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Inflammatory bowel diseases (IBD) encompass a group of chronic inflammatory disorders primarily affecting the gastrointestinal tract but capable of impacting various organs, including the eye, with uveitis being the most common ocular condition. We assessed uveitis prevalence and clinical features in a nationwide cohort of pediatric IBD. Among 4229 cases, six patients (four Crohn's disease, one ulcerative colitis, and one unclassified IBD) were identified, resulting in an overall prevalence rate of 141.8 per 100,000 patients. Uveitis onset varied: two before IBD, two after, and two concomitantly. Symptomatic uveitis occurred in 2/6 patients, with anterior involvement in all cases. Median follow‐up was 3 years (interquartile range 2–4.75 years). At the last follow‐up, 5/6 patients exhibited quiescent IBD, while 4/6 had inactive uveitis. One patient had ocular complications. Uveitis is a rare but potentially complicating manifestation of pediatric IBD. Inflammatory bowel diseases (IBD) are systemic disorders affecting primarily the gastrointestinal tract but encompassing a wide range of extraintestinal manifestations.Ocular involvement represents a common extraintestinal manifestation (EIM) in adult IBD, whereas lower prevalence has been reported in pediatric cohorts. Inflammatory bowel diseases (IBD) are systemic disorders affecting primarily the gastrointestinal tract but encompassing a wide range of extraintestinal manifestations. Ocular involvement represents a common extraintestinal manifestation (EIM) in adult IBD, whereas lower prevalence has been reported in pediatric cohorts. In a nationwide pediatric IBD cohort, uveitis prevalence was 141.8 per 100,000 patients (six cases out of 4229 patients).Uveitis onset varies as regards to IBD, with symptomatic ocular EIM occurring in only one out of three cases. At the last follow‐up, most of the patients had quiescent uveitis, albeit one of them had developed ocular complications. In a nationwide pediatric IBD cohort, uveitis prevalence was 141.8 per 100,000 patients (six cases out of 4229 patients). Uveitis onset varies as regards to IBD, with symptomatic ocular EIM occurring in only one out of three cases. At the last follow‐up, most of the patients had quiescent uveitis, albeit one of them had developed ocular complications.

Gossip-based communication protocols are often touted as being robust. Not surprisingly, such a claim relies on assumptions under which gossip protocols are supposed to operate. In this paper, we discuss and in some cases expose some of these assumptions and discuss how sensitive the robustness of gossip is to these assumptions. This analysis gives rise to a collection of new research challenges.

The clinical usefulness of pancreatic elastography (PE) in the assessment of the pancreatic texture before pancreatic resection still remains uncertain. The aims are: to evaluate the value of pancreatic stiffness in both healthy volunteers and patients affected by pancreatic tumor; to evaluate the ability of PE in predicting clinically relevant postoperative pancreatic fistula (CR-POPF). Pancreatic stiffness of healthy subjects was compared with those of pancreatic tumors measuring shear wave velocity (SWV). In the last group, the ability of preoperative SWV in predicting CR-POPF was evaluated using linear regression. Ninety subjects were consecutively enrolled. No difference was found in SWV in the two groups (1.33 ± 0.31 vs 1.26 ± 0.30, p= 0.337). Multivariate analyses showed that male gender was associated with a softer pancreas (OR 0.74, CI 0.55–0.98, p= 0.035). In the 45 patients suitable for a secondary endpoint, the presence of soft pancreas assessed by surgeon’s palpation (OR 61.21; CI 2.14– > 1000; p= 0.016) and preoperative risk score (OR 1.72; CI 1.01–2.96; p= 0.049) was predictors of CR-POPF. SWV showed a trend in predicting CR-POPF. The pancreatic stiffness far to the pancreatic neoplasm is the same as healthy controls. SWV showed a trend in predicting CR-POPF but the clinical utility is limited.

Growing concern surrounds the impact of social media platforms on public discourse1–4and their influence on social dynamics5–9, especially in the context of toxicity10–12. Here, to better understand these phenomena, we use a comparative approach to isolate human behavioural patterns across multiple social media platforms. In particular, we analyse conversations in different online communities, focusing on identifying consistent patterns of toxic content. Drawing from an extensive dataset that spans eight platforms over 34 years—from Usenet to contemporary social media—our findings show consistent conversation patterns and user behaviour, irrespective of the platform, topic or time. Notably, although long conversations consistently exhibit higher toxicity, toxic language does not invariably discourage people from participating in a conversation, and toxicity does not necessarily escalate as discussions evolve. Our analysis suggests that debates and contrasting sentiments among users significantly contribute to more intense and hostile discussions. Moreover, the persistence of these patterns across three decades, despite changes in platforms and societal norms, underscores the pivotal role of human behaviour in shaping online discourse.

This study analyzed the vaginal microbiome profiles in postmenopausal women with and without vulvovaginal atrophy (VVA) and assessed the effect of ospemifene and systemic hormone treatment on the vaginal microbiome of women with VVA. Women with VVA were characterized by a signifi cant reduction of Lactobacillus and a significant increase of bacterial diversity compared to women without VVA; both treatments improved vaginal microbiota, and ospemifene reduced potential harmful bacteria such as Staphylococcus and Clostridium.

Study objectives: (1) To determine the incidence of expiratory flow limitation (FL) at ICU admission, at the time of extubation, and at ICU discharge in intubated patients with COPD receiving [...]

Study objectives: Supplemental oxygen is used in hypoxemic patients with chronic airways obstruction (CAO) because it reduces pulmonary artery pressure and prolongs life. The purpose of this study was to [...]

Adult studies suggest that patients with isolated colonic Crohn disease (L2 CD) exhibit unique characteristics differentiating them from patients with ileo-caecal (L1) CD and ulcerative colitis (UC). We aimed to characterize clinical features and outcomes of paediatric patients with L2. Retrospective data was collected through the Porto Inflammatory Bowel Disease group of the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) on Paediatric patients with L2, L1 or UC at different time-points. Outcome measures included time to first flare, hospital admissions, initiation of anti-tumor necrosis factor-alpha (TNFa) drug, stricture and surgery. Three hundred patients were included: 102 L1, 94 L2 and 104 UC. Rates of hematochezia at presentation were 14.7%, 44.7% and 95.2%, while rates of fever were 12.7%, 26.6% and 2.9%, for patients with L1, L2 and UC, respectively (P< 0.001 for all comparisons). Skip lesions were identified in 65% of patients with L2, and granulomas in 36%, similar to L1 patients. Rates of anti-Saccharomyces cerevisiae antibodies (ASCA) and perinuclear antineutrophil cytoplasmic (pANCA) positivity significantly differed between the three groups: 25.4% and 16.7% for patients with L2, compared with 55.2% and 2.3%, and 1.8% and 52.9% for patients with L1 and UC, respectively. Response rates to exclusive enteral nutrition were comparable between L1 and L2 (78.3–82.4%), as was the response to oral steroids (70.4–76.5%) in the three groups. While times to first flare and admission were similar between groups, patients with L1 were commenced on anti-TNFa earlier. Moreover, stricturing phenotype and need for colectomy were very rare in patients with L2. Significant differences are observed in the clinical presentation and outcomes of Paediatric patients with L2, compared to patients with L1 and UC.

Mucosal biopsy specimens obtained by routine endoscopy from 108 human subjects, including one patient with thiamine deficiency, were incubated at 37 [degrees] C in oxygenated calcium-free Krebs-Ringer solution (pH 7.5) containing tritiated thiamine and [[sup.14.C]]dextran as a marker of adherent mucosal water. The amount of labeled thiamine taken up was measured radiometrically. In subjects with no clinical evidence of thiamine deficiency, 1) thiamine uptake by duodenal mucosa had a hyperbolic time course, reaching equilibrium at 10 min; 2) thiamine concentrations [is less than] 2.5 [Mu]mol/L were taken up predominantly by a saturable mechanism displaying Michaelis-Menten kinetics ([K.sub.m] 4.4 [Mu]mol/L and [J.sub.max] 2.3 pmol [multiplied by] mg wet [tissue.sup.-1] 6 [min.sup.-1]), whereas higher concentrations were taken up by passive diffusion; 3) thiamine transport had different capacities along the gastrointestinal tract (duodenum [much greater than] colon [is greater than] stomach); and 4) thiamine uptake was competitively inhibited in the duodenum by thiamine analogs, albeit with a different order of potency compared with rats, and was blocked by 2,4-dinitrophenol. In the thiamine-deficient patient, the duodenal saturable uptake was increased, with higher [K.sub.m] and [J.sub.max] values. In conclusion, physiologic concentrations of thiamine were transported in human small intestine by a specific mechanism dependent on cellular metabolism, whose transporters appear to be down-regulated.

The interest towards renewable energy resources is increasing, and in particular it concerns wind and hydro powers, where the key point regards their efficient conversion into electric energy. To this end, control techniques can be used to meet this purpose, especially the ones relying on fuzzy models, due to their capabilities to manage nonlinear dynamic processes working in different conditions, and affected by faults, measurement errors, uncertainty and disturbances. The design methods addressed in this paper were already developed and validated for wind turbine plants, and important results can be achieved from their appropriate design and application to hydroelectric plants. This is the key issue of the paper, which recalls some considerations on the proposed solutions, as well as their validation to these energy conversion systems. Note that works available in the related literature that consider both wind and hydraulic energy conversion systems investigate a limited number of common issues, thus leading to little exchange opportunities and reduced common research aspects. Another important point addressed in the paper is that the proposed control design solutions are able to take into account the different working conditions of these power plants. Moreover, faults, uncertainty, disturbance and model-reality mismatch effects are also considered when analyzing the reliability and robustness features of the derived control schemes. To this end, proper hardware-in-the-loop tools are considered to verify and validate the developed control schemes in more realistic environments.

Supplemental Digital Content is available in the text.

Digestive perianastomotic ulcerations (DPAU) resembling Crohn disease lesions are long-term complications of intestinal resections, occurring in children and young adults. They are known to be uncommon, severe and difficult to treat. In the absence of recommendations, we performed a large European survey among the members of the ESPGHAN working group on inflammatory bowel disease (IBD) in order to collect the experience of expert pediatric gastroenterologists on DPAU. Fifty-one patients (29 boys and 22 girls) were identified from 19 centers in 8 countries. Most patients were followed after necrotizing enterocolitis (n = 20) or Hirschsprung disease (n = 11). The anastomosis was performed at a median age (interquartile range) of 6 [1–23] months, and first symptoms occurred 39 [22–106] months after surgery. Anemia was the most prevalent symptom followed by diarrhea, abdominal pain, bloating, and failure to thrive. Hypoalbuminemia, elevated CRP, and fecal calprotectin were common. Deep ulcerations were found in 59% of patients usually proximally to the anastomosis (68%). During a median follow-up of 40 [19–67] months, treatments reported to be the most effective included exclusive enteral nutrition (31/35, 88%), redo anastomosis (18/22, 82%), and alternate antibiotic treatment (37/64, 58%). Unfortunately, persistence of symptoms, failure to thrive, and abnormal laboratory tests at last follow-up in most of patients show the burden of DPAU lacking optimal therapy and incomplete understanding of the pathophysiology.

Regulatory T (Treg) cells are a barrier for tumor immunity and a target for immunotherapy. Using single-cell transcriptomics, we found that CD4+T cells infiltrating primary and metastatic colorectal cancer and non-small-cell lung cancer are highly enriched for two subsets of comparable size and suppressor function comprising forkhead box protein P3+Tregand eomesodermin homolog (EOMES)+type 1 regulatory T (Tr1)-like cells also expressing granzyme K and chitinase-3-like protein 2. EOMES+Tr1-like cells, but not Tregcells, were clonally related to effector T cells and were clonally expanded in primary and metastatic tumors, which is consistent with their proliferation and differentiation in situ. Using chitinase-3-like protein 2 as a subset signature, we found that the EOMES+Tr1-like subset correlates with disease progression but is also associated with response to programmed cell death protein 1–targeted immunotherapy. Collectively, these findings highlight the heterogeneity of Tregcells that accumulate in primary tumors and metastases and identify a new prospective target for cancer immunotherapy.

Mucosal healing (MH) and histological healing (HH) have been recently proposed as a novel treatment target for inflammatory bowel disease (IBD). The aim of the present study was to evaluate real-life achievement of such outcomes in a cohort of pediatric patients with IBD treated with anti-TNF-alpha (ATA) agents. A retrospective analysis was performed on patients affected by IBD who received ATA and were followed up at two referral centers. Incidence and cumulative rates for MH and HH for each group were calculated. Of 170 (105 Crohn's disease [CD] and 65 ulcerative colitis [UC]) patients, 78 with CD and 56 with UC underwent endoscopic re-assessment during the study period. MH was achieved by 32 CD (41%) and 30 UC (53.6%) patients; 26 CD (33.3%) and 22 UC (39.3%) patients achieved HH. MH incidence rate was 19.1/1000 and 47/1000 person-months, whereas HH incidence rate was 15.5/1000 and 34.7/1000 person-months for CD and UC, respectively. Remission at the end of induction was associated with higher MH and HH rates (HR: 2.43, P= 0.049 and HR: 2.94, P= 0.046, respectively) in CD. In UC, adalimumab was associated with lower MH and HH rates (HR: 0.16, P= 0.004 and HR: 0.07, P= 0.003). We reported a real-life experience arising from a large cohort of pediatric IBD who received ATA scheduled treatment. Less than half of patients with CD and only a little >50% of UC patients achieved MH. Microscopical inflammation was observed in 18.8% CD and 26.7% UC patients who achieved MH. Overall, MH and HH rates appear lower compared to previously published data.

Restructuring activities have been necessary during the lockdown phase of the coronavirus disease 2019 (COVID-19) pandemic. Few data are available on the post-lockdown phase in terms of health-care procedures in inflammatory bowel disease (IBD) care, and no data are available specifically from IBD units. We aimed to investigate how IBD management was restructured during the lockdown phase, the impact of the restructuring on standards of care and how Italian IBD units have managed post-lockdown activities. A web-based online survey was conducted in two phases (April and June 2020) among the Italian Group for IBD affiliated units within the entire country. We investigated preventive measures, the possibility of continuing scheduled visits/procedures/therapies because of COVID-19 and how units resumed activities in the post-lockdown phase. Forty-two referral centres participated from all over Italy. During the COVID-19 lockdown, 36% of first visits and 7% of follow-up visits were regularly done, while >70% of follow-up scheduled visits and 5% of first visits were done virtually. About 25% of scheduled endoscopies and bowel ultrasound scans were done. More than 80% of biological therapies were done as scheduled. Compared to the pre-lockdown situation, 95% of centres modified management of outpatient activity, 93% of endoscopies, 59% of gastrointestinal ultrasounds and 33% of biological therapies. Resumption of activities after the lockdown phase may take three to six months to normalize. Virtual clinics, implementation of IBD pathways and facilities seem to be the main factors to improve care in the future. Italian IBD unit restructuring allowed quality standards of care during the COVID-19 pandemic to be maintained. A return to normal appears to be feasible and achievable relatively quickly. Some approaches, such as virtual clinics and identified IBD pathways, represent a valid starting point to improve IBD care in the post-COVID-19 era.

T cell memory relies on the generation of antigen-specific progenitors with stem-like properties. However, the identity of these progenitors has remained unclear, precluding a full understanding of the differentiation trajectories that underpin the heterogeneity of antigen-experienced T cells. We used a systematic approach guided by single-cell RNA-sequencing data to map the organizational structure of the human CD8+memory T cell pool under physiological conditions. We identified two previously unrecognized subsets of clonally, epigenetically, functionally, phenotypically and transcriptionally distinct stem-like CD8+memory T cells. Progenitors lacking the inhibitory receptors programmed death-1 (PD-1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) were committed to a functional lineage, whereas progenitors expressing PD-1 and TIGIT were committed to a dysfunctional, exhausted-like lineage. Collectively, these data reveal the existence of parallel differentiation programs in the human CD8+memory T cell pool, with potentially broad implications for the development of immunotherapies and vaccines.

Sexual and reproductive issues are essential elements of well-being in cisgenders as well as for the transgender population. Gender-affirming hormonal treatments (GAHTs) aim to induce phenotypical changes congruent with the desired gender and subsequent reduction of gender dysphoria. While genital surgical procedures including hysterectomy and/or adenectomy cause permanent loss of ability to conceive, GAHT may induce a varying degree of reversible loss of fertility. For these reasons, transgender men and women need to be counseled concerning contraceptive options and potential effects of treatment on reproductive function before initiating GAHT. The literature reports that sexual activity with genital involvement is performed by less than half of transgender persons who have been sexually active with a partner in the past. Testosterone (T) is the most commonly used compound in transmen and usually leads to amenorrhea within 1–12 months from first administration, however cessation of menses does not mean anovulation. Some studies report cases of unintended pregnancies among transgender men under masculinizing therapy, therefore T treatment cannot be considered a contraceptive option. Currently available contraceptive options have pros and cons in transmen and scarce literature exists on their use. The effects of GAHT on fertility in transwomen are even less well known. Prolonged estrogen exposure induces sperm suppression and morphological changes of the spermatozoa, however the degree of resulting pregnancy protection is unclear. Further research to inform the contraceptive counseling in this population is mandatory.

Inflammatory bowel diseases can occur with a wide range of extraintestinal symptoms, among which pyostomatitis vegetans, that is a rare but almost pathognomonic finding. We report the case of a 9-year-old female patient affected by ulcerative colitis and recently treated for an oral candidiasis, who experienced a relapse in her ulcerative colitis (PUCAI 50), preceded by the return of whitish lesions in the oral cavity, initially misdiagnosed and unsuccessfully treated as candidiasis and then recognized as pyostomatitis vegetans. Bloody diarrhea was treated with oral beclomethasone, with rapid remission of ulcerative colitis and disappearance of pyostomatitis vegetans. After 2 years, ulcerative colitis is in sustained remission with oral mesalamine and pyostomatitis vegetans has not recurred. Pyostomatitis vegetans is considered a marker of ulcerative colitis relapse among adult population, and although very few pediatric cases are described, it is very important to remember it in the differential diagnosis of the oral manifestations and comorbidities of inflammatory bowel diseases.

Assessment of adherence to gluten-free diet in celiac disease (CD) is generally recommended. Few data are available about consequences of transition from the referral center to the general pediatrician (GP) once remission is achieved. Adherence was assessed in patients referred to the GP for an annual basis follow-up, called back for re-evaluation. Immunoglobulin A (IgA) antitissue transglutaminase (anti-tTG) antibodies and the Biagi score (BS) were determined at last follow-up at the referral center (V1), and at re-evaluation (V2). Patients were classified as adherent (BS 3–4, IgA anti-tTG <7?U/mL) and nonadherent (BS 0–2, IgA anti-tTG =7). Scores of adherence were correlated with personal and clinical data. We evaluated 200 patients. Overall, we found good adherence rates in 94.95% of patients at V1 and 83.5% at V2. IgA anti-tTG were negative in 100% at V1 and 96.97% at V2. BS is 3 to 4 in 94.5% at V1 and 84% at V2. Adherence at V2 was significantly worse than V1 (P?

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The interrogation of single cells is revolutionizing biology, especially our understanding of the immune system. Flow cytometry is still one of the most versatile and high-throughput approaches for single-cell analysis, and its capability has been recently extended to detect up to 28 colors, thus approaching the utility of cytometry by time of flight (CyTOF). However, flow cytometry suffers from autofluorescence and spreading error (SE) generated by errors in the measurement of photons mainly at red and far-red wavelengths, which limit barcoding and the detection of dim markers. Consequently, development of 28-color fluorescent antibody panels for flow cytometry is laborious and time consuming. Here, we describe the steps that are required to successfully achieve 28-color measurement capability. To do this, we provide a reference map of the fluorescence spreading errors in the 28-color space to simplify panel design and predict the success of fluorescent antibody combinations. Finally, we provide detailed instructions for the computational analysis of such complex data by existing, popular algorithms (PhenoGraph and FlowSOM). We exemplify our approach by designing a high-dimensional panel to characterize the immune system, but we anticipate that our approach can be used to design any high-dimensional flow cytometry panel of choice. The full protocol takes a few days to complete, depending on the time spent on panel design and data analysis. This protocol describes the design, application and computational analysis of high-dimensional fluorescent antibody panels for flow cytometry. Up to 28 colors can be characterized to study complex cellular populations such as the immune system.

Very few data regarding the use of infliximab in children with very early-onset inflammatory bowel disease (VEO-IBD) have been reported. We aimed to assess the efficacy and the safety of infliximab in children with VEO-IBD compared with older children. Children treated with infliximab were identified within the Italian IBD registry. The primary outcome was the rate of clinical remission at weeks 14 and 54. Secondary outcomes included the proportion of partial clinical response, treatment duration, and incidence of adverse events. Forty-two children with VEO-IBD were compared with 130 children with IBD. Despite significantly higher infliximab withdrawals in VEO-IBD patients during induction (42.9% vs 7.7% p?

Anti-tumor necrosis factor antibodies have led to a revolution in the treatment of inflammatory bowel diseases (IBD); however, a sizable proportion of patients does not respond to therapy. There is increasing evidence suggesting that treatment failure may be classified as mechanistic (pharmacodynamic), pharmacokinetic, or immune-mediated. Data regarding the contribution of these factors in children with IBD treated with infliximab (IFX) are still incomplete. The aim was to assess the causes of treatment failure in a prospective cohort of pediatric patients treated with IFX. This observational study considered 49 pediatric (median age 14.4) IBD patients (34 Crohn disease, 15 ulcerative colitis) treated with IFX. Serum samples were collected at 6, 14, 22 and 54 weeks, before IFX infusions. IFX and anti-infliximab antibodies (AIA) were measured using enzyme linked immunosorbent assays. Disease activity was determined by Pediatric Crohn's Disease Activity Index or Pediatric Ulcerative Colitis Activity Index. Clinical remission, defined as a clinical score <10, was obtained by 76.3% of patients at week 14 and by 73.9% at week 54. Median trough IFX concentration was higher at all time points in patients achieving sustained clinical remission. IFX levels during maintenance correlated also with C-reactive protein, albumin, and fecal calprotectin. After multivariate analysis, IFX concentration at week 14 >3.11 µg/mL emerged as the strongest predictor of sustained clinical remission. AIA concentrations were correlated inversely with IFX concentrations and directly with adverse reactions. Most cases of therapeutic failure were associated with low serum drug levels. IFX trough levels at the end of induction are associated with sustained long-term response.

CD8+ T cells infiltrating tumors are largely dysfunctional, but whether a subset maintains superior functionality remains ill defined. By high-dimensional single cell analysis of millions of CD8+ T cells from 53 individuals with lung cancer, we defined those subsets that are enriched in tumors compared with cancer-free tissues and blood. Besides exhausted and activated cells, we identified CXCR5+ TIM-3– CD8+ T cells with a partial exhausted phenotype, while retaining gene networks responsible for stem-like plasticity and cytotoxicity, as revealed by single cell sequencing of the whole transcriptome. Ex vivo, CXCR5+ TIM-3– CD8+ T cells displayed enhanced self-renewal and multipotency compared with more differentiated subsets and were largely polyfunctional. Analysis of inhibitory and costimulatory receptors revealed PD-1, TIGIT, and CD27 as possible targets of immunotherapy. We thus demonstrate a hierarchy of differentiation in the context of T cell exhaustion in human cancer similar to that of chronically infected mice, which is further shown to disappear with disease progression.

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Purpose: The Memorial Anxiety Scale for Prostate Cancer (MAX-PC) is a self-report questionnaire that was developed in English to assess prostate cancer (PCa)-related anxiety. The aim of this study was to perform a cultural adaptation for the tool to be used in a population of Italian men on active surveillance (AS).Methods: A total of 222 patients with localized PCa who were recruited for the Prostate Cancer Research International: Active Surveillance (PRIAS) protocol completed the MAX-PC. Psychometric analysis was performed to assess reliability indexes. A Spearman rank correlation was used to test the association between MAX-PC scales and other questionnaires and was used for longitudinal analysis.Results: Cronbach coefficients and item to total correlation demonstrated good internal consistency. Some items related to the repetition of the PSA test showed a large floor effect and thus were poorly effective in measuring anxiety for PSA testing in patients on AS. Confirmatory factor analysis partly failed to reproduce the structure of the original version. A modified version of MAX-PC, excluding the items with a large floor effect, was thus considered for AS patients. Factor analysis on this version demonstrated considerable consistency with the presence of 3 subscales: anxiety related to PCa, anxiety related to PSA testing, and anxiety related to the fear of tumor progression. Longitudinal analysis showed an acceptable validity over time. The MAX-PC was correlated with the anxious preoccupation subscale of the Mini-Mental Adjustment to Cancer scale.Conclusions: A slightly modified version of the MAX-PC was developed for use in Italian men on AS. This instrument appears to be a valid and reliable tool that measures anxiety in men with PCa who are enrolled in AS programs.

Water distribution networks (WDNs) are complex combinations of nodes and links, and the current tendency is to modify their topological structure through the closure of isolation valves for monitoring and water quality reasons. For their analysis, several approaches based on graph theory have recently been proposed, mainly considering steady‐state flow conditions. However, in their real functioning, WDNs are continuously subjected to pressure transients generated by maneuvers on regulation devices or by users' activity. This study investigates the application of some metrics from graph theory, already used in the context of steady‐state analysis, for assessing the effects of changes in the topological structure of a network—due for example, to sectorization or branching operations—on its transient response when subjected to maneuvers on devices such as hydrants, pumps, etc. or users' activity. The analysis shows that some connectivity metrics can effectively reflect the dynamic pressure behavior of the network and, thus, provide useful indications for design and management operations taking into account unsteady flow features. Analysis of changes in the transient response of a Water Distribution Network (WDN) due to topological structure modificationsApplication of Connectivity Metrics (CMs) for characterizing the transient response of a WDNAnalysis of the pro and cons of different CMs in reflecting the dynamic behavior of a WDN Analysis of changes in the transient response of a Water Distribution Network (WDN) due to topological structure modifications Application of Connectivity Metrics (CMs) for characterizing the transient response of a WDN Analysis of the pro and cons of different CMs in reflecting the dynamic behavior of a WDN

Purpose To evaluate the outcomes of active surveillance (AS) on patients with low-risk prostate cancer (PCa) and to identify predictors of disease reclassification.Methods In 2005, we defined an institutional AS protocol (Sorveglianza Attiva Istituto Nazionale Tumori [SAINT]), and we joined the Prostate Cancer Research International: Active Surveillance (PRIAS) study in 2007. Eligibility criteria included clinical stage ≤T2a, initial prostate-specific antigen (PSA) <10 ng/mL, and Gleason Pattern Score (GPS) ≤3 + 3 (both protocols); ≤25% positive cores with a maximum core length containing cancer ≤50% (SAINT); and ≤2 positive cores and PSA density <0.2 ng/mL/cm3(PRIAS). Switching to active treatment was advised for a worsening of GPS, increased positive cores, or PSA doubling time <3 years. Active treatment-free survival (ATFS) was assessed using the ­Kaplan-Meier method. Factors associated with ATFS were evaluated with a multivariate Cox proportional hazards model.Results A total of 818 patients were included: 200 in SAINT, 530 in PRIAS, and 88 in personalized AS monitoring. Active treatment-free survival was 50% after a median follow-up of 60 months. A total of 404/818 patients (49.4%) discontinued AS: 274 for biopsy-related reclassification, 121/404 (30%) for off-protocol reasons, 9/404 (2.2%) because of anxiety. Biopsy reclassification was associated with PSA density (hazard ratio [HR] 1.8), maximum percentage of core involvement (HR 1.5), positive cores at diagnostic biopsy (HR 1.6), older age (HR 1.5), and prostate volume (HR 0.6) (all p<0.01). Patients from SAINT were significantly more likely to discontinue AS than were the patients from PRIAS (HR 1.65, p<0.0001).Conclusions Five years after diagnosis, 50% of patients with early PCa were spared from active treatment. Wide inclusion criteria are associated with lower ATFS. However, at preliminary analysis, this does not seem to affect the probability of unfavorable pathology.

Purpose To investigate the presence of regret in patients about having followed an active surveillance (AS) protocol. The secondary aim was to identify variables that influence regret.Methods From February 2006 to May 2014, 204 patients discontinued the AS protocols and were invited to enter the study. Sociodemographic variables were collected at AS enrollment, together with health-related quality of life (Functional Assessment of Cancer Therapy-Prostate version [FACT-P]) and coping (Mini-Mental Adjustment to Cancer). Patients were asked to complete a Treatment Regret Scale as well as the FACT-P questionnaire. Clinical data were gathered, as well as time of stay within the AS protocol, reason for discontinuing AS, kind of post-AS treatment, and time elapsed since AS discontinuation. Questionnaires were completed by 105 patients (51.5% of those who had been invited to enter the study).Results Most of the patients had a low or null degree of regret on the Treatment Regret Scale from 0 to 100 (82/105 patients [78.1%] obtained a score <30, and about 30% of the sample had a score equal to zero). Only 5 patients (4.7%) scored 60 or more, indicating some degree of regret. None of the statistical tests between regret scores and a number of analyzed variables reached significance.Conclusions These results show that the degree of regret about following an AS protocol and after its discontinuation because of entering active treatment was very low. The regret after AS was not related to sociodemographic or clinical factors.

We analyze modularity for a B-M-Etriblock protein designed to self-assemble into antifouling coatings. Previously, we have shown that the design performs well on silica surfaces when Bis taken to be a silica-binding peptide, Mis a thermostable trimer domain, and Eis the uncharged elastin-like polypeptide (ELP), E= (GSGVP)40. Here, we demonstrate that we can modulate the nature of the substrate on which the coatings form by choosing different solid-binding peptides as binding domain Band that we can modulate antifouling properties by choosing a different hydrophilic block E. Specifically, to arrive at antifouling coatings for gold surfaces, as binding block Bwe use the gold-binding peptide GBP1 (with the sequence MHGKTQATSGTIQS), while we replace the antifouling blocks Eby zwitterionic ELPs of different lengths, EZn= (GDGVP-GKGVP)n/2, with n= 20, 40, or 80. We find that even the B-M-Eproteins with the shortest Eblocks make coatings on gold surfaces with excellent antifouling against 1% human serum (HS) and reasonable antifouling against 10% HS. This suggests that the B-M-Etriblock protein can be easily adapted to form antifouling coatings on any substrate for which solid-binding peptide sequences are available.

The elastic energy dissipation coefficient and dynamic elasticity modulus were measured in the 3-4000 Hz frequency range by an inverted torsion pendulum and a vibrating reed technique on nanocrystalline aluminium samples obtained by mechanical attrition. The anelasticity spectra in the 300-700 K range on as-prepared samples with average grain size in the 20-40 nm range strongly depends on low temperature annealing treatments. A relaxational damping peak P1 at 460 K (3Hz) is observed in samples after thermal annealing without appreciable grain growth. A second peak P2 located at higher temperatures occurs when the grain size exceeds 100 nm.

At the Water Engineering Laboratory of the University of Perugia, Italy, a wide experimental program has been carried out in a polymeric pipe network with two 100 × 100 m square loops. The aim of this program is to analyze the dynamic response of the system to transients caused by a change in water consumption. To emphasize such a response, transients are generated by the complete and fast closure of an end‐user, located at the downstream end of a service line. During tests, the combined effect of simultaneous consumers, whose consumption is varied both deterministically and stochastically, has been analyzed. The tests allow examining the propagation of the generated pressure waves within the network for different water consumption variations and end‐user locations. The lessons learnt from the experimental results may help the water utility managers to identify the reasons for the higher frequency of occurrence and severity of faults in some specific portions of water distribution networks apparently “similar” to others where damages are less frequent and severe. Several laboratory transient tests are carried out in a polymeric looped water distribution network (WDN) due to deterministic and stochastic consumption variationsThe results may help the water utilities to identify the reasons for the high occurrence and severity of faults in some portions of WDNsThe reasons for faults may be repetitive and fast consumption changes, especially at night, and a high small‐diameter pipe percentage Several laboratory transient tests are carried out in a polymeric looped water distribution network (WDN) due to deterministic and stochastic consumption variations The results may help the water utilities to identify the reasons for the high occurrence and severity of faults in some portions of WDNs The reasons for faults may be repetitive and fast consumption changes, especially at night, and a high small‐diameter pipe percentage

This paper proposes a data-driven approach oriented to the design of a fault tolerant fuzzy controller for regulating the speed of a Francis turbine included in a hydroelectric system simulated in the Matlab and Simulink environments. The nonlinear characteristics of hydraulic turbine and the inelastic water hammer effects are considered to simulate the dynamic process. This strategy is suggested for enhancing the regulator derivation that could represent an alternative to the standard controllers in typical hydroelectric systems. The controller development requires the knowledge of the dynamic model of the monitored system, which is achieved by means of a fuzzy modelling and identification scheme. This feature of the work, followed by the proposed solution relying on a data-driven approach, represents the key point when on-line implementations are considered for a viable application of the proposed scheme. Moreover, by means of this design scheme, the proposed strategy is also able to provide a fault tolerant controller. In particular, the fault tolerance properties are achieved by using a so-called passive approach. It is assumed that the fault considered in this work affects the electric servomotor used as governor. The performances of the fault tolerant fuzzy controller is compared to that of a PID regulator and an adaptive PID controller scheme already implemented for the simulated hydroelectric system.

Two methods, namely the velocity-area method and the entropy method, for assessing with uncertainty discharge measurements at gauged river sites are analysed and compared; uncertainty is represented through the grey number technique. Two different approaches for the 'greyification' of both methods are presented. In the first approach, the uncertainty affecting each measurement used to estimate the discharge is characterized by means of a grey number: all the grey uncertainty components are then combined through grey mathematics. In the second approach, greyification is applied to the relationship expressing the total uncertainty on the discharge measurement provided by the EN ISO 748 guidelines. Results of the application of the proposed methods to measurement data pertaining to three different gauged sections of the Tiber River, in central Italy, show that the first greyification approach leads to a broader discharge uncertainty estimate with respect to the second. Furthermore, as the greyification approach and the flow area quantification are the same, the velocity-area and entropy methods provide nearly the same estimate of the uncertainty affecting the discharge measurements, i.e., the grey discharges provided by the two methods are very similar. This testifies in favour of the entropy method, which is simpler than the other from an operative viewpoint. [ABSTRACT FROM AUTHOR]

AbstractSybil attacks, in which an adversary forges a potentially unbounded number of identities, are a danger to distributed systems and online social networks. The goal of sybil defense is to accurately identify sybil identities.This article surveys the evolution of sybil defense protocols that leverage the structural properties of the social graph underlying a distributed system to identify sybil identities. We make two main contributions. First, we clarify the deep connection between sybil defense and the theory of random walks. This leads us to identify a community detection algorithm that, for the first time, offers provable guarantees in the context of sybil defense. Second, we advocate a new goal for sybil defense that addresses the more limited, but practically useful, goal of securely white-listing a local region of the graph.

Purpose:Hereditary hemorrhagic telangiectasia (HHT) is an autosomal-dominant vascular dysplasia characterized by telangiectases and arteriovenous malformations. Three causative genes are known: ENG (HHT-1), ACVRL1 (HHT-2), and SMAD4 (mutated in HHT in association with juvenile polyposis). Gastrointestinal bleeding is the most common symptom after epistaxis. The stomach and the duodenum are the main gastrointestinal sites of telangiectases. Our aim was to explore gastrointestinal tract of consecutive HHT patients to assess distribution, number, size, and type of telangiectases in relation to genotype.Methods:HHT patients underwent gastroduodenoscopy, video capsule endoscopy, and colonoscopy. Molecular analysis of ENG and ACVRL1 was performed to identify the disease-causing mutation.Results:Twenty-two patients (13 men; mean age: 59?±?9 years) were analyzed: 7 with HHT-1, 13 with HHT-2, and 2 undefined. Gastrointestinal telangiectases were identified as follows: at gastroduodenoscopy in 86% of HHT-1 patients and in 77% of HHT-2 patients, at video capsule endoscopy in all HHT-1 patients and in 84% of HHT-2 patients, and at colonoscopy in 1 patient for each group. HHT-1 showed multiple telangiectases with a higher prevalence, more relevant in the duodenum.Conclusion:Our data demonstrate extensive involvement of the gastrointestinal tract with a more severe association in HHT-1. Gastroduodenoscopy provides significant information on gastrointestinal involvement, and video capsule endoscopy may be added in selected patients. Colonic polyps/adenomas were identified as occasional findings.Genet Med 16 1, 3–10.

This paper presents an approach based on grey numbers to represent the total uncertainty of a conceptual rainfall-runoff model. Using this approach, once the grey numbers representing the model parameters have been properly defined, it is possible to obtain simulated discharges in the form of intervals (grey numbers) whose envelope defines a band which represents the total model uncertainty. The application to a real case showed that the construction of this band, according to a rigorous application of grey number theory, involves long computational times. However, these times can be significantly reduced using a simplified computing procedure with minimal approximations in the quantification of the simulated grey discharge. Relying on this simplified procedure, the conceptual rainfall-runoff grey model was then calibrated in order to respect a predefined level of model uncertainty, i.e. the band obtained from the envelope of simulated grey discharges had to include an assigned percentage of observed discharges and was at the same time as narrow as possible. Finally, the uncertainty bands were compared with the ones obtained using a well-established approach for characterising uncertainty, the Generalised Likelihood Uncertainty Estimation (GLUE) method. The results of the comparison showed that the proposed approach may represent a valid tool for characterising the total uncertainty of a rainfall-runoff model. [ABSTRACT FROM AUTHOR]

A grey-based technique for characterizing the rating curve uncertainty due to discharge measurement errors and its effect on flood frequency analysis is here presented. On the basis of river stage and discharge measurements, the grey parameters of the rating curve are estimated by using a grey non-linear regression. Commencing with this grey rating curve and a set of annual maximum stages, we show how the probability distribution (here assumed of EV1 type) of the grey annual maximum discharges can be estimated. The grey EV1 distribution can be estimated through two approaches, the first of which directly exploits the grey discharges corresponding to the annual maximum stages, whereas with the second approach two different sets of extreme (crisp) discharges, and therefore two EV1 distributions of extreme (crisp) values which delimit the grey discharges of a given return period, are obtained by considering the lower and upper limits of the grey parameters of the rating curve. The methodology is illustrated using data pertaining to a gauged section of the River Po (Italy). The results show that the first approach yields a wider grey EV1 distribution with respect to that resulting from the second approach: physical justification of this is given. [ABSTRACT FROM AUTHOR]

Adult autoimmune enteropathy (AIE) is a rare cause of malabsorption syndrome unresponsive to dietary restriction. Its diagnostic hallmarks are small-bowel villous atrophy and antienterocyte autoantibodies. Therapy is based mainly on nutritional support and immunosuppression. We treated a 61-year-old woman with corticosteroid-refractory AIE and life-threatening malabsorption syndrome with systemic infusions of autologous, bone marrow–derived, mesenchymal stromal cells (MSCs) as rescue therapy. The MSCs were expanded ex vivo following a previously used Good Manufacturing Practice procedure, and 2 intravenous infusions of 1.8 × 106MSCs/kg body weight were administered 2 weeks apart. Analysis of circulating and mucosal regulatory T-and B-cell numbers, and of serum and secretory immunoglobulin levels, was performed before and after treatment. The MSC infusions were safe and effective, leading to disappearance of disease hallmarks and recovery from the life-threatening condition. Increases in mucosal regulatory T-cell numbers and secretory immunoglobulin levels were also observed. The benefit, however, was transient, and a further MSC infusion resulted in the same short efficacy. This case encourages the use of MSCs to treat patients with life-threatening, corticosteroid-refractory AIE and suggests that MSC infusion can attenuate, albeit transiently, the autoimmune attack.

This paper proposes an innovative procedure for identifying, in the event of accidental or intentional contamination of a water distribution system, the optimal scheduling of activation of a pre-selected set of flow control devices which will serve to minimise the volume of contaminated water consumed by users after the detection of the contaminant in the system. The constraints are represented by the number of available response teams and the maximum speed at which these teams can travel along the roadway. The optimal scheduling of device activation is sought by means of an optimisation process based on a genetic algorithm (GA) which interacts with a mixed integer linear programming (MILP) solver in order to ensure the feasibility of the scheduling identified. The optimisation procedure is coupled to a hydraulic and quality simulator, which enables a calculation of the volumes of contaminated water consumed by users, and a dynamic cache memory, which, by storing information on the system's behaviour as the optimisation process progresses, serves to limit the computational times. The application of the procedure to a highly complex real water distribution system shows that the optimisation process is robust and efficacious and produces a smaller volume of contaminated water consumed by the users than when the activation of all the devices was completed in the shortest amount of time. [ABSTRACT FROM AUTHOR]