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Abstract Efficient predictive biomarkers are needed for immune checkpoint inhibitor (ICI)-based immunotherapy in non-small cell lung cancer (NSCLC). Testing the predictive value of single nucleotide polymorphisms (SNPs) in programmed cell death 1 (PD-1) or its ligand 1 (PD-L1) has shown contrasting results. Here, we aim to validate the predictive value of PD-L1 SNPs in advanced NSCLC patients treated with ICIs as well as to define the molecular mechanisms underlying the role of the identified SNP candidate. rs822336 efficiently predicted response to anti-PD-1/PD-L1 immunotherapy in advanced non-oncogene addicted NSCLC patients as compared to rs2282055 and rs4143815. rs822336 mapped to the promoter/enhancer region of PD-L1, differentially affecting the induction of PD-L1 expression in human NSCLC cell lines as well as their susceptibility to HLA class I antigen matched PBMCs incubated with anti-PD-1 monoclonal antibody nivolumab. The induction of PD-L1 expression by rs822336 was mediated by a competitive allele-specificity binding of two identified transcription factors: C/EBPβ and NFIC. As a result, silencing of C/EBPβ and NFIC differentially regulated the induction of PD-L1 expression in human NSCLC cell lines carrying different rs822336 genotypes. Analysis by binding microarray further validated the competitive allele-specificity binding of C/EBPβ and NFIC to PD-L1 promoter/enhancer region based on rs822336 genotype in human NSCLC cell lines. These findings have high clinical relevance since identify rs822336 and induction of PD-L1 expression as novel biomarkers for predicting anti-PD-1/PD-L1-based immunotherapy in advanced NSCLC patients.

The COVID-19 pandemic has left behind mental health issues like anxiety, depression, and sleep disorders among survivors. This study assessed the efficacy of spa therapy in enhancing psychological well-being and sleep quality in individuals with chronic arthro-rheumatic, respiratory, and otorhinolaryngological diseases, including COVID-19 recoverees. Our prospective observational study included 144 Caucasian subjects from three Italian spas who underwent a 2-week spa therapy cycle, involving balneotherapy and/or inhalation treatments. Symptoms were assessed with the Visual Analogue Scale (VAS), psychological well-being with Depression Anxiety Stress Scales-21 items (DASS-21), and sleep quality with the Insomnia Severity Index (ISI). Significant reductions in VAS scores for arthro-rheumatic, respiratory, and otorhinolaryngological symptoms were observed after spa therapy, as well as for DASS-21 and ISI scores for sleep quality, transitioning to less severe insomnia categories. Females had more pronounced improvements in DASS-21 scores and sleep quality. Subjects with and without prior SARS-CoV-2 infection experienced significant reductions in anxiety, depression, and stress, with more pronounced improvements in those without prior infection. COVID-19 survivors also showed significant ISI score improvements. Spa therapy is a promising complementary treatment for improving mental health and sleep quality in chronic disease patients, including COVID-19 survivors.

Abstract Childhood obesity and its associated comorbidities are highly prevalent diseases that may add to any other possible health problem commonly affecting the pediatric age. Uncertainties may arise concerning drug dosing when children with obesity need pharmacologic therapies. In general, in pediatric practice, there is a tendency to adapt drug doses to a child’s total body weight. However, this method does not consider the pharmacological impact that a specific drug can have under a two-fold point of view, that is, across various age and size groups as well. Moreover, there is a need for a therapeutic approach, as much as possible tailored considering relevant interacting aspects, such as modification in metabolomic profile, drug pharmacokinetics and pharmacodynamics. Taking into account the peculiar differences between children with overweight/obesity and those who are normal weight, the drug dosage in the case of obesity, cannot be empirically determined solely by the per kg criterion. In this narrative review, we examine the pros and cons of several drug dosing methods used when dealing with children who are affected also by obesity, focusing on specific aspects of some of the drugs most frequently prescribed in real-world practice by general pediatricians and pediatric subspecialists.

Treatment of acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS) is difficult in older patients with comorbidities and high-risk disease factors. Venetoclax, the first-in-class Bcl-2 inhibitor, has proven efficacy and safety in combination with azacytidine for treatment of high-risk myeloid diseases. In this single-center real-life retrospective study, a total of 27 consecutive patients treated with azacytidine plus venetoclax were included, and clinical outcomes, hematological improvements, and biomarkers of responsiveness to therapy were compared to those observed in an historical cohort of 95 consecutive patients treated with azacytidine as single agent. Azacytidine plus venetoclax was effective and safe in older and frail AML and high-risk MDS patients, with median overall survival of 22.3 months, higher than that reported in phase III trial (14.7 months), and higher than that of historical cohort (5.94 months). Progression-free survival was higher in patients treated with the drug combination compared to those treated with azacytidine as single agent (p = 0.0065). Clinical benefits might increase when azacytidine and venetoclax are administered as upfront therapy (p = 0.0500). We showed that Tim-3 expression could be a promising therapeutic target in refractory/relapsed patients, and galectin-9 a biomarker of responsiveness to therapy. Moreover, patients treated with azacytidine and venetoclax displayed a higher overall survival regardless the presence of negative prognostic markers at diagnosis (e.g., increased WT1 copies and/or normalized blast count). These encouraging results in a real-world setting supported efficacy and safety of azacytidine plus venetoclax as upfront therapy in AML and high-risk MDS, with clinical outcomes comparable to those of clinical trials when an appropriate venetoclax management with bone marrow assessment at every first, second, fourth, and eighth cycle, and dose adjustments for toxicities are performed.

Pain is an unpleasant sensory and emotional experience that affects every aspect of a patient’s life and which may be treated through different pharmacological and non-pharmacological approaches. Analgesics are the drugs most commonly used to treat pain, and in specific situations, the use of opioids may be considered with caution. These drugs, in fact, do not always induce optimal analgesia in patients, and several problems are associated with their use. The purpose of this narrative review is to describe the pharmacological approaches currently used for the management of chronic pain. We review several aspects, from the pain-scale-based methods currently available to assess the type and intensity of pain, to the most frequently administered drugs (non-narcotic analgesics and narcotic analgesics), whose pharmacological characteristics are briefly reported. Overall, we attempt to provide an overview of different pharmacological treatments while also illustrating the relevant guidelines and indications. We then report the strategies that may be used to reduce problems related to opioid use. Specifically, we focus our attention on therapeutic drug monitoring (TDM), a tool that could help clinicians select the most suitable drug and dose to be used for each patient. The actual potential of using TDM to optimize and personalize opioid-based pain treatments is finally discussed based on recent scientific reports.

Visceral leishmaniasis (VL) is a chronic parasitosis which is hypoendemic in the Mediterranean area but hyperendemic in areas such as Bihar, Sudan, and Northeastern Brazil. Leishmania donovani and Leishmania infantum are the main etiological agents. After infection by vectors (phlebotomine sandflies), VL symptoms range from a low-symptomatic disease to a rapidly evolving severe syndrome. When VL affects immunocompromised adults, the infection frequently appears paucisymptomatic or as an insidious clinical manifestation with atypical signs and low-grade fever. Patients with human immunodeficiency virus (HIV) infection and organ-transplant recipients have an increased risk of VL and HIV/VL coinfection, which is worrying risk factor in Southwestern Europe and many hyperendemic areas. The availability of effective therapies is limited, and the prognosis of the patients with immunocompromised status is unpredictable. Compared with other therapies, treatment based on the use of liposomal amphotericin B is associated with a lower incidence of side effects, but the cost precludes its use in low-income countries. Antimonials are the longest-used drugs. However, adverse reactions are common, and the mechanisms of resistance to this class of drugs have been enhanced. Miltefosine, the only oral drug available, has uncertain effectiveness against L. infantum infection. Data about the efficacy of paromomycin are also limited. Relapses and resistance to drugs are observed in patients with VL/HIV coinfection.

Vascular aging is linked to reduce NO bioavailability, endothelial dysfunction, oxidative stress, and inflammation. We previously showed that a 4-week treatment of middle-aged Wistar rats (MAWRs, 46 weeks old) with Moringa oleifera seed powder (MOI, 750 mg/kg/day) improved vascular function. Here, we investigated the involvement of SIRT1 in MOI-induced vascular improvement. MAWRs were treated with a standard or MOI-containing diet. Young rats (YWR, 16 weeks old) were the controls and received a standard diet. The hearts and aortas were harvested to evaluate SIRT1 and FOXO1 expression via Western blot and/or immunostaining, SIRT1 activity via a fluorometric assay, and oxidative stress using the DHE fluorescent probe. In the hearts and aortas, SIRT1 expression, reduced in MAWRs compared to YWRs, was enhanced in MOI MAWRs. In the hearts, SIRT1 activity did not differ between YWRs and MAWRs, whereas it was increased in MOI MAWRs compared with them. In the aortas, SIRT1 activity decreased in MAWRs, and it was similar in the MOI MAWRs and YWRs. FOXO1 expression increased in the nuclei of MAWR aortas compared to YWR and was reversed in MOI MAWRs. Interestingly, MOI treatment normalized oxidative stress enhanced in MAWRs, in both the heart and aorta. These results demonstrate the protective role of MOI against cardiovascular dysfunction due to aging via enhanced SIRT1 function and subsequently reduced oxidative stress.

Background: Proper health education and lifestyle information to be adopted during pregnancy are crucial for the well-being of the pregnant women and the health of the child. The aim of our study was to evaluate the impact of proper health education and lifestyle information to be adopted during pregnancy on obstetrical, neonatal and infant outcomes. Methods: A retrospective single-center cohort study was carried out including all consecutive pregnant women admitted to our Institution, from December 2019 to February 2021. The study outcomes were the difference in obstetrical, neonatal and infant outcomes between women differentiated by Body Mass Index (BMI) at the end of pregnancy (i.e., normal weight vs overweight, and normal weight vs obese), physical activity (yes vs no), and smoking during pregnancy (yes vs no). Results: Ninety-one women were included. Compared with normal weight women, obese women showed an increased incidence of major maternal pathologies (p = 0.048) and caesarean delivery (p = 0.042). Regarding physical activity, significant differences were observed between pregnant women who do and do not perform physical activity with a lower value of the incidence of spontaneous vaginal delivery (p = 0.025) in sedentary women. Compared with non-smoking groups, smoking women showed significantly higher BMI at the end of pregnancy (p = 0.036), lower neonatal weight (p = 0.001) and lower Apgar index (p = 0.033). Lastly, the percentage of infants with weight and height percentiles within the mean value did not differ significantly among mothers stratified by BMI, physical activity and smoking. Conclusions: Our data, in agreement with the literature, confirm that the proper information and education about lifestyle changes, particularly regarding BMI and smoking during pregnancy, can improve the health of the women and newborn.

BackgroundLevodopa (LD) is the most effective drug in the treatment of Parkinson’s disease (PD). Unfortunately, prolonged use of LD leads to complications, mainly motor/non-motor fluctuations (MNMF) and dyskinesias (DYS). Women seem more prone to develop such LD-related complications. Nonetheless, there is a paucity of prospective studies examining gender-related predictors of MNMF and DYS. Among several factors, which concur with a very complex scenario, changes in LD pharmacokinetics influence the drug’s effectiveness. The present study aimed to assess gender-related differences in LD pharmacokinetics in patients with PD at their first-ever intake of LD.Materials and MethodsThis is a multicentric study enrolling patients with PD, who were LD-naïve and received a single dose of LD/benserazide (100/25 mg) formulation. All participants gave their written informed consent, and the study was approved by the local Ethics Committees. To measure plasma LD concentrations and pharmacokinetic parameters (AUC, Cmax, Tmax, t1/2), fasting blood samples were collected before drug intake and then at 8-time points until 260 min. LD concentrations were measured by ultra-high-performance liquid chromatography coupled with mass spectrometry (UHPLC-MS). Multiple linear regression analyses were performed to identify the predictors of the parameters.ResultsThirty-five patients (16 women and 19 men) were consecutively enrolled. Area under curve (AUC) and maximum plasma concentration (Cmax) were significantly higher in women than men (p = 0.0006 and p = 0.0014, respectively). No statistically significant difference was found regarding Tmax and t1/2. Multiple linear regression analyses revealed that female sex (β = 1.559116, 95% CI 0.8314479 2.286785; p < 0.0001) and body mass index (BMI) (β = −0.0970631, 95% CI −0.1733004 −0.0208258; p = 0.014) significantly predicted AUC. Only female sex significantly predicted Cmax (β = 1,582.499, 95% CI 731.581 2,433.417; p = 0.001). Moreover, only BMI significantly predicted t1/2 (β = 0.0756267, 95% CI 0.0143407 0.1369126; p = 0.017). Stratifying by gender, BMI was confirmed to significantly predict t1/2 in women (β = 0.1300486, 95% CI 0.0172322 0.242865; p = 0.027), but not in men.ConclusionThis study provides novel insights on gender differences in LD pharmacokinetics, possibly contributing to the later development of motor complications and dyskinesia in PD.

Based on their chemical composition, salus per aquam (spa) mineral waters (or medical mineral waters) can be classified as sulphurous, sulphate, bicarbonate etc. Sulphate mineral waters where the predominant element is sulphate anion SO42−, are frequently used in clinical therapy. In this review, we describe and analyze the current scientific knowledge concerning the therapeutic effect of sulphate mineral waters in the treatment of several disorders.Moreover, we underline how important is to integrate spa treatments with other therapeutic approaches to meet the various needs that can arise during a specific pathological state.

Hand-Foot syndrome (HFS) and diarrhoea are dose-limiting Adverse Drug Reactions (ADRs) of capecitabine-based chemotherapy. Four polymorphisms in the dihydropyrimidine dehydrogenase (DPYD) gene, encoding the DPD enzyme responsible for the metabolism of fluoropyrimidines, such as capecitabine, are strongly associated with severe ADRs, and their screening should be performed before starting treatment. Moreover, capecitabine-related toxicity may worsen due to drug-drug and drug-supplement interactions. Here we investigated factors responsible for severe HFS and diarrhoea presented by two patients, non-carriers of the recommended DPYD single nucleotide polymorphisms (SNPs) but carriers of other genetic variants suggested to increase the risk of capecitabine-related ADRs. Through careful therapy recognition, we demonstrated that, unbeknownst to the oncologists, the patients were taking folic acid during the treatment with capecitabine at a dosage higher than 2000 mg/m2, which is the maximum tolerated dose when folate is administered. To resolve the ADRs, the therapy had to be drastically changed. In one case, dose reduction of capecitabine and discontinuation of lipid-lowering agents were carried out. In the other case, discontinuation of capecitabine and folic acid and capecitabine re-administration were performed after a month. Genetic and environmental factors should be considered good predictors of severe capecitabine-related toxicity. Medication reconciliation should be encouraged to avoid the harmful consequences of inappropriate treatments.

Cenobamate (CNB) is the newest antiseizure medication (ASM) approved by the FDA in 2019 to reduce uncontrolled partial-onset seizures in adult patients. Marketed as Xcopri in the USA or Ontozry in the EU (tablets), its mechanism of action has not been fully understood yet; however, it is known that it inhibits voltage-gated sodium channels and positively modulates the aminobutyric acid (GABA) ion channel. CNB shows 88% of oral bioavailability and is responsible for modifying the plasma concentrations of other co-administered ASMs, such as lamotrigine, carbamazepine, phenytoin, phenobarbital and the active metabolite of clobazam. It also interferes with CYP2B6 and CYP3A substrates. Nowadays, few methods are reported in the literature to quantify CNB in human plasma. The aim of this study was to develop and validate, according to the most recent guidelines, an analytical method using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC–MS/MS) to evaluate CNB dosage in plasma samples. Furthermore, we provided a preliminary clinical application of our methodology by evaluating the pharmacokinetic parameters of CNB in two non-adult patients. Plasma levels were monitored for two months. Preliminary data showed a linear increase in plasma CNB concentrations, in both patients, in agreement with the increase in CNB dosage. A seizure-free state was reported for both patients at the dose of 150 mg per day.

Ficus rubiginosa plant extract showed antimicrobial activity, but no evidence concerning its antiviral properties was reported. The antiviral activity of the methanolic extract (MeOH) and its n-hexane (H) and ethyl acetate (EA) fractions against Herpes simplex virus-1 (HSV-1), Human coronavirus (HCoV) -229E, and Poliovirus-1 (PV-1) was investigated in the different phases of viral infection in the VERO CCL-81 cell line. To confirm the antiviral efficacy, a qPCR was conducted. The recorded cytotoxic concentration 50% was 513.1, 298.6, and 56.45 µg/mL for MeOH, H, and EA, respectively, assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay after 72 h of treatment. The Ficus rubiginosa leaf extract inhibited the replication of HSV-1 in the early stages of infection, showing a complete inhibition up to 0.62, 0.31, and 1.25 µg/mL. Against HCoV-229E, a total inhibition up to 1.25 µg/mL for MeOH and H as well as 5 µg/mL for EA was observed. Otherwise, no activity was recorded against PV-1. The leaf extract could act directly on the viral envelope, destructuring the lipid membrane and/or directly blocking the enriched proteins on the viral surface. The verified gene inhibition suggested that the treatments with M, H, and EA impaired HSV-1 and HCoV-229E replication, with a greater antiviral efficiency against HSV-1 compared to HCoV-229E, possibly due to a greater affinity of Ficus rubiginosa towards membrane glycoproteins and/or the different lipid envelopes.

Antimicrobial resistance represents a serious threat for global health, causing an unacceptable burden in terms of morbidity, mortality and healthcare costs. In particular, in 2017, carbapenem-resistant organisms were listed by the WHO among the group of pathogens for which novel treatment strategies are urgently needed. Fortunately, several drugs and combinations have been introduced in recent years to treat multi-drug-resistant (MDR) bacteria. However, a correct use of these molecules is needed to preserve their efficacy. In the present paper, we will provide an overview on the epidemiology and mechanisms of resistance of the most common MDR Gram-negative bacteria, proposing a treatment algorithm for the management of infections due to carbapenem-resistant bacteria based on the most recent clinical evidence.

The COVID-19 pandemic has reached direct and indirect medical and social consequences with a subset of patients who rapidly worsen and die from severe-critical manifestations. As a result, there is still an urgent need to identify prognostic biomarkers and effective therapeutic approaches. Severe-critical manifestations of COVID-19 are caused by a dysregulated immune response. Immune checkpoint molecules such as Programmed death-1 (PD-1) and its ligand programmed death-ligand 1 (PD-L1) play an important role in regulating the host immune response and several lines of evidence underly the role of PD-1 modulation in COVID-19. Here, by analyzing blood sample collection from both hospitalized COVID-19 patients and healthy donors, as well as levels of PD-L1 RNA expression in a variety of model systems of SARS-CoV-2, including in vitro tissue cultures, ex-vivo infections of primary epithelial cells and biological samples obtained from tissue biopsies and blood sample collection of COVID-19 and healthy individuals, we demonstrate that serum levels of PD-L1 have a prognostic role in COVID-19 patients and that PD-L1 dysregulation is associated to COVID-19 pathogenesis. Specifically, PD-L1 upregulation is induced by SARS-CoV-2 in infected epithelial cells and is dysregulated in several types of immune cells of COVID-19 patients including monocytes, neutrophils, gamma delta T cells and CD4+ T cells. These results have clinical significance since highlighted the potential role of PD-1/PD-L1 axis in COVID-19, suggest a prognostic role of PD-L1 and provide a further rationale to implement novel clinical studies in COVID-19 patients with PD-1/PD-L1 inhibitors.

Background: The safety of healthcare workers exposed to formaldehyde remains a great matter of concern for healthcare management units. This work aimed at describing the results of a combined monitoring approach (environmental and biological) to manage occupational exposure to formaldehyde in a hospital setting. Design and Methods: Environmental monitoring of working spaces and biological monitoring of urinary formaldehyde in 16 exposed healthcare workers of the Anatomic Pathology Unit of a University Hospital in Southern Italy was performed on a four-year timescale (2016-2019). Results: Values of aero-dispersed formaldehyde identified were on average low; although workers' urinary formaldehyde levels were also minimal, the statistical analysis highlighted a slight weekly accumulation. Conclusions: Our data confirm that both environmental and biological monitoring are important to identify risk situations, in particular when values of hazardous compounds are below the accepted occupational exposure levels.

Chemical risk in hospital settings is a growing concern that health professionals and supervisory authorities must deal with daily. Exposure to chemical risk is quite different depending on the hospital department involved and might origin from multiple sources, such as the use of sterilizing agents, disinfectants, detergents, solvents, heavy metals, dangerous drugs, and anesthetic gases. Improving prevention procedures and constantly monitoring the presence and level of potentially toxic substances, both in workers (biological monitoring) and in working environments (environmental monitoring), might significantly reduce the risk of exposure and contaminations. The purpose of this article is to present an overview on this subject, which includes the current international regulations, the chemical pollutants to which medical and paramedical personnel are mainly exposed, and the strategies developed to improve safety conditions for all healthcare workers.

IntroductionIntrahepatic cholangiocarcinoma (ICC) is a rare hepatobiliary cancer characterized by a poor prognosis and a limited response to conventional therapies. Currently chemotherapy is the only therapeutic option for patients with Stage IV ICC. Due to the poor response rate, there is an urgent need to identify novel molecular targets to develop novel effective therapies. Precision oncology tests utilizing targeted next-generation sequencing (NGS) platforms have rapidly entered into clinical practice. Profiling the genome and transcriptome of cancer to identify potentially targetable oncogenic pathways may guide the clinical care of the patient.Case presentationWe present a 56-year-old male patient affected with metastatic ICC, whose cancer underwent several precision oncology tests by different NGS platforms. A novel BAP1 mutation (splice site c.581-17_585del22) and a RAD21 amplification were identified by a commercial available platform on a metastatic lesion. No germline BAP1 mutations were identified. Several lines of evidences indicate that PARP inhibitor administration might be an effective treatment in presence of BAP1 and/or RAD21 alterations since both BAP1 and RAD21 are involved in the DNA repair pathway, BAP1 interacts with BRCA1 and BRCA1-mediated DNA repair pathway alterations enhance the sensitivity to PARP inhibitor administration. In this case, after failing conventional therapies, patient was treated with PARP inhibitor olaparib. The patient had a partial response according to RECIST criteria with an overall survival of 37.2 months from the time of diagnosis of his ICC. Following 11.0 months on olaparib treatment, sustained stable disease control is ongoing. The patient is still being treated with olaparib and no significant toxicity has been reported.ConclusionThese findings have clinical relevance since we have shown PARP inhibitor as a potential treatment for ICC patients harboring BAP1 deletion and RAD21 amplification. We have also highlighted the utility of NGS platforms to identify targetable mutations within a cancer.

BackgroundThe prevention or early treatment of pathological scars is the most appropriate therapeutic approach. Gels and patches containing onion extract and allantoin are safe and effective in patients with scars of various origins and severity. However, no controlled studies have evaluated the effects of the patch formulation in women after Cesarean delivery. This study aimed to investigate the effects of a patch containing Allium cepa and allantoin on Cesarean section (C-section) scars.MethodsThis is an observational study. Women were consecutively recruited at the University Hospital of Salerno and subdivided into two groups considering the number of C-section. Group A included subjects without and group B with a history of C-section. Scars assessment was made using digital photographs and the Patient and Observer Scar Assessment Scale (POSAS). After 4 weeks, the C-section of the women who had applied a patch containing Allium cepa and allantoin and those of women who had not used any products (controls) were re-evaluated as at baseline. The Observers independently performed the scars assessment at baseline and after 4 weeks. Data are expressed as the difference of the POSAS scores after 4 weeks minus the POSAS scores at baseline. The statistical significance was established at a p value

Objectives Poor worldwide rate of blood pressure control is largely due to poor adherence to antihypertensive (AHT) drug treatment. The question of whether sex affects adherence has long been debated but conflicting findings have been reported on this issue. Our objective was to evaluate sex differences in the adherence to AHT therapy.Research design and methods Studies were identified through a systematic search of PubMed, CINAHL, PsycINFO, Web of Science and Google Scholar (through January 2020) and manual handsearching of relevant articles. Observational studies reporting adherence to AHT drugs measured by self-report or pharmacy refill prescription-based methods among men and women were included. Summarised estimates of ORs with 95% CIs were calculated using random-effects model and meta-regression models.Results From 12 849 potentially relevant publications, 82 studies (15 517 457 men and 18 537 599 women) were included. No significant between-sex differences in adherence to AHT were observed, whether all study-specific estimates were summarised (ORs 1.04, 95% CI 1.00 to 1.09, p=0.07), nor estimates were pooled according to the method for measuring adherence. Among patients aged 65 years or older, lower self-reported adherence was observed in women (ORs 0.84, 95% CI 0.72 to 0.97, p=0.02), while the main result remained unchanged according to other subgroup analyses.Conclusions Definitive evidence of sex differences in adherence to AHT therapy cannot be drawn. Our little knowledge about factors affecting adherence, in particular of sex effect among elderly, urgently requires high-quality studies investigating these issues.

To date, there are no specific therapeutic strategies for treatment of COVID-19. Based on the hypothesis that complement and coagulation cascades are activated by viral infection, and might trigger an acute respiratory distress syndrome (ARDS), we report clinical outcomes of 17 consecutive cases of SARS-CoV-2-related ARDS treated (N = 7) with the novel combination of ruxolitinib, a JAK1/2 inhibitor, 10 mg/twice daily for 14 days and eculizumab, an anti-C5a complement monoclonal antibody, 900 mg IV/weekly for a maximum of three weeks, or with the best available therapy (N = 10). Patients treated with the combination showed significant improvements in respiratory symptoms and radiographic pulmonary lesions and decrease in circulating D-dimer levels compared to the best available therapy group. Our results support the use of combined ruxolitinib and eculizumab for treatment of severe SARS-CoV-2-related ARDS by simultaneously turning off abnormal innate and adaptive immune responses.

Hydropinotherapy is a salus per aquam (Spa) treatment suitable as a complementary approach to treat several diseases, which strongly affect the quality of life (QoL). Hydropinotherapy with sulphurous mineral water exerts benefits thanks to components, such as hydrogen sulphide, which is considered mainly responsible for antioxidant and hypoglycaemic effects. Such properties, linked from each other, could favour an improvement in patients’ QoL. However, data on humans are scarce. This study aimed to investigate whether a cycle of sulphurous hydropinotherapy was able to modify plasma levels of glucose and reactive oxygen metabolites (ROMs) and improve QoL in patients suffering from several chronic disorders. A prospective, observational study involved patients with gastrointestinal diseases who received a prescription of a cycle of sulphurous hydropinotherapy (S-HT). Age- and sex-matched control group was enrolled (No S-HT). Glycaemia and plasma concentration of ROMs were measured in all subjects. The impact of spa treatment on the QoL was assessed using the Short Form 36 Health Status Survey questionnaire (SF-36). All parameters were measured at baseline and at the end of a 2-week treatment. Between the groups, no differences were found in glycaemia and ROMs at baseline. In the S-HT group, a reduction in glycaemia and ROMs, both in respect to baseline (p = 0.005 and p = 0.031, respectively) and to control group, as shown by the delta value calculated, as the difference between the values at 2 weeks and baseline (p = 0.0009 and p = 0.0001, respectively). In the S-HT, delta ROMs was the best predictor of delta glycaemia with a direct linear correlation (beta = 0.559, 95% CI 0.471 to 0.647, p < 0.0001). In the S-HT, the SF-36 total score was improved both when compared with baseline (p = 0.002) and with No S-HT (p = 0.001). Sulphurous hydropinotherapy induces a decrease in glycaemia and ROM levels, also ameliorating the patients’ QoL. Therefore, it could be considered a useful complementary therapeutic approach.

Epilepsy is a widely diffused neurological disorder including a heterogeneous range of syndromes with different aetiology, severity and prognosis. Pharmacological treatments are based on the use, either in mono- or in polytherapy, of antiseizure medications (ASMs), which act at different synaptic levels, generally modifying the excitatory and/or inhibitory response through different action mechanisms. To reduce the risk of adverse effects and drug interactions, ASMs levels should be closely evaluated in biological fluids performing an appropriate Therapeutic Drug Monitoring (TDM). However, many decisions in TDM are based on the determination of the total drug concentration although measurement of the free fraction, which is not bound to plasma proteins, is becoming of ever-increasing importance since it correlates better with pharmacological and toxicological effects. Aim of this work has been to review methodological aspects concerning the evaluation of the free plasmatic fraction of some ASMs, focusing on the effect and the clinical significance that drug-protein binding has in the case of widely used drugs such as valproic acid, phenytoin, perampanel and carbamazepine. Although several validated methodologies are currently available which are effective in separating and quantifying the different forms of a drug, prospective validation studies are undoubtedly needed to better correlate, in real-world clinical contexts, pharmacokinetic monitoring to clinical outcomes.

Pharmacogenomics can identify polymorphisms in genes involved in drug pharmacokinetics and pharmacodynamics determining differences in efficacy and safety and causing inter-individual variability in drug response. Therefore, pharmacogenomics can help clinicians in optimizing therapy based on patient’s genotype, also in psychiatric and neurological settings. However, pharmacogenetic screenings for psychotropic drugs are not routinely employed in diagnosis and monitoring of patients treated with mood stabilizers, such as carbamazepine and valproate, because their benefit in clinical practice is still controversial. In this review, we summarize the current knowledge on pharmacogenetic biomarkers of these anticonvulsant drugs.

G protein-coupled receptors (GPCRs) are the most important regulators of cardiac function and are commonly targeted for medical therapeutics. Formyl-Peptide Receptors (FPRs) are members of the GPCR superfamily and play an emerging role in cardiovascular pathologies. FPRs can modulate oxidative stress through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent reactive oxygen species (ROS) production whose dysregulation has been observed in different cardiovascular diseases. Therefore, many studies are focused on identifying molecular mechanisms of the regulation of ROS production. FPR1, FPR2 and FPR3 belong to the FPRs family and their stimulation triggers phosphorylation of intracellular signaling molecules and nonsignaling proteins that are required for NADPH oxidase activation. Some FPR agonists trigger inflammatory processes, while other ligands activate proresolving or anti-inflammatory pathways, depending on the nature of the ligands. In general, bacterial and mitochondrial formylated peptides activate a proinflammatory cell response through FPR1, while Annexin A1 and Lipoxin A4 are anti-inflammatory FPR2 ligands. FPR2 can also trigger a proinflammatory pathway and the switch between FPR2-mediated pro- and anti-inflammatory cell responses depends on conformational changes of the receptor upon ligand binding. Here we describe the detrimental or beneficial effects of the main FPR agonists and their potential role as new therapeutic and diagnostic targets in the progression of cardiovascular diseases.

Reactive oxygen species (ROS) are molecules involved in signal transduction pathways with both beneficial and detrimental effects on human cells. ROS are generated by many cellular processes including mitochondrial respiration, metabolism and enzymatic activities. In physiological conditions, ROS levels are well-balanced by antioxidative detoxification systems. In contrast, in pathological conditions such as cardiovascular, neurological and cancer diseases, ROS production exceeds the antioxidative detoxification capacity of cells, leading to cellular damages and death. In this review, we will first describe the biology and mechanisms of ROS mediated oxidative stress in cardiovascular disease. Second, we will review the role of oxidative stress mediated by oncological treatments in inducing cardiovascular disease. Lastly, we will discuss the strategies that potentially counteract the oxidative stress in order to fight the onset and progression of cardiovascular disease, including that induced by oncological treatments.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that is very complex and heterogeneous. If not adequately treated, RA patients are likely to manifest excess of morbidity and disability with an important impact on the quality of life. Pharmacological treatment is based on the administration of the disease-modifying antirheumatic drugs (DMARDs), subdivided into conventional synthetic (csDMARDs), targeted synthetic (tsDMARDs), and biological (bDMARDs). bDMARDs are now frequently administered in patients, both as alternative treatment and together with csDMARDs. Unfortunately, there is a therapeutic response variability both to old and new drugs. Therefore, to identify pre-therapeutic and on-treatment predictors of response is a priority. This review aims to summarize recent advances in understanding the causes of the variability in treatment response in RA, with particular attention to predictive potential of autoantibodies and DMARD pharmacogenetics. In recent years, several biomarkers have been proposed to personalize the therapy. Unfortunately, a magic bullet does not exist, as many factors concur to disease susceptibility and treatment outcomes, acting around the patient’s congenital background. Models integrating demographic, clinical, biochemical, and genetic data are needed to enhance the predictive capacity of specific factors singularly considered to optimize RA treatment in light of multidisciplinary patient management.

Pancreatic cancer (PC) is one of the most aggressive cancers in the world. Several extracellular factors are involved in its development and metastasis to distant organs. In PC, the protein Annexin A1 (ANXA1) appears to be overexpressed and may be identified as an oncogenic factor, also because it is a component in tumor-deriving extracellular vesicles (EVs). Indeed, these microvesicles are known to nourish the tumor microenvironment. Once we evaluated the autocrine role of ANXA1-containing EVs on PC MIA PaCa-2 cells and their pro-angiogenic action, we investigated the ANXA1 paracrine effect on stromal cells like fibroblasts and endothelial ones. Concerning the analysis of fibroblasts, cell migration/invasion, cytoskeleton remodeling, and the different expression of specific protein markers, all features of the cell switching into myofibroblasts, were assessed after administration of wild type more than ANXA1 Knock-Out EVs. Interestingly, we demonstrated a mechanism by which the ANXA1-EVs complex can stimulate the activation of formyl peptide receptors (FPRs), triggering mesenchymal switches and cell motility on both fibroblasts and endothelial cells. Therefore, we highlighted the importance of ANXA1/EVs-FPR axes in PC progression as a vehicle of intercommunication tumor cells-stroma, suggesting a specific potential prognostic/diagnostic role of ANXA1, whether in soluble form or even if EVs are captured in PC.

Heart Failure (HF) is a syndrome, which implies the existence of different phenotypes. The new categorization includes patients with preserved ejection fraction (HFpEF), mid-range EF (HFmrEF), and reduced EF (HFrEF) but the molecular mechanisms involved in these HF phenotypes have not yet been exhaustively investigated. Sirt1 plays a crucial role in biological processes strongly related to HF. This study aimed to evaluate whether Sirt1 activity was correlated with EF and other parameters in HFpEF, HFmrEF, and HFrEF. Seventy patients, HFpEF (n = 23), HFmrEF (n = 23) and HFrEF (n = 24), were enrolled at the Cardiology Unit of the University Hospital of Salerno. Sirt1 activity was measured in peripheral blood mononuclear cells (PBMCs). Angiotensin-Converting Enzyme 2 (ACE2) activity, Tumor Necrosis Factor-alpha (TNF-α) and Brain Natriuretic Peptide (BNP) levels were quantified in plasma. HFpEF showed lower Sirt1 and ACE2 activities than both HFmrEF and HFrEF (p < 0.0001), without difference compared to No HF controls. In HFmrEF and HFrEF a very strong correlation was found between Sirt1 activity and EF (r2 = 0.899 and r2 = 0.909, respectively), and between ACE2 activity and Sirt1 (r2 = 0.801 and r2 = 0.802, respectively). HFrEF showed the highest TNF-α levels without reaching statistical significance. Significant differences in BNP were found among the groups, with the highest levels in the HFrEF. Determining Sirt1 activity in PBMCs is useful to distinguish the HF patients’ phenotypes from each other, especially HFmrEF/HFrEF from HFpEF.

Ectopic pregnancy (EP) is the implantation of an embryo outside the endometrial cavity of the uterus. Signs and symptoms of EP may arise between the 6th and the 8th week of gestation and include vaginal bleeding, lower abdominal and pelvic pain. Frequently EPs implant in the fallopian tubes. A rare EP is the interstitial pregnancy, a life-threatening condition being responsible for nearly 20% of all deaths caused by EPs. Because of its unique location, the diagnosis is difficult and based on signs and specific criteria together with measuring of serum β-hCG. Usually, EP is treated by surgical approach, which is associated with increased morbidity, decreased fertility and increased likelihood of hysterectomy and uterine rupture in a subsequent pregnancy. Early diagnosis is crucial to life saving and allowing alternative therapeutic interventions such as pharmacological treatments. Methotrexate (MTX) represents the mainstay therapy. There is no standard care for the interstitial pregnancy for what concerns either surgical or pharmacological approaches. We reported a case of a 36-year-old woman admitted to the Hospital of Salerno-Italy with a value of serum β-hCG of 35,993 IU/L. Transvaginal ultrasonography revealed an empty uterine cavity and a mass of 35.7 mm in diameter characterized by a hypoechoic central area. The patient was in stable haemodynamic condition and no haematologic, renal and hepatic impairments were recorded. Despite the high serum β-hCG levels, a pharmacological approach was preferred to a surgical one. The patient was treated with intramuscular administration of MTX in daily dose of 1 mg/Kg alternated with 0.1 mg/kg folinic acid for 5 days. The patient remained hospitalized for 20 days and no side effects were reported. The decrease of the serum β-hCG was monitored and more than 15% reduction was detected between the 4th and the 7th day after the beginning of the treatment. The serum β-hCG became undetectable 35 days after. A multidosing intramuscular administration of MTX was effective and safe even in the presence of very high serum β-hCG levels. Together with similar cases reported in literature, the present results can contribute to improve the decision making in the treatment of the interstitial pregnancy.

Although several efforts have been made in the search for genetic and epigenetic patterns linked to diseases, a comprehensive explanation of the mechanisms underlying pathological phenotypic plasticity is still far from being clarified. Oxidative stress and inflammation are two of the major triggers of the epigenetic alterations occurring in chronic pathologies, such as neurodegenerative diseases. In fact, over the last decade, remarkable progress has been made to realize that chronic, low-grade inflammation is one of the major risk factor underlying brain ageing. Accumulated data strongly suggest that phytochemicals from fruits, vegetables, herbs, and spices may exert relevant immunomodulatory and/or anti-inflammatory activities in the context of brain aging. Starting by the evidence that a common denominator of aging and chronic degenerative diseases is represented by inflammation, and that several dietary phytochemicals are able to potentially interfere with and regulate the normal function of cells, in particular neuronal components, aim of this review is to summarise recent studies on neuroinflammaging processes and proofs indicating that specific phytochemicals may act as positive modulators of neuroinflammatory events. In addition, critical pathways involved in mediating phytochemicals effects on neuroinflammaging were discussed, exploring the real impact of these compounds in preserving brain health before the onset of symptoms leading to inflammatory neurodegeneration and cognitive decline.

Despite inflammatory and immune mechanisms participating to atherogenesis and dendritic cells (DCs) driving immune and non-immune tissue injury response, the interactions between DCs and vascular smooth muscle cells (VSMCs) possibly relevant to vascular pathology including atherogenesis are still unclear. To address this issue, immature DCs (iDCs) generated from CD14+ cells isolated from healthy donors were matured either with cytokines (mDCs), or co-cultured (ccDCs) with human coronary artery VSMCs (CASMCs) using transwell chambers. Co-culture induced DC immunophenotypical and functional maturation similar to cytokines, as demonstrated by flow cytometry and mixed lymphocyte reaction. In turn, factors from mDCs and ccDCs induced CASMC migration. MCP-1 and TNFα, secreted from DCs, and IL-6 and MCP-1, secreted from CASMCs, were primarily involved. mDCs adhesion to CASMCs was enhanced by CASMC pre-treatment with IFNγ and TNFα ICAM-1 and VCAM-1 were involved, since the expression of specific mRNAs for these molecules increased and adhesion was inhibited by neutralizing antibodies to the counter-receptors CD11c and CD18. Adhesion was also inhibited by CASMC pre-treatment with the HMG-CoA-reductase inhibitor atorvastatin and the PPARγ agonist rosiglitazone, which suggests a further mechanism for the anti-inflammatory action of these drugs. Adhesion of DCs to VSMCs was shown also in vivo in rat carotid 7 to 21 days after crush and incision injury. The findings indicate that DCs and VSMCs can interact with reciprocal stimulation, possibly leading to perpetuate inflammation and vascular wall remodelling, and that the interaction is enhanced by a cytokine-rich inflammatory environment and down-regulated by HMGCoA-reductase inhibitors and PPARγ agonists.

BACKGROUND AND AIM:Warfarin is the most frequently prescribed anticoagulant worldwide. However, warfarin therapy is associated with a high risk of bleeding and thromboembolic events because of a large interindividual dose-response variability. We investigated the effect of genetic and non genetic factors on warfarin dosage in a South Italian population in the attempt to setup an algorithm easily applicable in the clinical practice. MATERIALS AND METHODS:A total of 266 patients from Southern Italy affected by cardiovascular diseases were enrolled and their clinical and anamnestic data recorded. All patients were genotyped for CYP2C9 2, 3, CYP4F2 3, VKORC1 -1639 G>A by the TaqMan assay and for variants VKORC1 1173 C>T and VKORC1 3730 G>A by denaturing high performance liquid chromatography and direct sequencing. The effect of genetic and not genetic factors on warfarin dose variability was tested by multiple linear regression analysis, and an algorithm based on our data was established and then validated by the Jackknife procedure. RESULTS:Warfarin dose variability was influenced, in decreasing order, by VKORC1-1639 G>A (29.7%), CYP2C9 3 (11.8%), age (8.5%), CYP2C9 2 (3.5%), gender (2.0%) and lastly CYP4F2 3 (1.7%); VKORC1 1173 C>T and VKORC1 3730 G>A exerted a slight effect (