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Abstract Background/aims In order to make the centers more attractive to trial sponsors, in recent years, some research institutions around the world have pursued projects to reorganize the pathway of trial activation, developing new organizational models to improve the activation process and reduce its times. This study aims at analyzing and reorganizing the start-up phase of trials conducted at the Research and Innovation Department (DAIRI) of the Public Hospital of Alessandria (Italy). Methods A project was carried out to reorganize the trial authorization process at DAIRI by involving the three facilities responsible for this pathway: clinical trial center (CTC), ethics committee secretariat (ESC), and administrative coordination (AC). Lean Thinking methodology was used with the A3 report tool, and the analysis was carried out by monitoring specific key performance indicators, derived from variables representing highlights of the trials’ activation pathway. The project involved phases of analysis, implementation of identified countermeasures, and monitoring of timelines in eight 4-month periods. The overall mean and median values of studies activation times were calculated as well as the average times for each facility involved in the process. Results In this study, 298 studies both sponsored by research associations and industry with both observational and interventional study design were monitored. The mean trial activation time was reduced from 218 days before the project to 56 days in the last period monitored. From the first to the last monitoring period, each facility involved achieved at least a halving of the average time required to carry out its activities in the clinical trials’ activation pathway (CTC: 55 days vs 23, ECS: 25 days vs 8, AC 29 days vs 10). Average activation time for studies with agreement remains longer than those without agreement (100 days vs. 46). Conclusions The reorganization project emphasized the importance of having clinical and administrative staff specifically trained on the trial activation process. This reorganization led to the development of a standard operating procedure and a tool to monitor the time (KPIs of the process) that can also be implemented in other clinical centers.

The prevalence of malnutrition in patients is very high in Europe (>70%). An Italian FADOI-SINPE survey revealed that malnutrition is an underestimated problem by internists. The AMIDO study examines malnutrition in Acqui Terme Hospital (Alessandria, Italy) Internal Medicine Department patients. Patients were screened for malnutrition using the Malnutrition Universal Screening Tool (MUST) upon admission. 268 patients (49.63% male) were enrolled, with a median age of 83 years. At admission, the prevalence of malnutrition risk was 48.88%. The proportion of patients who came from home resulted to have a slight decreasing trend among the three subgroups according to MUST (84.67%, 82.76%, and 73.53% in increasing order of MUST score respectively), but was not statistically significant (P=0.10). Dementia [odds ratio (OR): 6.36; 95% confidence interval (CI): 2.52-18.63], heart failure (OR: 2.45; 95% CI: 1.33-4.57), neoplasm (OR: 2.24; 95% CI: 1.08-4.77) and infectious diseases (OR: 2.27; 95% CI: 1.226-4.274) increase malnutrition odds. Increasing attention to malnutrition risk is crucial for patients with dementia, neoplasm, heart failure, and infectious diseases, which raise malnutrition risk probability.

17-β-estradiol, involved in mesothelioma pathogenesis, and its precursors were explored as potential biomarkers for the early diagnosis of mesothelioma. Using enzyme-linked immunosorbent assay(ELISA) for 17-β-estradiol and ultra-high performance liquid chromatography/tandem mass spectrometry(UHPLC-MS/MS) for 19 17-β-estradiol precursors, a comprehensive analysis of 20steroid hormones was conducted in the serum of mesothelioma patients(n=67), asbestos-exposed healthy subjects(n=39), and non-asbestos-exposed healthy subjects(n=35). Bioinformatics analysis explored three potential serum biomarkers: 17-β-estradiol, DHEA-S, and androstenedione. The results revealed significant differences in 17-β-estradiol levels between mesothelioma patients and both non-asbestos-exposed and asbestos-exposed healthy subjects. No significant variations in serum 17-β-estradiol levels were observed among mesothelioma patients at different stages, suggesting its potential as an early diagnostic marker. 17-β-estradiol levels were similar in mesothelioma patients with environmental and occupational asbestos exposure, while males with occupational asbestos exposure exhibited significantly higher levels of 17-β-estradiol compared to females. Significant reduction in androstenedione and an increase in DHEA-S were observed in asbestos-exposed individuals compared to non-asbestos-exposed individuals. The analysis of DHEA-S-androstenedione-17-β-estradiol signature score showed an increase in asbestos-exposed individuals and mesothelioma patients compared to non-asbestos-exposed individuals, and this score effectively distinguished between the groups. The Cancer Genome Atlas data was utilized to analyze the expression of 5-α-reductase1 and hydroxysteroid-17β-dehydrogenase2 genes. The findings indicated that mesothelioma patients with elevated gene values for 5-α-reductase1 and hydroxysteroid-17β-dehydrogenase2 have a worse or better prognosis on overall survival, respectively. In conclusion, this study suggests 17-β-estradiol, DHEA-S, and androstenedione as biomarkers for mesothelioma risk and early diagnosis of mesothelioma in asbestos-exposed individuals, aiding timely intervention and improved care.

Given the ongoing COVID-19 pandemic, there is a need to identify SARS-CoV-2 and to differentiate it from other respiratory viral infections, especially influenza A and B, in various critical settings. Since their introduction, the use of rapid antigen tests has spread worldwide, but there is variability in their diagnostic accuracy. In the present study, we evaluated the clinical performance of the ID NOW™ COVID-19 2.0, a molecular point-of-care test (POCT) based on enzymatic isothermal amplification for the differential diagnosis of SARS-CoV-2 and influenza A/B in a pediatric emergency setting. A cohort of pediatric patients admitted between December 2022 and February 2023 were simultaneously tested with the POCT and standard laboratory molecular assay. Our findings showed high negative agreement of the POCT assay across the different age groups for SARS-CoV-2, influenza A, and influenza B (more than 98.0%), while its positive agreement varied significantly for the abovementioned viral species from 50.0% to 100%. These results highlight the potential of the ID NOW™ COVID-19 2.0 POCT assay as a reliable and rapid tool for excluding SARS-CoV-2 and influenza A/B infections in symptomatic pediatric patients, although its variable positive agreement suggests a need for confirmatory RT-qPCR testing in certain clinical and epidemiological settings in order to ensure accurate diagnosis and appropriate patient management.

Asbestos research, identification, and quantification have been performed over the years, and the relationship between fiber inhalation and lung disease development is well defined. The same cannot be said for the gastroenteric system: the International Agency for Research on Cancer (IARC) believes that colorectal cancer (CRC) could be associated with asbestos exposure, but research has not demonstrated a casual nexus between exposure and CRC, despite highlighting an association tendency. The combination of scanning electron microscopy (SEM) and energy-dispersive spectroscopy (EDS) is the most applied technique in asbestos fiber identification in tissues and intestinal mucosa. In this study, SEM/EDS was applied to evaluate the presence of asbestos fibers and bodies (ABs) inside the tissue of eleven patients affected by CRC who had undergone environmental exposure due to living in an asbestos-polluted area where an Eternit plant had been active in the past. This technique was coupled with optical microscopy (OM) to verify whether the latter could be applied to evaluate the presence of these mineral phases, with the goal of understanding its suitability for identifying fibers and ABs in colon tissues. In addition to verifying the presence of fibers, this study allowed us to identify the deposition site of said fibers within the sample and possibly detect associated tissue reactions using OM, over a shorter time and at lower costs. Despite being a preliminary and descriptive work, the obtained results allowed us to propose a method involving first-sample OM observation to identify regulated (fibers with a length ≥ 5 μm, a thickness ≤ 3 μm, and a length/thickness ratio > 3) asbestos phases and ABs in the extra-respiratory system. In fact, OM and SEM/EDS provided similar information: no asbestiform morphology or ABs were found, but phyllosilicates and other inorganic materials were identified. This research needs to be continued using higher-resolution techniques to definitively rule out the presence of these fibers inside tissues whilst also increasing the number of patients involved.

Breast milk is the natural source of nutrition for infants, but while it supports their health, it can also be a potential source of toxic inorganic particulate matter, and this applies to both breast milk and industrially produced milk. The aim of the present study was to evaluate the presence of nanoparticles in both breast milk and formula milk samples. We collected and analyzed, via a new electron scanning microscopic procedure, 19 samples of breast milk from Italian women and 19 formula milk samples produced by different companies. Organic–inorganic agglomerates were detected in 58% of formula and in 63% of breast milk samples, respectively. In addition, a significantly (p < 0.05) greater size of nanoparticles was observed in formula milk samples. The results, showing the presence of inorganic nanosized particles in breast and artificial milk, may lead to future studies aimed at investigating possible nanosized contamination of milk and identifying early prevention strategies for women and animals involved in the food chain.

Fecal Microbiota Transplantation (FMT) represents a promising therapeutic tool under study for several purposes and is currently applied to the treatment of recurrent Clostridioides difficile infection. However, since the use of fresh stool was affected by several issues linked to donor screening, the development of a frozen stool bank is a reliable option to standardize FMT procedures. Nevertheless, different environmental factors impact microbial viability. Herein, we report the effect of different thawing temperatures and storage conditions on bacterial suspensions in the FMT procedure. In total, 20 stool samples were divided into aliquots and tested across a combination of different storing periods (15, 30; 90 days) and thawing procedures (4 °C overnight, room temperature for 1 h; 37 °C for 5 min). Focusing on storage time, our data showed a significant reduction in viability for aerobic and anaerobic bacteria after thawing for 15 days, while no further reductions were observed until after 90 days. Instead, among the different thawing procedures, no significant differences were observed for aerobic bacteria, while for anaerobes, thawing at 37 °C for 5 min was more effective in preserving the bacterial viability. In conclusion, the frozen fecal microbiota remained viable for at least three months, with an excellent recovery rate in all three thawing conditions.

Abstract The epigenetic role of microRNAs is established at both physiological and pathological levels. Dysregulated miRNAs and their targets appear to be a promising approach for innovative anticancer therapies. In our previous study, circulating miR-197-3p tested dysregulated in workers ex-exposed to asbestos (WEA). Herein, an epigenetic investigation on this circulating miRNA was carried out in sera from malignant pleural mesothelioma (MPM) patients. MiR-197-3p was quantified in MPM (n = 75) sera and comparatively analyzed to WEA (n = 75) and healthy subject (n = 75) sera, using ddPCR and RT-qPCR techniques. Clinicopathological characteristics, occupational, non-occupational information and overall survival (OS) were evaluated in correlation studies. MiR-197-3p levels, analyzed by ddPCR, were significantly higher in MPM than in WEA cohort, with a mean copies/µl of 981.7 and 525.01, respectively. Consistently, RT-qPCR showed higher miR-197-3p levels in sera from MPM with a mean copies/µl of 603.7, compared to WEA with 336.1 copies/µl. OS data were significantly associated with histologic subtype and pleurectomy. Circulating miR-197-3p is proposed as a new potential biomarker for an early diagnosis of the MPM onset. Indeed, miR-197-3p epigenetic investigations along with chest X-ray, computed tomography scan and spirometry could provide relevant information useful to reach an early and effective diagnosis for MPM.

Abstract Background This study aimed to explore whether explainable Artificial Intelligence methods can be fruitfully used to improve the medical management of patients suffering from complex diseases, and in particular to predict the death risk in hospitalized patients with SARS-Cov-2 based on admission data. Methods This work is based on an observational ambispective study that comprised patients older than 18 years with a positive SARS-Cov-2 diagnosis that were admitted to the hospital Azienda Ospedaliera “SS Antonio e Biagio e Cesare Arrigo”, Alessandria, Italy from February, 24 2020 to May, 31 2021, and that completed the disease treatment inside this structure. The patients’medical history, demographic, epidemiologic and clinical data were collected from the electronic medical records system and paper based medical records, entered and managed by the Clinical Study Coordinators using the REDCap electronic data capture tool patient chart. The dataset was used to train and to evaluate predictive ML models. Results We overall trained, analysed and evaluated 19 predictive models (both supervised and unsupervised) on data from 824 patients described by 43 features. We focused our attention on models that provide an explanation that is understandable and directly usable by domain experts, and compared the results against other classical machine learning approaches. Among the former, JRIP showed the best performance in 10-fold cross validation, and the best average performance in a further validation test using a different patient dataset from the beginning of the third COVID-19 wave. Moreover, JRIP showed comparable performances with other approaches that do not provide a clear and/or understandable explanation. Conclusions The ML supervised models showed to correctly discern between low-risk and high-risk patients, even when the medical disease context is complex and the list of features is limited to information available at admission time. Furthermore, the models demonstrated to reasonably perform on a dataset from the third COVID-19 wave that was not used in the training phase. Overall, these results are remarkable: (i) from a medical point of view, these models evaluate good predictions despite the possible differences entitled with different care protocols and the possible influence of other viral variants (i.e. delta variant); (ii) from the organizational point of view, they could be used to optimize the management of health-care path at the admission time.

Since its first appearance in late 2019 in Wuhan, China, severe acute respiratory syndrome caused by Coronavirus 2 (SARS-CoV-2) has had a major impact on healthcare facilities around the world. Although in the past year, mass vaccination and the development of monoclonal antibody treatments have reduced the number of deaths and severe cases, the circulation of SARS-CoV-2 remains high. Over the past two years, diagnostics have played a crucial role in virus containment both in health care facilities and at the community level. For SARS-CoV-2 detection, the commonly used specimen type is the nasopharyngeal swab, although the virus can be identified in other matrices such as feces. Since fecal microbiota transplantation (FMT) assumes significant importance in the treatment of chronic gut infections and that feces may be a potential vehicle for transmission of SARS-CoV-2, in this study we have evaluated the performance of the rapid cartridge-based RT-PCR test STANDARD™ M10 SARS-CoV-2 (SD Biosensor Inc., Suwon, South Korea) using fecal samples. The results obtained indicates that STANDARD™ M10 SARS-CoV-2 can detect SARS-CoV-2 in stool samples even at low concentration. For this reason, STANDARD™ M10 SARS-CoV-2 could be used as reliable methods for the detection of SARS-CoV-2 in fecal samples and for the screening of FMT donors.

Asbestos is a term that includes six fibrous mineral phases related to different lung diseases, including asbestosis, lung cancer, and Malignant Pleural Mesothelioma (MPM). Since the last century, these minerals have been widely studied under their mineralogical/chemical and physical aspects with in vivo and in vitro studies to understand the mechanisms of their carcinogenicity. There are several techniques described in the literature, as optical and electron microscopies, for the identification of coated (asbestos bodies, ABs) and uncoated fibers, but only micro-Raman spectroscopy permits a sure characterization of these minerals—and of the related phases—directly in the histological sections of pulmonary parenchyma without any manipulation. In this case, the risk of the loss of associated inorganic phases from asbestos bodies (ABs) and fibers (e.g.: iron or carbonaceous micro-particles) is avoided. Asbestos bodies are produced by the activity of alveolar macrophages with degradation/inactivation of asbestos fibers. Inside the alveolar macrophages, organic and inorganic material settles on the foreign fibers forming an iron-rich proteic and carbonaceous coating. In this study, Variable Pressure Scanning Electron Microscopy with annexed Electron Dispersive Spectroscopy (VP-SEM/EDS) and micro-Raman spectroscopy were applied to the characterization of the phases in the ABs. Characterization of carbonaceous materials (CMs), observed in pristine asbestos phases in previous works, was therefore performed, addressing the micro-Raman laser beam on different points of the asbestos bodies, and Raman mappings on ABs were carried out for the first time. Coupling the data obtained by VP-SEM/EDS and micro-Raman spectroscopy, it was possible to collect information about the iron and carbonaceous phases adhered to the fibers, probably lost during the classical tissue digestion procedures. Information about both mineral and carbonaceous components might be useful to understand the whole structure of “asbestos bodies” and the inflammogenic and carcinogenic effects of the asbestos phases coupled to CMs, that might derive from cigarette smoke or from environmental pollution; this study might be useful to deepen also the possible detrimental role of ABs in the tissues.

To carry out effective and quick identification of SARS-CoV-2 from nasopharyngeal swabs and contain outbreaks, reliable and rapid tools are needed. Herein, we compared a rapid antigen test based on active microfluidic technology to an RT-qPCR assay in pediatric and young adult patients admitted to the Pediatric Emergency Unit of a Children’s Hospital. Nasopharyngeal swabs collected from patients with suspected COVID-19 disease and from those without COVID-19 related symptoms, but requiring hospitalization, were performed with both antigen test and RT-qPCR assays. We included 375 patients with a median age of 5 years in the study, with an estimated overall prevalence of 7.2%. Overall, we observed a specificity of 97.4% (95% CI: 94.9–98.7) and a sensitivity of 66.6% (95% CI: 46.0–82.7) with a positive likelihood ratio (LR+) of 25.8 (95% CI: 12.8–51.8). In the subgroup of symptomatic patients, the specificity and the sensitivity were 95.2% (95% CI: 89.4–98.0) and 80.0% (95% CI: 44.2–96.5) respectively; LR+ was 16.6 (95% CI: 7.19–38.6). In the asymptomatic subset, the performance showed a specificity of 98.7% (95% CI: 95.8–99.7), a sensitivity of 58.8% (95% CI: 33.5–80.6), and an LR+ of 43.7 (95% CI: 13.3–144.0). Compared to RT-qPCR, the new microfluidic-based antigen test showed higher specificity (>95%) in the pediatric population, thus representing a suitable point-of-care testing (POCT) in a clinical setting with low prevalence of COVID-19.

Different types of tissues respond differently to the action of oxidative stress. The visual system is very sensitive to oxidative action due to continuous exposure to light. In consideration of the growing interest of scientific studies towards various compounds endowed with antioxidant and anti-inflammatory properties, we performed a review of the literature focusing on the use of some antioxidant molecules for the treatment of conditions affecting the visual system. In this study, we focused on the ability of two antioxidant agents, the small molecule α-lipoic acid (ALA) and the enzyme superoxide dismutase (SOD), to influence the neurodegenerative physiological processes related to aging and oxidative stress affecting the ocular segment. The literature data report that ALA and SOD can protect against neurodegenerative effects both the optic nerve and retina and, if administered together, they are able to lower the levels of oxidative stress, thus preventing neurodegeneration and reducing the apoptotic process.

Given the ongoing pandemic, there is a need to identify SARS-CoV-2 and differentiate it from other respiratory viral infections in various critical settings. Since its introduction, rapid antigen testing is spreading worldwide, but diagnostic accuracy is extremely variable and often in disagreement with the manufacturer’s specifications. Our study compared the clinical performances of two microfluidic rapid antigen tests towards a molecular assay, starting from positive samples. A total of 151 swabs collected at the Microbiology and Virology Laboratory of A.O. “SS Antonio e Biagio e C. Arrigo” (Alessandria, Italy) for the diagnosis of SARS-CoV-2 were simultaneously tested to evaluate accuracy, specificity, and agreement with the RT-qPCR results. Both assays showed an overall agreement of 100% for negative specimens, while positive accuracy comprised between 45.10% and 54.90%. According to the manufacturer’s instructions, the greatest correlation between the antigenic and molecular assays was observed for the subset with high viral load (18/19, 94.74%), while it dramatically decreased for other subsets. Moreover, the ability to differentiate between SARS-CoV-2 and Flu provides an added value and could be addressed in an epidemic context. However, an in-house validation should be performed due to differences observed in performance declared by manufacturers and those actually obtained.

Objective: To examine caregivers' experiences and training needs after radical cystectomy with urinary diversion for the first three months following the patient's discharge. Methods: This study applied a phenomenological design approach through open-ended interviews and descriptive analysis. Phenomenology applied to empirical research requires researchers to explore the empirical facts narrated by partici-pants. This study followed the Consolidated Criteria for Reporting Qualitative Research guidelines, a 32 – item checklist for inter-views and focus groups. The study population included caregivers of bladder cancer patients, admitted to three Italian hospitals. Data were collected between March 2020 and March 2022. Results: Fifty-two caregivers of patients who underwent cystecto-my with urinary diversion from three Italian hospitals (41 males and 11 females) participated to the study. The data analysis con-verged in the identification of three themes – with sub-themes –that included various aspects of the caregiver’s lived experiences: 1) living with the burden of being indispensable, for the family member, 2) feeling abandoned by institutions, 3) tiredness and less willingness to look after the relative due to work burden. Conclusions: Our study demonstrates that the caregiver of a patient with bladder cancer and urostomy in the first three months of hospital discharge is very worried and stressed. Despite the training program received in hospital, the caregiver does not recognize the newly acquired skills and has difficulty applying them. Further study would be required.

This study aims to observe the clinical characteristics and outcomes of recovered patients from Coronavirus Disease (COVID-19) related to the vaccination status. We examined results of 205 COVID-19-recovered patients from 15 December 2021 to 1 March 2022 in two hospitals of Local Health Authority of Alessandria (Italy) during the fourth pandemic wave. 77% of patients were hospitalized for acute respiratory failure (ARF) with radiological pneumonia pattern (recovered for COVID), 23% for other causes with occasional positivity finding (recovered with COVID). 32% of patients were not vaccinated for Sars-COV-2, 37% had three doses, 25% two doses, 5% only one dose. All patients without vaccination were hospitalized for ARF and they had a 7 times higher risk of hospitalization than the vaccinated. 60% of all patients had >3 comorbidities, of these 50% was vaccinated with three doses. In the fourth pandemic wave compared to the other not all patients were hospitalized for ARF and pneumonia and the presence of comorbidities >3 is a risk factor for hospitalization regardless of vaccination status. This justifies the administration of the fourth dose to frail patients.

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Background: Quality of life issues is a crucial burden in breast cancer (BC) survivors with relevant implications in terms of survivorship and health-care costs. The increasing long-term survival of these patients provides new challenges, with translational research now focusing on innovative and tailored approaches to improve their complex management. In this scenario, several emerging biomarkers have the potential to improve the clinical rehabilitative management of patients with BC. However, to date, guidelines supporting biomarker implementation in this area are still lacking. Therefore, the aim of this systematic review was to summarize the currently available biomarkers that might be potentially integrated into rehabilitation practice to promote a precision medicine approach to BC survivorship issues.Methods: On 9th March 2022, PubMed, Scopus, Web of Science, Cochrane, and PEDro were systematically searched for randomized controlled trials (RCTs) assessing rehabilitation interventions in BC patients. Molecular biomarker modifications induced by physical exercise have been assessed through the review of the study protocols and published results. The Jadad scale was used to assess the quality of the studies included.Results: Out of 2,224 records, 22 studies were included in the present systematic review. Exercise therapy showed significant results in 15 RCTs, in terms of metabolic biomarkers, including glycemic and insulin profile, and lipid profile (p ≤ 0.05). Similarly, 12 studies underlined significant effects in inflammation and immune response biomarkers, including TNF-α, IL-6, IL-10, C-reactive protein, leptin, and adiponectin (p ≤ 0.05). On the other hand, cardiac biomarkers were assessed in three studies without reporting significant differences after exercise therapy (p = NS). The quality assessment identified 19 RCTs as high-quality studies and three RCTs of low quality.Conclusion: Our findings reveal significant biochemical perturbations in key molecules induced by physical exercise in patients with BC, suggesting room for the implementation of actionable biomarkers. Future research might clarify the role of biomarkers on treatment effectiveness monitoring, to optimize rehabilitative strategies tailored to patient’s needs.

Abstract Background Based on previous studies highlighting that the induction of cyclooxygenase-2 (COX-2) and high prostaglandin E2 (PGE2) levels contribute to the pathogenesis of malignant pleural mesothelioma (MPM), and that aromatase (CYP19A1), an enzyme that plays a key role in estrogen biosynthesis, along with estradiol (E2) were expressed in MPM, this study aimed to investigate the possible interplay between COX-2 and CYP19A1 in the pathogenesis of mesothelioma, as well as the underlying mechanism. Methods The interaction between COX-2 and CYP19A1 was first investigated on different MPM lines upon PGE2, and COX-2 inhibitor (rofecoxib) treatment by western blot, RT-PCR. The key regulatory pathways involved in the COX-2 and CYP19A1 axis were further studied in MPM cells, after rofecoxib and exemestane (CYP19A1 inhibitor) treatment in monotherapy and in combination, by cell cycle distribution, western blot, and combination index analysis. To explore the role of COX-2/CYP19A1 axis in 3D preclinical models of MPM cells, we analyzed the effect of combination of COX-2 and CYP19A1 inhibitors in mesosphere formation. Immunohistochemical analysis of MPM mesosphere and specimens was utilized to evaluate the involvement of COX-2 on the CYP19A1 activity and the relationship between E2 and COX-2. Results PGE2 or rofecoxib treatment caused in MPM cells an increased or decreased, respectively, CYP19A1 expression at mRNA and protein levels. The effect of rofecoxib and exemestane combination in MPM cell proliferation was synergistic. Activation of caspase-3 and cleavage of PARP confirmed an apoptotic death for MPM cell lines. Increased expression levels of p53, p21, and p27, downregulation of cyclin D1 and inhibition of Akt activation (pAKT) were also found. The antagonistic effect of rofecoxib and exemestane combination found only in one cell line, was reverted by pretreatment with MK2206, a pAKT inhibitor, indicating pAKT as an actionable mediator in the COX-2-CYP19A1 axis. Reduction of size and sphere-forming efficiency in MPM spheres after treatment with both inhibitor and a decrease in COX-2 and E2 staining was found. Moreover, immunohistochemical analysis of 46 MPM samples showed a significant positive correlation between COX-2 and E2. Conclusions Collectively, the results highlighted a novel COX-2/CYP19A1 axis in the pathogenesis of MPM that can be pharmacologically targeted, consequently opening up new therapeutic options.

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

Trauma is a major cause of mortality throughout the world. Traumatic pain—acute, sudden, or chronic—is defined as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage”. Patients’ perceptions of pain assessment and management have become an important criterion and relevant outcome measure for healthcare institutions. Several studies show that 60–70% of ER patients experience pain, and more than half of them express a feeling of sorrow, which can be moderate or severe, at triage. The few studies that have analyzed how pain is assessed and managed in these departments agree that approximately 70% of patients receive no analgesia or receive it with remarkable delay. Specifically, less than half of the patients receive treatment for pain during admission and 60% of discharged patients have higher intensity pain than at admission. Trauma patients are also the ones who most commonly report low satisfaction with pain management. Associated with this lack of satisfaction, we can describe the poor use of tools for measuring and recording pain, poor communication among caregivers, inadequate training in pain assessment and management, and widespread misconceptions among nurses about the reliability of patients’ estimation of pain. The aim of this article is to review the scientific literature to explore the methodologies of pain management in trauma patients attending the emergency room and analyzing their weaknesses as a starting point to improve the approach to this, unfortunately too often, underestimated issue. A literature search was performed using the major databases to identify relevant studies in indexed scientific journals. The literature showed that the multimodal approach in trauma patients is the best approach to pain management. It is becoming increasingly crucial to manage the patient on multiple fronts. Drugs acting on different pathways can be administered together at lower doses, minimizing risks. Every emergency department must have staff trained in the assessment and immediate management of pain symptoms as this allows the reduction of mortality and morbidity and shortens hospital stays, contributing to early mobilization, reduced hospital costs, and enhanced patient satisfaction and quality of life.

Objectives: La Peyronie's disease tends to be underdiagnosed and undertreated. In Italy it affects about 7% of the population aged between 50 and 70 years old. The aim of this study is to evaluate the quality of life of patients undergoing iontophoretic therapy with verapamil and treatment outcomes at a two-year interval. Materials and methods: This study evaluated 128 patients subjected to treatment cycles over a period of two years. Questionnaires were administered to the patients at the beginning and end of each cycle of iontophoretic therapy in order to monitor the degree of presumed anxiety, depression, pain and the associated quality of life. Result: This prospective descriptive observational study included 128 patients aged between 42 and 74 years presenting pain during erection and/or coital intercourse, which ceased in 108 cases, diminished in 12 and remained present in 4. Concerning the penile deviation, which was present in all patients (128 cases), it disappeared in 6 cases, regressed in 90 cases, while it remained unchanged in 32 cases. As for the plaque consistency on palpation, in 42 patients the plaque was no longer present, in 50 cases the consistency diminished, while in 36 patients it remained unchanged. None of the cases evidenced an aggravation of the clinical condition. 57% of the evaluated patients had high levels of anxiety in the first cycle of iontophoretic sessions and low levels of depression. Anxiety decreased in 32% of cases. Depression was not related to pain but to sexual dysfunction. About 80 % of the patients assessed had an increase in quality of life at the end of the two-year follow-up. Conclusions: In conclusion, it can be claimed that iontophoresis combined with verapamil therapy can improve patients' quality of life and offer them psychophysical well-being and an acceptable sexual relationship, thus decreasing anxiety and depression levels.

Malignant pleural mesothelioma (MPM) is a rare and fatal disease of the pleural lining. Up to 80% of the MPM cases are linked to asbestos exposure. Even though its use has been banned in the industrialized countries, the cases continue to increase. MPM is a lethal cancer, with very little survival improvements in the last years, mirroring very limited therapeutic advances. Platinum-based chemotherapy in combination with pemetrexed and surgery are the standard of care, but prognosis is still unacceptably poor with median overall survival of approximately 12 months. The genomic landscape of MPM has been widely characterized showing a low mutational burden and the impairment of tumor suppressor genes. Among them, BAP1 and BLM are present as a germline inactivation in a small subset of patients and increases predisposition to tumorigenesis. Other studies have demonstrated a high frequency of mutations in DNA repair genes. Many therapy approaches targeting these alterations have emerged and are under evaluation in the clinic. High-throughput technologies have allowed the detection of more complex molecular events, like chromotripsis and revealed different transcriptional programs for each histological subtype. Transcriptional analysis has also paved the way to the study of tumor-infiltrating cells, thus shedding lights on the crosstalk between tumor cells and the microenvironment. The tumor microenvironment of MPM is indeed crucial for the pathogenesis and outcome of this disease; it is characterized by an inflammatory response to asbestos exposure, involving a variety of chemokines and suppressive immune cells such as M2-like macrophages and regulatory T cells. Another important feature of MPM is the dysregulation of microRNA expression, being frequently linked to cancer development and drug resistance. This review will give a detailed overview of all the above mentioned features of MPM in order to improve the understanding of this disease and the development of new therapeutic strategies.

Germline mutations in the tumor suppressor gene BRCA1-associated protein-1 (BAP1) lead to BAP1 tumor predisposition syndrome (BAP1-TPDS), characterized by high susceptibility to several tumor types, chiefly melanoma, mesothelioma, renal cell carcinoma, and basal cell carcinoma. Here, we present the results of our ten-year experience in the molecular diagnosis of BAP1-TPDS, along with a clinical update and cascade genetic testing of previously reported BAP1-TPDS patients and their relatives. Specifically, we sequenced germline DNA samples from 101 individuals with suspected BAP1-TPDS and validated pathogenic variants (PVs) by assessing BAP1 somatic loss in matching tumor specimens. Overall, we identified seven patients (7/101, 6.9%) carrying six different germline BAP1 PVs, including one novel variant. Consistently, cascade testing revealed a total of seven BAP1 PV carriers. In addition, we explored the mutational burden of BAP1-TPDS tumors by targeted next-generation sequencing. Lastly, we found that certain tumors present in PV carriers retain a wild-type BAP1 allele, suggesting a sporadic origin of these tumors or a functional role of heterozygous BAP1 in neoplastic development. Altogether, our findings have important clinical implications for therapeutic response of BAP1-TPDS patients.

Background Patients with cancer are particularly susceptible to SARS-CoV-2 infection. The systemic inflammatory response is a pathogenic mechanism shared by cancer progression and COVID-19. We investigated systemic inflammation as a driver of severity and mortality from COVID-19, evaluating the prognostic role of commonly used inflammatory indices in SARS-CoV-2-infected patients with cancer accrued to the OnCovid study.Methods In a multicenter cohort of SARS-CoV-2-infected patients with cancer in Europe, we evaluated dynamic changes in neutrophil:lymphocyte ratio (NLR); platelet:lymphocyte ratio (PLR); Prognostic Nutritional Index (PNI), renamed the OnCovid Inflammatory Score (OIS); modified Glasgow Prognostic Score (mGPS); and Prognostic Index (PI) in relation to oncological and COVID-19 infection features, testing their prognostic potential in independent training (n=529) and validation (n=542) sets.Results We evaluated 1071 eligible patients, of which 625 (58.3%) were men, and 420 were patients with malignancy in advanced stage (39.2%), most commonly genitourinary (n=216, 20.2%). 844 (78.8%) had ≥1 comorbidity and 754 (70.4%) had ≥1 COVID-19 complication. NLR, OIS, and mGPS worsened at COVID-19 diagnosis compared with pre-COVID-19 measurement (p

BackgroundIndividual differences in susceptibility to SARS-CoV-2 infection, symptomatology and clinical manifestation of COVID-19 have thus far been observed but little is known about the prognostic factors of young patients.MethodsA retrospective observational study was conducted on 171 patients aged ≤ 65 years hospitalized in Alessandria's Hospital from 1st March to 30th April 2020 with laboratory confirmed COVID-19. Epidemiological data, symptoms at onset, clinical manifestations, Charlson Comorbidity Index, laboratory parameters, radiological findings and complications were considered. Patients were divided into two groups on the basis of COVID-19 severity. Multivariable logistic regression analysis was used to establish factors associated with the development of a moderate or severe disease.FindingsA total of 171 patients (89 with mild/moderate disease, 82 with severe/critical disease), of which 61% males and a mean age (± SD) of 53.6 (± 9.7) were included. The multivariable logistic model identified age (50-65 vs 18-49; OR = 3.23 CI95% 1.42-7.37), platelet count (per 100 units of increase OR = 0.61 CI95% 0.42-0.89), c-reactive protein (CPR) (per unit of increase OR = 1.12 CI95% 1.06-1.20) as risk factors for severe or critical disease. The multivariable logistic model showed a good discriminating capacity with a C-index value of 0.76.InterpretationPatients aged ≥ 50 years with low platelet count and high CRP are more likely to develop severe or critical illness. These findings might contribute to improved clinical management.

Objective: To investigate the incidence of diabetic cystopathy in relation to age, gender, type of diabetes, duration of diabetic disease and clinical evidence of peripheral neuropathy and to analyze the physiopathology of the various forms of diabetic cystopathy due to sensory impairment, motor-sensory impairment, motor impairment and hyperreflexia. Materials and methods: In a retrospective multicenter cohort study the medical records of a cohort of 126 diabetic patients with (128 patients) or without (48 patients) urological symptoms were analyzed. Patients were observed at the Città di Alessandria Clinic of Policlinico di Monza and/or at the outpatient clinic of Alessandria Hospital from June 2018 to June 2020. The study excluded patients with central and/or peripheral neuropathy, spina bifida (mylomeningocele or meningocele) or spina bifida occulta; with persistent urinary infections; in anticholinergic treatment for enteric dysfunctions; in medical treatment for cervical-prostatic-urethral obstruction; with vaginal and/or rectal prolapse of II, III, IV degree; with previous spinal or pelvic surgery including radical prostatectomy, Wertheim hysterectomy or colorectal surgery. All the patients were studied with computed tomography (CT) scan of the urinary tract, voiding cystourethrography (VCUG), uroflowmetry, cystomanometry with intrinsic pressure assessment and compliance evaluation, electromyography (EMG) of the anal sphincter, pressure flow analysis, urethral pressure profile and, when advised, pharmacological tests. Results: Out of 126 diabetic patients, 48 did not show any signs or symptoms of urine voiding dysfunction; 30 were men and 18 women with an average age of 62.6 years; 20 had type I diabetes and were in treatment with insulin and 28 type II diabetes treated with oral hypoglycemic medication. The remaining 78 patients (48 men and 30 women), with an average age of 64.8 years, presented urological symptoms; 31 had type I diabetes and 47 had II type diabetes. Conclusions: Diagnosis of the various forms of diabetic cystopathy and early treatment decreases complications and consequently accesses to outpatient facilities and hospital admissions, resulting in an improved quality of life.

Background The current economic constraints cause hospital management to use the available public resources as rationally as possible. At the same time, there is the necessity to improve current scientific knowledge. This is even more relevant in the case of patients with malignant pleural mesothelioma (MPM), given the severity of the disease, its dismal prognosis, and the cost of chemotherapy drugs. This work aims to evaluate the standard cost of patients with MPM, supporting physicians in their decision-making process in relation to budget constraints, as well as policymakers with respect research policy. Methods The authors conducted a retrospective cost analysis on all the patients with MPM who were first admitted to a reference hospital specialized in MPM care between 2014 and 2015, collecting data on their diagnostic pathways and active treatments, as well as on the related official fees for each procedure. Then, using a multiple regression model, we estimated the overall expected cost of a patient with MPM treated in our hospital, to be born by the Regional Healthcare System based on the chosen clinical pathway. Results According to results, the economic impact of caring for a patient with MPM is mostly related to the selected active treatments, with drug and hospitalization costs as main drivers. Our analysis suggests that the expected reimbursed fee to care for a patient with MPM is equal to € 18 214.99, with chemotherapy and monitoring costs equal to € 12 861.43 and hospitalization cost equal to € 5353.55. This cost decreases to € 320.18 in the case of enrollment in an experimental trial of first-line treatment. In the other cases (second-line or third-line trials), the expected cost borne by the healthcare system for treating patients grows exponentially (€ 40,124.18 and € 59 839.94, respectively). Conclusion Experimental trials might be a solution to decrease the economic burden for the public healthcare system only in the case of first-line treatments, where the cost of chemotherapy is relevant. Nevertheless, policy-makers have to accept the sharing of this economic burden between society and the pharmaceutical industry to broaden the current scientific knowledge.

Spatial distribution heterogeneity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been observed in several countries. While previous studies have covered vast geographic areas, detailed analyses on smaller territories are not available to date. The aim of our study was to understand the spatial spread of SARS-CoV-2 in a province of Northern Italy through the analysis of positive nasopharyngeal (NP) swabs. The study was conducted on subjects who lived in the province of Alessandria with at least one positive NP swab between 2 March and 22 December 2020. To investigate if clustering occurred, the proportion of SARS-CoV-2 positive subjects over the total number of residents in each small administrative subregion was calculated and then mapped. A total of 17,260 subjects with at least one positive NP swab were included; the median age was 54 years (Interquartile range 38–72) and 54.9% (n = 9478) of our study population were female. Among the 192 towns scanned, 26 showed a prevalence between 5% and 7.5%, one between 7.5% and 10% and two with more than 10% positive swabs. The territories with a higher prevalence of positive subjects were located in areas with at least one nursing home and potential clusters were observed within these structures. The maps produced may be considered a useful and important monitoring system to identify areas with a significant and relevant diffusion of SARS-CoV-2.

Perioperative stress detection in children with congenital heart disease (CHD), particularly in the brain, is still limited. Among biomarkers, γ-amino-aminobutyric acid (GABA) assessment in biological fluids appears to be promising for its regulatory action on the cardiovascular and cerebral systems. We aimed to investigate cyanotic (C) or non-cyanotic (N) CHD children for GABA blood level changes in the perioperative period. We conducted an observational study in 68 CHD infants (C: n = 33; N: n = 35) who underwent perioperative clinical, standard laboratory and monitoring parameter recordings and GABA assessment. Blood samples were drawn at five predetermined time-points before, during and after surgery. No significant perioperative differences were observed between groups in clinical and laboratory parameters. In C, perioperative GABA levels were significantly lower than N. Arterial oxygen saturation and blood concentration significantly differed between C and N children and correlated at cardiopulmonary by-pass (CPB) time-point with GABA levels. The present data showing higher hypoxia/hyperoxia-mediated GABA concentrations in C children suggest that they are more prone to perioperative cardiovascular and brain stress/damage. The findings suggest the usefulness of further investigations to detect the “optimal” oxygen concentration target in order to avoid the side effects associated with re-oxygenation during CPB.