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Precision Medicine is a reality in selected medical areas, as oncology, or in excellent healthcare structures, but it is still far to reach million patients who could benefit from this medical concept. Here, we sought to highlight how the time is ripe to achieve horizontal delivery to a significant larger audience of patients, represented by the poly-treated patients. Combination therapies are frequent (especially in the elderly, to treat comorbidities) and are related to decreased drug safety and efficacy, disease’s exacerbation, additional treatments, hospitalization. But the recent development and validation of bioinformatic tools, aimed to automatic evaluation and optimization of poly-therapies, according to the unique individual characteristics (including genotype), is ready to change the daily approach to pharmacological prescription.

Smoking is the most significant avoidable risk factor. Responsible for a wide range of diseases such as cardiovascular diseases and acute or chronic respiratory diseases. It is frequently associated with interstitial pulmonary diseases and notably, it can be a cause of idiopathic pulmonary fibrosis. In this report, lung nodules and idiopathic pulmonary fibrosis were presented in a heavy smoker.

The kinetics of postvaccination serum anti-Spike IgG concentration were determined in 1,541 health care workers (Sant'Andrea Hospital of Rome, Italy) with no prior infection by SARS-COV-2. Anti-Spike IgG were measured at 3, 12, and 24 weeks after the completion of the primary vaccine cycle (two doses of the BNT162b2 vaccine by Biontech/Pfizer) and 3 weeks apart a third BNT162b2 dose. Stratification of the study population by age (decades from 21-30 to 61-70) highlighted that 24 weeks after cycle completion all age groups had an order of magnitude reduction in serum IgG titers. Considering older adults (age 61-70), they had significantly lower serum IgG titers at each time point compared with younger people, except after the booster dose, which induced similar and elevated IgG titers despite the age.

Deficiency of dihydropyrimidine dehydrogenase (DPD), encoded by the

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.

Simple Summary Our analysis of a 17-gene expression signature resulted in being significantly different among patients with clear cell renal cancer cell (ccRCC) who reported a recurrence-free survival (RFS) >5 years and patients with a RFS < 1 year. This Genomic Signatures could be useful to better identify good prognosis (with favorable genomic signature) against poor prognosis (with unfavorable genomic signature) ccRCC. Accordingly, both follow-up and treatment could be profoundly personalized for patients with neodiagnosis of ccRCC in the near future. Abstract The Identification of reliable Biomarkers able to predict the outcome after nephrectomy of patients with clear cell renal cell carcinoma (ccRCC) is an unmet need. The gene expression analysis in tumor tissues represents a promising tool for better stratification of ccRCC subtypes and patients’ evaluation. Methods: In our study we retrospectively analyzed using Next-Generation expression analysis (NanoString), the expression of a gene panel in tumor tissue from 46 consecutive patients treated with nephrectomy for non-metastatic ccRCC at two Italian Oncological Centres. Significant differences in expression levels of selected genes was sought. Additionally, we performed a univariate and a multivariate analysis on overall survival according to Cox regression model. Results: A 17-gene expression signature of patients with a recurrence-free survival (RFS) < 1 year (unfavorable genomic signature (UGS)) and of patients with a RFS > 5 years (favorable genomic signature (FGS)) was identified and resulted in being significantly correlated with overall survival of the patients included in this analysis (HR 51.37, p < 0.0001). Conclusions: The identified Genomic Signatures may serve as potential biomarkers for prognosis prediction of non-metastatic RCC and could drive both follow-up and treatment personalization in RCC management.

Migraine is considered one of the most disabling neurological disorder with a high socioeconomic burden. Pharmacological management includes many classes of drugs which in the most cases, are administrated in polytherapy. The therapeutic scheme of migraineurs is often affected by comorbidities which need concomitant medications, thus increasing the risk of side effects related to drug-drug interactions. Pharmacogenetics is a promising tool to achieve a personalized cure based on individual genetic profile while the availability of free online knowledge bases allows to check the potential DDIs of selected medications. Combining, these approaches may offer to clinicians a useful tool to improve the appropriateness of migraine polytherapy choice, aiming to increase the efficacy and reduce the toxicity of pharmacological treatments.

Marina Borro,1 Giovanna Gentile,1 Sally H Preissner,2 Leda Marina Pomes,1 Björn-Oliver Gohlke,3 Antonio Del Casale,4 Andreas Eckert,3 Paolo Marchetti,5 Saskia Preissner,2 Robert Preissner,3,6 Maurizio Simmaco1 1Department of Neurosciences, Mental Health and Sensory Organs, Faculty of Medicine and Psychology, Sapienza University and Laboratory of Clinical Biochemistry, Sant’Andrea Hospital, Rome, Italy; 2Department Oral and Maxillofacial Surgery, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany; 3Science-IT and Institute of Physiology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany; 4Department of Clinical and Dynamic Psychology, Faculty of Medicine and Psychology, Sapienza University, Rome, Italy; 5Medical Oncology Unit, Sant’Andrea Hospital, Rome, Italy; 6Drug-PIN AG, Lugano, SwitzerlandCorrespondence: Marina BorroDepartment of Neurosciences, Mental Health and Sensory Organs, Faculty of Medicine and Psychology, Sapienza University and Laboratory of Clinical Biochemistry, Sant’Andrea Hospital, Via di Grottarossa 1035, Rome, ItalyTel +390633775457Fax +390633776664Email marina.borro@uniroma1.itPurpose: Inefficacy and safety concerns are main medications’ problems, especially in the case of poly-therapies, when drug–drug interactions may alter the expected drug disposition. Ongoing efforts are aimed to establish drug selection processes aimed to preemptive evaluation of a plethora of factors affecting patient’s specific drug response, including pharmacogenomic markers, in order to minimize prescription of improper medications. In previous years, we established at the University Hospital Sant’Andrea of Rome, Italy, a Precision Medicine Service based on a multi-disciplinary experts’ team. The team is in charge to produce a drug therapy counselling report, including pharmacogenomic, pharmacokinetic and pharmacodynamic considerations. In this study, we aimed to evaluate the performance of this established “manual” process of therapy selection with a novel bioinformatic tool, the Drug-PIN system.Patients and Methods: A total of 200 patients diagnosed with Major Depressive Disorders or a depressive episode in Bipolar Disorder, with at least three previous failed treatments, who underwent pharmacogenomic profiling and therapy counselling in the Sant’Andrea Hospital from 2017 to 2020. The baseline poly-therapy of these patients was re-evaluated and optimized by Drug-PIN. Results of the Drug-PIN poly-therapy evaluation/optimization were compared with the results of the original poly-therapy evaluation/optimization by therapy counselling. To compare the results between the two processes, the risk associated with each poly-therapy was classified as low, moderate, or high.Results: The number of baseline poly-therapies classified in low-, moderate- or high-risk did not change significantly between manual system or Drug-PIN system. As the counselling process, also the Drug-PIN system produces a significant decrease in the predicted treatment-associated risk.Conclusion: Drug-PIN substantially replicates the output of the counselling process, allowing a substantial reduction in the time needed for therapy evaluation. Availability of an effective bioinformatic tool for proper drug selection is expected to exponentially increase the actuation of targeted therapy strategies.Keywords: poly-therapy, pharmacogenomics, Precision Medicine, Drug-PIN, drug–drug interactions

Background: Multiple chemical sensitivity (MCS) is a chronic condition with somatic, cognitive and affective symptoms that follow contact with chemical agents at usually non toxic concentrations. We aimed to assess the role of genetic polymorphisms involved in oxidative stress on anxiety and depression in MCS. Materials & methods: Our study investigated the CAT rs1001179, MPO rs2333227, PON1 rs662 and PON1 rs705379 polymorphisms in MCS. Results: The AG genotype of the PON1 rs662 and the TT and CT genotypes of the PON1 rs705379 were involved in anxiety and depression. Discussion: These results are in line with existing evidence of PON1 involvement in MCS and suggest a further role of this gene in the exhibition of anxiety and depression in this disease.

Background Two methods for detecting synovial fluids alpha defensins are available: the enzyme-linked immunosorbent assay and the lateral flow test. For both, the proper role and accuracy remain uncertain. The purpose of this study was to assess the accuracy of the matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) for alpha defensin detection in synovial fluids of patients with total knee arthroplasty/total hip arthroplasty failures. The hypothesis was that the alpha defensin measurement through MALDI-TOF MS assay could be a high sensitive and specific test for periprosthetic joint infections (PJI) diagnosis as compared with Musculoskeletal Infection Society (MSIS) criteria. Methods The study included 138 patients. The 2018 MSIS criteria were used to diagnose PJIs. Synovial fluids were assessed for routinely synovial fluid tests and alpha defensin measurement through MALDI-TOF MS. Sensitivity, specificity, overall diagnostic accuracy, positive and negative predictive values, receiver operator curves, and area under the curve were calculated. Results As per the 2018 MSIS criteria, 59 PJIs (43%) and 79 aseptic failures (57%) were diagnosed. The MALDI-TOF MS assay showed an overall accuracy of 94.9%. The sensitivity was 93%, the specificity was 96%, the positive predictive value was 95%, and the negative predictive value was 95%. Receiver operator curves analysis demonstrates an area under the curve of 0.95 (P Conclusion The MALDI-TOF MS assay showed high sensitivity and specificity for alpha defensin detection in case of total knee arthroplasty/total hip arthroplasty failures. The advantages of the technology, such as the few milliliters of sample needed, the rapidity of obtaining results, and the cost-effectiveness of the procedure could make the MALDI-TOF MS alpha defensin assay a useful and widespread test in clinical practice.

In corpus atrophic gastritis (CAG), hypochlorhydria makes plausible the overgrowth of intragastric bacteria, whose role in gastric carcinogenesis is under debate.To characterize the antrum/corpus composition of the gastric bacterial microbiota in CAG patients compared to controls without CAG.A cross-sectional monocentric study on consecutive patients with known histological diagnosis of CAG undergoing gastroscopy for gastric cancer surveillance and patients without CAG undergoing gastroscopy for dyspepsia or anemia (108 biopsies from 55 patients, median age 61.5). Genomic DNA from one antral and one corpus biopsy from each case (n = 23) and control (n = 32) was extracted. Gastric microbiota was assessed by sequencing hypervariable regions of the 16SrRNA gene.Bacterial abundance and diversity were significantly lower in CAG cases than in controls (p 0.001). Firmicutes were more frequent in cases, Bacteroidetes and Fusobacteria in controls (p 0.0001). Streptococcaceae were more abundant in cases (p 0.0001), Prevotellaceae in controls (p 0.0001). The genus Streptococcus was positively correlated with severe OLGA/OLGIM stages linked to a higher risk of gastric cancer.Gastric bacterial microbiota in CAG showed a reduced abundance and complexity but was characterized by higher colonization of Firmicutes, in particular Streptococcus, increased in subjects with severe atrophy/metaplasia stages at higher risk of gastric cancer.

Background: Cigarette smoke is the main avoidable cause of COPD .Only a portion of patients who smoke and with a pack-year greater than 20 develop COPD. Aim: To determine if high nicotine metabolism ratio,3-hydroxycotinine/cotinine (NMR) >0.4 could be associated with COPD development and exacerbation risk. Methods: Eighty patients were recruited in a smoking cessation outpatients service. The patients underwent salivary cotinine and hydroxy-cotinine level detection by mass-spectrometry. Patients were also evaluated by spirometry . Results: the mean age was 53.8, the mean pack year was 34 and Fagestrom’s test mean value was 4.6. The CAT questionnaire mean score was 16.5, and the mean body mass index (BMI) value was 25.4. Patients COPD were found to be nicotine metabolizers faster than patients without COPD with OR 3.3 (table 1) ( p 0.4) in comparison with mild level ( p 10 versus CAT In a logistic regression analysis a significant influence of mMRC (p

Immune dysregulation is a hallmark of patients infected by SARS-CoV2 and the balance between immune reactivity and tolerance is a key determinant of all stages of infection, including the excessive inflammatory state causing the acute respiratory distress syndrome. The kynurenine pathway (KP) of tryptophan (Trp) metabolism is activated by pro-inflammatory cytokines and drives mechanisms of immune tolerance. We examined the state of activation of the KP by measuring the Kyn:Trp ratio in the serum of healthy subjects (n = 239), and SARS-CoV2-negative (n = 305) and -positive patients (n = 89). Patients were recruited at the Emergency Room of St. Andrea Hospital (Rome, Italy). Kyn and Trp serum levels were assessed by HPLC/MS-MS. Compared to healthy controls, both SARS-CoV2-negative and -positive patients showed an increase in the Kyn:Trp ratio. The increase was larger in SARS-CoV2-positive patients, with a significant difference between SARS-CoV2-positive and -negative patients. In addition, the increase was more prominent in males, and positively correlated with age and severity of SARS-CoV2 infection, categorized as follows: 1 = no need for intensive care unit (ICU); 2 ≤ 3 weeks spent in ICU; 3 ≥ 3 weeks spent in ICU; and 4 = death. The highest Kyn:Trp values were found in SARS-CoV2-positive patients with severe lymphopenia. These findings suggest that the Kyn:Trp ratio reflects the level of inflammation associated with SARS-CoV2 infection, and, therefore, might represent a valuable biomarker for therapeutic intervention., Highlights • The Kynurenine:Tryptophan ratio is an activation biomarker of the kynurenine pathway. • The kynurenine pathway has a key role in the regulation of the immune system. • The Kyn:Trp ratio is significantly increased in SARS-CoV2-postive patients. • The increase is more prominent in males than in females' SARS-CoV2-positive patients. • Increased Kyn:Trp ratio is associated with lymphopenia and COVID-19 severity.

The COVID-19/SARS-CoV-2 pandemic struck health, social and economic systems worldwide, and represents an open challenge for scientists &mdash, coping with the high inter-individual variability of COVID-19, and for policy makers &mdash, coping with the responsibility to understand environmental factors affecting its severity across different geographical areas. Air pollution has been warned of as a modifiable factor contributing to differential SARS-CoV-2 spread but the biological mechanisms underlying the phenomenon are still unknown. Air quality and COVID-19 epidemiological data from 110 Italian provinces were studied by correlation analysis, to evaluate the association between particulate matter (PM)2.5 concentrations and incidence, mortality rate and case fatality risk of COVID-19 in the period 20 February&ndash, 31 March 2020. Bioinformatic analysis of the DNA sequence encoding the SARS-CoV-2 cell receptor angiotensin-converting enzyme 2 (ACE-2) was performed to identify consensus motifs for transcription factors mediating cellular response to pollutant insult. Positive correlations between PM2.5 levels and the incidence (r = 0.67, p &lt, 0.0001), the mortality rate (r = 0.65, p &lt, 0.0001) and the case fatality rate (r = 0.7, p &lt, 0.0001) of COVID-19 were found. The bioinformatic analysis of the ACE-2 gene identified nine putative consensus motifs for the aryl hydrocarbon receptor (AHR). Our results confirm the supposed link between air pollution and the rate and outcome of SARS-CoV-2 infection and support the hypothesis that pollution-induced over-expression of ACE-2 on human airways may favor SARS-CoV-2 infectivity.

Background Obstructive Sleep Apnoea syndrome (OSAS) is considered a systemic inflammatory disease and is characterized by intermittent hypoxia that can damage the integrity of intestinal barrier and alter gut microbiota composition in adults and animal models. To date there is only one study on snoring children and microbiota but no studies are present on paediatric OSAS related dysbiosis. Study objectives To evaluate gut microbiota composition in OSAS children in respect to healthy subjects and investigate the role of sleep parameters in changing gut microbiome. Methods Sixteen children divided in OSAS and healthy groups. Stool samples were collected from both the two groups to assess gut microbiota composition using 16S rRNA sequencing and a nocturnal pulsossimetry and polysomnography were performed in OSAS children. Results OSAS children showed a decreased microbial diversity in respect to healthy subjects in terms of number of observed species and Chao1 index (p = 0,01). Firmicutes/Bacteroidetes ratio was directly correlated to Sleep Clinical Record (p = 0,03). The abundance of several inflammation-related strains (Proteobacteria, Clostridiaceae, Oscillospiraceae, Klebsiella) were found significantly modified in relation to sleep parameters. Bacteria implied in the gut barrier integrity (Desulfovibrionaceae, Bacteroides fragilis and Faecalibacterium prausnitzii) were found significantly different in the two study groups and correlated with sleep parameters. Conclusions OSAS children showed a lower microbiota diversity in respect to heathy subjects and an increase of inflammation and gut barrier disruptors-related strains probably induced by intermittent hypoxia. Further studies should be conducted to understand the role of gut microbiota in OSAS physiopathology and comorbidities in children.

Obstructive sleep apnea syndrome (OSAS) is a multifactorial and common disorder affecting 10-17% of men and 3-9% of women. A low vitamin D serum concentration has been reportedly linked to OSAS susceptibility, but the underlying molecular genetic mechanisms are poorly understood thus far. We report here original findings on the ways in which vitamin D receptor (VDR) gene polymorphic variation (FokI, BsmI, ApaI, and TaqI polymorphisms) impacts serum vitamin D concentration and, additionally, susceptibility to OSAS. In a sample of 176 consecutive subjects (144 patients with OSAS and 32 healthy controls) phenotyped by full polysomnography (PSG), we characterized human genetic variation in VDR using the Sequenom MassARRAY iPLEX platform. A logistic regression analysis was employed to account and correct for covariates such as sex, age, body mass index, and comorbidities. Importantly, we observed that the FokI CC genotype frequency was markedly higher in patients with OSAS compared with controls (50.7% vs. 28.1%; p = 0.027). VDR FokI polymorphism explained 14.5% of vitamin D serum concentration variability. Moreover, the VDR FokI polymorphism was also associated with excessive daytime sleepiness (p = 0.016). To the best of our knowledge, this is the first clinical genetics study examining the role of VDR polymorphic variation on OSAS as phenotyped using full PSG. We call for further studies of vitamin D-related mechanisms that might contribute to OSAS risk in independent populations.

Patients affected by mental disorders smoke more than the general population. The reasons behind this habit are genetic, environmental, etc. This study aims to investigate the correlations between some polymorphisms and the smoking habits and nicotine dependence in patients with psychiatric disorders. We recruited 88 patients with treatment-resistant mental disorders, including 35 with major depressive disorder, 43 with bipolar spectrum disorder, and 10 with schizophrenia spectrum disorder. We carried out a clinical and psychometric assessment on current smoking habits, years of smoking, number of daily cigarettes, and level of nicotine addiction. The patients performed a peripheral blood sample for DNA analyses of different polymorphisms. We searched for correlations between the measures of nicotine addiction and analysed genotypes. The expression of the T allele of the DRD2 rs1800497 and DRD3 rs6280 polymorphisms significantly correlated with a lower level of nicotine dependence and lower use of cigarettes. We did not find significant correlations between nicotine dependence and OPRM1 rs1799971, COMT rs4680 and rs4633 polymorphisms, CYP2A6 rs1801272 and rs28399433, or 5-HTTLPR genotype. Concluding, DRD2 rs1800497 and DRD3 rs6280 polymorphisms are involved in nicotine dependence and cigarette smoking habits in patients with treatment-resistant mental disorders

Migraine is a common neurological disorder with a complex pathophysiology. It has been estimated that incidence between adults of current headache disorder is about 50%. Different studies show that this condition has an important and complex genetic component in response to drug therapy. Areas covered: This review shows and summarizes the importance of the polymorphisms associated with the major antimigraine drug metabolizing enzymes. The research of bibliographic databases has involved only published peer-reviewed articles from indexed journals. Expert opinion: Pharmacogenetics is based on the identification of polymorphism and promises personalized therapy with efficacy and reduction of adverse events. The association between genotype and an altered metabolizer status could guide clinical decision to evade concomitant treatments and adverse events. The introduction of routine genetic testing could help to choose the efficacy drug on the individual and genetic profile.

Treatment-resistant depression (TRD) reduces affected patients’ quality of life and leads to important social health care costs. Pharmacogenomics-guided treatment (PGT) may be effective in the cure of TRD. The main aim of this study was to evaluate the clinical changes after PGT in patients with TRD (two or more recent failed psychopharmacological trials) affected by bipolar disorder (BD) or major depressive disorder (MDD) compared to a control group with treatment as usual (TAU). We based the PGT on assessing different gene polymorphisms involved in the pharmacodynamics and pharmacokinetics of drugs. We analyzed, with a repeated-measure ANOVA, the changes between the baseline and a 6 month follow-up of the efficacy index assessed through the Clinical Global Impression (CGI) scale, and depressive symptoms through the Hamilton Depression Rating Scale (HDRS). The PGT sample included 53 patients (26 BD and 27 MDD), and the TAU group included 52 patients (31 BD and 21 MDD). We found a significant within-subject effect of treatment time on symptoms and efficacy index for the whole sample, with significant improvements in the efficacy index (F = 8.544; partial η² = 0.077, p < 0.004) and clinical global impression of severity of illness (F = 6.818; partial η² = 0.062, p < 0.01) in the PGT vs. the TAU group. We also found a significantly better follow-up response (χ² = 5.479; p = 0.019) and remission (χ² = 10.351; p = 0.001) rates in the PGT vs. the TAU group. PGT may be an important option for the long-term treatment of patients with TRD affected by mood disorders, providing information that can better define drug treatment strategies and increase therapeutic improvement.

Fluoropyrimidines combined with other agents are commonly used for gastrointestinal cancer treatment. Considering that severe toxicities occur in 30% of patients, we aimed to structure a nomogram to predict toxicity, based on metabolic parameter and patients' characteristics. We retrospectively enrolled patients affected by gastrointestinal tract cancers. Pretreatment 5-fluorouracil (5-FU) degradation rate and DPYD, TSER, MTHFR A1298T, and C677T gene polymorphisms were characterized. Data on toxicities were collected according to CTCAE v3.0. Multivariate logistic regression analysis was used to structure a nomogram. 642 patients were enrolled (384 men; 258 female; median age: 67 years, range: 27-87): 449 (69.9%) patients were affected by colorectal cancer; 118 (18.4%) by gastroesophageal cancer; 66 (10.3%) by pancreatic cancer; and nine (1.4%) by other cancers. Grade 3-4 toxicities were observed in 118 (18.4%) patients and were most frequently observed in patients with altered 5-FU degradation rate (43.5 and 26.7% of the patients in the poor metabolizer and in the ultrarapid metabolizer group respectively, vs. 17% in the normal metabolizer group) and in DPYD heterozygous mutated patients (83.3% of the patients). Age, DPYD status, the number of drugs administered, and 5-FU degradation rate value were associated to severe toxicities. On the basis of these findings, we structured a nomogram to assess a score to predict the risk of developing severe toxicity. Compared with the available pharmacogenetic tests, this approach can be applied to the whole population, predicting the risk for severe toxicity, with an easy, low-cost, and not invasive technique.

5-Fluorouracil is commonly used for gastrointestinal cancer treatment in an adjuvant setting; however, the toxicity can lead to a reduction, delay, or discontinuation of treatment. We retrospectively investigated the association between the 5-fluorouracil degradation rate (5-FUDR) and genetic polymorphisms of TSER, DPYD, and MHTFR with toxicity in colorectal cancer patients treated with adjuvant FOLFOX. Pretreatment 5-FUDR and MTHFR A1298T or C677T, TSER, and DPYD gene polymorphisms were characterized in stages II-III colorectal cancer patients. Patients were classified into three metabolic classes according to the 5-FUDR value. Association with toxicities was evaluated retrospectively using logistic regression analysis. Overall, 126 patients were selected (35 women, 91 men). Seven patients were poor metabolizers, 116 patients were normal metabolizers and three patients were ultra-rapid metabolizers. The median 5-FUDR was 1.53 ng/ml/10 cells/min (range: 0.42-2.57 ng/ml/10 cells/min). Severe, rate-limiting toxicities (grades 3-4) were encountered in 22.2% of patients. No associations between MTHFR or TSER polymorphisms and toxicity were detected, whereas 5-FUDR showed a statistically significant association with toxicity (P=0.0047). The DPYD heterozygous mutation was detected in only one patient, who showed grade 4 hematological toxicity and a lower 5-FUDR value. The 5-FUDR value seems not to be affected by MTHFR and TSER polymorphisms. Compared with the available pharmacogenomics tests, the pretreatment evaluation of 5-FUDR increases the proportion of identified colorectal patients at high risk for severe toxicity. Thus, it appears to be a suitable pretreatment toxicity biomarker in a subgroup of patients in whom dose-intensity maintenance is the key factor.

Rationale Detection of α-defensins in synovial fluid is gaining more and more interest in the field of correct diagnosis of periprosthetic joint infections (PJIs). At present, they can be assessed by a quantitative enzyme-linked immunosorbent assay which is expensive and time-consuming and by a qualitative lateral flow immunoassay which is rapid but quite expensive and whose clinical sensitivity is debated. Thus, developing an alternative rapid, accurate, and low-cost assay for α-defensins is important to make α-defensins actionable as novel key clinical markers. Methods Synovial fluid (SF) samples were obtained from 18 patients undergoing revision of primary joint arthroplasty. Of these, eight met the 2013 Musculoskeletal Infection Society (MSIS) criteria for PJIs, the remaining were classified as aseptic failure. Microbiological analysis and Synovasure assays were carried out on all samples. Sample preparation and the matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) settings were adjusted to detect human neutrophil peptide (HNP)-1, -2 and -3 and to obtain optimal results in term of sensitivity and stability. Results MALDI-TOF MS was able to detect HNPs in SF from septic patients. No signals for HNPs were detected in SF from aseptic failure. The limits of detection (LOD) were 2.5 and 1.25 μg/mL for HNP-2 and HNP-1, respectively. The turnaround time of the analysis is 20 min, and SF samples are stable at -20°C for up to 3 days. Assay sensitivity, specificity, and positive and negative predictive values (PPV and NPV) were 100% for all parameters. On the same SF samples, the Synovasure assay showed lower sensitivity specificity, and PPV and NPV of 87.5%, 90%, 87.5% and 90%, respectively. Microbiological analysis of SF confirmed the presence of bacteria only in SF MSIS-positive patients. Conclusions The reported MALDI-TOF MS assay was able to detect and differentiate HNPs in SF samples and showed a slightly better diagnostic accuracy than the Synovasure assay.

The Coronavirus Disease (Covid-19) pandemic is rapidly spreading across the world, representing an unparalleled challenge for health care systems. There are differences in the estimated fatality rates, which cannot be explained easily. In Italy, the estimated case fatality rate was 12.7% in mid-April, while Germany remained at 1.8%. Moreover, it is to be noted that different areas of Italy have very different lethality rates. Due to the complexity of Covid-19 patient management, it is of paramount importance to develop a well-defined clinical workflow in order to avoid the inconsistent management of patients. The Integrated Care Pathway (ICP) represents a multidisciplinary outline of anticipated care to support patient management in the Sant’Andrea Hospital, Rome. The main objective of this pilot study was to develop a new ICP evaluated by care indicators, in order to improve the COVID-19 patient management. The suggested ICP was developed by a multi-professional team composed of different specialists and administrators already involved in clinical and management processes. After a review of current internal practices and published evidences, we identified (1) the activities performed during care delivery, (2) the responsibilities for these activities, (3) hospital structural adaptation needs and potential improvements, and (4) ICP indicators. The process map formed the basis of the final ICP document; 160 COVID-19 inpatients were considered, and the effect of the ICP implementation was evaluated over time during the exponential phase of the COVID-19 pandemic. In conclusion, a rapid adoption of ICP and regular audits of quality indicators for the management of COVID-19 patients might be important tools to improve the quality of care and outcomes.

Multiple Chemical Sensitivity (MCS) is a chronic and/or recurrent condition with somatic, cognitive, and affective symptoms following a contact with chemical agents whose concentrations do not correlate with toxicity in the general population. Its prevalence is not well defined, it mainly affects women between 40 and 50 years, without variations in ethnicity, education and economic status. We aimed to assess the core symptoms of this illness in a sample of Italian patients. Two physicians investigated different symptoms with a checklist compilation in 129 patients with MCS (117 women). We conducted a categorical Principal Component Analysis (CATPCA) with Varimax rotation on the checklist dataset. A typical triad was documented: hyperosmia, asthenia, and dyspnoea were the most common symptoms. Patients also frequently showed cough and headache. The CATPCA showed seven main factors: 1, neurocognitive symptoms, 2, physical (objective) symptoms, 3, gastrointestinal symptoms, 4, dermatological symptoms, 5, anxiety-depressive symptoms, 6, respiratory symptoms, 7, hyperosmia and asthenia. Patients showed higher mean prevalence of factors 7 (89.9%), 6 (71.7%), and 1 (62.13%). In conclusion, MCS patients frequently manifest hyperosmia, asthenia, and dyspnoea, which are often concomitant with other respiratory and neurocognitive symptoms. Considering the clinical association that is often made with anxiety, more studies are necessary on the psychosomatic aspects of this syndrome. Further analytical epidemiological studies are needed to support the formulation of aetiological hypotheses of MCS.

Impaired energy metabolism may play a role in the pathogenesis of neurodevelopmental disorders including fragile X syndrome (FXS). We checked brain energy status and some aspects of cell bioenergetics, namely the activity of key glycolytic enzymes, glycerol-3-phosphate shuttle and mitochondrial respiratory chain (MRC) complexes, in the cerebral cortex of the Fmr1 knockout (KO) mouse model of FXS. We found that, despite a hyperactivation of MRC complexes, adenosine triphosphate (ATP) production via mitochondrial oxidative phosphorylation (OXPHOS) is compromised, resulting in brain energy impairment in juvenile and late-adult Fmr1 KO mice. Thus, an altered mitochondrial energy metabolism may contribute to neurological impairment in FXS.

Introduction: Human aging is characterized by increasing vulnerability not only to diseases, but also to the treatments applied to that diseases. Geriatric depression is a frequent mental disorder often requiring pharmacological treatment, which commonly is added to other medications taken to treat chronic or acute co-morbidities. The challenges of appropriate treatment of elderly are increasingly recognized as an urgent health problem.Areas covered: The challenges of appropriate geriatric anti-depressant prescription, and the role of novel tools developed by Precision Medicine. The data were obtained searching in MEDLINE: pharmacokinetics, pharmacodynamics, pharmacogenetics, antidepressants, drug-drug interactions and elderly, in the period 1994–2016.Expert commentary: The Precision Medicine approach take advantage by novel decision-supporting tools, as pharmacogenomic testing, drug-drug interactions evaluation and therapeutic drug monitoring, allowing to improve informed-decision making in presc...

5-Fluorouracil is among the most widely used anticancer drug, but a fraction of treated patients develop severe toxicity, with potentially lethal injuries. The predictive power of the available pretreatment assays, used to identify patients at risk of severe toxicity, needs improvements. This study aimed to correlate a phenotypic marker of 5-fluorouracil metabolism (the individual degradation rate of 5-fluorouracil-5-FUDR) with 15 functional polymorphisms in the dihydropyrimidine dehydrogenase gene (DPYD). Single SNP (single-nucleotide polymorphism) analysis revealed that the SNPs rs1801160, rs1801265, rs2297595 and rs3918290 (splice site variant IVS14+1G>A) were significantly associated with a decreased value of 5-FUDR, and the rs3918290 causing the larger decrease. Multi-SNP analysis showed that a three-SNP haplotype (Hap7) involving rs1801160, rs1801265 and rs2297595 causes a marked decrease in 5-FUDR, comparable to that caused by the splice site variant rs3918290, which is the main pharmacogenetic marker associated with severe fluorouracil toxicity. The similar effect played by Hap7 and by the splice site variant rs3918290 upon individual 5-FUDR suggests that Hap7 could also represent a similar determinant of fluorouracil toxicity. Haplotype assessment could improve the predictive value of DPYD genetic markers aimed at the pre-emptive identification of patients at risk of severe 5-fluorouracil toxicity.The Pharmacogenomics Journal advance online publication, 28 July 2015; doi:10.1038/tpj.2015.56.

Background: One-lung ventilation (OLV) is a ventilation procedure used for pulmonary resection which may results in lung injury. The aim of this study was to evaluate the local inflammatory cytokine response from the dependent lung after OLV and its correlation to VT. The secondary aim was to evaluate the clinical outcome of each patient. Methods: Twenty-eight consecutive patients were enrolled. Ventilation was delivered in volume-controlled mode with a VT based on predicted body weight (PBW). 5 cmH2O positive end-expiratory pressure (PEEP) and FiO2 0.5 were applied. Bronchoalveolar lavage (BAL) was performed in the dependent lung before and after OLV. The levels of pro-inflammatory interleukins (IL-1α, IL-1β, IL-6, IL-8), tumor necrosis factor alpha (TNFα), vascular endothelial growth factor (VEGF), endothelial growth factor (EGF), monocyte chemoattractant protein-1 (MCP-1) and anti-inflammatory cytokines, such as interleukins (IL-2, IL-4, IL-10) and interferon (IFN-γ), were evaluated. Subgroup analysis: to analyze the VT setting during OLV, all patients were ventilated within a range of 5–10 mL/kg. Thirteen patients, classified as a conventional ventilation (CV) subgroup, received 8–10 mL/kg, while 15 patients, classified as a protective ventilation (PV) subgroup, received 5–7 mL/kg. Results: Cytokine BAL levels after surgery showed no significant increase after OLV, and no significant differences were recorded between the two subgroups. The mean duration of OLV was 64.44±21.68 minutes. No postoperative respiratory complications were recorded. The mean length of stay was for 4.00±1.41 days in the PV subgroup and 4.45±2.07 days in the CV group; no statistically significant differences were recorded between the two subgroups (P=0.511). Conclusions: Localized inflammatory cytokine response after OLV was not influenced by the use of different VT. Potentially, the application of PEEP in both ventilation strategies and the short duration of OLV could prevent postoperative complications.

Background: The aim of the study was to assess the association of single nucleotide polymorphisms (SNPs) C677T and A1298C in the methylenetetrahydrofolate reductase gene with colorectal, esophageal/gastric and pancreatic cancer in a cohort of Italian patients. Methods: A total of 790 cancer patients and 202 healthy controls were genotyped and distributions in genotype and allele frequencies were compared by Chi-squared analysis and logistic regression analysis. Results: According to most of previous findings, we found an effect of the C677T variant, but no effect of the A1298C, in colorectal and esophageal/gastric, whereas no association was evidenced with pancreatic cancer. We found that only homozygous TT carriers of the C677T variant had an increased risk for onset of cancer. Conclusion: This result could be related to dietary and behavioral habits of the analyzed population, which could mitigate the deleterious effect of the T allele in heterozygosity and it highlights the importance to validate genetic determinant of cancer risk in different population and geographical areas. World J Oncol. 2015;6(4):394-397 doi: http://dx.doi.org/10.14740/wjon930w

LY379268 and LY354740, two agonists of mGlu2/3 metabotropic glutamate receptors, display different potencies in mouse models of schizophrenia. This differential effect of the two drugs remains unexplained. We performed a proteomic analysis in cultured cortical neurons challenged with either LY379268 or LY354740. Among the few proteins that were differentially influenced by the two drugs, Rab GDP dissociation inhibitor-β (Rab GDIβ) was down-regulated by LY379268 and showed a trend to an up-regulation in response to LY354740. In cultured hippocampal neurons, LY379268 selectively down-regulated the α isoform of Rab GDI. Rab GDI inhibits the activity of the synaptic vesicle-associated protein, Rab3A, and is reduced in the brain of schizophrenic patients. We examined the expression of Rab GDI in mice exposed to prenatal stress ("PRS mice"), which have been described as a putative model of schizophrenia. Rab GDIα protein levels were increased in the hippocampus of PRS mice at postnatal days (PND)1 and 21, but not at PND60. At PND21, PRS mice also showed a reduced depolarization-evoked [(3)H]d-aspartate release in hippocampal synaptosomes. The increase in Rab GDIα levels in the hippocampus of PRS mice was reversed by a 7-days treatment with LY379268 (1 or 10 mg/kg, i.p.), but not by treatment with equal doses of LY354740. These data strengthen the validity of PRS mice as a model of schizophrenia, and show for the first time a pharmacodynamic difference between LY379268 and LY354740 which might be taken into account in an attempt to explain the differential effect of the two drugs across mouse models.

OPN and Gal-3 Predict VT/VF in Heart Failure Patients Background Myocardial extracellular matrix remodelling provides electrical heterogeneity entailing ventricular tachycardia/fibrillation (VT/VF) in heart failure (HF) patients. Osteopontin (OPN) and Galectin-3 (Gal-3) are fibrosis markers and may reflect the extension of the arrhythmogenic substrate. We assessed whether plasma OPN and Gal-3 predict the risk of sustained VT/VF in a cohort of HF patients with implantable cardioverter-defibrillator (ICD). Methods A total of 75 HF patients underwent pre-ICD implantation clinical evaluation and assessment of plasma OPN and Gal-3. The primary endpoint was the time to the occurrence of the first sustained VT/VF. Hazard ratios (HR) were derived from Cox proportional-hazards analysis. Results Patients with coronary artery disease (CAD) had higher plasma OPN (79.8 ± 44.0 ng/mL vs. 66.0 ± 31.8 ng/mL; P = 0.04). Both Gal-3 (r = −0.38; P = 0.01) and OPN (r = −0.27; p = 0.01) were negatively related to estimated glomerular filtration rate. After 29 ± 17 months, 20 patients (27%) reached the primary endpoint. Patients with VT/VF had higher plasma OPN and Gal-3 (97.4 ± 51.7 ng/mL vs. 65.9 ± 31.3 ng/mL; P = 0.002 and 19.7 ± 8.5 ng/mL vs. 16.2 ± 6.2 ng/mL; P = 0.05). In univariate analysis, OPN (log-OPN, HR: 32.4; 95%CI: 3.9–264.7; P = 0.001) and Gal-3 (HR: 1.05; 95%CI: 1.00–1.11; P = 0.04) predicted sustained VT/VF. In multivariable analysis, both OPN (HR: 41.4; 95%CI: 3.8–441.9; P = 0.002) and Gal-3 (HR: 1.06; 95%CI: 1.00–1.12; P = 0.03) retained their prognostic power after correction for age, sex, history of MI, EF, NYHA class, eGFR, use of ACE-I, and amiodarone. Conclusions Plasma OPN and Gal-3 predict sustained VT/VF in HF patients at high risk for SCD. Larger prospective studies should outline the role of these biomarkers in predicting SCD on top of conventional risk stratification.

System-wide adoption of Personalised Healthcare requires an active and flexible but highly integrated infrastructure, joining many different competences and technologies and allowing continuous upgrading, also through self-learning processes. In this system, clinics and diagnostics would no longer be partitioned, according to a stepwise scheme, from other disciplines as basic science, information technologies, ethics and policies. Each player constitutes a node of a cabled network, where input and output from each node are automatically transferred to all nodes, to systematically retune and coordinate the global activity. Since 2005 the Sant'Andrea Hospital of Rome is an in-house built model of Personalised Healthcare Service, which auto-catalytically drives its own development, which may furnish good evidence that translation of Personalised Medicine into clinical practice is not so elusive. The interaction between usually distant academic departments and wards (as Biochemistry, Internal Medicine, Psychiatry, Oncology), favoured by a farsighted management of hospital resources by the administrators, allowed to create a shared, innovative laboratory, the Advanced Molecular Diagnostics Unit (DiMA). The availability of advanced technologies, as mass spectrometry and medium-to-high throughput DNA analysis paved the way to a “real-time” evaluation of the benefits brought into the “real-world” clinical practice by implementation of new diagnostics aimed to therapy tailoring. This allowed the start up of a health service based on the principles of personalised medicine, in order to optimize the amount of tests necessary to evaluate the patient, to interpret the results correctly and, finally, to plan a personalised therapy and to periodically evaluate and/or modify it, to obtain the best clinical results with the least side effects. Our OMICS platform for personalised medicine offers the following combined approaches: i) Epigenetics, to obtain information on the regulation of gene expression and to evaluate the methylation profile change during hypomethylation therapies; ii) Functional genomics, to measure genetic expression in normal and pathologic conditions, in order to define genetic expression profiles; iii) Structural genomics, which defines genomic differences with clinical impact in the patient populations; iv) Metabolomics and terapeutic drug managment, to define all molecules of interest in a specific clinical context and the actual drug and metabolite concentration during therapies. The MIFAR (Metabolismo Integrato FARmaci – drug metabolism integration) including about 60 gene variants has been developed. The data interpretation is ruled out using the Charite Bioinformatic platform (Berlin DE) and allows adaptation of drug therapies to the individual MIFAR profile, improving efficacy and safety of treatments. The DiMA Unit provides pharmacogenomics and theranostics report for at least 5,000 patients/year.

Migraine is one of the most common diseases in the world, with high economical and subjective burden. Migraine acute therapy is nowadays based on specific and non-specific drugs but up to 40% of episodic migraineurs still have unmet treatment needs and over 35% do not benefit from triptans administration. Serotonin-1F receptors have been identified in trigeminal system and became an ideal target for anti-migraine drug development as potential trigeminal neural inhibitors. Lasmiditan, a novel serotonin1F receptor agonist, showed specific affinity in vitro for the receptor without any vasoconstrictive action and inhibited markers associated with electrical stimulation of trigeminal ganglion in migraine animal models. Areas covered: This article reviews both preclinical and clinical studies on lasmiditan as a potential acute therapy for migraine, as well as pharmacokinetic and pharmacodynamic features. It also summarizes safety and tolerability data gathered in the various human studies. Expert opinion: The absence of vasoconstrictive effects makes lasmiditan a promising novel migraine acute therapy. Although preclinical and Phase I and II studies established a significant efficacy, the limited knowledge about pharmacokinetics and metabolism, the high rate of non-serious central nervous system side effects and the lack of larger studies remain still a matter of concern that should be addressed in future studies.