Analysis of DTC nutrigenetic services in Italy: state of the art, agreement to the ESHG statement and future outlooks

Background: In both USA and Europe operate companies selling Direct-to-consumer genetic tests (DTC). These tests are offered to healthy people aiming to identify predispositions to complex diseases and to take preventive measures. Several DTC-nutrigenetic tests (DNTs) are available on the market. They propose the definition of a personalized diet, on the basis of the investigated genetic variants, which would reduce the risk of developing those diseases which have been associated to specific genetic markers. However, the risk/benefit balance of exposing unselected population to genetic testing without any medical surveillance is far from be established. Furthermore, it lacks an accepted procedure to select which genetic markers needs to be investigated, to evaluate their specific role and, as consequence, to define a personalized diet. Within this context, the European Society of Human Genetics (ESHG) released a statement regarding the DTC tests that has been ratified by several national societies including the Italian one. 
In the present study we analyzed the DNT offered in Italy, the state of the art and the abidance with the ESHG statement. 
Methods: We queried web search engine for the DNT offered to italian population, portraying a non-specialized customer. We examined the DNTs vendor websites and/or directly contacted the companies to collect information on: 1) genetic marker essayed, 2) diseases and phenotypes considered and 3) kind of dietary advices provided. Finally, we evaluated the abidance to the ESHG statement. The study was conducted between November, 2010 and May, 2011.
Results: Six companies operate in Italy with a total of seven different DNTs offered. Both studied phenotypes and investigated genetic markers were very different among companies, with a relative higher level of agreement for phenotype than for genes. None of the companies described the methods used to select markers and to define diet advices. None of the companies showed a complete agreement to the statement of the ESHG. 
Conclusion: Although DNT companies' efforts are worthy, a standardization of methods and a more strictly agreement with ESHG statement should be encouraged

Assessment of the design criteria for concentric V-braced steel structures according to Italian and European codes

The critical review of design methodologies provided by the NTC2008, in agreement with the European seismic code (Eurocode 8) for steel Concentrically Braced Frames with chevron (or inverted V) diagonals (CBF-V), carried out by deepening the seismic behaviour of such typical steel seismic resistant structures, aims to provide more efficient design criteria able to ensure adequate safety levels under seism. As reference case studies, common structural configurations of CBF-V are designed according to the NTC2008 provisions. Each case study is designed through both the Linear Static (LS) and Dynamic (LD) analysis. For braces either Circular Hollow Sections (CHS) or HE profiles are used. General critical issues have been evidenced in the design process. The seismic performance of investigated structures is evaluated by non-linear static analyses, in order to appraise the most relevant behavioural issues, like the behaviour factor, the failure modes and the effectiveness of the capacity design criteria. A discussion on the obtained results has allowed to point out the pros and cons of the current design approach

Ground deformation and source geometry of the 30 October 2016 Mw 6.5 Norcia earthquake (Central Italy) investigated through seismological data, DInSAR measurements, and numerical modelling

We investigate the Mw 6.5 Norcia (Central Italy) earthquake by exploiting seismological data, DInSAR measurements, and a numerical modelling approach. In particular, we first retrieve the vertical component (uplift and subsidence) of the displacements affecting the hangingwall and the footwall blocks of the seismogenic faults identified, at depth, through the hypocenters distribution analysis. To do this, we combine the DInSAR measurements obtained from coseismic SAR data pairs collected by the ALOS-2 sensor from ascending and descending orbits. The achieved vertical deformation map displays three main deformation patterns: (i) a major subsidence that reaches the maximum value of about 98 cm near the epicentral zones nearby the town of Norcia; (ii) two smaller uplift lobes that affect both the hangingwall (reaching maximum values of about 14 cm) and the footwall blocks (reaching maximum values of about 10 cm). Starting from this evidence, we compute the rock volumes affected by uplift and subsidence phenomena, highlighting that those involved by the retrieved subsidence are characterized by significantly higher deformation values than those affected by uplift (about 14 times). In order to provide a possible interpretation of this volumetric asymmetry, we extend our analysis by applying a 2D numerical modelling approach based on the finite element method, implemented in a structural-mechanic framework, and exploiting the available geological and seismological data, and the ground deformation measurements retrieved from the multi-orbit ALOS-2 DInSAR analysis. In this case, we consider two different scenarios: the first one based on a single SW-dipping fault, the latter on a main SW-dipping fault and an antithetic zone. In this context, the model characterized by the occurrence of an antithetic zone presents the retrieved best fit coseismic surface deformation pattern. This result allows us to interpret the subsidence and uplift phenomena caused by the Mw 6.5 Norcia earthquake as the result of the gravitational sliding of the hangingwall along the main fault plane and the frictional force acting in the opposite direction, consistently with the double couple fault plane mechanism

Immunophenotyping of peripheral blood cells allows to discriminate MIS-C and Kawasaki disease

Background: The pathogenesis of the novel described multisystem inflammatory syndrome in children (MIS-C) and Kawasaki disease (KD) is still debated as it is not clear if they are the same or different nosological entities. However, for both the diseases a rapid and unequivocal diagnosis is mandatory to start the therapy before the onset of severe complications. In this study, we aimed to evaluate the white cell populations in MIS-C and KD as potential markers to discriminate between the two diseases. Methods: We studied white cell populations by flow cytometry in 46 MIS-C and 28 KD patients in comparison to 70 age-matched healthy children. Results: MIS-C patients had a significant lymphopenia that involved both B and T populations while KD patients showed a significant neutrophilia and thrombocythemia. Granulocyte/lymphocyte ratio helped to diagnose both MIS-C and KD with a high diagnostic sensitivity, while a multivariate analysis of granulocyte and T lymphocyte number contributed to discriminate between the two diseases. Conclusions: The relevant lymphopenia observed in MIS-C patients suggests that the disease would be a post-infectious sequel of COVID-19 immunologically amplified by a massive cytokine release, while the significant neutrophilia and thrombocythemia observed in KD confirmed that the disorder has the genesis of a systemic vasculitis. The analysis of a panel of circulating cells may help to early diagnose and to discriminate between the two diseases. Supplementary information: The online version contains supplementary material available at 10.1186/s41231-022-00128-2

Risk of preeclampsia in of women who underwent chorionic villus sampling

OBJECTIVE: To assess the risk of preeclampsia in women who underwent chorionic villus sampling (CVS). STUDY DESIGN: This is a retrospective, single-center, cohort study. All consecutive singleton gestations who underwent chorionic villus sampling from January 2014 to January 2016 were included in the study. The primary outcome was the incidence of preeclampsia. Subgroup analysis in women with beta thalassemic trait was performed. Logistic regression, presented as adjusted odds ratio (aOR) with the 95% of confidence interval (CI), was performed. RESULTS: Five hundred forty-seven women who underwent CVS, and 1532 women who did not were analyzed. Women who underwent CVS had a significantly lower risk of preeclampsia (4.4 versus 8.0%; aOR 0.53, 95%CI 0.34-0.83), and late-onset preeclampsia (3.3 versus 6.1%; aOR 0.52, 95%CI 0.31-0.87). No statistically significant differences were found in preeclampsia with severe features, early-onset preeclampsia, and preterm birth (PTB). Women who underwent CVS due to thalassemic trait had a lower incidence of preeclampsia compare to those women who did not undergo CVS (3.3 versus 8.0%; aOR 0.39, 95%CI 0.14-0.87), while no differences were found comparing women who underwent CVS due to thalassemic trait with women who underwent CVS due to other reasons. CONCLUSIONS: Women who underwent first trimester CVS had a lower risk of preeclampsia compared to those who did not

MIS-C: A COVID-19-associated condition between hypoimmunity and hyperimmunity

: Multisystem inflammatory syndrome in children (MIS-C) is a rare, severe complication of COVID-19. A better knowledge of immunological, cellular, and genetic characteristics of MIS-C could help better understand the pathogenesis of the disease and contribute to identifying specific diagnostic biomarkers and develop targeted therapies. We studied 37 MIS-C children at hospital admission and 24 healthy controls analyzing serum cytokines (IFN-α, IFN-β, IFN-γ, IL-6, IL-10, IL-17A, IL-12p70 and TNF), lymphocyte populations by flow cytometry and 386 genes related to autoimmune diseases, autoinflammation and primary immunodeficiencies by NGS. MIS-C patients showed a significant increase of serum IFNγ (despite a significant reduction of activated Th1) and ILs, even if with a great heterogeneity among patients, revealing different pathways involved in MIS-C pathogenesis and suggesting that serum cytokines at admission may help to select the inflammatory pathways to target in each patient. Flow cytometry demonstrated a relevant reduction of T populations while the percentage of B cell was increased in agreement with an autoimmune pathogenesis of MIS-C. Genetic analysis identified variants in 34 genes and 83.3% of patients had at least one gene variant. Among these, 9 were mutated in more patients. Most genes are related to autoimmune diseases like ATM, NCF1, MCM4, FCN3, and DOCK8 or to autoinflammatory diseases associated to the release of IFNγ like PRF1, NOD2, and MEF. Thus, an incomplete clearance of the Sars-CoV2 during the acute phase may induce tissue damage and self-antigen exposure and genetic variants can predispose to hyper-reactive immune dysregulation events of MIS-C-syndrome. Type II IFN activation and cytokine responses (mainly IL-6 and IL-10) may cause a cytokine storm in some patients with a more severe acute phase of the disease, lymphopenia and multisystemic organ involvement. The timely identification of such patients with an immunocytometric panel might be critical for targeted therapeutic management

Clinical pharmacogenetics of methotrexate

It is well known that interindividual variability can affect the response to many drugs in relation to age, gender, diet, and organ function. Pharmacogenomic studies have also documented that genetic polymorphisms can exert clinically significant effects in terms of drug resistance, efficacy and toxicity by modifying the expression of critical gene products (drug-metabolizing enzymes, transporters, and target molecules) as well as pharmacokinetic and pharmacodynamic parameters. A growing body of in vitro and clinical evidence suggests that common polymorphisms in the folate gene pathway are associated with an altered response to methotrexate (MTX) in patients with malignancy and autoimmune disease. Such polymorphisms may also induce significant MTX toxicity requiring expensive monitoring and treatment. Although the available data are not conclusive, they suggest that in the future MTX pharmacogenetics could play a key role in clinical practice by improving and tailoring treatment. This review describes the genetic polymorphisms that significantly influence MTX resistance, efficacy, and toxicity

Plasma proteins containing damaged L-isoaspartyl residues are increased in uremia: Implications for mechanism

Plasma proteins containing damaged L-isoaspartyl residues are increased in uremia: Implications for mechanism.BackgroundSeveral alterations of protein structure and function have been reported in uremia. Impairment of a transmethylation-dependent protein repair mechanism possibly related to a derangement in homocysteine metabolism is also present in this condition, causing erythrocyte membrane protein damage. Homocysteine may affect proteins via the accumulation of its parent compound S-adenosylhomocysteine (AdoHcy), a powerful in vivo methyltransferase inhibitor. However, since plasma homocysteine is mostly protein bound, a direct influence on protein structures cannot be ruled out. We measured the levels of L-isoaspartyl residues in plasma proteins of uremic patients on hemodialysis. These damaged residues are markers of molecular age, which accumulate when transmethylation-dependent protein repair is inhibited and/or protein instability is increased.MethodsL-isoaspartyl residues in plasma proteins were quantitated using human recombinant protein carboxyl methyl transferase (PCMT). Plasma concentrations of homocysteine metabolites were also measured under different experimental conditions in hemodialysis patients.ResultsThe concentration of damaged plasma proteins was increased almost twofold compared to control (controls 147.83 ± 17.75, uremics 282.80 ± 26.40 pmol of incorporated methyl groups/mg protein, P < 0.003). The major protein involved comigrated with serum albumin. Although hyperhomocysteinemia caused a redistribution of thiols bound to plasma proteins, this mechanism did not significantly contribute to the increase in isoaspartyl residues. The S-adenosylmethionine (AdoMet)/AdoHcy concentration ratio, an indicator of the flux of methyl group transfer, was altered. This ratio was partially corrected by folate treatment (0.385 ± 0.046 vs. 0.682 ± 0.115, P < 0.01), but protein L-isoaspartate content was not.ConclusionsPlasma protein damage, as determined by protein L-isoaspartyl content, is increased in uremia. This alteration is to be ascribed to an increased protein structural instability, rather than the effect of hyperhomocysteinemia

The role of nasal washes in CF patients affected by chronic rhinosinusitis

Cystic Fibrosis (CF) presents multiorgan manifestations that include chronic rhinosinusitis (CRS) with or without nasal polyposis. Nasal washes (NWs) are widely used in clinical practice especially in CF patients, although their effectiveness on Ear Nose Throat (ENT) symptoms is controversial. In this study we evaluate the performance and the safety of a NWs solution, with or without surfactant, to reduce symptoms and bacterial load. Materials and methods We enrolled 20 CF patients (mean age: 27,6 years) with CRS, confirmed by nasal endoscopy. All patients, colonized by Pseudomonas Aeruginosa, performed daily a NW by physiological solution or by saline solution with surfactant (Naridek). All patients, at the time of enrollment, filled out a sinonasal questionnaire (SANQ11) and they received instructions for proper washing. During follow-up, we evaluated the reduction of the bacterial load in the nasal lavage. We assess the nasal cavities by endoscopy (2.7 mm 30° rigid endoscope - Storz, Tuttlingen, Germany) according to a modified Lund Kennedy endoscopic scoring system: - rhinorrhea (present = 0, mild = 1, purulent = 2); - edema, and hyperemia (absent = 0, mild = 1 or severe =2) - nasal mucosa (eutrophic = 1; hyperemic = 2; dystrophic = 3); - left and right turbinate hypertrophy (none = 0; mild = 1; medium = 2; and serious = 3). All subjects underwent the Sniffin’Sticks to evaluate the olfactory performance. Results Twelve patients completed 4 months of treatment: 6 patients performed the treatment with Naridek and 6 patients with physiological solution. Due to the small sample size, the scores were added together to have an overall indication of the treatment. (Table1) Nasal endoscopy ENT signs score Olfactory performance SNAQ 11 Naridek V1 80 72* 169 197** Naridek V4 15* 15* 159 98** Physiological solution V1 68 61 151 166 Physiological solution V4 52 39 159 152 *P<0.05 ** p< 0,01 The bacterial colonization in NWs shows no statistically significant difference. However, in 2 patients, we detected a reduction of the bacterial load. While there was no difference in the saline-treated group. Conclusions Considering our small sample we can only draw some great deal to think about: - treatment with NWs allows an improvement of the ENT symptoms and is well tolerated by patients. These data are confirmed by the ENT signs score and by the reduction of the SNAQ11 score in both treatment arms; - the solution with surfactant (Naridek) significantly improves the ENT signs and decreases the nasal endoscopy and the SNAQ11 scores; - no benefit was detected at the evaluation of olfactory performance. In conclusion, even if further confirmations are necessary on broader cases, it seems to emerge as significant the role of surfactant in the therapeutic advantage of NWs