selected. Males comprised 57%. Mean age was 68±15. There were 197 patients treated with intensive chemotherapy. The remaining 171 unfit for intensive chemotherapy were older (72±14) and with more comorbidities (e.g. hypertension, chronic lung diseases and chronic kidney disease). Only patients treated with intensive chemotherapy underwent an allogeneic stem cell transplantation (41; 33%) during the one year after the index date. Within the first and second follow-up year, respectively: 41.1% and 26.9% of subjects treated with intensive chemotherapy (144) survived (median survival time: 7.8 months); 25.7% and 18.7% of those unfit for intensive chemotherapy (139) survived (1.2 months). Difference was significant (p<0.0001). Within one and two years after transplantation (41 patients), 73.5% and 67.3% of subjects survived, respectively., Conclusion: This study, by showing the incidence of acute myeloid leukemia in Italy in 2017, the proportion of patients treated with intensive chemotherapy from the new diagnosis, the use of allogeneic stem cell transplantation and two-year survival, integrated evidence on large and unselected populations and may help to improve treatment strategies of older acute myeloid leukemia patients.

Introduction: The neo-vascular age-related macular degeneration (nAmd) is a frequent cause of vision loss, although the intravitreal (Ivt) injections of anti-Vegf (vascular endothelial growth factor) have improved functional outcomes. This study has assessed the healthcare and economic burden on the Italian national health service (Inhs) for patients with nAmd and new users of anti-Vegf., Methods: From the database of Fondazione Ricerca e Salute (ReS), people aged ≥55 and with an in-hospital diagnosis of nAmd and/or an injection of anti-Vegf (aflibercept, ranibizumab, pegaptanib; index date) in 2018 are selected. Those with other conditions treated with anti-Vegf and with an Ivt injection before 2018 are excluded. New users of anti-Vegf are analyzed by sex, age, comorbidities, Ivt administrations, switch of anti-Vegf, local outpatient specialist services (with some focuses) and direct healthcare costs charged to the Inhs Results. In 2018, of 8125 inhabitants aged ≥55 with nAmd (4.6x1000 inhab.; mean age 76±9; F: 50%), 1513 (19%) are new users of Ivt anti-Vegf (mean age 74±9), whose incidence (0.9x1000) increased with age until 84 years old. A proportion of 60.7% had ≥2 comorbidities (mainly hypertension, dyslipidemia and diabetes). Within the 2nd follow-up year, only 598 patients are still treated (60% were lost). On average, 4.8 Ivt injections in the first and 3.1 in the second year are registered. On average, the total cost charged to the Inhs per new user of anti-Vegf was € 6726 (Ivt anti-Vegf accounted for the 76%) and € 3282 (hospitalizations for causes different from nAmd accounted for the 47%), during the first and the second year, respectively., Conclusions: This analysis suggests that in Italy people with nAmd and new users of anti-Vegf are elderly, affected by many comorbidities, treated with Ivt anti-VEGF less than what is required and authorized to achieve a benefit, undergo very few follow-up outpatient specialist visits and tests and, within the 2nd year, their hospitalizations for causes different from nAmd mainly weighs on the total expenditure charged to the Inhs.

Background: Limited data exist to predict the development of psoriatic arthritis (PsA) in patients with psoriasis (PsO)., Objective: To analyze factors associated with incident PsA in patients with PsO, and to develop a predictive algorithm for progression to arthritis using a full set of variables and a restricted one applicable to administrative data., Methods: Cohort study within the PsoReal registry in Italy. Multivariable generalized linear models were used to assess factors associated with PsA and to derive a predictive model., Results: Among 8895 patients, 226 PsA cases were identified (incidence 1.9 per 100 patient-years). Independent predictors in the full model were as follows: female sex, age 40 to 59 years, body mass index ≥ 25, chronic-plaque PsO features, presence of palmoplantar pustulosis, hospitalization for PsO in the last 5 years, and previous use of systemic PsO therapy (area under the receiver operating characteristic curve = 0.74). Female sex, age 40 to 59 years, hospitalization for PsO, and previous use of systemic PsO therapy were independent predictors in the restricted model (area under the receiver operating characteristic curve = 0.72)., Limitations: Lack of other potential predictors for PsA., Conclusion: Our models could be used by clinicians and health authorities when planning intervention and population surveillance. Future studies should confirm our models using larger datasets and additional variables., Competing Interests: Conflicts of interest Dr Naldi has received honoraria as a scientific consultant for Abbvie, Almirall, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Leo, Lilly, Novartis, and Sanofi. Dr Heidemeyer has received honoraria as a scientific consultant for Abbvie and Almirall. The remaining authors have no conflicts of interest., (Copyright © 2023 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Preterm infants can develop many complications related to organs underdevelopment. Respiratory distress syndrome (RDS) is considered the most important cause of morbidity and mortality in these patients. Traditional therapies for severe RDS, such as mechanical ventilation, come with a potential risk for pneumothorax and bronchopulmonary dysplasia while evidence on chest physiotherapy in preterm infants are controversial in terms of feasibility, tolerability and safety. The use of the positive expiratory pressure (PEP) mask is known in the pediatric field especially in cystic fibrosis for the removal of secretions and lung re-expansion. However, no literature exists on the application and effectiveness of this treatment modality for the respiratory rehabilitation of preterm infants. In this study, we aimed to assess the efficacy of a respiratory rehabilitation protocol based on PEP mask in a preterm infant with respiratory distress syndrome., Case Report: A Caucasian girl born at 26 + 5 weeks of gestational age with respiratory distress syndrome was treated with mechanical ventilation, oxygen therapy and PEP-mask., Clinical Rehabilitation Impact: Three weeks of PEP mask led to a significant clinical and radiological improvement of the lung's function with progressive reduction of the oxygen supplement and mechanical ventilation until complete weaning off. Given the absence of literature on this subject, further studies should be conducted to confirm these preliminary observations.

Introduction: The community-acquired pneumonia (Cap) and the acute exacerbation of chronic obstructive pulmonary disease (Aecopd) frequently receive wrong therapies, leading to the increase of healthcare consumption resources, direct and indirect costs, and antimicrobial resistance. This study identified Cap and Aecopd hospitalized events, and analyzed them in terms of comorbidities, antibiotic use, re-hospitalizations, diagnostics and costs, from the perspective of the Italian national health service (Inhs)., Methods: From the database of Fondazione Ricerca e Salute (ReS), hospitalizations for Cap and Aecopd from 2016 to 2019. Demographics, comorbidities and mean in-hospital stay at the baseline, antibiotics reimbursed by the Inhs within 15 days before and after the index event, outpatient diagnostics performed before the event and in-hospital diagnostics, and direct costs charged to the Inhs, are assessed., Results: From 2016 to 2019 (~5 million inhabitants/year), 31,355 events of Cap (1.7x1000/year) and 42,489 events of Aecopd (4.3x1000 inhabitants aged ≥45/year) were identified, of which 32% and 26.5%, respectively, were treated with antibiotics before the hospitalization. The highest frequency of hospitalizations and comorbidities, and the longest mean in-hospital stays are found among elderly. Events not treated before and after the hospitalization showed the longest in-hospital stay. More than 12 Ddd (defined daily dose) are dispensed after the discharge. Local outpatient diagnostics are performed before the admission to <1% of the events; in-hospital diagnostics are registered in 5.6% and 1.2% of Cap and Aecopd, respectively, discharge forms. About 8% and 24% of Cap and Aecopd, respectively, are re-hospitalized during one subsequent year, mainly within one month. The mean expenditures per event of Cap and Aecopd were € 3646 and € 4424, respectively: hospitalizations, antibiotics and diagnostics accounted for the 99%, 1% and <0.1% of the total expense, respectively., Conclusions: This study provided a very high dispensation of antibiotics after the hospitalization for Cap and Aecopd, while a very low use of differential diagnostics available within the observed periods, to the detriment of the enforcement actions proposed at institutional levels.

Mast cells (MCs) are tissue cells that are derived from bone marrow stem cells that contribute to allergic reactions, inflammatory diseases, innate and adaptive immunity, autoimmunity, and mental disorders. MCs located near the meninges communicate with microglia through the production of mediators such as histamine and tryptase, but also through the secretion of IL-1, IL-6 and TNF, which can create pathological effects in the brain. Preformed chemical mediators of inflammation and tumor necrosis factor (TNF) are rapidly released from the granules of MCs, the only immune cells capable of storing the cytokine TNF, although it can also be produced later through mRNA. The role of MCs in nervous system diseases has been extensively studied and reported in the scientific literature; it is of great clinical interest. However, many of the published articles concern studies on animals (mainly rats or mice) and not on humans. MCs are known to interact with neuropeptides that mediate endothelial cell activation, resulting in central nervous system (CNS) inflammatory disorders. In the brain, MCs interact with neurons causing neuronal excitation with the production of neuropeptides and the release of inflammatory mediators such as cytokines and chemokines. This article explores the current understanding of MC activation by neuropeptide substance P (SP), corticotropin-releasing hormone (CRH), and neurotensin, and the role of pro-inflammatory cytokines, suggesting a therapeutic effect of the anti-inflammatory cytokines IL-37 and IL-38.

Introduction: Rheumatoid arthritis (Ra) and diabetes are often associated with chronic multimorbidity and share the high risk of development of major cardiovascular events (Mace). This study aimed to identify and analyse patients with only Ra, Ra + diabetes, and only diabetes, in terms of comorbidities and new occurrence of Cv events, from the perspective of the Italian national health service (Inhs)., Methods: Starting from the Fondazione ricerca e salute (ReS)'s database, through the record linkage of administrative healthcare data, cohorts with only Ra, Ra + diabetes and only diabetes have been selected, characterized (age and sex), and analysed by comorbidity (depression, dyslipidemia, hypertension, hemorrhagic stroke and ischemic stroke/transient ischemic attack - Tia, coronary artery disease - Cad, heart failure - Hf, chronic liver disease, periphery artery disease - Pad, chronic kidney disease, asthma/chronic obstructive pulmonary disease - Copd, neoplasia) and by new Cv events (Hf, Cad and ischemic stroke/Tia) within two follow-up years (Kaplan-Meier curves). A logistic regression model defined contribution and type of association of some variables on new Cv events., Results: In 2018, from 5.375.531 Inhs beneficiaries in the ReS database, 13.698 (0.25%) were affected by only Ra, 1728 (0.03%) by Ra + diabetes, 347,659 (6.8%) by only diabetes. The only Ra cohort was composed by more females, younger and with less comorbidities patients. Proportions of 79.3%, 70.8% and 38.5% of patients with Ra + diabetes, only diabetes and only Ra were affected by 2 to ≥4 comorbidities: among patients with Ra + diabetes, comorbidities showed the highest frequencies, mainly hypertension, dyslipidemia and asthma/Copd. Within two follow-up years, about 8% of patients with diabetes with/without Ra developed a new Cv event (vs 3% with only Ra). The presence of Ra/diabetes or Ra + diabetes, male sex, older age and comorbidities of interest resulted significantly (p<0.01) associated with a higher Cv risk., Conclusions: Comorbidities and the co-presence of diabetes in patients with Ra determine a complicated framework with high risk of Cv events. It is worthy include more complex patients in clinical trials, in order to generate evidence useful for even more multidisciplinary medical teams.

Background: Recent successful findings (i.e. DAPA-HF trial) in patients with heart failure (HF) with/without diabetes treated with sodium-glucose co-transporter inhibitors (SGLT2-I) have fostered real-world data analyses. Fondazione Ricerca e Salute's (ReSD) administrative and Health Search's (HSD) primary healthcare databases were combined in the ReS-HS DB Consortium, to identify and characterize HF-patients eligible to SGLT2-I, and assess their costs charged to the Italian National Health Service (INHS)., Methods and Results: Eligibility to SGLT2-I was HF diagnosis, age ≥ 18 years, reduced (≤40%) ejection fraction (HFrEF) and glomerular filtration rate (GFR) ≥30 ml/min. The HSD, including 13,313 HF-patients (1.5% of the total HSD population) was used to develop and test the algorithms for imputing HFrEF and GFR ≥ 30 ml/min, based on a set of covariates, to the ReSD, including 67,369 (1.5% of the total ReSD population). Subjects eligible to SGLT2-I were 2187 in HSD (61.1% of HFrEF); after the imputation, 15,145 in ReSD (58.8% of HFrEF). Prevalence of eligibility to SGLT2-I was higher in males then in females and increased with age; diabetic patients were 44.3% and 33.4% of HSD and ReSD populations eligible to SGLT2-I, respectively. Estimated from ReSD, the mean annual cost charged to the INHS per patient with HF eligible to SGLT2-I was €7122 (68% due to hospitalizations)., Conclusions: Approximately 20% of patients with HF was eligible to SGLT2-I. Real-world data can identify, quantify and characterize patients eligible to SGLT2-Is and assess related costs for the health care system, thus providing useful information to Regulatory Decision makers., Competing Interests: Declaration of Competing Interest The financial support for this study was provided with a funding agreement ensuring maintenance of author independence in study design, data interpretation, writing, and decisions to publish. APM received personal fees for the participation in clinical studies supported by Bayer, Novartis Italia, Fresenius and AstraZeneca Italia, outside the present work. The other authors declare no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: The adoption of a Care Pathway (CP) allows the healthcare management of patients suffering from high-epidemiological impact chronic diseases. The continuity of care of these patients is one of the main purposes of the community-based healthcare reform, foreseen in the 6th Mission of the National recovery and resilience plan. Fondazio-ne Ricerca e Salute (ReS) collects and analyses regional CPs approved in Italy, through the Pdta Net database., Methods: Fondazione ReS has retrieved all the CPs approved by Italian Regions and Autonomous provinces until 12/31/2021 within institutional websites, through specific keywords. The quali- and quantitative analysis of CPs was based on the approving Region, the publication year, the disease (distinguishing between high-epidemiological impact chronic diseases and rare conditions) and clinical area. Following the 5-year experience gained by Fondazione ReS in terms of CPs' aims and organization for the full realization of an evidence-based healthcare of chronic patients, all data collected until 12/31/2021 underwent an in-depth double-blinded quality control. This control was aimed to make the Pdta Net database as representative as possible of the existing documents closest to a real CP., Results: From 2005 to 2021, 729 regional CPs have been approved: 404 on high-impact chronic diseases and 220 on rare conditions. The CPs of chronic diseases, mostly edited by Piemonte (45 CPs), Campania (34) and Toscana (33) Regions, mainly concern on diabetes (19), chronic obstructive pulmonary disease (15), heart failure (13), stroke, multiple sclerosis and colorectal neoplasms (12 each one), breast cancer (11), dementia and chronic kidney disease (10 each one). Most of the CPs on rare diseases have been edited by Regions with an established Rare Disease Network, i.e., Lombardia (125 CPs), Lazio (74) and Toscana (40): neurology (61) and oncology (52) were the most represented clinical areas., Conclusions: The high number of CPs approved in Italy confirms an increasing interest of the healthcare institutions. The collected CPs show an extreme variety of titles, text structures and disease choices. Given the absence of an institutional observatory and of devotees of shared and harmonized CPs, annually Pdta Net makes available an updated and complete overview of these governance tools, which are essential for the upcoming changes of the Italian national health service.

Objective: Knee osteoarthritis (KOA) is a degenerative and inflammatory disease with a rising incidence and prevalence worldwide. Various therapeutic strategies have been proposed over time, depending on the degrees of severity and usually based on individual clinical practice. However, several European and international scientific societies published guidelines, to provide practical clinical stepwise guidance and to facilitate individualized therapeutic decisions regarding the management of KOA. The aim of this prospective multicentre observational study was to describe the real outpatient territorial management of patients with knee osteoarthritis and to compare it with the ESCEO guidelines, in order to identify operational strategies for delivering patient-centric care., Materials and Methods: The educational project was divided in three modules: the first and the last through webinar; the second held in daily practice. The participants had to register structured observations., Results: The project has been joined by 155 discussants, and the 2,656 observations collected allowed the understanding of the most common therapeutic approaches for knee osteoarthritis on the Italian territory., Conclusions: The educational project proved to be useful for updating on the state of the art of therapeutic management of knee osteoarthritis, and to increase expertise in detecting prevention and treatment strategies according to ESCEO guidelines to apply in the Real-Life context.

Much evidence suggests autoimmunity in the etiopathogenesis of periodontal disease. In fact, in periodontitis, there is antibody production against collagen, DNA, and IgG, as well as increased IgA expression, T cell dysfunction, high expression of class II MHC molecules on the surface of gingival epithelial cells in inflamed tissues, activation of NK cells, and the generation of antibodies against the azurophil granules of polymorphonuclear leukocytes. In general, direct activation of autoreactive immune cells and production of TNF can activate neutrophils to release pro-inflammatory enzymes with tissue damage in the gingiva. Gingival inflammation and, in the most serious cases, periodontitis, are mainly due to the dysbiosis of the commensal oral microbiota that triggers the immune system. This inflammatory pathological state can affect the periodontal ligament, bone, and the entire gingival tissue. Oral tolerance can be abrogated by some cytokines produced by epithelial cells and activated immune cells, including mast cells (MCs). Periodontal cells and inflammatory-immune cells, including mast cells (MCs), produce cytokines and chemokines, mediating local inflammation of the gingival, along with destruction of the periodontal ligament and alveolar bone. Immune-cell activation and recruitment can be induced by inflammatory cytokines, such as IL-1, TNF, IL-33, and bacterial products, including lipopolysaccharide (LPS). IL-1 and IL-33 are pleiotropic cytokines from members of the IL-1 family, which mediate inflammation of MCs and contribute to many key features of periodontitis and other inflammatory disorders. IL-33 activates several immune cells, including lymphocytes, Th2 cells, and MCs in both innate and acquired immunological diseases. The classic therapies for periodontitis include non-surgical periodontal treatment, surgery, antibiotics, anti-inflammatory drugs, and surgery, which have been only partially effective. Recently, a natural cytokine, IL-37, a member of the IL-1 family and a suppressor of IL-1b, has received considerable attention for the treatment of inflammatory diseases. In this article, we report that IL-37 may be an important and effective therapeutic cytokine that may inhibit periodontal inflammation. The purpose of this paper is to study the relationship between MCs, IL-1, IL-33, and IL-37 inhibition in acute and chronic inflamed gingival tissue.

Background: Parkinson's disease is still incurable, and several factors are considered when defining pharmacological therapy., Objective: The aim of this study was to describe the prescription pattern of monoamine oxidase B inhibitors (MAO-BIs) marketed in Italy (selegiline, rasagiline, safinamide) as an add-on to levodopa among new users of MAO-BIs, from the perspective of the Italian National Health Service., Patients and Methods: Through cross-linkage of administrative healthcare data in the Ricerca e Salute (ReS) database, adults with a supply of one or more MAO-BIs in 2017, and with no other MAO-BI use since 2013, were selected. Levodopa had to be supplied within 30 days before/after the MAO-BI. The incidence, use, sex, age, comorbidities, 2-year prescription patterns (i.e., switches, proportion of treated patients per semester/year, mean daily milligrams/monthly tablets supplied, discontinuation, change to other anti-Parkinson drug) of patients taking MAO-BIs were provided., Results: In 2017, 1059 new users received an MAO-BI (incidence 22.6 × 100,000 adults) combined with levodopa: 502 subjects (10.7 × 100,000) were treated with selegiline, 161 (3.4 × 100,000) were treated with rasagiline, and 396 (8.4 × 100,000) were treated with safinamide. The cohorts mainly consisted of males with a median age of ≥ 74 years. Treatment incidences increased with age. Switches occurred in 18.0%, 11.0%, and 4.3% of the selegiline, rasagiline, and safinamide cohorts, respectively. Most of the patients switching from selegiline/safinamide changed to rasagiline, while most of the patients switching from rasagiline changed to safinamide. From the first to second years, patient numbers reduced by ≤ 50%, and the daily milligrams/monthly tablets slightly increased. Six-month discontinuation occurred in > 50% of all cohorts, and ≥ 65% of discontinuing patients changed to another anti-Parkinson drug., Conclusions: This analysis described the heterogeneous use of MAO-BIs as an add-on to levodopa in Italy. Further clinical trials and real-world studies are encouraged to update the few existing guidelines and to align clinical practice strategies., (© 2022. The Author(s).)

Background: Patterns of real-world antiplatelet therapy (APT) are reported to differ from guideline recommendations. This study describes patterns of APT during the year following a hospital diagnosis of acute coronary syndrome (ACS) and possible implications in terms of revascularization rates, rehospitalizations, and costs for the Italian National Health Service. Methods: From >5 million people, patients discharged (=index date) with primary/secondary ACS diagnosis in 2017 were identified by cross-linkage of administrative health data collected by the Ricerca e Salute (ReS) Foundation. Patients were characterized by revascularization rates at index date, APT at one month and one year (with appropriate coverage defined as ≥80% of defined daily doses), and rehospitalizations and healthcare costs during follow-up. Results: From the 2017 ReS database, 7966 (1.46 × 1000 inhabitants) were discharged alive with an ACS diagnosis. Most were >69 years and male. Of these, 83% (6640/7966) received ≥1 recommended antiplatelet agent within one month (treated group): 23% (1870/7966) as single and 60% (4770/7966) as dual APT. Among the 53% undergoing revascularization, 81% received dual APT at one month. Of the 78% with the same APT at one year, 66% showed appropriate coverage. For subjects treated and untreated with APT at one month, one-year rehospitalization rates were 54% and 66%, respectively, and mean per capita costs were EUR 14,316 and EUR 16,552, respectively (hospitalization driving >80% of costs). Conclusions: Among survivors of a hospitalized ACS diagnosis, this analysis shows relatively high APT under-treatment at one month and one year, associated with fewer index revascularization rates, more rehospitalizations, and greater costs. Further initiatives to understand undertreatment and poor adherence should lead to improved health management and savings.

Objective: This observational retrospective analysis aimed to describe antibiotic prescription pattern in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and community-acquired pneumonia (CAP) and their costs, from the Italian National Health Service perspective., Methods: From the ReS database, a cross-linkage of Italian healthcare administrative databases through a unique anonymous code allowed to select subjects aged ≥12 years, supplied with at least an antibacterial for systemic use (ATC code: J01) from 01/01/2017 to 12/31/2017 and evaluable until the end of 2018. Prescriptions of different antibiotics on the same date were excluded. The prescription pattern was assessed for patients with an AECOPD (aged ≥50) or a CAP event (aged ≥12) in 2017. A 30-day cost analysis after the antibacterial supply and according to absence/presence (15 days before/after the supply) of AECOPD/CAP hospitalization was performed., Results: In 2017, among patients aged ≥12 (~5 million), 1,845,268 were supplied with ≥1 antibacterial (37.2%). Antibacterial prescriptions potentially related to AECOPD were 39,940 and 4,059 to CAP: quinolones were the most prescribed (37.2% and 39.0%, respectively), followed by third-generation cephalosporins (25.5%; 27.5%), penicillins (15.4%; 14.9%), and macrolides (14.4%; 11.3%); the 30-day mean cost was €709 and €2,889. An association AECOPD/CAP-antibacterial supply costed more when the hospitalization occurred 15 days after the antibiotic supply (€5,006 and €4,966, respectively)., Conclusions: Findings confirmed the very high use of antimicrobials in Italy and highlighted the urgent need of improving current prescribing practices and developing new molecules, to stop the incessant spread of antimicrobial resistance and related socioeconomic impacts., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: This retrospective observational study aimed at describing patients on hemodialysis with/without uremic pruritus (UP), their healthcare resource consumption and costs from the perspective of the Italian National Health Service (INHS). Methods: Through the cross-linkage of the healthcare administrative data collected in the ReS (Ricerca e Salute) database from 2015 to 2017, patients undergoing in-hospital/outpatient hemodialysis (index date) for ≥2 years were selected. After the exclusion of subjects with other causes of pruritus, UP/non-UP cohorts were created based on the presence/absence of UP-related treatment supplies and characterized. Treatments, hospitalizations and costs were analyzed. Results: Of 1239 patients on hemodialysis for ≥2 years (20.2% of all hemodialysis subjects), 218 (17.6%) were affected by UP. Both cohorts were mostly males and elderly. One year before and after the index date, 58.1% and 65.1% of UP patients received UP-related treatments, of which >50% were treated with antihistamines (mostly cetirizine), 10% gabapentin and 1.4% ultraviolet light therapy. The mean annual overall cost per patient with/without UP was €37,065/€35,988. Outpatient specialist services accounted for 80% (>77% hemodialysis), hospitalizations for 10% (>60% hemodialysis). Conclusions: Though the prevalence of UP and related healthcare costs charged to the INHS were underestimated, the burden of UP was not negligible. High-efficiency dialytic therapies performed 3 to UP patients seemed to largely weigh on the overall mean annual cost. The availability of specific and effective treatments for UP might offer cost and healthcare offsets., (Copyright by Società Italiana di Nefrologia SIN, Rome, Italy.)

Frailty is a highly prevalent condition in the elderly that has been increasingly considered as a crucial public health issue, due to the strict correlation with a higher risk of fragility fractures, hospitalization, and mortality. Among the age-related diseases, sarcopenia and dysphagia are two common pathological conditions in frail older people and could coexist leading to dehydration and malnutrition in these subjects. "Sarcopenic dysphagia" is a complex condition characterized by deglutition impairment due to the loss of mass and strength of swallowing muscles and might be also related to poor oral health status. Moreover, the aging process is strictly related to poor oral health status due to direct impairment of the immune system and wound healing and physical and cognitive impairment might indirectly influence older people's ability to carry out adequate oral hygiene. Therefore, poor oral health might affect nutrient intake, leading to malnutrition and, consequently, to frailty. In this scenario, sarcopenia, dysphagia, and oral health are closely linked sharing common pathophysiological pathways, disabling sequelae, and frailty. Thus, the aim of the present comprehensive review is to describe the correlation among sarcopenic dysphagia, malnutrition, and oral frailty, characterizing their phenotypically overlapping features, to propose a comprehensive and effective management of elderly frail subjects.

Background: Intradermal therapy (mesotherapy) is a technique used to inject drugs into the surface layer of the skin. The intradermal micro deposit allows to modulate the kinetics of drugs, slowing down its absorption and prolonging the local mechanism of action. This technique is applied in the treatment of some forms of localized pain when a systemic drug-saving effect is useful, when it is necessary to synergize with other pharmacological or non-pharmacological thera-pies, when other therapies have failed or cannot be used., Aim: The purpose of our study was to evaluate the effect of a mixture with respect to its lower concentration. We also wanted to evaluate the number of sessions needed to reach the therapeutic goal (50% reduction in pain from baseline) in patients with acute or chronic neck pain., Method: We analyzed retrospectively data from 62 patients with cervicobrachial pain treated with intradermal drugs. Group A received a mixture of drugs; group B received half the dose of drugs., Results: Patients who received a lower concentration of drugs achieved similar results to those who received a higher dose. The therapeutic goal was achieved on average with 3.5 + 1.7 sessions on a weekly basis (min 1; max 9). Subjects in group A required 4+1.7 treatments (min 1; max 9), while subjects in group B required 3+1.5 treatments (min 1; max 7)., Conclusions: Our study confirms that even a lower dose of drugs can induce a clinically useful result. This study confirms that the useful effect of mesotherapy is only partly due to the pharmacological action. Further randomized prospective studies are needed to standardize the technique in the various pain syndromes, but it is recommended to follow the guidelines of the Italian Society of Mesotherapy to ensure patients receive appropriate treatment.

Background: Intra-articular hip injections for osteoarthritis represent a useful instrument to reduce pain and disability in the common clinical practice. Several medications can be injected locally with different level of evidence-based efficacy., Objective: The objective of this systematic review is to investigate the effectiveness of intra-articular injections of different medications or substances for the pain treatment and the management of disability in subjects affected by hip osteoarthritis., Methods: Two reviewers selected independently randomised controlled trials published in the last 10 years, using PubMed and Scopus databases. The risk of bias was evaluated with Cochrane library assessment tool., Results: 12 randomised controlled trials have been selected. We found 8 papers comparing hyaluronic acid with platelet rich plasma, with corticosteroids and with saline solution; 1 paper compares two types of hyaluronic acid with different molecular weights; 3 papers study the effects of corticosteroids alone or compared to ketorolac or saline solution., Conclusions: The studies reviewed were heterogeneous regarding sample size, level of osteoarthritis, evaluated with Kellegren-Lawrence score, medications used and follow up timings. However, we have observed that intra-articular injections of platelet-rich plasma seem to decrease pain at short term and disability at long term, in patients affected by hip osteoarthritis better than hyaluronic acid. The association of hyaluronic acid and corticosteroids could give better results compared to hyaluronic acid alone, while the use of intra-articular ketorolac and saline solution requires more studies., (© 2021. The Author(s).)

Background: Catheter ablation (CA) is recommended for treating paroxysmal/persistent atrial fibrillation (AF) as an alternative to antiarrhythmic drugs after failure or intolerance, or as first-line in limited cases. This study has described patients affected by AF and treated or not with CA, from the perspective of the Italian National Healthcare System (INHS)., Methods: From the healthcare administrative data collected in the ReS (Ricerca e Salute) database, from 2016 to 2017, patients with main/secondary diagnosis of AF (index date) were split into two cohorts by presence/absence of CA procedure in the same hospital discharge form. The cohorts were characterized by gender, age, comorbidities. Consumptions (DDD) of antiarrhythmic, anticoagulant, antiplatelet and antihypertensive drugs, hospitalizations for AF, hemorrhagic stroke/intracranial hemorrhage, ischemic stroke/transient ischemic attack, extra cranial major bleeding and heart failure, outpatient specialist care and healthcare costs paid by the INHS were assessed., Results: Out of >5 million inhabitants in 2016-2017, 33,940 patients were hospitalized with a diagnosis of AF, 990 (2.9%) were treated with CA in the same hospitalization (32,950 without CA). Patients with CA were mostly males (66.8%; 48.5% without CA). On average, they were aged (±SD) 65±12 (78±11 without CA) and affected by one comorbidity (≥3 in patients without CA). During the observational period, beta-blockers were the most prescribed to both cohorts, followed by antiarrhythmic drugs to patients with CA and by direct oral anticoagulants to those without. The 29.7% of subjects with CA were hospitalized due to relevant cardiovascular diagnoses during the previous year (7.4% without CA) and 93.4% in the first follow-up year (29.7% without CA). The 80-90% of cohorts resorted to the outpatient specialist care. Electrocardiograms and the cardiology visits were performed to the 62.5% and 31.1% of the cohort with CA (39.5% and 13% without CA) in the first follow-up year. On average, the INHS spent about € 4000 in the previous year and around € 10,000 in the first follow-up year per patient of both cohorts, while around € 3000 and € 4000 for a patient respectively with and without CA. At least half of the total costs were due to hospitalizations, followed by pharmaceuticals and outpatient specialist care., Conclusions: This study confirm a post-CA suboptimal monitoring.

Background: This study describes patients with coronary artery disease (CAD) who are eligible for secondary prevention and assesses their healthcare consumption and costs from the perspective of the Italian National Health Service (INHS)., Methods: From the Fondazione Ricerca e Salute's database, which collects Italian healthcare administrative data, all patients aged ≥ 35, with ≥1 primary in-hospital CAD diagnosis and/or procedure on the coronary arteries, or with the specific disease exemption code, and who are suitable for long-term secondary prevention treatments, were identified in 2018 and analyzed. Demographics, comorbidities, one-year supplied drugs, hospitalizations, and costs were analyzed., Results: From >3 million inhabitants aged ≥ 35, 46,063 (1.3%) were identified (72.1% males, mean age 70 ± 12; approximately 50% with ≥3 comorbidities). During a one-year follow-up, 96.4% were treated with ≥1 drug for secondary prevention (mainly antiplatelets and lipid lowering agents), 69.4% with ≥1 concomitant cardiovascular drug, and 95.8% with ≥1 concomitant non-cardiovascular therapy. Within one year, 30.6% of patients were hospitalized at least once, mostly due to non-cardiovascular events. Calculated by mean, the INHS paid EUR 6078 per patient., Conclusions: This analysis confirms the relevant burden of CAD for patients with many comorbidities and who are frequently hospitalized, and the burden on the INHS. A multidisciplinary healthcare approach is encouraged to improve patients' outcomes and reduce costs for the INHS.

Introduction: The association between an ACE-inhibitor and a beta-blocker is recommended in case of complicated arterial hypertension and heart failure with reduced ejection fraction. This retrospective drug-utilization study has described its chronic use from the Italian National Healthcare Service perspective., Methods: From the ReS (Ricerca e Salute) database, collecting Italian healthcare administrative data, patients receiving an ACE-inhibitor or a beta-blocker from 2013 to 2019 were selected. The prevalence of use (patients treated/1000 inhabitants) and of continuous treatment (patients treated for ≥80% period from the supply to the end of the same year - by means of dosage units - per 1000 inhabitants) of each single active substance were assessed. Among patients continuously treated, those supplied with an ACE-inhibitor and a beta-blocker (unfixed and fixed combinations) were analyzed in terms of prevalence of continuous treatment. Subjects treated with the unfixed combination ramipril-bisoprolol in 2019 were characterized by gender and age., Results: The prevalence of ACE-inhibitors' use increased from 49.7/1000 inhab. in 2013 to 50.2 in 2019: ramipril was the most supplied each year (28.9 to 31.6/1000 inhab.). The prevalence of continuous treatment increased from 27.4 to 28.3/1000 inhab.: ramipril the most continuously dispensed (16 to 18/1000 inhab.). The prevalence of beta-blockers' use increased from 61.0 to 90.4/1000 inhab.: bisoprolol the most supplied and with the highest increase (27.1 to 52.2/1000 inhab.). The prevalence of continuous treatment increased from 33.1 to 55.8/1000 inhab.: bisoprolol the most continuously dispensed (18 to 37/1000 inhab.). Among patients with continuous supplies, from 49,843 a 51,496 were treated with associations between an ACE-inhibitor and a beta-blocker on an ongoing basis. Half of them were continuously treated with the unfixed combination ramipril-bisoprolol (4.3 to 4.8/1000 inhab.). In 2019, subjects with continuous supplies of ramipril-bisoprolol were mainly males (63.4%) and elderly (mean age 71±12), and the prevalence of use increased with age., Conclusions: These findings, together with recommendations from the main international guidelines encourage to make available also ramipril and bisoprolol as fixed dose combination, in order to simplify the therapy administration and improve the adherence, especially among elderly and patients with multimorbidity.