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Anemia is one of the most frequent extra-intestinal manifestations of inflammatory bowel disease. Insidious onset, variability of symptoms and lack of standardized screening practices may increase the risk of underestimating its burden in children with IBD. Despite its relevance and peculiarity in everyday clinical practice, this topic is only dealt with in a few documents specifically for the pediatric field. The aim of the current guidelines is therefore to provide pediatric gastroenterologists with a practical update to support the clinical and therapeutic management of children with IBD and anemia. A panel of 19 pediatric gastroenterologists and 1 pediatric hematologist with experience in the field of pediatric IBD was agreed by IBD Working group of the Italian Society of Gastroenterology, Hepatology and Nutrition (SIGENP) to produce the present article outlining practical clinical approaches to the pediatric patient with IBD and anemia. The levels of evidence and recommendations have been defined for each part of the statement according to the GRADE system. [ABSTRACT FROM AUTHOR]

Transition is a crucial process in the care of IBD patients, although it remains largely heterogeneous. To provide an overview of the transition process in Italy and to investigate the perspective of the paediatric and adult physicians. An online survey was developed by the Italian Group for Inflammatory Bowel Diseases (IG-IBD) and the Italian Society of Paediatric Gastroenterology, Hepatology and Nutrition (SIGENP). 104 physicians (62 paediatric and 42 adult gastroenterologists) participated to the survey. The disease status was ranked with the highest priority among the key elements of the transition process. The age of the patient was perceived with a higher priority by paediatric gastroenterologists than by adult ones ( p < 0.01). In most cases, the transition was organized through one or more joint meetings. Only less than 25 % of responders reported to involve other professions during transition. The struggle in leaving paediatric setting was perceived as the main obstacle to an effective transition process. Paediatric IBD gastroenterologists ranked the struggle in leaving the paediatric setting and the attending physician as higher critical point than adult gastroenterologists. The current survey provided a snapshot of the IBD transition process in Italy. The present findings highlight the need to embed transitional care in healthcare policy. [ABSTRACT FROM AUTHOR]

The successful implementation of Business Process Management (BPM) requires a holistic perspective. Previous studies have found that the adoption of BPM Methods (BPMM) indirectly contributes to Process Performance (PP) by building a culture that supports BPM. This study examines the mediating role of BPM Culture (BPMC) and the moderating role organization size on the Performance of BPMM and Processes in Situbondo Regency and Surabaya City. Surveys were designed and distributed to employees in each agency. The results are analyzed using PLS-SEM. The results reveal that organizational size also influences the BPMC relationship between BPMM and PP. [ABSTRACT FROM AUTHOR]

The natural history of ulcerative proctitis (UP) has been poorly investigated in children. We aimed to compare the disease course of children with UP at diagnosis to the other locations and to identify extension predictors. This was a multicenter, observational study carried out from data prospectively entered in the SIGENP-IBD-Registry. Children with ulcerative colitis (UC) diagnosis and at least 1-year follow-up were included. On the basis of Paris classification UP patients were identified and compared with the other locations. 872 children were enrolled (median age at diagnosis: 11.2 years; M/F: 426/446), of whom 78 (9%) with UP. Kaplan–Meier analysis demonstrated increased cumulative probabilities of disease extension in the E1 group [1 year: 20.3%; 5 years: 52.7%; 10 years: 72.4%] compared to E3 group [1 year: 8.5%; 5 years: 24.9% and 10 years: 60.1%, p=0.001]. No differences were observed comparing E1 and E2 groups [p=0.4]. Cumulative probabilities of surgery at 1, 5 and 10 years were 1.3, 2.8 and 2.8% in the E1 group and 2.5, 8 and 12.8% in the E2–E3-E4 group, respectively (p=0.1). Cox regression analysis demonstrated that PUCAI>35 at diagnosis was associated with endoscopic extension (HR=4.9; CI 95% 1.5-15.2, p=0.006). UP is associated with similar short and long-term outcomes compared to other locations. [ABSTRACT FROM AUTHOR]

• The EEG is one of the most useful technologies for brain research and clinical neurology. • The acquired traces are visibly displayed, but various studies investigate the translation of brain waves in sound. • The analog EEG was equipped with an auditory output, the pen-on-paper noise made by the writer unit, useful to facilitate the diagnosis of epileptic disorders. • Early digital EEG devices could be equipped with special software to duplicate the pen-on-paper noise digitally. • Nowadays, auditory neurofeedback has applications in therapeutic interventions, cognitive improvement, and basic research. The electroencephalogram (EEG) is one of the most useful technologies for brain research and clinical neurology, characterized by non-invasiveness and high time resolution. The acquired traces are visibly displayed, but various studies investigate the translation of brain waves in sound (i.e., a process called sonification). Several articles have been published since 1934 about the sonification of EEG traces, in the attempt to identify the "brain-sound." However, for a long time this sonification technique was not used for clinical purposes. The analog EEG was in fact already equipped with an auditory output, although rarely mentioned in scientific papers: the pen-on-paper noise made by the writer unit. EEG technologists often relied on the sound that pens made on paper to facilitate the diagnosis. This article provides a sample of analog video-EEG recordings with audio support representing the strengths of a combined visual-and-auditory detection of different types of seizures. The purpose of the present article is to illustrate how the analog EEG "sounded," as well as to highlight the advantages of this pen-writing noise. It was considered so useful that early digital EEG devices could be equipped with special software to duplicate it digitally. Even in the present days, the sonification can be considered as an attempt to modify the EEG practice using auditory neurofeedback with applications in therapeutic interventions, cognitive improvement, and basic research. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is associated with substantial morbidity and mortality, highlighting a critical need for novel therapies. AB-1002, an engineered AAV vector gene therapy candidate, delivers a constitutively active form of protein phosphatase inhibitor (I-1c) to restore cardiomyocyte intracellular calcium homeostasis. Preliminary results from an ongoing Phase (Ph) 1 trial (NCT04179643) of AB-1002 showed favourable safety and tolerability. Here we describe the design of AB-1002 Ph 2 trial (GenePHIT; NCT05598333) to evaluate efficacy, safety, and tolerability. This phase 2 adaptive, double-blind, placebo-controlled, randomized, multi-centre trial (currently US; European sites planned) includes a 52-week observation and 4-year follow-up period. Eligible patients are ≥18 years of age with non-ischaemic cardiomyopathy and New York Health Association (NYHA) Class III HF symptoms (Figure). Patients will be randomized 1:1:1 (n=30-50/treatment arm), including a single dose of AB-1002 administered via antegrade intracoronary infusion at 1 of 2 different doses, or placebo, all in addition to standard of care. The primary endpoint will evaluate efficacy at 52 weeks based on the composite endpoint by modified win ratio, which includes cardiovascular-related death, change in NYHA classification, and for the responders, improvements in LVEF (≥5%), pVO2 ≥1.5 mL/kg/min, and 6MWT >30 metres. Key secondary efficacy endpoints include functional status and hospitalisations at 24 and 52 weeks, by assessing changes over time in NYHA classification, LVEF, pVO2, 6MWT, biomarkers (NT-proBNP, troponin), quality of life questionnaires (MLHFQ, KCCQ), and physiological assessments. Key safety endpoints will be assessed through 52 weeks and include TEAEs and SAEs. Exploratory endpoints will evaluate AAV2i8 antibody titres, T-cell response to AAV2i8 capsid and I-1c, and optional right ventricular biopsy testing. Long-term follow-up will assess TEAEs, SAEs, and number of HF hospitalisations. Data safety monitoring board assessment will occur every 3 months. Primary efficacy endpoint will compare both active dose groups combined versus placebo using the joint rank test. Key secondary endpoints will be analyzed using Analysis of Covariance with baseline as a continuous covariate. Multiple imputations will be used to address missing data. Interim efficacy analysis will be performed using a Bayesian adaptive sample size algorithm. GenePHIT is currently recruiting and will evaluate the efficacy, safety, and tolerability of intracoronary infusion of AB-1002, a gene therapy targeting ventricular dysfunction in HF. [ABSTRACT FROM AUTHOR]

The present study aimed at evaluating Italian epidemiological trends of pediatric inflammatory bowel diseases (IBD) over the period 2009–2018. Data from 1969 patients enrolled in the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition Registry, by 49 pediatric IBD centers throughout the country, were analyzed, comparing three different time intervals (2009–2012, 2013–2015, 2016–2018). The number of new IBD diagnoses ranged from 175 to 219 per year, evenly distributed over the examined period of time. From 2009 to 2018, the minimal incidence ranged from 1.59 to 2.04 /105 inhabitants aged < 18 years, with an overall slight predominance of ulcerative colitis (UC) over Crohn's disease (CD) (ratio: 1.1). Mean diagnostic delay was 6.8 months for CD and 4.1 months for UC, with a significant reduction for CD when comparing the three-time intervals (p =0.008). The most frequent disease locations according to the Paris classification were ileocolonic for CD (41.3%) and pancolitis for UC (54.6%). The minimal incidence rate in Italy seems to have stabilized over the last two decades, even if it has increased when compared to previous reports. UC is still slightly more prevalent than CD in our country. Diagnostic delay significantly decreased for CD, reflecting an improved diagnostic capacity. [ABSTRACT FROM AUTHOR]

Few data are available regarding the trend of IgA anti-transglutaminase antibodies (TGA-IgA) in children with celiac disease (CD) on a gluten-free diet (GFD). Our aim is to examine the normalization time of CD serology in a large pediatric population, and its predictors. We retrospectively evaluated the normalization time of TGA-IgA and its predictive factors (age, sex, ethnicity, symptoms, associated diabetes/thyroiditis, Marsh stage, TGA-IgA and endomysial antibody levels at diagnosis, diet adherence), in 1024 children diagnosed from 2000 to 2019 in three pediatric Italian centers, on a GFD. TGA-IgA remission was reached in 67,3%, 80,7%, 89,8% and 94,9% after 12, 18, 24 and 36 months from starting a GFD, respectively (median time = 9 months). TGA-IgA >10´upper limit of normal at diagnosis (HR = 0.56), age 7–12 years old (HR = 0.83), poor compliance to diet (HR = 0.69), female sex (HR = 0.82), non-Caucasian ethnicity (HR = 0.75), and comorbidities (HR = 0.72) were independent factors significantly associated with longer time to normalization. Our population is the largest in the literature, with the majority of patients normalizing CD serology within 24 months from starting a GFD. We suggest a special attention to patients with comorbidities, language barriers or age 7–12 years for a proper management and follow-up. [ABSTRACT FROM AUTHOR]

Duodenal polyps and superficial mucosal lesions (DP/SMLs) are poorly characterised. To describe a series of endoscopically-diagnosed extra-ampullary DPs/SMLs. This is a retrospective study conducted in a tertiary referral Endoscopy Unit, including patients who had DPs or SMLs that were biopsied or removed in 2010–2019. Age, gender, history of familial polyposis syndromes, DP/SML characteristics were recorded. Histopathological, immunohistochemical and molecular analyses were performed. 399 non-ampullary DP/SMLs from 345 patients (60.6% males; median age 67 years) were identified. Gastric foveolar metaplasia represented the most frequent histotype (193 cases, 48.4%), followed by duodenal adenomas (DAs; 77 cases, 19.3%). Most DAs (median size 6 mm) were sessile (Paris Is; 48%), intestinal-type (96.1%) with low-grade dysplasia (93.5%). Among syndromic DAs (23%), 15 lesions occurred in familial adenomatous polyposis 1, two were in MUTYH -associated polyposis and one was in Peutz-Jeghers syndrome (foveolar-type, p53-positive, low-grade dysplasia). Only one (3.3%) tubular, low-grade DA showed mismatch repair deficiency (combined loss of MLH1 and PMS2 , heterogeneous MSH6 expression), and it was associated with a MLH1 gene germline mutation (Lynch syndrome). DPs/SMLs are heterogeneous lesions, most of which showing foveolar metaplasia, followed by low-grade, intestinal-type, non-syndromic DAs. MMR-d testing may identify cases associated with Lynch syndrome. [ABSTRACT FROM AUTHOR]

Currently, available data on preventive measures for Human Papillomavirus (HPV) infection and cervical cancer in the transgender assigned female at birth (AFAB) community are extremely limited. Our aim was to analyze adherence to primary and secondary cervical cancer prevention screening programs among transgender AFAB people attending our gender clinic. Transgender AFAB people attending our center were recruited. Anamnestic data were collected for each person through completion of a medical history form and medical records. Variables recorded included previous HPV vaccination, adherence to regional screening programs (Pap smear or HPV DNA test), subject age, duration of current or prior gender-affirming hormone therapy (GAHT) and whether gender affirmation surgery (GAS) with hysterectomy had been performed. Open questions regarding reasons for not undergoing screening tests were also included. In this cross-sectional study, 263 AFAB transgender people were included, with a mean age of 30.6 ± 10.5 years. GAS with hysterectomy had been performed on 37.6 % of these people. Of our participants, 71.7 % who were born after 1998 (the first cohort to receive HPV vaccination invitations in Italy) had been vaccinated for HPV. Seventy-four-point-nine percent of participants who were still eligible for cervical screening had never undergone Pap smear or HPV DNA testing, whereas those who had undergone at least one cervical screening had done so on average 4.2 ± 4.5 years ago. HPV vaccination prevalence in the AFAB transgender population born after 1998 is in line with the Italian AFAB general population. However, adherence to cervical cancer screening programs in the transgender AFAB population appears to be lower in comparison to the cisgender population. Further efforts are required from the medical community to enhance AFAB transgender people's adherence to HPV vaccination and to cervical screening. [ABSTRACT FROM AUTHOR]

IBD management has been significantly affected during the COVID-19 lockdown with potential clinical issues. The aim of this study was to analyse the impact of COVID-19 pandemic on the Italian paediatric IBD cohort. This was a multicentre, retrospective, cohort investigation including 21 different Italian IBD referral centres. An electronic data collection was performed among the participating centres including: clinical characteristics of IBD patients, number of COVID-19 cases and clinical outcomes, disease management during the lockdown and the previous 9 weeks. 2291 children affected by IBD were enrolled. We experienced a significant reduction of the hospital admissions [604/2291 (26.3%) vs 1281/2291 (55.9%); p < 0.001]. More specifically, we observed a reduction of hospitalizations for new diagnosis (from n = 44 to n = 27) and endoscopic re-evaluations (from n = 46 to n = 8). Hospitalization for relapses and surgical procedures remained substantially unchanged. Biologic infusions did not significantly vary [393/2291 (17.1%) vs 368/2291 (16%); p = 0.3]. Telemedicine services for children with IBD were activated in 52.3% of the centres. In 42/2291(1.8%) children immunosuppressive therapies were adapted due to the concurrent COVID-19 pandemic. Due to the several limitations of the lockdown, cares for children with IBD have been kept to minimal standards, giving priorities to the urgencies and to biologics' infusions and implementing telemedicine services. [ABSTRACT FROM AUTHOR]

Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2, spreading in Italy during the first months of 2020, abruptly changed the way of practicing medicine in this country. As a consequence of the lockdown, the diagnostic and therapeutic management of paediatric chronic conditions, such as inflammatory bowel disease (IBD) has been affected. During the peak of COVID-19 pandemic, elective visits, endoscopies and infusions have been postponed, with potential clinical and psychological impact on disease course and a high likelihood of increasing waiting lists. While slowly moving back towards normality, clinicians need to recognize the best ways to care for patients with IBD, carefully avoiding risk factors for new potential epidemic outbreaks. In this uncertain scenario until the development and spread of COVID-19 vaccine, it is necessary to continue to operate with caution. Hereby we provide useful indications for a safer and gradual restarting of routine clinical activities after COVID-19 peak in Italy. [ABSTRACT FROM AUTHOR]

We conducted a survey to investigate to what extent the fear of COVID-19 has influenced the patients decision to undergo or to cancel endoscopic procedures. We collected data from 847 patients from 13 centres. The main indication for endoscopy was anemia, followed by pain and unexplained weight loss. The percentage of not presenters progressively increased throughout the three weeks of study, from 15.1% at the beginning to 48.2% at the end. 37 (34.2%) upper GI endoscopies and 112 (56.3 %) colonoscopies showed an organic cause explaining the symptoms presented by the patients, respectively; 5 cases of gastric cancer (4.6%) and 16 cases of colorectal cancer (CRC) (6.0%), respectively, were detected; during the second week the percentage of organic diseases found at upper endoscopy was 19 (33.3%) with 5 cancer (8.7%), and 61 (49.1%) at colonoscopy, with 2 CRC (1.6%); finally, during the third week the corresponding figures were 19 (48.7%) for upper GI examinations, with 3 gastric cancers (7.7%), and 43 (60.5%) with 4 (6.5%) CRC cases found.We conclude that patients weighted the fear of having a clinically relevant disease with the fear of becoming infected by coronavirus, and a relevant percentage of them (29.4%) decided not to attend the endoscopy suites at the scheduled date. [ABSTRACT FROM AUTHOR]

Data on the epidemiology and risk factors for pouchitis following restorative proctocolectomy and ileal pouch-anal anastomosis (IPAA) in pediatric patients with ulcerative colitis (UC) are scarce. To determine incidence, risk factors and clinical outcome of pouchitis following IPAA in children. This multicenter, retrospective cohort study, included all pediatric UC patients who underwent colectomy and IPAA from January 2010 to December 2016. Eighty-five patients were enrolled. During a median post-surgical period of 24.8 (range: 1.0–72.0) months following IPAA, 38 (44.7%) patients developed pouchitis, including 6 (15.8%) who developed chronic pouchitis. Kaplan–Meier survival estimates of the cumulative probability for pouchitis were 14.6% at 1 year and 27.3% and 51.5% at 2 and 5 years, respectively. Multiple Cox regression model showed that older age at colectomy (hazard ratio, HR: 0.89, p = 0.008) was a protective factor, whereas chronic active colitis as indication for surgery (HR: 4.45, p < 0.001), and a 3-stage IPAA (HR: 2.86, p = 0.028) increased the risk for pouchitis. Long-term risk for pouchitis is significantly high in pediatric-onset UC after IPAA. Younger age at colectomy, chronic active colitis as indication for surgery and 3-stage IPAA may increase the risk for pouchitis. [ABSTRACT FROM AUTHOR]

Oral mucosa epithelial stem cells from a patient affected by Ectrodactyly-Ectodermal dysplasia-Clefting (EEC) syndrome carrying the R279H mutation in the TP63 gene were reprogrammed into human induced pluripotent stem cells (hiPSCs) with episomal vectors. The generated UNIPDi003-A-hPSC line retained the mutation of the parental cells and showed a normal karyotype upon long term culture. Analysis of residual transgenes expression showed that the episomal vectors were eliminated from the cell line. UNIPDi003-A-hiPSCs expressed the undifferentiated state marker alkaline phosphatase along with a panel of pluripotency markers, and formed embryoid bodies capable of expressing markers belonging to all the three germ layers. [ABSTRACT FROM AUTHOR]

Human oral mucosa epithelial stem cells (hOMESCs) were obtained from a fresh oral biopsy collected from a healthy subject at the Fondazione Banca degli Occhi del Veneto (FBOV). An integration-free reprogramming protocol was applied exploiting episomal plasmids transfected into cells using a Nucleofector device. Around day 20 post transfection, several human induced pluripotent stem cell (hiPSC) colonies were manually picked and expanded. One of these (UNIPDi001-A-hiPSCs) expressed undifferentiated state marker alkaline phosphatase along with a panel of pluripotency state markers and was able to differentiate into the derivatives of all the three germ layers. [ABSTRACT FROM AUTHOR]

Transgene free UNIPDi002-A-human induced pluripotent stem cell (hiPSC) line was generated by Sendai Virus Vectors reprogramming from human oral mucosal epithelial stem cells (hOMESCs) of a patient affected by ectrodactyly-ectodermal dysplasia-clefting (EEC)-syndrome, carrying a mutation in exon 8 of the TP63 gene (R304Q). The UNIPDi002-A-hiPSC line retained the mutation of the parental R304Q-hOMESCs and displayed a normal karyotype. No residual expression of transgenes nor Sendai virus vector sequences were detected in the line at passage 8. UNIPDi002-A-hiPSC expressed a panel of pluripotency-associated markers and could form embryoid bodies expressing markers belonging to the three germ layers ectoderm, endoderm and mesoderm. [ABSTRACT FROM AUTHOR]

Summary Background & aims Through inhibition of iron absorption and iron mobilization from tissue stores, hepcidin exerts a negative control on iron homeostasis. Hepcidin, in fact, promotes the degradation of ferroportin (Fpn1), the iron exporter molecule expressed on the membrane of hepatocytes and macrophages, thus preventing iron release from cells to plasma. Hepcidin effects on enterocytes, however, are less clear. Aim of the present study was to further investigate the regulation of iron absorption by hepcidin. Methods The transcriptional response of human duodenal mucosa to hepcidin was investigated using organ cultures of duodenal biopsies perendoscopically collected from healthy controls. Biopsies were cultured for 4 h with or without hepcidin-25 and were then assayed for the expression of iron-related genes. Results In samples that had not been exposed to hepcidin, correlations were found between the expression of genes involved in iron absorption: DMT1 , Fpn1 , Dcytb and HCP1 . In ex vivo experiments hepcidin down-regulated mRNA levels of the iron transporters Fpn1 , and DMT1 , of the ferric reductase Dcytb , of the ferroxidase hephaestin , and of the putative heme carrier protein HCP1 . Conclusions Through the reported transcriptional changes hepcidin can modulate several steps of the iron absorption process, including the reduction of dietary iron by Dcytb, its uptake by enterocytes through DMT1, the mucosal uptake of heme iron by HCP1, and enterocyte iron release to plasma by Fpn1 in conjunction with hephaestin. [ABSTRACT FROM AUTHOR]

This study compares different recently proposed methods for Pressure-Driven snapshot simulations of water distribution networks using the EPANET software interface and proposes a new one. The proposed method is based on the insertion of a sequence of devices consisting of a General Purpose Valve (GPV), a fictitious junction, a reach with a check valve and a reservoir at each water demand node. The proposed method differs from other methods previously proposed in the literature – and similarly based on the insertion of sequences of devices consisting of a valve and a reservoir or emitter – in that it uses a GPV. In fact the GPV allows the user to define the relationship between the flow (i.e. supplied demand) and available pressure, making the proposed sequence of devices capable of representing different relationships among these variables, unlike the other non-iterative methods already proposed in the scientific literature, in which the relationship is implicitly fixed by the structure of the sequence of devices used. Applications to two case studies and comparison with the results of the non-iterative methods already proposed in the scientific literature highlight the accuracy and flexibility of the proposed method and show, by contrast, the unreliability and limits, in terms of precision, of some of the methods previously proposed in the literature. [ABSTRACT FROM AUTHOR]

Abstract: Alvisi V, Marangoni E, Zannoli S, Uneddu M, Uggento R, Farabegoli L, Ragazzi R, Milic-Emili J, Belloni GP, Alvisi R, Volta CA. Pulmonary function and expiratory flow limitation in acute cervical spinal cord injury. Objective: To identify the nature of the changes of respiratory mechanics in patients with middle cervical spinal cord injury (SCI) and their correlation with posture. Design: Clinical trial. Setting: Acute SCI unit. Participants: Patients with SCI (N=34) at C4-5 level studied within 6 months of injury. Interventions: Patients were assessed by the negative expiratory pressure test, maximal static respiratory pressure test, and standard spirometry. Main Outcome Measures: The following respiratory variables were recorded in both the semirecumbent and supine positions: (1) tidal expiratory flow limitation (TEFL); (2) airway resistances; (3) mouth occlusion pressure developed 0.1 seconds after occluded inspiration at functional residual capacity (P0.1); (4) maximal static inspiratory pressure (MIP) and maximal static expiratory pressure (MEP); and (5) spirometric data. Results: TEFL was detected in 32% of the patients in the supine position and in 9% in the semirecumbent position. Airway resistances and P0.1 were much higher compared with normative values, while MIP and MEP were markedly reduced. The ratio of forced expiratory volume in 1 second to forced vital capacity was less than 70%, while the other spirometric data were reduced up to 30% of predicted values. Conclusions: Patients with middle cervical SCI can develop TEFL. The presence of TEFL, associated with increased airway resistance, could increase the work of breathing in the presence of a reduced capacity of the respiratory muscles to respond to the increased load. The semirecumbent position and the use of continuous positive airway pressure can be helpful to (1) reduce the extent of TEFL and avoid the opening/closure of the small airways; (2) decrease airway resistance; and (3) maintain the expiratory flow as high as possible, which aids in the removal of secretions. [Copyright &y& Elsevier]

A methodology for the control of a pumping plant feeding a tank is presented. This methodology is aimed at minimizing the energy costs by maximizing pumping during off-peak electricity tariff periods. It is based on trigger levels which are variable during the day according to a prefixed pattern in order to ensure that the water level in the elevated tank is at its minimum and maximum values at the end of the peak and off-peak tariff periods respectively. The pattern of the trigger levels is defined by solving a multi-objective problem aimed at minimizing the energy costs and the number of pump switches. The methodology was applied to the real case of a pumping plant feeding an elevated tank for daily balance which, in turn, feeds a small town in northern Italy; one week of hourly observed total consumptions was considered. This methodology was compared with other two methodologies typically used for pump control, i.e. pump scheduling and fixed trigger levels. The results show that the proposed methodology allows for achieving energy costs that are definitively lower than those obtainable by using fixed trigger levels, and comparable with those obtainable by using pump scheduling, being the number of pump switches the same. On the other hand, unlike the pump scheduling, the methodology presented does not require any water demand forecast and scheduling optimization to be repeated daily, thus representing an effective and efficient tool for pumping plant operation. [ABSTRACT FROM AUTHOR]

Background Immune mechanisms have been implicated in nonceliac gluten sensitivity (NCGS), a condition characterized by intestinal and/or extraintestinal symptoms caused by the ingestion of gluten in non-celiac/non-wheat allergic individuals. Aims We investigated innate and adaptive immunity in self-reported NCGS versus celiac disease (CD). Methods In the supernatants of ex vivo -cultured duodenal biopsies from 14 self-reported NCGS patients, 9 untreated and 10 treated CD patients, and 12 controls we detected innate cytokines – interleukin (IL)-15, tumor necrosis factor-α, IL-1β, IL-6, IL-12p70, IL-23, IL-27, IL-32α, thymic stromal lymphopoietin (TSLP), IFN-α-, adaptive cytokines – interferon (IFN)-γ, IL-17A, IL-4, IL-5, IL-10, IL-13-, chemokines – IL-8, CCL1, CCL2, CCL3, CCL4, CCL5, CXCL1, CXCL10-, granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF). Results Mucosal innate and adaptive cytokines, chemokines and growth factors did not differ between self-reported NCGS, treated CD and controls. On the contrary, IL-6, IL-15, IL-27, IFN-α, IFN-γ, IL-17A, IL-23, G-CSF, GM-CSF, IL-8, CCL1 and CCL4 were significantly higher in untreated CD than in self-reported NCGS, treated CD and controls, while TSLP was significantly lower in untreated CD than in self-reported NCGS, treated CD and controls. Conclusion In our hands, patients with self-reported NCGS showed no abnormalities of the mucosal immune response. [ABSTRACT FROM AUTHOR]

This paper presents a linearization approach to be used within the framework of water distribution system optimization problems where the searching algorithm is guided by the ranking of the possible solutions characterized by a system performance indicator such as the resilience index. The results obtained in addressing two different problems applied to real water distribution systems, namely, identification of the optimal placement of flow meters in a district meter area and multi-objective design of a water distribution system, show that a linearized hydraulic simulator although not capable of correctly describing the hydraulic functioning of the network, nonetheless enables each solution it finds to be assigned a value of the performance indicator whose ranking closely approximates the ranking of the corresponding solution that would be obtained if the full hydraulic simulator was used. This ensures significant reductions in computational times. [ABSTRACT FROM AUTHOR]

This paper proposes the application of three different methods for preserving the correlation between duration and intensity of synthetically generated water demand pulses. The first two methods, i.e., the Iman and Canover (1982) method and the Gaussian copula ( Nelsen, 1999 ) respectively, are derived from the known statistical approaches, though they had never been applied to the context of demand pulse generation. The third is a novel methodology developed in this work and is a variation in the Gaussian cupola approach. Applications carried out to reproduce the demand pulses measured in one household prove that the three methods are effective and applicable under general conditions. [ABSTRACT FROM AUTHOR]

Background Few case reports describe the clinical features of pancreatic involvement in inflammatory bowel disease. Aim To investigate prevalence and disease course of inflammatory bowel disease children with pancreatitis and with exclusive hyperamylasemia and hyperlipasemia. Methods We used a web-registry to retrospectively identify paediatric inflammatory bowel disease patients with hyperamylasemia and hyperlipasemia. Participants were re-evaluated at 6 months and 1 year. Results From a total of 649 paediatric patients, we found 27 with hyperamylasemia and hyperlipasemia (4.1%). Eleven patients (1.6%) fulfilled diagnostic criteria for acute pancreatitis. Female gender was significantly associated with acute pancreatitis ( p = 0.04). Twenty-five children (92.5%) had colonic disease. At 6 months 1/11 children with acute pancreatitis (9%) showed acute recurrent pancreatitis, while 1 patient (9%) had persistent hyperamylasemia and hyperlipasemia. At 12 months, 1 patient showed chronic pancreatitis (9.1%). Of the 16 children with exclusive hyperamylasemia and hyperlipasemia, 4 developed acute pancreatitis (25%), while 1 patient (6.2%) still presented exclusive hyperamylasemia and hyperlipasemia at 6 months. At 12 months, 11/16 patients (68.7%) reached a remission of pancreatic involvement, whereas 5 remaining patients (32.3%) had persistent hyperamylasemia and hyperlipasemia. Conclusions In inflammatory bowel disease children, acute pancreatitis is more common in colonic disease and in female gender. Pancreatic function should be monitored, considering that pancreatic damage may evolve. [ABSTRACT FROM AUTHOR]

An application of the Model Conditional Processor (MCP) is here presented to assess the predictive uncertainty in water demand forecasting related to water distribution systems. The MCP allows for the estimate of the forecast and its uncertainty through the elaboration of the forecasts provided by more than one deterministic forecasting model. The approach is applied to the hourly water consumptions of a town in the northern Italy and the results highlight its effectiveness, provided that the data set used for the parameterization is effectively representative of the accuracy of the real time water demand-forecasting model. [ABSTRACT FROM AUTHOR]

Abstract: A procedure for spatial aggregation of synthetic water demand time series is presented. Starting from synthetic water demand time series generated at user level and reproducing mean and variance of the corresponding observed series, the procedure allows the aggregated series to preserve the statistics of interest observed at the aggregation level considered. The procedure uses a method proposed by Iman and Conover (1982): the synthetic user water demand time series are reordered to preserve the observed spatial correlations of appropriate lag-time; then, the spatial aggregation of these series leads to a series representative of the user group reproducing the corresponding means and variances for the different hours of the generic day. Four different ways of performing this aggregation have been investigated and compared. Application to a case study consisting of the water demands of 21 users highlights that the approaches considered show different levels of effectiveness in reproducing the statistics, but overall the procedure proposed is a valid tool for the bottom-up generation of synthetic water demand time series. [Copyright &y& Elsevier]

Abstract: A procedure for the districtualization of a water distribution system is presented. The procedure is based on the use of techniques derived from graph theory and is aimed at identifying a “near optimal solution” in terms of (a) allocating all the network nodes among an assigned number of DMAs and (b) determining which pipes should be closed to delimit such districts and which pipes should be left open and fitted with flow meters in order to maximize the resilience of the entire system after the creation of districts. The application of the proposed procedure to a real water distribution system proved its robustness and effectiveness. The results obtained show that the procedure makes it possible to identify very good solutions in terms of resilience and minimum pressures when reference to the peak water demand and fire-flow conditions is made. [Copyright &y& Elsevier]

The role of putative preneoplastic enterochromaffin-like cell lesions, either hyperplastic or dysplastic, in the genesis of type 1 enterochromaffin-like cell neuroendocrine tumors associated with type A chronic atrophic gastritis, their actual neoplastic risk, and their precise histogenetic mechanism deserve further clarification by specific histopathologic studies coupled with patient follow-up. A total of 100 patients with severe type A chronic atrophic gastritis, enterochromaffin-like cell hyperplasia, and antral G-cell hyperplasia were endoscopically and histologically followed up for a median of 90.1 months (total of 9118 person-months). Preneoplastic enterochromaffin-like cell lesions and newly developed neuroendocrine tumors were investigated histologically and histochemically, in parallel with enterochromaffin-like cell lesions found in nontumor mucosa of another 32 well-characterized and previously reported type 1 neuroendocrine tumors. Both neuroendocrine and nonneuroendocrine mucosa changes were analyzed and statistically evaluated. During follow-up, 7 of 100 patients developed neuroendocrine tumors: 5 were in a group of 20 cases with previous enterochromaffin-like cell dysplasia and 2 were among 80 cases showing only enterochromaffin-like cell hyperplasia throughout the study (hazard ratio, 20.7; P < .001). The severity of enterochromaffin-like cell hyperplasia at first biopsy, with special reference to linear hyperplasia with 6 chains or more per linear millimeter, also increased the risk of neuroendocrine tumor development during follow-up (hazard ratio, 13.0; P < .001). Enterochromaffin-like cell microinvasive dysplastic lesions arising at the epithelial renewal zone level, in connection with immature proliferating mucous-neck cells, were found to be linked to early intramucosal neuroendocrine tumor histogenesis. Both enterochromaffin-like cell dysplasia and severe hyperplasia indicate increased risk of neuroendocrine tumor development in type A chronic atrophic gastritis with hypergastrinemia/G-cell hyperplasia. © 2013 Elsevier Inc. All rights reserved. [ABSTRACT FROM AUTHOR]

Abstract: Networked films of carbon nanotubes (CNTs) have been grown by Chemical Vapor Deposition (CVD) technology onto cost-effective alumina substrate, coated by Cobalt nanocatalyst for growing the CNTs. The sidewalls of the CNTs films have been functionalized by spray-coating with two different metalloporphyrins (MPP), consisting of a Tetraphenylporphyrin coordinated by a central metal of zinc (Zn-TPP) and manganese (Mn-TPP). The surface-modification of the CNTs with layers of Zn-TPP and Mn-TPP provides enhanced sensitivity and broad selectivity to volatile organic compounds (VOCs). The chemical interactions of these MPP-modified CNTs films with different tested VOCs (alcohols, esters, aromatics, ketones) have been investigated using the miniaturized two-pole chemiresistors technique. The sensor response in terms of p-type electrical conductance in the MPP-modified CNTs-chemiresistors exhibits a good sensing performance, at room temperature. The findings show a VOC adsorption occuring by sensing characteristics of response-concentration relationships as a combined Langmuir-Henry behaviour [Copyright &y& Elsevier]

Neurohypophyseal peptides potently stimulate myogenic differentiation by acting through different receptors of the same family. Here, we show that L6C5 myogenic cells express, at a high density, a single class of V1a Arg8-vasopressin (AVP) receptor. The expression of the vasopressin receptor of type 1a (V1aR) is significantly higher in proliferating myoblasts than in differentiated myotubes. The differentiation-related decrease of V1aR expression was evident both at the mRNA and at the protein level as shown by the reduction of [3H]-AVP binding. However, in L6C5 cells transfected with a synthetic construct containing the luciferase gene driven by the 2 kb upstream region of V1aR, we observed a stimulation of the activity of the promoter when the cells were cultured in differentiative medium. The down-regulation of the V1aR correlated with a decreased half-life of its mRNA (half-life 5.86±0.74 hr in 10% fetal bovine serum [FBS] versus 3.53±0.72 hr in 1% FBS). Cyclosporine A and dexamethasone, but not 5′-azacytidine, treatments of cells in differentiation medium restored the V1aR level to that measured in proliferating L6C5 cells, thus confirming the role of post-transcriptional mechanisms in the modulation of V1aR expression. Taken together, these data show that mRNA stability plays a role in modulating protein expression during the myogenic differentiation process. [ABSTRACT FROM AUTHOR]

Abstract: Proper management of Helicobacter pylori infection in clinical practice – when supported by evidence-based data – is expected to produce substantial cost-efficacy advantages. This consideration has prompted the Cervia Working Group to organise a meeting of experts to update the National Guidelines on the diagnosis and treatment of H. pylori infection in Italy. Recommendations in the new European Guidelines were considered in the National setting, here in the light of factors such as the incidence of gastric cancer and gastric lymphoma, the accessibility to different diagnostic tools, the prevalence of bacterial resistance against antibiotics, and the availability of different drugs. The main revisions in respect to the previous guidelines include H. pylori eradication in non-ulcer dyspepsia patients and in non-steroidal, anti-inflammatory drug users, as well as in patients with idiopathic thrombocytopenic purpura and iron deficiency anaemia. The stool antigen test is now accepted as a valid test for confirmation of H. pylori eradication following therapy. New therapeutic approaches have been recommended for both first- (sequential therapy) and second-line (levofloxacin-based) treatment in our country. [Copyright &y& Elsevier]

Summary: At present, no information exists on the neoplastic potential of the immature hyperproliferative and atypical lesions of the gastric mucosa, which have been recently labeled “indefinite for dysplasia.” In addition, uncertainties still exist concerning the risk contribution of intestinal metaplasia (IM) type and extension, as well as Helicobacter pylori infection. In this study, 471 dyspeptic patients showing IM 10% or higher (median, 40; 25th-75th percentile, 20-60) in antral, angulus, or corpus endoscopic biopsies were submitted to repeated examinations (median, 3; 2-5) over 52 (26-85) months of follow-up, during which 44 neoplastic cases were recorded. IM extension, incomplete, sulfomucin-positive, or CAR5 antigen–positive IM; H pylori infection; and indefinite-for-dysplasia lesions (IDLs), as found at first examination, all showed significant neoplastic potential. However, only IDL, ongoing H pylori infection, and patient''s age retained independent predictive power in a multivariate model. On the other hand, IM extension 20% or higher proved to be more sensitive as first screening parameter for identification of subjects with increased neoplastic risk. We suggest that patients with IM, when infected, should undergo H pylori eradication to reduce their cancer risk; only those bearing IDL or very extensive IM (which strongly correlates with IDL) should be followed up with endoscopies and biopsies. [Copyright &y& Elsevier]

Summary: Weaning from mechanical ventilation could be defined as the gradual process of transferring the respiratory work of breathing from the ventilator to the patient. The primary goal of weaning is timeliness, which implies that weaning should be started neither too late nor too early. Discontinuation of mechanical ventilation and removal of artificial airway are easily obtained in the majority of patients since about 70–80% of the patients are extubated when routine clinical criteria are fulfilled. This, however, is not always the case. In fact, about 20–30% of the patients present a difficult weaning. Patients require mechanical ventilation support when either the ventilatory and/or gas exchange capabilities of their respiratory system fail. This respiratory failure can be the results of impairment between the load imposed on the respiratory system and the capacity of the respiratory muscle to perform this increased work of breathing. The factors that limit the weaning process can be summarized as follows: (1) oxygenation, (2) respiratory load (Table 1) and capacity of the respiratory muscle to accomplish this load, (3) cardiovascular performance, and (4) psychological factors. To quantify these factors a great number of weaning indices have been proposed. None have been demonstrated to be able to predict the weaning success, apart from patients with chronic obstructive pulmonary disease. The probability of remaining on mechanical ventilation is statistically higher in patients undergoing uncontrolled clinical practice when compared to a fixed protocol previously agreed. [Copyright &y& Elsevier]

Abstract: Recent developments in anti-cancer gene therapy suggest that the idea of a magic bullet for cancer may not be a pipe dream. Viral-based anti-cancer vectors for gene therapy have been used preferentially in this regard, but recent results from clinical trials have raised serious concerns as to their safety. For this reason, the development of non-viral vectors able to deliver drugs or suicide genes specifically to cancer cells is of paramount importance. In this context, great interest has been raised by recent reports that several proteins, including viral protein 3 (VP3 or Apoptin) from Chicken Anemia Virus, are capable of selectively killing tumor cells. Intriguingly, VP3''s anti-cancer activity is strongly linked to its ability to localize more efficiently in the nucleus of cancer and transformed cells than that of normal, non-transformed cells with a tumor cell-specific nuclear targeting signal (tNTS) located at the C-terminus of the protein. Clearly, the VP3 tNTS is an exciting prospect to enhance non-viral-mediated cancer cell killing. This review will discuss recent advances in the understanding of the mechanism responsible for VP3 tumor-specific nuclear localization, including its specific phosphorylation, and the implications for the enhancement of anti-cancer therapy. It also proposes alternative strategies to develop tNTSs for anti-cancer therapies. [Copyright &y& Elsevier]

Abstract: Background.: This prospective study examined the appropriate use of colonoscopy in an open-access system with the American Society for Gastrointestinal Endoscopy guidelines and determined whether the American Society for Gastrointestinal Endoscopy guidelines were associated with relevant endoscopic findings. Methods.: In a cohort of 2221 consecutive patients referred for colonoscopy, the proportion of patients who underwent colonoscopy for appropriate indications was prospectively assessed. The relationship between appropriateness and the presence of clinically relevant endoscopic diagnoses was assessed by calculating (1) the positive and negative likelihood ratio of the indications; and (2) the change in the probability of relevant endoscopic diagnoses in the presence of the American Society for Gastrointestinal Endoscopy criteria. Results.: The rate for ‘generally not indicated’ colonoscopies was 37%. Relevant endoscopic diagnoses were present in 28.5% of cases with American Society for Gastrointestinal Endoscopy indications versus 20.1% of patients without appropriate indications. However, the risk of finding relevant diagnoses was significantly increased by American Society for Gastrointestinal Endoscopy criteria application (odds ratio (OR) 1.58; 99% CI 1.20–2.07; p <0.01). Furthermore, in both endoscopic situations (appropriate and not appropriate), the likelihood ratio, positive and negative, varied very little, suggesting a low predictivity for serious pathologies by the appropriate procedure. Conclusions.: The use of an appropriateness evaluation system makes it possible to increase the probability of finding relevant endoscopic diseases. However, the exclusive use of such a system for selecting patients to undergo colonoscopy involves a relatively high risk of colorectal neoplasms going undetected. [Copyright &y& Elsevier]