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Objective We investigated the contribution to sporadic focal epilepsies (FE) of ultrarare variants in genes coding for the components of complexes regulating mechanistic Target Of Rapamycin (mTOR)complex 1 (mTORC1). Methods We collected genetic data of 121 Italian isolated FE cases and 512 controls by Whole Exome Sequencing (WES) and single‐molecule Molecular Inversion Probes (smMIPs) targeting 10 genes of the GATOR1, GATOR2, and TSC complexes. We collapsed “qualifying” variants (ultrarare and predicted to be deleterious or loss of function) across the examined genes and sought to identify their enrichment in cases compared to controls. Results We found eight qualifying variants in cases and nine in controls, demonstrating enrichment in FE patients (P = 0.006; exact unconditional test, one‐tailed). Pathogenic variants were identified in DEPDC5 and TSC2, both major genes for Mendelian FE syndromes. Interpretation Our findings support the contribution of ultrarare variants in genes in the mTOR pathway complexes GATOR and TSC to the risk of sporadic FE and a shared genetic basis between rare and common epilepsies. The identification of a monogenic etiology in isolated cases, most typically encountered in clinical practice, may offer to a broader community of patients the perspective of precision therapies directed by the underlying genetic cause.

Prevention is essential to reduce Colorectal Cancer (CRC) mortality. We previously reported a panel of four genes: CEACAM6, LGALS4, TSPAN8, COL1A2 (CELTiC) able to discriminate patients with CRC. Here, we assessed the CELTiC panel by quantitative polymerase chain reaction, in the blood of 174 healthy subjects, who resulted negative to the faecal immunochemical test (FITN). Using non-parametric statistic and multinomial logistic models, the FITN were compared to previously analysed subjects: 36 false positive FIT (NFIT), who were negative at colonoscopy, 36 patients with low risk lesions (LR) and 92 patients with high risk lesions or CRC (HR/CRC). FITN showed a significantly lower expression of the four genes when compared to HR/CRC. Moreover, FITN showed a significantly lower expression of TSPAN8 and COL1A2 compared to NFIT and LR patients. The multinomial logistic model confirmed that TSPAN8 alone specifically discriminated FITN from NFIT, LR and HR/CRC, while LGALS4 was able to differentiate FITN from false positive FIT. Finally, ROC curves analysis of the comparisons between FITN and HR/CRC, LR or NFIT reported AUC greater than 0.87, with a sensitivity and specificity of 83% and 76%, respectively. The CELTiC panel was confirmed a useful tool to identify CRC patients and to discriminate false FIT positive subjects.

Background and aimNo marker to categorise the severity of chronic intestinal failure (CIF) has been developed. A 1-year international survey was carried out to investigate whether the European Society for Clinical Nutrition and Metabolism clinical classification of CIF, based on the type and volume of the intravenous supplementation (IVS), could be an indicator of CIF severity.MethodsAt baseline, participating home parenteral nutrition (HPN) centres enrolled all adults with ongoing CIF due to non-malignant disease; demographic data, body mass index, CIF mechanism, underlying disease, HPN duration and IVS category were recorded for each patient. The type of IVS was classified as fluid and electrolyte alone (FE) or parenteral nutrition admixture (PN). The mean daily IVS volume, calculated on a weekly basis, was categorised as 3 L/day. The severity of CIF was determined by patient outcome (still on HPN, weaned from HPN, deceased) and the occurrence of major HPN/CIF-related complications: intestinal failure-associated liver disease (IFALD), catheter-related venous thrombosis and catheter-related bloodstream infection (CRBSI).ResultsFifty-one HPN centres included 2194 patients. The analysis showed that both IVS type and volume were independently associated with the odds of weaning from HPN (significantly higher for PN 1 L/day), patients’ death (lower for FE, p=0.079), presence of IFALD cholestasis/liver failure and occurrence of CRBSI (significantly higher for PN 2–3 and PN >3 L/day).ConclusionsThe type and volume of IVS required by patients with CIF could be indicators to categorise the severity of CIF in both clinical practice and research protocols.

BACKGROUND: Coronary artery ectasia (CAE) is associated with ascending aortic (AA) ectasia. The purpose of this study is to evaluate the diagnostic performance of different echocardiographic parameters (EP) in predicting the presence of CAE. METHODS: Four hundred-eighteen patients with AA ectasia candidate to coronary angiography were identified and divided in two groups in respect of the presence of CAE. Receiver-operating characteristic curves areas (AUC) were used to assess the discrimination power of the following EP: aortic annulus diameter, sinuses of Valsalva (SV) diameter, sino-tubular junction (STJ) diameter, AA diameter, STJ to SV ratio (STJ-to-SV) and STJ to AA ratio (STJ-to-AA). All these parameters were indexed by body surface area. The relationship between the best EP and the presence of CAE was investigated by means of multivariable logistic regression. RESULTS: The rate of CAE in the study population was 32%. On univariable logistic regression, aortic annulus, STJ, STJ-to-SV and STJ-to-AA were associated with the presence of CAE after Bonferroni correction. STJ-to-SV emerged as the parameter with the best discrimination power (AUC=0.81) compared to STJ (AUC=0.69), STJ-to-AA (AUC=0.68), aortic annulus (AUC=0.59), AA (AUC=0.56) and SV (AUC=0.55); (p for comparison

Background Unanticipated difficult airway is a potentially life-threatening event during elective surgery or management of critical conditions. Nevertheless, predicting difficult mask ventilation currently remains a challenge due to the poor sensitivity of available clinical tests. Our primary goal was to verify whether preoperative upper airway ultrasound measurements were useful to predict difficult face mask ventilation. Our secondary goal was to evaluate clinical characteristics and differences between patients who are difficult to ventilate and patients who are not. Methods We performed a prospective observational study, enrolling 250 adult patients selected for colorectal, gastric, bariatric and pancreatic elective surgery between September 2017 and October 2018. We performed a preoperative US assessment of the airways, following a standardized protocol. We measured the hyomental distance (DIM), the thickness of the base of the tongue (SBL), the thickness of the soft tissues anterior to the hyoid bone (STTi), thyro-hyoid distance (DTI), the thickness of soft tissue anterior to the epiglottis (STTe), to the arytenoid (STTa) and to the commissure of the vocal cords (STTcv). Results SBL had a predictive role of difficult mask ventilation in curarized and noncurarized patients for values higher than 50mm. Hyomental distance with hyperextension of the head and subluxation of the mandible (DIMs) had a predictive role in the curarized patient (protective parameter). Conclusions Airways ultrasound evaluation could be an important tool to predict difficult mask ventilation. Further studies are necessary to validate the parameters found and correlate them to the preoperative clinical evaluation.

BACKGROUND: Although a 1-year duration of dual antiplatelet therapy (DAPT) is used in many patients after drug-eluting stent (DES) implantation, the evidence supporting this duration is uncertain. OBJECTIVES: The authors investigated the risk-benefit profile of 1-year vs≤6-month DAPT after DES using 2 novel scores to risk stratify bleeding and ischemic events. METHODS: Ischemic and bleeding risk scores were generated from ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents), a multicenter, international, "all-comers" registry that enrolled 8,665 patients treated with DES. The risk-benefit profile of 1-year vs≤6-month DAPT was then investigated across risk strata from an individual patient data pooled dataset of 7 randomized trials that enrolled 15,083 patients treated with DES. RESULTS: In the derivation cohort, the ischemic score and the bleeding score had c-indexes of 0.76 and 0.66, respectively, and both were well calibrated. In the pooled dataset, no significant difference was apparent in any ischemic endpoint between 1-year and≤6-month DAPT, regardless of the risk strata. In the overall dataset, there was no significant difference in the risk of clinically relevant bleeding between 1-year and≤6-month DAPT; however, among 2,508 patients at increased risk of bleeding, 1-year compared with≤6-month DAPT was associated with greater bleeding (HR: 2.80; 95%CI: 1.12-7.13) without a reduced risk of ischemic events in any risk strata, including those with acute coronary syndromes. These results were consistent in a network meta-analysis. CONCLUSIONS: In the present large-scale study, compared with≤6-month DAPT, a 1-year duration of DAPT was not associated with reduced adverse ischemic events in any risk strata (including acute coronary syndromes) but was associated with greater bleeding in patients at increased risk of bleeding.

PURPOSE: The assessment of liver fibrosis is essential in the management of patients with chronic liver diseases. Liver biopsy is considered the gold standard procedure for this purpose, though the recent development of new elastosonographic techniques to measure liver stiffness (LS) noninvasively is promising. Point quantification elastography (PQE) showed good results but less is known about the level of skill needed to obtain reliable results. The aim of the study was to evaluate the reproducibility of PQE in assessing LS in healthy subjects comparing three operators with different expertise. METHODS: Between December 2012 and April 2013, 50 consecutive healthy volunteers (18 males, 32 females), median age 30 years (range 25–66) and BMI 22.4 (range 16.7–33.6) were submitted to PQE (iU22 Philips, Bothell, WA, USA) by three operators: two US and elastography providers (one expert and one with intermediate skill) and a skilled transient elastography (Fibroscan) operator with no expertise in US. Intra- and inter-observer agreements were assessed by intraclass correlation coefficient (ICC). RESULTS: PQE measurement was obtained in all subjects by all evaluators. No significant differences of mean liver stiffness were found among operators (P = 0.980). Intra-observer agreement was excellent 0.918 (0.941 for expert, 0.917 for intermediate and 0.888 for novice). The ICC of the inter-observer agreement among the three ratters was excellent (0.882) and was higher in normal than overweight patients (0.923 vs. 0.603; P = 0.011). CONCLUSION: PQE is a reliable and reproducible non-invasive method for the assessment of LE, and can be performed also by a non-experienced operator.

ObjectiveTo optimise treatment of patients with pulmonary arterial hypertension (PAH), the 2015 European Society of Cardiology/European Respiratory Society guidelines recommend using risk stratification, with the aim of patients achieving low-risk status. Previous analyses of registries made progress in using risk stratification approaches, however, the focus is often on patients with a low-risk prognosis, whereas most PAH patients are in intermediate-risk or high-risk categories. Using only six parameters with high prognostic relevance, we aimed to demonstrate a pragmatic approach to individual patient risk assessment to discriminate between patients at low risk, intermediate risk and high risk of death.MethodsRisk assessment was performed combining six parameters in four criteria: (1) WHO functional class, (2) 6 min walk distance, (3) N-terminal pro-brain natriuretic peptide (BNP)/BNP plasma levels or right atrial pressure and (4) cardiac index or mixed venous oxygen saturation. Assessments were made at baseline and at first follow-up after 3–4 months.Results725 PAH treatment-naive patients were analysed. Survival estimates between risk groups were statistically significant at baseline and first follow-up (pConclusionThe simplified risk-assessment method can discriminate idiopathic, connective-tissue-disease-associated and congenital-heart-disease-associated PAH patients into meaningful high-risk, intermediate-risk and low-risk groups at baseline and first follow-up. This pragmatic approach reinforces targeting a low-risk profile for PAH patients.

Background A noninvasive blood test for the early detection of colorectal cancer (CRC) is highly required. We evaluated a panel of 4 mRNAs as putative markers of CRC. Materials and Methods We tested LGALS4, CEACAM6, TSPAN8, and COL1A2, referred to as the CELTiC panel, using quantitative reverse transcription polymerase chain reaction, on subjects with positive fecal immunochemical test (FIT) results and undergoing colonoscopy. Using a nonparametric test and multinomial logistic model, FIT-positive subjects were compared with CRC patients and healthy individuals. Results All the genes of the CELTiC panel displayed statistically significant differences between the healthy subjects (n = 67), both low-risk (n = 36) and high-risk/CRC (n = 92) subjects, and those in the negative-colonoscopy, FIT-positive group (n = 36). The multinomial logistic model revealed LGALS4 was the most powerful marker discriminating the 4 groups. When assessing the diagnostic values by analysis of the areas under the receiver operating characteristic curves (AUCs), the CELTiC panel reached an AUC of 0.91 (sensitivity, 79%; specificity, 94%) comparing normal subjects to low-risk subjects, and 0.88 (sensitivity, 75%; specificity, 87%) comparing normal and high-risk/CRC subjects. The comparison between the normal subjects and the negative-colonoscopy, FIT-positive group revealed an AUC of 0.93 (sensitivity, 82%; specificity, 97%). Conclusion The CELTiC panel could represent a useful tool for discriminating subjects with positive FIT findings and for the early detection of precancerous adenomatous lesions and CRC.

Perineural invasion (PNI) hinders the ability to establish local control of oral squamous cell carcinoma (OSCC). To date, PNI can be evaluated only in surgical specimens and not in preoperative biopsy material, rendering timely therapeutic planning impossible. Insulin-like growth factor-II mRNA binding protein-3 (IMP3) expression appears to be of diagnostic and prognostic utility for many solid tumours, and laminin-5 expression in surgical specimens has been identified as a valid predictor of neural spread of head-and-neck neoplasms. The ability to use preoperative biopsy material to identify patients exhibiting PNI is fundamental for good management of OSCC. We examined a series of 64 consecutive patients treated (primarily via surgery) for OSCC between 2009 and 2014 at the Maxillofacial Surgery Unit, University of Bologna. We evaluated IMP3 and laminin-5 expression in preoperative biopsy material using immunohistochemistry and quantitative reverse transcription polymerase chain reaction. We sought to correlate expression of IMP3 and laminin-5 with PNI evident in surgical specimens. Expression of IMP3 and laminin-5 in preoperative biopsy material appeared to be predictive of PNI in patients with OSCC (P

Objectives The purpose of this study was to compare conventional 2-dimensional (2D) B-mode sonography with 3-dimensional (3D) sonography for assessing gallbladder volume and contractility. Methods Gallbladder volume and contractility were evaluated in 32 healthy volunteers after fasting and abstinence from smoking for 8 hours and after a standardized balanced liquid meal. The gallbladder was evaluated with 2D sonography (with the use of the ellipsoid method) and with 3D sonography using a volumetric matrix probe. Both measurements were made by an operator who was skilled in sonography and an unskilled operator. The group of volunteers was subdivided into 2 subgroups including 16 participants, which represented the “2 moments” of acquisition by the techniques, particularly for the unskilled operator. Results The postprandial volumes obtained with 3D sonography were significantly lower in comparison to the volumes obtained with 2D sonography (P= .013), and there was a significant difference between the measurements made by the skilled and unskilled operators only for 2D sonography (P< .001), whereas between the 2 moments of acquisition by the 3D technique, there was no significant difference. The reproducibility of the technique for evaluation of gallbladder volumes was higher for 3D sonography than 2D sonography, particularly for the postprandial evaluation. Conclusions The new 3D sonographic method using a volumetric matrix probe is a simple, reliable, and more reproducible technique than conventional 2D sonography, even if performed by an unskilled operator, and it allows a reliable stimulation test for a gallbladder dynamic study.

Background: Acute abdominal pain (AAP) is one of the most common causes of referral to an emergency department (ED), but information about its impact is limited. Objectives: The objectives of this article are to define the prevalence of AAP among ED visits in a large university hospital and analyze its main clinical features. Methods: All patients admitted at the Sant’Orsola, Malpighi University Hospital of Bologna ED on 12 a priori selected sample days in 2013 were included. General data were recorded for each patient. A total of 192 clinical variables were recorded for each patient with abdominal pain. Results: During the observation period the ED assisted 2623 patients with a daily admission rate of 219 20 (mean SD). Of these, 239 patients complained of AAP as their chief complaint at entry (prevalence = 9.1%). AAP prevalence was significantly higher in females than in males (10.4% vs. 7.8%; OR = 1.37; p = 0.021) as well as in foreign over Italian patients (13.2% vs. 8.5%; OR = 1.64; p = 0.007). The most frequent ED operative diagnoses were non-specific abdominal pain (n = 86, 36.0%) and gastrointestinal (GI) tract-related pain (n = 79, 33.1%; n = 19 upper GI, n = 60 lower GI). Conclusions: AAP is a common cause of referral at EDs. Despite technological advances, non-specific abdominal pain is still the main operative diagnosis.

Background. The effectiveness of a homeopathic syrup on cough has been demonstrated in an adult population in a previous double-blind randomized study. The present prospective observational study investigated children affected by wet acute cough caused by non-complicated URTIs, comparing those who received the homeopathic syrup versus those treated with the homeopathic syrup plus antibiotic. Objectives. The aims were: 1) to assess whether the addition of antibiotics to a symptomatic treatment had a role in reducing the severity and duration of acute cough in a pediatric population, as well as in improving cough resolution; 2) to verify the safety of the two treatments. Methods. Eighty-five children were enrolled in an open study: 46 children received homeopathic syrup alone for 10 days and 39 children received homeopathic syrup for 10 days plus oral antibiotic treatment (amoxicillin/clavulanate, clarithromycin, and erythromycin) for 7 days. To assess cough severity we used a subjective verbal category-descriptive (VCD) scale. Results. Cough VCD score was significantly (P

Despite the increasing availability and effectiveness of non-invasive screening for foetal aneuploidies, most women of advanced maternal age (AMA) still opt for invasive tests. A retrospective cross-sectional survey was performed on women of AMA undergoing prenatal invasive procedures, in order to explore their motivations and the outcome of preliminary genetic counselling according to the approach (individual or group) adopted. Of 687 eligible women, 221 (32.2%) participated: 117 had received individual counselling, while 104 had attended group sessions. The two groups did not differ by socio-demographic features. The commonest reported reason to undergo invasive tests was AMA itself (67.4%), while only 10.4% of women mentioned the opportunity of making informed choices. The majority perceived as clear and helpful the information received at counselling, and only 12.7% had doubts left that, however, often concerned non-pertinent issues. The impact of counselling on risk perception and decisions was limited: a minority stated their perceived risk of foetal abnormalities had either increased (6.8%) or reduced (3.6%), and only one eventually declined invasive test. The 52.6% of women expressed a preference toward individual counselling, which also had a stronger impact on perceived risk reduction (P=0.003). Nevertheless, group counselling had a more favourable impact on both clarity of understanding and helpfulness (P=0.0497 and P=0.035, respectively). The idea that AMA represents an absolute indication for invasive tests appears deeply rooted; promotion of non-invasive techniques may require extensive educational efforts targeted to both the general population and health professionals.

BACKGROUND: A few studies have assessed the short-term effects of low-dose nicotine e-cigarettes, while data about nicotine-free e-cigarettes (NF e-cigarettes) are scanty. Concerns have been expressed about the use of NF e-cigarettes, because of the high concentrations of propylene glycol and other compounds in the e-cigarette vapor. METHODS: This laboratory-based study was aimed to compare the effects of ad libitum use of a NF e-cigarette or and a traditional cigarette for 5 min in healthy adult smokers (n = 10) and non-smokers (n = 10). The main outcome measures were pulmonary function tests, fraction of exhaled nitric oxide (FeNO) and fractional concentration of carbon monoxide (FeCO) in exhaled breath. RESULTS: The traditional cigarette induced statistically significant increases in FeCO in both smokers and non-smokers, while no significant changes were observed in FeNO. In non-smokers, the traditional cigarette induced a significant decrease from baseline in FEF75 (81 % ± 35 % vs 70.2 % ± 28.2 %, P = 0.013), while in smokers significant decreases were observed in FEF25 (101.3 % ± 16.4 % vs 93.5 % ± 31.7 %, P = 0.037), FEV1 (102.2 % ± 9.5 % vs 98.3 % ± 10 %, P = 0.037) and PEF (109.5 % ± 14.6 % vs 99.2 % ± 17.5 %, P = 0.009). In contrast, the only statistically significant effects induced by the NF e-cigarette in smokers were reductions in FEV1 (102.2 % ± 9.5 % vs 99.5 ± 7.6 %, P = 0.041) and FEF25 (103.4 % ± 16.4 % vs 94.2 % ± 16.2 %, P = 0.014). DISCUSSION: The present study demonstrated that the specific brand of NF e-cigarette utilized did not induce any majoracute effects. In contrast, several studies have shown that both traditional cigarettes and nicotine-containing e-cigarettes have acute effects on lung function. Our study expands on previous observations on the effects of NF e-cigarettes, but also for the first time describes the changes induced by smoking one traditional cigarette in a group of never smokers. CONCLUSIONS: The short-term use of the specific brand of NF e-cigarette assessed in this study had no immediate adverse effects on non-smokers and only small effects on FEV1 and FEF25 in smokers. The long-term health effects of NF e-cigarette use are unknown but worthy of further investigations. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02102191.