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Abstract Background Prescribing errors put an enormous burden on health and the economy, claiming implementation of effective methods to prevent/reduce them. Polypharmacy regimens (five or more drugs) are highly prone to unacknowledged prescribing errors, since the complex network of drug-drug interactions, guidelines and contraindications is challenging to be adequately evaluated in the prescription phase, especially if different doctors are involved. Clinical decision support systems aimed at polypharmacy evaluation may be crucial to recognize and correct prescribing errors. Methods A commercial clinical decision support system (Drug-PIN®) was applied to estimate the frequency of unrecognized prescribing errors in a group of 307 consecutive patients accessing the hospital pre-admission service of the Sant’Andrea Hospital of Rome, Italy, in the period April-June 2023. Drug-PIN® is a two-step system, first scoring the risk (low, moderate or high) associated with a certain therapy-patient pair, then allowing therapy optimization by medications exchanges. We defined prescribing errors as cases where therapy optimization could achieve consistent reduction of the Drug-PIN® calculated risk. Results Polypharmacy was present in 205 patients, and moderate to high risk for medication harm was predicted by Drug-PIN® in 91 patients (29.6%). In 58 of them (63.7%), Drug-PIN® guided optimization of the therapy could be achieved, with a statistically significant reduction of the calculated therapy-associated risk score. Patients whose therapy cannot be improved have a statistically significant higher number of used drugs. Considering the overall study population, the rate of avoidable prescribing errors was 18.89%. Conclusions Results suggest that computer-aided evaluation of medication-associated harm could be a valuable and actionable tool to identify and prevent prescribing errors in polypharmacy. We conducted the study in a Hospital pre-admission setting, which is not representative of the general population but represents a hotspot to intercept fragile population, where a consistent fraction of potentially harmful polypharmacy regimens could be promptly identified and corrected by systematic use of adequate clinical decision support tools.

Background: Type 2 diabetes mellitus (T2DM) is characterized by disrupted glucose homeostasis and metabolic abnormalities, with oxidative stress and inflammation playing pivotal roles in its pathophysiology. Poly(ADP-ribosyl)ation (PARylation) is a post-translational process involving the addition of ADP-ribose polymers (PAR) to target proteins. While preclinical studies have implicated PARylation in the interplay between oxidative stress and inflammation in T2DM, direct clinical evidence in humans remains limited. This study investigates the relationship between oxidative stress, PARylation, and inflammatory response in T2DM patients. Methods: This cross-sectional investigation involved 61 T2DM patients and 48 controls. PAR levels were determined in peripheral blood cells (PBMC) by ELISA-based methodologies. Oxidative stress was assessed in plasma and PBMC. In plasma, we monitored reactive oxygen metabolites (d-ROMs) and ferric-reducing antioxidant power. In PBMC, we measured the expression of antioxidant enzymes SOD1, GPX1 and CAT by qPCR. Further, we evaluated the expression of inflammatory mediators such as IL6, TNF-α, CD68 and MCP1 by qPCR in PBMC. Results: T2DM patients exhibited elevated PAR levels in PBMC and increased d-ROMs in plasma. Positive associations were found between PAR levels and d-ROMs, suggesting a link between oxidative stress and altered PAR metabolism. Mediation analysis revealed that d-ROMs mediate the association between HbA1c levels and PAR, indicating oxidative stress as a potential driver of increased PARylation in T2DM. Furthermore, elevated PAR levels were found to be associated with increased expression of pro-inflammatory cytokines IL6 and TNF-α in the PBMC of T2DM patients. Conclusions: This study highlights that hyperactivation of PARylation is associated with poor glycemic control and the resultant oxidative stress in T2DM. The increase of PAR levels is correlated with the upregulation of key mediators of the inflammatory response. Further research is warranted to validate these findings and explore their clinical implications.

Objectives: Evaluate the prevalence of genetic factors in a large population of infertile subjects and define the seminological, hormonal, and ultrasonographic features for each alteration. Methods: This single-center retrospective study included male partners of infertile couples undergoing genetic investigations due to oligozoospermia or azoospermia evaluated from January 2012 to January 2022. The genetic investigations consist of karyotype, CFTR gene mutations plus variant of the IVS8-5T polymorphic trait, Y chromosome microdeletion, and Next Generation Sequencing panel to analyze genes implicated in congenital hypogonadotropic hypogonadism (CHH). Results: Overall, 15.4% (72/466) of patients received a diagnosis of genetic cause of infertility. Specifically, 23 patients (31.9%) harbor mutations in the CFTR gene, 22 (30.6%) have a 47, XXY karyotype, 14 (19.4%) patients show a Y chromosome microdeletion, 7 (9.7%) have structural chromosomal anomalies, and 6 (8.3%) have CHH. Overall, 80.6% of patients were azoospermic and 19.4% oligozoospermic (sperm concentration 3.5 ± 3.8 million/mL). Almost all patients presented hormonal alterations related to the specific genotype, while the main ultrasound alterations were testicular hypoplasia, calcifications/microcalcifications, and enlarged/hyperechoic epididymis. Conclusions: The prevalence of genetic abnormalities in males of infertile couples was 15.4% in our Center. CFTR gene disease-causing variants resulted in more frequent, with various clinical features, highlighting the complexity and heterogeneity of the presentation. Other investigations are needed to understand if conditions like ring chromosomes and other translocations are related to infertility or are incidental factors.

Abstract Background Metastases are the major cause of cancer-related morbidity and mortality. By the time cancer cells detach from their primary site to eventually spread to distant sites, they need to acquire the ability to survive in non-adherent conditions and to proliferate within a new microenvironment in spite of stressing conditions that may severely constrain the metastatic process. In this study, we gained insight into the molecular mechanisms allowing cancer cells to survive and proliferate in an anchorage-independent manner, regardless of both tumor-intrinsic variables and nutrient culture conditions. Methods 3D spheroids derived from lung adenocarcinoma (LUAD) and breast cancer cells were cultured in either nutrient-rich or -restricted culture conditions. A multi-omics approach, including transcriptomics, proteomics, and metabolomics, was used to explore the molecular changes underlying the transition from 2 to 3D cultures. Small interfering RNA-mediated loss of function assays were used to validate the role of the identified differentially expressed genes and proteins in H460 and HCC827 LUAD as well as in MCF7 and T47D breast cancer cell lines. Results We found that the transition from 2 to 3D cultures of H460 and MCF7 cells is associated with significant changes in the expression of genes and proteins involved in metabolic reprogramming. In particular, we observed that 3D tumor spheroid growth implies the overexpression of ALDOC and ENO2 glycolytic enzymes concomitant with the enhanced consumption of glucose and fructose and the enhanced production of lactate. Transfection with siRNA against both ALDOC and ENO2 determined a significant reduction in lactate production, viability and size of 3D tumor spheroids produced by H460, HCC827, MCF7, and T47D cell lines. Conclusions Our results show that anchorage-independent survival and growth of cancer cells are supported by changes in genes and proteins that drive glucose metabolism towards an enhanced lactate production. Notably, this finding is valid for all lung and breast cancer cell lines we have analyzed in different nutrient environmental conditions. broader Validation of this mechanism in other cancer cells of different origin will be necessary to broaden the role of ALDOC and ENO2 to other tumor types. Future in vivo studies will be necessary to assess the role of ALDOC and ENO2 in cancer metastasis.

School is one of the main settings where it is useful to guarantee health promotion actions, as it is well known that diet and eating habits that are shaped in the early stages of life are maintained through adulthood. The objective of this study was to carry out the “Healthy Snack” project to promote nutritional education in primary schools in the Province of Belluno in the 2022–2023 school year, in which 925 students were enrolled, and to evaluate the intervention in terms of changes in eating habits during their school breaks. Following the workshops performed by the healthcare workers (HCWs), medals were awarded, taking into account the quality of the participating students’ mid-morning snacks, considering the food pyramid. The results collected in the annual survey period were related to the type and quantity of snacks consumed at school, and allowed students to gain a final score, comparing the period before and after the educational intervention to demonstrate the effectiveness of the actions promoted by HCWs and the increased nutritional quality of meals. In light of this evidence, public health strategies must continue to emphasize the importance of implementing health promotion interventions and actions aimed at children in order to prevent weight gain in this age group, and the potential development of cardiometabolic pathologies over their lifetime.

We report here a case of a patient affected by B-cell chronic lymphocytic leukemia (CLL) that developed COVID-19 during the actual SARS-CoV-2 outbreak. The coexistence of CLL and COVID-19 raises many questions regarding the possible increased risk of developing COVID-19 among patients with CLL, the problems in managing therapies for both diseases and, above all, the difficulties in diagnosing COVID-19 in patients affected by CLL. In our patient, an 84-year-old man, the recognition of COVID-19 was delayed because of its atypical clinical presentation and technical problems related to the methods used for the diagnosis. Based on the symptoms and the radiological aspect of the lung, the occurrence of COVID-19 was suspected. Repeated tests on oro/nasopharyngeal swabs gave negative results, causing a delay in the diagnosis. Moreover, different methods used to identify the SARS-CoV-2 antibodies in serum gave conflicting results, and only two tests were able to identify SARS-CoV-2 Abs of the IgG type. During the clinical course of unrecognized COVID-19, our patient developed severe complications and did not receive any specific treatment for the two diseases. Recognition of COVID-19 in patients with CLL is a challenging task and the most accurate methods are necessary to overcome the diagnostic difficulties encountered.

Improper drug prescription is a main cause of both drug-related harms (inefficacy and toxicity) and ineffective spending and waste of the healthcare system’s resources. Nowadays, strategies to support an improved, informed prescription process may benefit from the adequate use of pharmacogenomic testing. Using next-generation sequencing, we analyzed the genomic profile for three major cytochromes P450 (CYP2C9, CYP2C19, CYP2D6) and studied the frequencies of dysfunctional isozymes (e.g., poor, intermediate, or rapid/ultra-rapid metabolizers) in a cohort of 298 Italian subjects. We found just 14.8% of subjects with a fully normal set of cytochromes, whereas 26.5% of subjects had combined cytochrome dysfunction (more than one isozyme involved). As improper drug prescription is more frequent, and more burdening, in polytreated patients, since drug–drug interactions also cause patient harm, we discuss the potential benefits of a more comprehensive PGX testing approach to support informed drug selection in such patients.

Background and Objectives: The aim of this study was to evaluate the impact of medications on oxidative stress, inflammatory biomarkers and semen characteristics in males with idiopathic infertility. Materials and Methods: In this observational case-control clinical study, 50 men with idiopathic infertility were enrolled, of whom 38 (the study group) were on pharmacological treatment and 12 made up the control group. The study group was clustered according to the medications (Group A: anti-hypertensive, n = 10; Group B: thyroxine, n = 6; Group C: non-steroidal anti-inflammatory drugs, n = 13; Group D: miscellaneous, n = 6; Group E: lipid-lowering drugs, n = 4). Semen analyses were performed according to WHO 2010 guidelines. Interleukins (IL)-10, IL-1 beta, IL-4, IL-6, Tumor Necrosis Factor- alpha (TNF-alpha) and IL-1 alpha were determined using a solid-phase sandwich immunoassay. The diacron reactive oxygen metabolites, d-ROMs test, was performed by means of a colorimetric determination of reactive oxygen metabolites and measured with a spectrophotometer. Beta-2-microglobulin and cystatin-C were measured with an immunoturbidimetric analyzer. Results: No differences between the study and control groups for age and macroscopic and microscopic semen characteristics were found, nor were any differences found after clustering according to the drug categories. IL-1 alpha and IL-10 were significantly lower in the study group compared with the control group; IL-10 was significantly lower in groups A, B, C and D compared with the control group. Furthermore, a direct correlation between IL-1 alpha, IL-10 and TNF-alpha and leukocytes was found. Conclusions: Despite the sample size limitations, the data suggest a correlation between drug use and activation of the inflammatory response. This could clarify the pathogenic mechanism of action for several pharmacological classes on male infertility.

Ensuring safe meals with suitable hygienic-sanitary and nutritional features is an essential requirement to guarantee health in different settings. This study aims to evaluate the compliance of collective catering menus adopted in both school canteens and healthcare facilities in a regional area where specific guidelines have been issued, assessing many matters from food weight to single courses and from the use of wholegrain pasta and bread to the rotation of seasonal fruit and vegetables. Overall, 85 menus, edited by freelance professionals and endorsed by the Food Hygiene and Nutrition Service staff of the Local Health Authority, were assessed from 2018 to 2022, highlighting critical issues potentially attributable at a local level to the lack of complete knowledge of the existence of guidelines and official reference documents among nutrition professionals. Since the preliminary outcomes show non-compliance in both sectors investigated, it is essential to continue to strengthen the role of prevention departments entrusted with services dedicated to food and nutritional safety and promote joint official controls performed by healthcare workers and other professionals with different backgrounds in order to ensure safe food for the target population that use collective catering services. In school canteens and healthcare facilities, providing and administering food is an opportunity to promote health through a balanced diet and safe food and offers opportunities for the development of community well-being and the local economy in a sustainable manner, understood in economic, environmental and social terms.

Abstract Background Low T3 syndrome is frequent in patients admitted to intensive care units for critical illness and pneumonia. It has been reported also in patients with COVID-19, Hodgkin disease and chronic lymphocytic leukemia. We analyzed the clinical relevance of Low T3 syndrome in COVID-19 patients and, in particular, in those with associated hematological malignancies. Methods Sixty-two consecutive patients, hospitalized during the first wave of SARS-CoV-2 outbreak in Sant’Andrea University Hospital in Rome, were subdivided in 38 patients (Group A), showing low levels of FT3, and in 24 patients (Group B), with normal FT3 serum values. During the acute phase of the disease, we measured serum, radiologic and clinical disease severity markers and scores, in search of possible correlations with FT3 serum values. In addition, in 6 COVID-19 patients, 4 with Low T3 syndrome, including 2 with a hematological malignancy, and 2 with normal FT3 values, we performed, high-dimensional single-cell analysis by mass cytometry, multiplex cytokine assay and gene expression profiling in peripheral blood mononuclear cells (PBMC). Results Low FT3 serum values were correlated with increased Absolute Neutrophil Count, NLR and dNLR ratios and with reduced total count of CD3+, CD4+ and CD8+ T cells. Low FT3 values correlated also with increased levels of inflammation, tissue damage and coagulation serum markers as well as with SOFA, LIPI and TSS scores. The CyTOF analysis demonstrated reduction of the effector memory and terminal effector subtypes of the CD4+ T lymphocytes. Multiplex cytokine assay indicates that mainly IL-6, IP-10 and MCAF changes are associated with FT3 serum levels, particularly in patients with coexistent hematological malignancies. Gene expression analysis using Nanostring identified four genes differently expressed involved in host immune response, namely CD38, CD79B, IFIT3 and NLRP3. Conclusions Our study demonstrates that low FT3 serum levels are associated with severe COVID-19. Our multi-omics approach suggests that T3 is involved in the immune response in COVID-19 and coexistent hematological malignancy and new possible T3 target genes in these patients have been identified.

Actinic keratosis (AK) is a preneoplastic skin disorder which can rapidly progress to cutaneous squamous cell carcinomas (SCCs). In light of our previous findings, indicating a possible oncogenic role of the mesenchymal isoform of FGFR2 (FGFR2c) aberrantly expressed in AK keratinocytes, we analyzed the possible tumor-promoting role of this receptor in the stromal AK counterpart in this work. Molecular analysis showed that, particularly in early AK lesions, FGFR2c dermal upregulation is accompanied by the downregulation of the cancer-associated fibroblasts (CAF) transcription repressor CSL, the upregulation of the CAF activator ULK3, and the consequent CAF gene induction. Immunofluorescence and molecular analysis, coupled with silencing approaches by siRNA, applied on primary cultures of KIN I-derived fibroblasts, indicated that FGFR2c upregulation contribute to CAF signature and the increased autophagy in response to FGF2. Magnetic bead-based multiplex assay, combined with FGFR2 signaling shut-off approaches, indicated that, especially in response to FGF2, IL-6 secretion could depend on FGFR2c high expression and signaling, suggesting the possible establishment of FGFR2c-dependent secretory autophagy, contributing to tumor-promoting factor release. Overall, our results identified FGFR2c as a signaling molecule involved in controlling precancerous/stromal cell oncogenic crosstalk, pointing to this receptor as a possible early molecular marker predictive for AK’s rapid malignant progression.

Fatigue is a frequent symptom in hemodialysis (HD), and the indolamine-2,3-dioxygenase (IDO) metabolic trap has been hypothesized in the pathogenesis of fatigue. The association between IDO activity according to fatigue and its relationship with muscle mass and function in HD patients was verified. Chronic HD patients were considered, and fatigue was assessed. The plasma kynurenines and tryptophan ratio (Kyn/Trp), as surrogate of IDO activity, and interleukin (IL)-6 were measured. Muscularity was assessed by BIA and muscle strength by hand-grip dynamometer. 50 HD patients were enrolled, and fatigue was present in 24% of the cohort. Patients with fatigue showed higher Kyn/Trp (p = 0.005), were older (p = 0.007), and IL-6 levels resulted higher than in non-fatigue patients (p < 0.001). HD patients with fatigue showed lower intracellular water (surrogate of muscle mass) (p < 0.001), as well as lower hand grip strength (p = 0.02). The Kyn/Trp ratio positively correlated with IL-6 and ECW/ICW (p = 0.004 and p = 0.014). By logistic regression analysis, higher ICW/h2 was associated with lower odds of fatigue (OR, 0.10; 95% CI, 0.01 to 0.73). In conclusion, our cohort fatigue was associated with a higher Kyn/Trp ratio, indicating a modulation of IDO activity. The Kyn/Trp ratio correlated with IL-6, suggesting a potential role of IDO and inflammation in inducing fatigue and changes in muscularity.

A fully implantable active middle ear device has been proposed and indicated for the rehabilitation of bilateral moderate or moderate-to-severe sensorineural hearing loss, assuming it would overcome the disadvantages of a conventional hearing aid. The indications have further been extended to severe or severe-to-profound forms of hearing loss in the case of an expected limited or null efficacy of hearing aids. While the literature has highlighted several positive aspects of the device, including a better quality of life related to its invisibility, the improvement of auditory and perceptual functions has not been controlled for throughout a long period of follow-up. The present study aimed to verify the behavior of the auditory threshold, especially the bone conduction (BC) component, in the implanted ear in a group of implantees affected by initial bilateral symmetric hearing loss of different severity grades. The BC threshold was assessed preoperatively at activation and at the last follow-up (ranging from 4 to 12 years) in the implanted ear, and preoperatively and at the last follow-up in the contralateral ear, to monitor eventual deteriorated values in both ears over time. The pure tone average (PTA; 250–4,000 Hz), speech reception threshold (SRT) and the maximum word recognition score as a percentage (% WRS) and in dB HL were measured in the implanted ear to verify the efficacy of the device after the first fitting at device activation. A significant worsening of the BC threshold with respect to the baseline threshold was noticed during further follow-up. When comparing the implanted ear with the contralateral ear, a significant worsening of the bone PTA was assessed in the former with respect to the contralateral ear. Despite the worsened hearing found in the implanted ears, the beneficial gains in PTA and speech audiometry observed at the first activation remained constant at the follow-up, thus showing an extension of the efficacy of this device in aiding those with up to the most severe forms of sensorineural hearing loss.

Abstract SARS-CoV-2 infection shows a wide-ranging clinical severity, requiring prognostic markers. We focused on S100B, a calcium-binding protein present in biological fluids, being a reliable biomarker in disorders having inflammatory processes as common basis and RAGE as main receptor. Since Covid-19 is characterized by a potent inflammatory response also involving RAGE, we tested if S100B serum levels were related to disease severity. Serum samples (n = 74) were collected from hospitalized SARS-CoV-2 positive patients admitted to Covid center. Illness severity was established by admission clinical criteria and Covid risk score. Treatment protocols followed WHO guidelines available at the time. Circulating S100B was determined by ELISA assay. Statistical analysis used Pearson’s χ2 test, t-Test, and ANOVA, ANCOVA, Linear Regression. S100B was detected in serum from Covid-19 patients, significantly correlating with disease severity as shown both by the level of intensity of care (p

Abstract Background Radiotherapy-induced lymphopenia may be limiting the success of therapy and could also negatively affect the ability of immune system in mediating the bystander (BE) and abscopal effects (AE). A novel SBRT-based PArtial Tumor irradiation of HYpoxic clonogenic cells (SBRT-PATHY) for induction of the tumoricidal BE and AE by sparing the peritumoral immune microenvironment and regional circulating lymphocytes has been developed to enhance the radiotherapy therapeutic ratio of advanced lung cancer. The aim of this retrospective review of prospectively collected mono-institutional phase 2 study was to compare the outcomes between unconventional SBRT-PATHY and standard of care in unresectable stage IIIB/IV bulky NSCLC. Materials and methods Sixty patients considered inoperable or unsuitable for radical radio-chemotherapy were enrolled and treated using the following 3 regimens: SBRT-PATHY (group I, n = 20 patients), recommended standard of care chemotherapy (group II, n = 20 patients), and institutional conventional palliative radiotherapy (group III, n = 20 patients). Results Median follow-up was 13 months. The 1-year overall survival was 75, 60, and 20% in groups 1, 2 and 3, respectively (p = 0.099). The 1-year cancer specific survival was 90, 60, and 20% in groups 1, 2, and 3, respectively (p = 0.049). Bulky tumor control rate was 95% for SBRT-PATHY compared with 20% in the other two groups. BE and AE were seen by SBRT-PATHY in 95 and 45% of patients, respectively. Multi-variate analysis for cancer specific survival was significant for treatment effect with SBRT-PATHY (p

Deficiency of dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene, is associated with severe toxicity induced by the anti-cancer drug 5-Fluorouracil (5-FU). DPYD genotyping of four recommended polymorphisms is widely used to predict toxicity, yet their prediction power is limited. Increasing availability of next generation sequencing (NGS) will allow us to screen rare variants, predicting a larger fraction of DPD deficiencies. Genotype–phenotype correlations were investigated by performing DPYD exon sequencing in 94 patients assessed for DPD deficiency by the 5-FU degradation rate (5-FUDR) assay. Association of common variants with 5-FUDR was analyzed with the SNPStats software. Functional interpretation of rare variants was performed by in-silico analysis (using the HSF system and PredictSNP) and literature review. A total of 23 rare variants and 8 common variants were detected. Among common variants, a significant association was found between homozygosity for the rs72728438 (c.1974+75A>G) and decreased 5-FUDR. Haplotype analysis did not detect significant associations with 5-FUDR. Overall, in our sample cohort, NGS exon sequencing allowed us to explain 42.5% of the total DPD deficiencies. NGS sharply improves prediction of DPD deficiencies, yet a broader collection of genotype–phenotype association data is needed to enable the clinical use of sequencing data.

Background: Thyroid hormones (TH)s are master regulators of mitochondrial activity and biogenesis. Nonthyroidal illness syndrome (NTIS) is generally considered an adaptative response to reduced energy that is secondary to critical illness, including COVID-19. COVID-19 has been associated with profound changes in the cell energy metabolism, especially in the cells of the immune system, with a central role played by the mitochondria, considered the power units of every cell. Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects and alters mitochondrial functions, both to influence its intracellular survival and to evade host immunity. Aim of the study: This study was undertaken to analyze the oxidative balance and mitochondrial respiration in COVID-19 patients with and without NTIS to elucidate the role that thyroid hormones (TH)s play in this context. Methods: In our cohort of 54 COVID-19 patients, admitted to our University Hospital during the COVID-19 pandemic, we evaluated the generation of reactive oxygen species (ROS) by measuring the serum levels of derivatives of reactive oxygen metabolites (dROMs), and we analyzed the antioxidant capacity by measuring the serum biological antioxidant potential (BAP). We then analyzed the mitochondrial respiration in peripheral blood mononuclear cells (PBMC)s of 28 of our COVID-19 patients, using the seahorse instrument (Agilent). Results were correlated with the serum levels of THs and, in particular, of FT3. In addition, the role of T3 on bioelectrical impedance analysis (BIA) and mitochondrial respiration parameters was directly evaluated in two COVID-19 patients with NTIS, in which treatment with synthetic liothyronine (LT3) was given both in vivo and in vitro. Results: In our COVID-19 patients with NTIS, the dROMs values were significantly lower and the BAP values were significantly higher. Consequently, the oxidative stress index (OSi), measured as BAP/dROMs ratio was reduced compared to that observed in COVID-19 patients without NTIS, indicating a protective role exerted by NTIS on oxidative stress. In our COVID-19 patients, the mitochondrial respiration, measured in PBMCs, was reduced compared to healthy controls. Those with NTIS showed a reduced maximal respiratory capacity and a reduced proton leak, compared to those with normal FT3 serum values. Such lowered mitochondrial respiratory capacity makes the cells more vulnerable to bioenergetic exhaustion. In a pilot study involving two COVID-19 patients with NTIS, we could reinforce our previous observation regarding the role of T3 in the maintenance of adequate peripheral hydroelectrolytic balance. In addition, in these two patients, we demonstrated that by treating their PBMCs with LT3, both in vitro and in vivo, all mitochondrial respiration parameters significantly increased. Conclusions: Our results regarding the reduction in the serum levels of the reactive oxygen species (ROS) of COVID-19 patients with NTIS support the hypothesis that NTIS could represent an adaptative response to severe COVID-19. However, beside this beneficial effect, we demonstrate that, in the presence of an acute reduction of FT3 serum levels, the mitochondrial respiration is greatly impaired, with a consequent establishment of a hypoenergetic state of the immune cells that may hamper their capacity to react to massive viral infection.

Health visitors (HVs) and environmental health officers (EHOs) are the healthcare workers (HCWs) who, in the Italian National Health Service, mainly operate in the prevention departments of local health authorities, guaranteeing the territorial activities specifically declared with the respective professional profiles. During the SARS-CoV-2 pandemic, it was necessary to reallocate all HCWs supporting Hygiene and Public Health Services involved on the front lines of the emergency, in order to perform preventive activities and to take immediate action to fight the spread of the virus. By means of an IT survey consisting of three sections, this study investigated how 960 HVs and EHOs dealt with this reallocation, with the shifting in service assignment, and with the perceived level of fatigue and pressure, through the application of skills acquired from university training. The synergy among the preventive health professions, the ability to work in a multi-professional team, and the complementary training of HCWs represent the main strengths for overcoming future public health challenges, aimed at protecting human health.

The aim of this observational study was to develop a new quantitative liquid chromatography-mass spectrometry (LC-MS/MS) method for Therapeutic-Drug-Monitoring (TDM) of psychotropic drugs in seminal fluid to investigate potential gonadotoxic effects in patients with reduced fertility. After the validation of the LC-MS/MS method for psychotropics’ levels determination in seminal fluid, we included 20 male partners of infertile couples with idiopathic and/or unexplained male infertility, treated with psychotropic medications for more than 3 months and 10 untreated fertile controls. General and andrological clinical examination, semen analysis and seminal drugs, and metabolites levels determination were performed for each subject. Of the 20 patients included, 6 were treated with antidepressants; 4 with benzodiazepines and 10 with antipsychotics. Seminal drugs and metabolites levels were detectable in all samples. In particular, alprazolam, olanzapine, and levetiracetam showed seminal and serum similar concentrations, while fluoxetine, quetiapine, and aripiprazole were detectable, but seminal levels were significantly lower than the serum therapeutic range. Sperm progressive motility was significantly reduced in subjects treated with psychotropic drugs compared to the untreated controls (p = 0.03). Sperm concentration and progressive motility were significantly reduced in subjects treated with antipsychotics compared to the untreated controls and to the other classes of psychotropics (p < 0.05). In conclusion, this study reports a validated LC-MS/MS method for the detection of seminal psychotropic levels and preliminary data suggesting a potential correlation of seminal psychotropics with alterations of sperm concentration and motility. Pending larger studies, semen TDM might represent a new pivotal tool in the clinical management of reduced fertility in males treated with psychotropic medications.

Limiting transmission of SARS-CoV-2 from asymptomatic people assumes the paramount importance of keeping fragile subjects protected. We evaluated the utility of rapid SARS-CoV-2 antigen testing in asymptomatic subjects attending emergency departments in non-COVID-19 areas, using a single nasopharyngeal swab specimen collected in universal transport medium to perform both rapid antigen testing and rRT-PCR (used as reference standard) in a cohort of 899 patients. In the overall sample, the rapid antigen test had 43.9% sensitivity, 100% specificity, 100% positive predictive value, 93.6% negative predictive value. Considering subjects with rRT-PCR cycle threshold ≤30, the test had 80.4% sensitivity, 100% specificity, 100% positive predictive value, 98.8% negative predictive value. Considering subjects with rRT-PCR cycle threshold ≤25, the test had 94.7% sensitivity, 100% specificity, 100% positive predictive value and 99.7% negative predictive value. Despite low sensitivity, routine application of rapid antigen testing in the emergency department can lead to isolation in less than 30 min of about a half of asymptomatic COVID-19 subjects assigned to non-COVID-19 areas by clinical triage. The rapid test correctly identified 94.7% of asymptomatic patients with cycle threshold ≤ 25 that are supposed to be more infective; thus, it could be a useful measure to contain viral transmission in non-COVID-19 areas.

We previously examined the safety and immunogenicity of multiple vaccines administered to a military cohort, divided into two groups, the first composed of students at military schools, thus operating inside the national borders for at least 3 years, and the other formed of soldiers periodically engaged in a 9-month-long mission abroad (Lebanon). In the current study, we analyzed 112 individuals of this cohort, 50 pertaining to the first group and 62 to the second group, in order to examine the possible late appearance of side effects and to calculate the half-life of the induced antibodies. Moreover, the possible involvement of B-cell polyclonal activation as a pathogenetic mechanism for long term antibody persistence has even been explored. No late side effects, as far as autoimmunity and/or lymphoproliferation appearance, have been noticed. The long duration of the vaccine induced anti-HAV antibodies has been confirmed, whereas the antibodies induced by tetravalent meningococcal polysaccharide vaccine have been found to persist above the threshold for putative protection for a longer time, and anti-tetanus, diphtheria, and polio 1 and 3 for a shorter time than previously estimated. No signs of polyclonal B-cell activation have been found, as a possible mechanism to understand the long antibody persistence.

Background: Bone conductive implants (BCI) have been reported to provide greater beneficial effects for the auditory and perceptual functions of the contralateral ear in patients presenting with asymmetric hearing loss (AHL) compared to those with single-sided deafness (SSD). The aim of the study was to assess the effects of wearing a conventional hearing aid in the contralateral ear on BCI in terms of an improved overall auditory performance. Methods: eleven AHL subjects wearing a BCI in their worse hearing ear underwent an auditory evaluation by pure tone and speech audiometry in free field. This study group was obtained by adding to the AHL patients those SSD subjects that, during the follow-up, showed deterioration of the hearing threshold of the contralateral ear, thus presenting with the features of AHL. Four different conditions were tested and compared: unaided, with BCI only, with contralateral hearing aid (CHA) only and with BCI combined with CHA. Results: all of the prosthetic conditions caused a significant improvement with respect to the unaided condition. When a CHA was adopted, its combination with the BCI showed significantly better auditory performances than those achieved with the BCI only. Conclusions: the present study suggests the beneficial role of a CHA in BCI-implanted AHL subjects in terms of overall auditory performance.

We investigated 25 non-dipper normotensive vs 25 dipper normotensive patients. The aim of our study was to evaluate carotid intimal-medial thickness (IMT) in the two groups. At the admission patients underwent anamnesis and general examination, blood sampling for lipid profile measurement, glycemia, homocysteine, ambulatory blood pressure measurement to assess the circadian blood pressure profile, and Doppler ultrasound to measure carotid IMT. Our results showed that IMT is significantly higher in the non-dipper group (P

Military personnel of all armed forces receive multiple vaccinations and have been doing so since long ago, but relatively few studies have investigated the possible negative or positive interference of simultaneous vaccinations. As a contribution to fill this gap, we analyzed the response to the live trivalent measles/mumps/rubella (MMR), the inactivated hepatitis A virus (HAV), the inactivated trivalent polio, and the trivalent subunits influenza vaccines in two cohorts of Italian military personnel. The first cohort was represented by 108 students from military schools and the second by 72 soldiers engaged in a nine-month mission abroad. MMR and HAV vaccines had never been administered before, whereas inactivated polio was administered to adults primed at infancy with a live trivalent oral polio vaccine. Accordingly, nearly all subjects had baseline antibodies to polio types 1 and 3, but unexpectedly, anti-measles/-mumps/-rubella antibodies were present in 82%, 82%, and 73.5% of subjects, respectively (43% for all of the antigens). Finally, anti-HAV antibodies were detectable in 14% and anti-influenza (H1/H3/B) in 18% of the study population. At mine months post-vaccination, 92% of subjects had protective antibody levels for all MMR antigens, 96% for HAV, 69% for the three influenza antigens, and 100% for polio types 1 and 3. An inverse relationship between baseline and post-vaccination antibody levels was noticed with all the vaccines. An excellent vaccine immunogenicity, a calculated long antibody persistence, and apparent lack of vaccine interference were observed.

Rheumatoid arthritis (RA) is an autoimmune disorder in which gut and oral microbiota play a crucial role. Diet is a modifiable factor that can influence both microbiota composition and arthritis outcome; previous studies have suggested associations between dietary habits and RA, with contrasting results. We investigate the protective effect of the Mediterranean diet (MD) on disease activity and the gut microbiota profile in RA patients. Sixty consecutive RA patients were enrolled upon filling a validated 14-item questionnaire for the assessment of adherence to the Mediterranean diet (Prevention with Mediterranean Diet-PREDIMED). Then, 16S analysis was employed to explore the gut microbiota within the two cohorts of patients. Patients with high adherence to MD (20) had a significantly lower C-reactive protein (p < 0.037) and disease activity (p < 0.034) than the 40 patients with low/moderate adherence to MD. An inverse association between MD and disease activity was confirmed by multivariate analysis after adjustments for all the different demographic, clinical and serologic variables. A healthier gut microbiota composition was observed in the high adherence group, with a significant decrease in Lactobacillaceae and an almost complete absence of Prevotella copri with respect to the low/moderate adherence group. In conclusion, our findings support the protective role of MD on disease activity and microbiota composition in RA patients, and suggest the feasibility of shifting the habitual diet to modulate the gut microbiota and promote the benefits associated with MD.

Lipoprotein Lp(a) represents an independent risk factor for coronary artery disease (CAD). However, its association with CAD burden and lipid rich plaques prone to rupture in patients with acute coronary syndrome (ACS) still remains unknown. These data aim to investigate the association among serum Lipoprotein(a) (Lpa) levels, coronary atherosclerotic burden and features of culprit plaque in patients with ACS and obstructive CAD. For his reason, a total of 500 ACS patients were enrolled for the angiographic cohort and 51 ACS patients were enrolled for the optical coherence tomography (OCT) cohort. Angiographic CAD severity was assessed by Sullivan score and by Bogaty score including stenosis score and extent index, whereas OCT plaque features were evaluated at the site of the minimal lumen area and along the culprit segment. In the angiographic cohort, Lp(a) was a weak independent predictor of Sullivan score (p30 md/dl) compared to patients with lower Lp(a) levels (

Objective. Quantitative ultrasound (QUS) provides an estimate of bone mineral density (BMD) and also evaluates bone quality, which has been related to increased fracture risk in people with diabetes. This study aimed at assessing the correlates of calcaneal QUS parameters in diabetic subjects encompassing various degrees of micro and macrovascular complications and a wide-range of peripheral nerve function. Methods. Four hundred consecutive diabetic patients were examined by QUS to obtain values of broadband ultrasound attenuation (BUA), the speed of sound (SOS), quantitative ultrasound index (QUI), and BMD. Results. Among surrogate measures of complications, sensory and motor nerve amplitude and heart rate response to cough test and standing correlated with QUS parameters at univariate analysis, together with age, body mass index (BMI), waist circumference, lipid profile, and renal function. Multivariate analysis revealed that BUA, SOS, QUI, and BMD were independently associated with age, male gender, hemoglobin A1c, BMI (or fat, but not fat-free mass), and somatic and autonomic nerve function parameters. Conclusions. These data indicate that peripheral nerve dysfunction is associated with worse QUS parameters, possibly contributing to increased fracture risk in diabetes. The positive relation of QUS measures with adiposity needs further investigation. This trial is registered with ClinicalTrials.gov (NCT01600924).

A certain number of studies were carried out to address the question of how dysbiosis could affect the onset and development of rheumatoid arthritis (RA), but little is known about the reciprocal influence between microbiota composition and immunosuppressive drugs, and how this interaction may have an impact on the clinical outcome. The aim of this study was to characterize the intestinal microbiota in a groups of RA patients treatment-naïve, under methotrexate, and/or etanercept (ETN). Correlations between the gut microbiota composition and validated immunological and clinical parameters of disease activity were also evaluated. In the current study, a 16S analysis was employed to explore the gut microbiota of 42 patients affected by RA and 10 healthy controls. Disease activity score on 28 joints (DAS-28), erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, anti-cyclic citrullinated peptides, and dietary and smoking habits were assessed. The composition of the gut microbiota in RA patients free of therapy is characterized by several abnormalities compared to healthy controls. Gut dysbiosis in RA patients is associated with different serological and clinical parameters; in particular, the phylum of Euryarchaeota was directly correlated to DAS and emerged as an independent risk factor. Patients under treatment with ETN present a partial restoration of a beneficial microbiota. The results of our study confirm that gut dysbiosis is a hallmark of the disease, and shows, for the first time, that the anti-tumor necrosis factor alpha (TNF-α) ETN is able to modify microbial communities, at least partially restoring a beneficial microbiota.

Recently, diffuse-large-B-cell lymphoma (DLBCL) associated with serum IgM monoclonal component (MC) has been shown to be a very poor prognostic subset although, detailed pathological and molecular data are still lacking. In the present study, the clinicopathological features and survival of IgM-secreting DLBCL were analyzed and compared to non-secreting cases in a series of 151 conventional DLBCL treated with R-CHOP. IgM MC was detected in 19 (12.5%) out of 151 patients at disease onset. In 17 of these cases secretion was likely due to the neoplastic clone, as suggested by the expression of heavy chain IgM protein in the cytoplasm of tumor cells. In IgM-secreting cases immunoblastic features (p

Differences in postoperative outcome and recovery between patients subjected to laparoscopic-assisted versus open surgery for colorectal cancer (CRC) resection have been widely documented, though not specifically for right-sided tumors. We investigated the immunological responses to the different surgical approaches, by comparing postoperative data simultaneously obtained at systemic, local and cellular levels. A total of 25 right-sided CRC patients and controls were managed, assessing -in the immediate followup- the conventional perioperative parameters and a large panel of cytokines on plasma, peritoneal fluids and lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMC) tissue cultures. A general better recovery for patients operated with laparoscopy compared to conventional procedure, as indicated by the analysis of typical pre- and post-surgical parameters, was observed. The synchronous evaluation of 12 cytokines showed that preoperative plasma levels of the proinflammatory cytokines IL-6, IL-8, IL-1β, TNFα were significantly lower in healthy donors versus CRC patients and that such differences progressively increase with tumor stage. After surgery, the IL-6 and IL-8 increases were significantly higher in open compared to laparoscopic approach only in CRC at early stages. The postsurgical whole panel of cytokine levels were significantly higher in peritoneal fluids compared to corresponding plasma, but with no significant differences depending on kind of surgery or stage of disease. Then we observed that, pre- compared to the corresponding post-surgery derived LPS-stimulated PBMC cultures, produced higher supernatant levels of the whole cytokine panel. In particular IL-6 in vitro production was significantly higher in PBMC derived from patients subjected to laparoscopic versus open intervention, but -again- only in CRC at early stages of disease. Our results thus show that laparoscopy compared to open right resection is associated with a shorter compromission of the immunological homeostasis, mainly in early stages of right-CRC patients.