Alberto Ferrari

<h2>Summary</h2><h3>Background</h3> There is no evidence that phlebotomy alone is sufficient to steadily maintain haematocrit on target level in low-risk patients with polycythaemia vera. This study aimed to compare the efficacy and safety of ropeginterferon alfa-2b on top of the standard phlebotomy regimen with phlebotomy alone. <h3>Methods</h3> In 2017, we launched the Low-PV study, a multicentre, open-label, two-arm, parallel-group, investigator-initiated, phase 2 randomised trial with a group-sequential adaptive design. The study involved 21 haematological centres across Italy. Participants were recruited in a consecutive order. Participants enrolled in the study were patients, aged 18–60 years, with a diagnosis of polycythaemia vera according to 2008–16 WHO criteria. Eligible patients were randomly allocated (1:1) to receive either phlebotomy and low-dose aspirin (standard group) or ropeginterferon alfa-2b on top of the standard treatment (experimental group). Randomisation sequence was generated using five blocks of variable sizes proportional to elements of Pascal's triangle. Allocation was stratified by age and time from diagnosis. No masking was done. Patients randomly allocated to the standard group were treated with phlebotomy (300 mL for each phlebotomy to maintain the haematocrit values of lower than 45%) and low-dose aspirin (100 mg daily), if not contraindicated. Patients randomly allocated to the experimental group received ropeginterferon alfa-2b subcutaneously every 2 weeks in a fixed dose of 100 μg on top of the phlebotomy-only regimen. The primary endpoint was treatment response, defined as maintenance of the median haematocrit values of 45% or lower without progressive disease during a 12-month period. Analyses were done by intention-to-treat principle. The study was powered assuming a higher percentage of responders in the experimental group (75%) than in the standard group (50%). Here we report results from the second planned interim analysis when 50 patients had been recruited to each group. The trial is ongoing, and registered with ClinicalTrials.gov, NCT03003325. <h3>Findings</h3> Between Feb 2, 2017, and March 13, 2020, 146 patients were screened, and 127 patients were randomly assigned to the standard group (n=63) or the experimental group (n=64). The median follow-up period was 12·1 months (IQR 12·0–12·6). For the second pre-planned interim analysis, a higher response rate in the experimental group was seen (42 [84%] of 50 patients) than in the standard group (30 [60%] of 50 patients; absolute difference 24%, 95% CI 7–41%, p=0·0075). The observed z value (2·6001) crossed the critical bound of efficacy (2·5262), and the stagewise adjusted p value early showed superiority of experimental treatment. Thus, the data safety monitoring board decided to stop patient accrual for overwhelming efficacy and to continue the follow-up, as per protocol, for 2 years. Under the safety profile, no statistically significant difference between groups in frequency of adverse events of grade 3 or higher was observed; the most frequently reported adverse events were neutropenia (four [8%] of 50 patients) in the experimental group and skin symptoms (two [4%] of 50 patients) in the standard group. No grade 4 or 5 adverse events occurred. <h3>Interpretation</h3> Supplementing phlebotomy with ropeginterferon alfa-2b seems to be safe and effective in steadily maintaining haematocrit values on target in low-risk patients with polycythaemia vera. Findings from the current study might have implications for changing the current management of low-risk patients with polycythaemia vera. <h3>Funding</h3> AOP Orphan Pharmaceuticals, Associazione Italiana per la Ricerca sul Cancro

Very high resolution hyperspectral data should be very useful to provide detailed maps of urban land cover. In order to provide such maps, both accurate and precise classification tools need, however, to be developed. In this letter, new methods for classification of hyperspectral remote sensing data are investigated, with the primary focus on multiple classifications and spatial analysis to improve mapping accuracy in urban areas. In particular, we compare spatial reclassification and mathematical morphology approaches. We show results for classification of DAIS data over the town of Pavia, in northern Italy. Classification maps of two test areas are given, and the overall and individual class accuracies are analyzed with respect to the parameters of the proposed classification procedures.

In the last years, a growing amount of evidence has been produced regarding the role of leukocytosis as a risk factor for thrombosis in patients with myeloproliferative neoplasms, predominantly in polycythemia vera (PV) and essential thrombocythemia (ET). Results from epidemiologic studies on this issue, however, are inconclusive. We conducted a systematic review and meta-analysis of articles published in the last 12 years addressing the issue, according to a predefined protocol. Forty-one articles analyzing >30 000 patients met our inclusion criteria and were deemed of acceptable methodologic quality. In addition to data on thrombosis, data were collected on bleeding, hematologic evolution, secondary cancer, and death. The relative risk (RR) of thrombosis in the presence of leukocytosis was 1.59 (95% CI, 1.40-1.80), mainly accounted for by ET (RR, 1.65; 95% CI, 1.43-1.91) and arterial thrombosis (RR, 1.45; 95% CI, 1.13-1.86) subgroups; the effect was not significant in venous thrombosis alone. Sensitivity analyses considering recurrent events as well as white blood cell estimates adjusted or unadjusted for confounding factors confirmed the primary results. In addition, the pooled RR of studies that tested white blood cell counts in time-dependent models suggested a causative effect of leukocytes in the mechanism that triggers thrombosis. The effect of leukocytosis on bleeding (RR, 1.87; 95% CI, 1.26-2.77) and death (RR, 1.89; 95% CI, 1.59-2.23) was confirmed, whereas conclusions on hematologic evolutions and solid tumors were uncertain. To confirm the accuracy of these results, an investigation on individual patient data in a large collective archive of homogeneous patients is warranted.

We report the clinical presentation and risk factors for survival in 175 patients with myeloproliferative neoplasms (MPN) and COVID-19, diagnosed between February and June 2020. After a median follow-up of 50 days, mortality was higher than in the general population and reached 48% in myelofibrosis (MF). Univariate analysis, showed a significant relationship between death and age, male gender, decreased lymphocyte counts, need for respiratory support, comorbidities and diagnosis of MF, while no association with essential thrombocythemia (ET), polycythemia vera (PV), and prefibrotic-PMF (pre-PMF) was found. Regarding MPN-directed therapy ongoing at the time of COVID-19 diagnosis, Ruxolitinib (Ruxo) was significantly more frequent in patients who died in comparison with survivors (p = 0.006). Conversely, multivariable analysis found no effect of Ruxo alone on mortality, but highlighted an increased risk of death in the 11 out of 45 patients who discontinued treatment. These findings were also confirmed in a propensity score matching analysis. In conclusion, we found a high risk of mortality during COVID-19 infection among MPN patients, especially in MF patients and/or discontinuing Ruxo at COVID-19 diagnosis. These findings call for deeper investigation on the role of Ruxo treatment and its interruption, in affecting mortality in MPN patients with COVID-19.

Ruxolitinib is a recommended second-line treatment for the prevention of thrombosis in patients with polycythemia vera who become resistant or intolerant to hydroxyurea; however, evidence regarding its efficacy in terms of thrombosis reduction is uncertain. We searched Medline, Embase, and archives of abstracts from the European Hematology Association and the American Society of Hematology annual congresses from 2014 onward for randomized controlled trials comparing the treatment vs best available therapy (BAT). Our search retrieved 80 records; after screening of abstracts and full text, the total was reduced to 16. Evidence came from 4 randomized controlled trials, including 663 patients (1057 patients per year). We estimated a thrombosis risk ratio of 0.56 for ruxolitinib BAT, corresponding to an incidence of 3.09% and 5.51% patients per year, respectively. The number of thrombotic events reported with ruxolitinib was consistently lower than that with BAT in our sample, but, globally, the difference did not reach significance (P = .098). Hard evidence in favor of ruxolitinib is lacking; a clinical trial on selected patients at high risk of thrombosis would be warranted, but its feasibility is questionable.

<h3>Importance</h3> Women represent two-thirds of patients with Alzheimer disease (AD), and sex differences might affect results of randomized clinical trials (RCTs). However, little information exists on differences in sex as reported in RCTs for AD. <h3>Objective</h3> To assess the ratio of females to males and the reporting of sex-stratified data in large pharmaceutical RCTs for AD. <h3>Data Sources</h3> A search for pharmaceutical RCTs for AD was conducted on September 4, 2019, using ClinicalTrials.gov with the key word<i>Alzheimer disease</i>, and articles related to those trials were identified using the PubMed, Scopus, and Google Scholar databases. Searches were conducted between September 4 and October 31, 2019, and between April 15 and May 31, 2020. <h3>Study Selection</h3> Controlled RCTs that had more than 100 participants and tested the efficacy of drugs or herbal extracts were included. Of 1047 RCTs identified, 409 were published and therefore screened. A total of 77 articles were included in the final analysis, including 56 primary articles on AD, 13 secondary articles on AD, and 8 articles on mild cognitive impairment. <h3>Data Extraction and Synthesis</h3> The location and date of publication; number, sex, and age of patients enrolled; disease severity; experimental or approved status of the drug; and whether the study included a sex-stratified analysis in the protocol, methods, or results were extracted by 1 reviewer for each article, and the meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Data were analyzed using a mixed-effects model. <h3>Main Outcomes and Measures</h3> The mean proportion of women enrolled in the trials and the associations between prespecified variables were analyzed. The proportion of articles that included sex-stratified results and the temporal trends in the reporting of these results were also studied. <h3>Results</h3> In this review of 56 RCTs for AD involving 39 575 participants, 23 348 women (59.0%) were included. The mean (SD) proportion of women in RCTs of approved drugs was 67.3% (6.9%), and in RCTs of experimental drugs was 57.9% (5.9%). The proportion of women in RCTs of experimental drugs was significantly lower than the proportion of women in the general population with AD in the US (62.1%; difference, −4.56% [95% CI, −6.29% to −2.87%];<i>P</i> &lt; .001) and Europe (68.2%; difference, −10.67% [95% CI, −12.39% to −8.97%];<i>P</i> &lt; .001). Trials of approved drugs had a higher probability of including women than trials of experimental drugs (odds ratio [OR], 1.26; 95% CI, 1.05-1.52;<i>P</i> = .02). Both the severity of AD at baseline and the trial location were associated with the probability of women being enrolled in trials (severity: OR, 0.98; 95% CI, 0.97-1.00;<i>P</i> = .02; location in Europe: OR, 1.26; 95% CI, 1.05-1.52;<i>P</i> = .01; location in North America: OR, 0.81; 95% CI, 0.71-0.93;<i>P</i> = .002). Only 7 articles (12.5%) reported sex-stratified results, with an increasing temporal trend (<i>R</i>, 0.30; 95% CI, 0.05-0.59;<i>P</i> = .03). <h3>Conclusions and Relevance</h3> In this systematic review and meta-analysis, the proportion of women in RCTs for AD, although higher than the proportion of men, was significantly lower than that in the general population. Only a small proportion of trials reported sex-stratified results. These findings support strategies to improve diversity in enrollment and data reporting in RCTs for AD.

Abstract In a multicenter European retrospective study including 162 patients with COVID-19 occurring in essential thrombocythemia (ET, n = 48), polycythemia vera (PV, n = 42), myelofibrosis (MF, n = 56), and prefibrotic myelofibrosis (pre-PMF, n = 16), 15 major thromboses (3 arterial and 12 venous) were registered in 14 patients, of whom all, but one, were receiving LMW-heparin prophylaxis. After adjustment for the competing risk of death, the cumulative incidence of arterial and venous thromboembolic events (VTE) reached 8.5% after 60 days follow-up. Of note, 8 of 12 VTE were seen in ET. Interestingly, at COVID-19 diagnosis, MPN patients had significantly lower platelet count ( p &lt; 0.0001) than in the pre-COVID last follow-up.This decline was remarkably higher in ET (−23.3%, p &lt; 0.0001) than in PV (−16.4%, p = 0.1730) and was associated with higher mortality rate ( p = 0.0010) for pneumonia. The effects of possible predictors of thrombosis, selected from those clinically relevant and statistically significant in univariate analysis, were examined in a multivariate model. Independent risk factors were transfer to ICU (SHR = 3.73, p = 0.029), neutrophil/lymphocyte ratio (SHR = 1.1, p = 0.001) and ET phenotype (SHR = 4.37, p = 0.006). The enhanced susceptibility to ET-associated VTE and the associated higher mortality for pneumonia may recognize a common biological plausibility and deserve to be delved to tailor new antithrombotic regimens including antiplatelet drugs.

Targeted contact-tracing through mobile phone apps has been proposed as an instrument to help contain the spread of COVID-19 and manage the lifting of nation-wide lock-downs currently in place in USA and Europe. However, there is an ongoing debate on its potential efficacy, especially in light of region-specific demographics. We built an expanded SIR model of COVID-19 epidemics that accounts for region-specific population densities, and we used it to test the impact of a contact-tracing app in a number of scenarios. Using demographic and mobility data from Italy and Spain, we used the model to simulate scenarios that vary in baseline contact rates, population densities, and fraction of app users in the population. Our results show that, in support of efficient isolation of symptomatic cases, app-mediated contact-tracing can successfully mitigate the epidemic even with a relatively small fraction of users, and even suppress altogether with a larger fraction of users. However, when regional differences in population density are taken into consideration, the epidemic can be significantly harder to contain in higher density areas, highlighting potential limitations of this intervention in specific contexts. This work corroborates previous results in favor of app-mediated contact-tracing as mitigation measure for COVID-19, and draws attention on the importance of region-specific demographic and mobility factors to achieve maximum efficacy in containment policies.

Hydroxyurea is the standard treatment in high-risk patients with polycythemia vera. However, estimates of its effect in terms of clinical outcomes (thrombosis, bleeding, hematologic transformations and mortality) are lacking. We performed a meta-analysis to determine the absolute risk of events in recent cases of patients under hydroxyurea treatment. We searched for relevant articles or abstracts in the following databases: Medline, EMBASE, clinicaltrials.gov, WHO International Clinical Trials Registry, LILACS. Sixteen studies published from 2008 to 2018 reporting number of events using World Health Organization diagnosis for polycythemia vera were selected. Through a random effect logistic model, incidences, study heterogeneity and confounder effects were estimated for each outcome at different follow ups. Overall, 3,236 patients were analyzed. While incidences of thrombosis and acute myeloid leukemia were stable over time, mortality and myelofibrosis varied depending on follow-up duration. Thrombosis rates were 1.9%, 3.6% and 6.8% persons/year at median ages 60, 70 and 80 years, respectively. Higher incidence of arterial events was predicted by previous cardiovascular complication. Leukemic transformation incidence was 0.4% persons/year. Incidence of transformation to myelofibrosis and mortality were significantly dependent on age and follow-up duration. For myelofibrosis, rates were 5.0 at five years and 33.7% at ten years; overall mortality was 12.6% and 56.2% at five and ten years, respectively. In conclusion, we provide reliable risk estimates for the main outcomes in polycythemia vera patients under hydroxyurea treatment. These findings can help design comparative clinical trials with new cytoreductive drugs and prove the feasibility of using critical end points for efficacy, such as major thrombosis.

The main cause of intestinal failure is short bowel syndrome (SBS). The management goal for children with SBS is to promote intestinal adaptation while preserving growth and development with the use of parenteral nutrition (PN). This study evaluated the intestinal absorption rate in children with SBS, focusing on the role of the remnant colon. In addition, the relation between intestinal absorption rate, citrulline concentration, and small bowel length was studied. Thirty-two children with SBS on PN were included. They were divided into 3 groups according to the European Society for Clinical Nutrition and Metabolism (ESPEN) anatomical classification system: type 1 SBS (n = 9), type 2 (n = 13), and type 3 (n = 10). Intestinal absorption rate was assessed by a stool balance analysis of a 3-d collection of stools. Plasma citrulline concentrations were measured and the level of PN dependency was calculated. The total energy absorption rate did not differ significantly between the 3 groups: 68% (61–79% ) for type 1, 60% (40–77%) for type 2, and 60% (40–77%) for type 3 ( P = 0.45). Children with type 2 or 3 SBS had significantly shorter small bowel length than children with type 1: 28 cm (19–36 cm) and 16 cm (2–29 cm), respectively, compared with 60 cm (45–78 cm) ( P = 0.04). Plasma citrulline concentrations were lower in type 3 SBS but not significantly different: 15 µmol/L (11–25 µmol/L) in type 1, 14 µmol/L (7–21 µmol/L) in type 2 , and 9 µmol/L (6–14 µmol/L) in type 3 ( P = 0.141). A multivariate analysis confirmed the role of the remnant colon in providing additional energy absorption. This study demonstrated the importance of the colon as a salvage organ in children with SBS. Plasma citrulline concentrations should be interpreted according to the type of SBS. Efforts should focus on conservative surgery, early re-establishment of a colon in continuity, and preserving the intestinal microbiota.

Abstract Digital biomarkers are defined as objective, quantifiable physiological and behavioral data that are collected and measured by means of digital devices. Their use has revolutionized clinical research by enabling high-frequency, longitudinal, and sensitive measurements. In the field of neurodegenerative diseases, an example of a digital biomarker-based technology is instrumental activities of daily living (iADL) digital medical application, a predictive biomarker of conversion from mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) to dementia due to AD in individuals aged 55 + . Digital biomarkers show promise to transform clinical practice. Nevertheless, their use may be affected by variables such as demographics, genetics, and phenotype. Among these factors, sex is particularly important in Alzheimer’s, where men and women present with different symptoms and progression patterns that impact diagnosis. In this study, we explore sex differences in Altoida’s digital medical application in a sample of 568 subjects consisting of a clinical dataset (MCI and dementia due to AD) and a healthy population. We found that a biological sex-classifier, built on digital biomarker features captured using Altoida’s application, achieved a 75% ROC-AUC (receiver operating characteristic — area under curve) performance in predicting biological sex in healthy individuals, indicating significant differences in neurocognitive performance signatures between males and females. The performance dropped when we applied this classifier to more advanced stages on the AD continuum, including MCI and dementia, suggesting that sex differences might be disease-stage dependent. Our results indicate that neurocognitive performance signatures built on data from digital biomarker features are different between men and women. These results stress the need to integrate traditional approaches to dementia research with digital biomarker technologies and personalized medicine perspectives to achieve more precise predictive diagnostics, targeted prevention, and customized treatment of cognitive decline.

Abstract In the 2016 revised classification of myeloproliferative neoplasms pre-fibrotic primary myelofibrosis (pre-PMF) was recognized as a separate entity, distinct from essential thrombocythemia (ET). Owing that the majority of cases falling in the pre-PMF category were previously diagnosed as ET, one may question about the need to re-evaluate the results of epidemiologic, clinical, and molecular studies, and the results of clinical trials in the two entities. Based on a critical review of recently published studies, pre-PMF usually presents with a distinct clinical and hematological presentation and higher frequency of constitutional symptoms. JAK2V617F and CALR mutations in pre-PMF patients are superimposable to ET, whereas non-driver high-risk mutations are enriched in pre-PMF compared with ET. Thrombosis is not significantly different, whereas bleeding is more frequent in pre-PMF. Median survival is significantly shorter in pre-PMF and 10-year cumulative rates progression to overt myelofibrosis is 0–1% vs. 10–12%, and leukemic transformation is 1–2% vs. 2–6%, in ET and pre-fibrotic-PMF, respectively. Most patients fall in the lower prognostic IPSS group in which observation alone can be recommended. Patients at intermediate risk may require a symptom-driven treatment for anemia, splenomegaly or constitutional symptoms while cytoreductive drugs are indicated in the high-risk category.

Anhedonia is a relevant symptom in depression and schizophrenia. Chronic stress exposure induces in rats escape deficit, disrupts the dopaminergic response to palatable food and the competence to acquire sucrose self-administration (SA), thus configuring a possible model of motivational anhedonia. Repeated lithium administration reverts stress effects and brings back to control values the breaking point (BP) score, a measure of reward motivation. In this study, we tested on this model two antidepressants, imipramine and fluoxetine, and two antipsychotics, haloperidol and clozapine. The dopaminergic response to sucrose consumption was studied in non food-deprived rats in terms of dopamine D1 receptor signaling in the nucleus accumbens shell (NAcS). More specifically, we studied the modifications in dopamine and cAMP-regulated phosphoprotein of Mr 32,000 (DARPP-32) phosphorylation pattern following sucrose consumption. Fluoxetine reverted the escape deficit and showed no effects on dopaminergic response and sucrose SA. Imipramine reverted sucrose SA and dopamine response deficit in half of the rats and the escape deficit in all animals. Haloperidol did not affect stress-induced deficits. Clozapine-treated rats recovered the dopaminergic response to sucrose consumption and the competence to acquire sucrose SA, although they still showed the escape deficit, thus confirming that motivation toward reward may be dissociated from that to punishment escape. These results indicate that imipramine or fluoxetine are not endowed with a rapid onset antianhedonic effect. On the other hand, clozapine treatment showed a motivational antianhedonic activity similar to that observed after lithium treatment.

In behavioral research, data consisting of a per-subject proportion of “successes” and “failures” over a finite number of trials often arise. This clustered binary data are usually non-normally distributed, which can distort inference if the usual general linear model is applied and sample size is small. A number of more advanced methods is available, but they are often technically challenging and a comparative assessment of their performances in behavioral setups has not been performed. We studied the performances of some methods applicable to the analysis of proportions; namely linear regression, Poisson regression, beta-binomial regression and Generalized Linear Mixed Models (GLMMs). We report on a simulation study evaluating power and Type I error rate of these models in hypothetical scenarios met by behavioral researchers; plus, we describe results from the application of these methods on data from real experiments. Our results show that, while GLMMs are powerful instruments for the analysis of clustered binary outcomes, beta-binomial regression can outperform them in a range of scenarios. Linear regression gave results consistent with the nominal level of significance, but was overall less powerful. Poisson regression, instead, mostly led to anticonservative inference. GLMMs and beta-binomial regression are generally more powerful than linear regression; yet linear regression is robust to model misspecification in some conditions, whereas Poisson regression suffers heavily from violations of the assumptions when used to model proportion data. We conclude providing directions to behavioral scientists dealing with clustered binary data and small sample sizes.

ABSTRACT Background: The aim of this study is to compare the performance of antitissue transglutaminase (atTG) chemiluminescence immunoassay (CLIA) with the standard enzyme‐linked immunosorbent assay (ELISA) methods in monitoring celiac children after the start of gluten‐free diet (GFD). Methods: Celiac children diagnosed between 2005 and 2016 at our centre were classified into 2 groups based on serum assay (ELISA vs CLIA) used for atTG monitoring, and were compared on percentage of decrease and time to normalization of atTG on GFD. Results: Among 260 included children, the rate of normalization of atTG levels at 30 months’ follow‐up was 86% and 70% in ELISA and CLIA group, respectively ( P &lt; 0.01). Median time to normalization was 11.7 and 14.7 months in ELISA and CLIA group respectively ( P = 0.003). Marsh score at diagnosis was not associated with time to atTG normalization ( P = 0.770), whereas older age at diagnosis and higher baseline atTG predicted longer time to atTG normalization ( P = 0.01, P &lt; 0.01). Conclusions: The percentage and the time of the atTG normalization in celiac children on GFD should be interpreted according to the utilized assay: at 30 months’ follow‐up children tested by CLIA are less likely to normalize atTG levels compared to those tested by ELISA. Younger age at diagnosis and lower baseline atTG are predictors of earlier atTG normalization, regardless of the adopted assay.

We aimed to evaluate the role of liver biopsy to predict subclinical biliary strictures (BS) and assess the impact of BS on long-term allograft dysfunction following liver transplantation in children (LT). We reviewed all liver biopsies performed from 2012-2018. Percutaneous transhepatic cholangiography (PTC) was performed in patients presenting cholangiolar proliferation on cytokeratin-7 stained sections. We performed 271 biopsies in 161 children (86% with a left lateral segment); 44/161 (27%) presented with diffuse or multifocal cholangiolar proliferation. Among them, a tight BS was confirmed in 38/44 (86%, 24% of total) and it was managed by balloon dilatation. Cholangiolar proliferation showed a positive predictive value (PPV) for BS of 86.4%. Levels of alkaline phosphatase >325 IU/L predicted BS (P = .007). Dilatation of intrahepatic bile ducts on ultrasound was found only in 44% of patients with BS. Following a median follow-up of 9.2 years, only 15/38 (39%) patients resolved the BS. In conclusion subclinical BS is very common and probably underdiagnosed in these patients. Histological evidence of cholangiolar proliferation detectable by cytokeratin-7 immunostain should be preferred to liver function tests and ultrasound to suspect BS. BS in this setting should be regarded as a main cause of long-term allograft dysfunction.

The Pavia University History Museum, which houses historic items mainly connected to the physics and medicine fields, has focused in the past years on new ways to involve its public and to attract new audiences. Among different approaches, digital technologies have proven important to both external and internal communication. Lately, an Augmented Reality application has been made available to visitors, offering in one tool multimedia material of a historical-scientific nature: stories, 3D animations, images and user-generated video storytelling (developed mainly by University students, one of our least present demographics before the App, and younger students, who typically participate in the annual co-creative project). The App was designed to be as non-intrusive and discreet as possible, to preserve the historic ambiance of the museum, to unite social and educational aspects, to register user behaviour and to make the museum experience more vibrant and active and therefore captivating.

(1) Background: Despite progression in surgical techniques and immunological treatments, hepatic artery (HA) thrombosis and stenosis still develop as an early or late liver transplant (LT) complication. We aimed to compare superb microvascular imaging (SMI) with conventional Doppler imaging (CDI) in the assessment of HA in a cohort of pediatric patients undergoing follow-up ultrasound (US) for LT. (2) Methods: This prospective, observational study included 73 pediatric LT recipients (median age, 7 years; IQR, 5.8 years; 35 females) who underwent US during LT follow-up from March to December 2019. For each examination, CDI and SMI were separately assessed in terms of HA visibility and spectral waveform morphology (SWM). The former was scored based on HA discrimination from the blooming signal of the surrounding vessels, as follows: 0, not visible; 1, majority course hardly distinguishable; and 2, majority course clearly distinguishable. The latter was scored on a two-point scale: 0, combined venous and arterial SWM, and 1, pure arterial SWM. The patient's overall score was finally calculated by adding the two individual scores. (3) Results: Both the absolute scores and frequency of overall scores equal to 3 (maximum global score) were higher using SMI compared with CDI. The median overall score was 3 for SMI and 2 for CDI (p = 0.011; IQR = 1). An overall score equal to 3 was obtained in 74% and 49.3% of the study population using SMI and CDI, respectively (p = 0.002). This was attributable to a better score in HA visibility (p = 0.007). (4) Conclusions: SMI has shown promise for assessing HA in pediatric LT recipients, possibly serving as a complementary non-invasive tool of CDI in everyday practice.

Background Kasai portoenterostomy (KPE) is the preferred treatment for biliary atresia (BA) patients. It has been shown that the center caseload of KPE impacts on native liver survival. We aimed to define the impact of KPE caseload on complications at the time of liver transplantation (LT). Methods Retrospective data collection of LT for BA performed in our tertiary center between 2010 and 2018. The patients were grouped according to the caseload of the center that performed KPE: Group A (≥5 KPE/year) and Group B (<5 KPE/year). We analyzed total transplant time (TTT), hepatectomy time, amount of plasma and red blood cell (RBC) transfusions, occurrence of bowel perforations at LT. Results Among 115 patients, Group A (n 44) and Group B (n 71) were comparable for age, sex, PELD score, TTT. The groups differed for: median hepatectomy time (57 min, IQR = 50–67; vs 65, IQR 55–89, p = 0.045); RBC transfusions (95 ml, IQR 0–250; vs 200 ml, IQR 70–500, p = 0.017); bowel perforations (0/44 vs 15/71, p = 0.001). One-year graft loss in Group A vs Group B was 1/44 vs 7/71 (p = 0.239), whereas deaths were 0/44 vs 5/71 respectively (p = 0.183); 5/15 patients who had a perforation eventually lost the graft. Conclusions This study found an association between KPE performed in low caseload center and the incidence of complications at LT. These patients tend to have a worse outcome. The centralization of KPE to referral center represents an advantage at the time of LT. Mini abstract We studied the impact of Kasai portoenterostomy (KPE) caseload on complications at the time of liver transplantation (LT), in 115 patients. We found an association between KPE performed in low caseload center and increased bowel perforations and blood transfusions. We suggest to centralize to experienced center all children requiring KPE.

This paper is devoted to urban hyperspectral remote sensing. Very high resolution hyperspectral data are used to provide detailed maps of urban land cover, exploiting different classification tools. In particular, multiple classifications and spatial refinement step are used to improve the mapping accuracy. We show results on DAIS data over the town of Pavia, Northern Italy. The four flight lines over the area, kindly provided by DLR in the framework of the HySens project, are partially overlapping. This helps, besides the test of the classification procedure here presented, even to understand the advantages of combining different views of the same area.

Helicobacter pylori (HP) infection is endemic worldwide. The proposed treatment is expensive and there are few reports regarding reinfection rates in Brazil. The aim of this study was to compare the eradication rates obtained with two therapeutic options and to evaluate reinfection one year after treatment. This was a prospective randomized trial with 55 patients. Thirty-nine patients had active duodenal ulcer (DU) and 16 non-ulcer dyspepsia (NUD), and all tested positive for HP. Diagnosis was based on at least two positive tests: ultrarapid urease test, histology and/or culture. Patients were randomized to two groups: group OMC treated with 40 mg omeprazole (once a day), 500 mg metronidazole and 250 mg clarithromycin (twice daily) for 7 days, or group NA treated with 300 mg nizatidine (once a day) and 1000 mg amoxicillin (twice daily) for 14 days. Those patients in whom HP was eradicated were followed up for one year to evaluate reinfection. Twenty-five patients were randomized for OMC and 30 for NA. HP eradication occurred in 20/25 patients (80%) treated with OMC and 13/30 (43%) treated with NA (P = 0.01). After reallocation because of initial treatment failure, the overall eradication rate was 44/51 patients (86%). After an average follow-up of one year, we evaluated 34 patients (23 with DU and 11 with NUD). Reinfection occurred in 3/34 patients (7.6%). We conclude that OMC is effective for HP eradication, and that NA should not be used. Reinfection occurs in 7.6% of the patients in the first year after eradication.

The μ-opioid receptor (MOR) and dopamine D1 receptor are co-expressed in the medium spiny neurons of striatal areas and the signaling pathways activated by these two receptors are in functional competition. However, in certain conditions an integrated response mediated by the dopamine D1 receptor transduction system is observed. In mice, morphine administration induces hypermotility and this response has been described in terms of a β-arrestin2-dependent mechanism that favors prevalent dopamine D1 receptor activation. In rats, acute morphine administration induces hypermotility only when the animals are food-deprived (FD). We aimed to further investigate the functional interaction between the MOR and dopamine D1 receptors in striatal areas and we studied the effects of acute pharmacological MOR stimulation on motility and nucleus accumbens shell (NAcS) dopamine D1 receptor signaling in control rats and rats with reduced β-arrestin2 expression in the NAcS, either non food-deprived (NFD) or FD. Motility and dopamine D1 receptor signaling increased only in FD rats in a β-arrestin2-dependent way. Moreover, FD rats showed a β-arrestin2-dependent increase in the levels of MOR-dopamine D1 receptor heteromeric complexes in the NAcS. Sucrose consumption is accompanied by release of endogenous opioids and dopamine in the NAcS. We then examined MOR-dopamine D1 receptor interactions after sucrose consumption. Sucrose increased NAcS dopamine D1 receptor signaling in NFD and FD rats, and a reduction in β-arrestin2 expression prevented this effect selectively in FD rats. These results show the β-arrestin2-dependent prevalence of dopamine D1 receptor signaling in response to acute morphine or sucrose consumption elicited by food deprivation in rats.

Abstract Objectives Pulmonary hypertension (PH) is commonly reported in Philadelphia‐chromosome negative myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). PH may be diagnosed directly by right heart catheterization (RHC) or estimated by transthoracic echocardiography (TTE). Survival is shortened by PH but despite the potential significance of PH to management and prognosis of MPN, estimates of its prevalence in MPNs vary and risk factors for the condition are poorly established. We performed a systematic review and meta‐analysis of available studies to fill this void. Methods We searched EMBASE, MEDLINE, and Clinicaltrials.gov for the terms “pulmonary hypertension,” “myeloproliferative disorders,” “polycythemia vera,” “essential thrombocythemia,” and “myelofibrosis.” We restricted analysis to the 1999‐2019 window to improve uniformity of MPN diagnostic criteria. We retrieved 221 records and, after abstract and full‐text screening, identified 17 papers meeting criteria for inclusion in our meta‐analysis. A modified Newcastle‐Ottawa scale was used to assess quality. Results Results for 935 patients were available, 309 of these having PH (33%). Using logistic mixed‐effect regression, we found that diagnosis mode (RHC vs TTE) and MPN duration influenced PH prevalence. Studies employing predominantly TTE yielded prevalence estimates ~5‐fold higher than those using RHC (35% vs 7.2%). We identified MF and duration of MPN as significant risk factors for development of PH. Conclusions Prevalence of PH in MPNs is poorly understood with estimates ranging from 3.8% to 58%. Patients with MF and longer duration of disease seem at particularly high risk and should be carefully monitored for PH.

Abstract Background and study aims The real burden of urgent endoscopy in children has not been studied yet. Our aim was to evaluate the need for urgent endoscopy in children. Patients and methods Information was collected about all the calls that were received during the 24 hour on-call shift for pediatric endoscopy in the region of Ile-de-France (12.1 million inhabitants) during a 6 months period (February-July 2017). Results A total of 237 calls (19 calls/y/100,000 children) were collected regarding children of an average age of 3.2 years (range 2 days-18 years). Most of the calls (68 %) were for foreign body ingestions. Gastroscopy was required in 32 % of children: 24 % of those calling for foreign body ingestion, 48 % for gastrointestinal bleeding, 63 % for caustic ingestions (P = 0.01). The average time between the call and the urgent endoscopy were below the international recommendations for each situation. Conclusions Calling the endoscopist seems to have become a recurrent practice, although in most cases, urgent endoscopy did not appear necessary, especially for foreign body ingestion. This organization of pediatric endoscopy on call was able to guarantee the performance of urgent endoscopy in adequate timing for a highly populated region.

Objective: To predict the 3-months mortality in permanently bedridden medical non-oncologic inpatients.Patients and Methods: 2788 consecutive patients admitted in 5 Italian Internal Medicine units from January 2016 through January 2017 were prospectively screened; 644 oncologic patients were excluded; 2144 non-oncologic patients (1021 female) were followed-up for mortality for 6 months.Main outcome was 3-months mortality in permanently bedridden inpatients with at least 2 of: creatinine clearance < 35 ml/min; albumin < 2.5 g/dl; at least 2 hospital admissions in the previous 6 months.Advanced dementia and dysphagia were also recorded.Results: Mean age of the 2144 patients was 73.9 (SD, 14.9) years; 374 (17%) were permanently bedridden, 435 (20%) had a creatinine clearance < 35 ml/min, 217 (10%) albumin < 2,5 g/dl, 112 (5%) at least 2 hospital admissions in the previous 6 months.Seventy-seven (4%) patients were permanently bedridden with at least 2 of the above mentioned items, and 48 of them died within 3 months (62%) (p < 0.001;95% CI 51-73%).Regression coefficients of the variables associated with 3months mortality in multivariate analysis in 998 patients of unit 1 (training cohort) were used to create a simple score, which was validated in the 1146 patients of the other units (validation cohort) and performed well in predicting the 3-months mortality (https://www.ejcrim.com/beclap/).Conclusions: Approximately two out of three non-oncologic medical patients permanently bedridden having 2 of the abovementioned items are dead 3 months after index admission; a simple score including bedridden status, creatinine clearance, albumin, dysphagia, age and sex may help discuss management priorities.

Abstract Targeted contact-tracing through mobile phone apps has been proposed as an instrument to help contain the spread of COVID-19 and manage the lifting of nation-wide lockdowns currently in place in USA and Europe. However, there is an ongoing debate on its potential efficacy, especially in the light of region-specific demographics. We built an expanded SIR model of COVID-19 epidemics that accounts for region-specific population densities, and we used it to test the impact of a contact-tracing app in a number of scenarios. Using demographic and mobility data from Italy and Spain, we used the model to simulate scenarios that vary in baseline contact rates, population densities and fraction of app users in the population. Our results show that, in support of efficient isolation of symptomatic cases, app-mediated contact-tracing can successfully mitigate the epidemic even with a relatively small fraction of users, and even suppress altogether with a larger fraction of users. However, when regional differences in population density are taken into consideration, the epidemic can be significantly harder to contain in higher density areas, highlighting potential limitations of this intervention in specific contexts. This work corroborates previous results in favor of app-mediated contact-tracing as mitigation measure for COVID-19, and draws attention on the importance of region-specific demographic and mobility factors to achieve maximum efficacy in containment policies.

Background. Percutaneous transhepatic cholangiography (PTC) is an established treatment in the management of biliary strictures. The aim of our study was to determine the incidence of PTC-related infectious complications in transplanted children, and identify their precise aetiol-ogy. Methods. We retrospectively reviewed all PTC performed from January 2017 to October 2020 in our center. Before the procedure, all patients received antibiotic prophylaxis defined as first line, while second line was used in case of previously microbiological isolation. Cholangitis was defined as fever (&gt;38.5°) and elevated inflammatory markers after PTC, while sepsis included hemodynamic instability in addition to cholangitis. Results. One hundred and fifty-seven PTCs from 50 pediatric recipients were included. The overall incidence of cholangitis and sepsis after PTC was 44.6% (70/157) and 3.2% (5/157), respectively, with no fatal events. Blood cultures yielded positive results in 15/70 cases (21.4%). Enterococcus faecium and Pseudomonas aeruginosa were the most common isolated pathogens. Multidrug-resistant (MDR) pathogens were found in 11/50 patients (22%). Conclusion. PTC is associated with a relatively high rate of post-procedural cholangitis, although with low rate of sepsis and no fatal events. Blood cultures allowed to find a precise aetiology in roughly a quarter of the cases, showing prevalence of Enterococcus faecium and Pseudomonas aeruginosa.

Abstract Background One of the major challenges in Alzheimer’s disease (AD) is the identification of individuals at the earliest stages, who might benefit from disease‐modifying therapies. People presenting with clinical syndromes such as subjective cognitive decline (SCD), or mild cognitive impairment (MCI) harboring AD pathology are at high risk of cognitive worsening over time. Digital biomarkers could enable early, accurate and accessible diagnoses, and thus, streamline the patient journey to specialized care. Methods We included 102 participants from the β‐AARC cohort, established at the Barcelonaβeta Brain Research Center (BBRC), consisting of individuals seeking medical advice on their cognitive performance, mostly in primary care settings. Participants were classified as SCD (n = 94; age 66.4 [6.2] years; MMSE score 28.5 [1.3]) or MCI (n = 8; age 70.1 [4.6] years; MMSE score 26.3 [2.8]) after objective cognitive testing (Table 1). All had core CSF biomarkers (Aβ42/40, ptau‐181, t‐tau) determined with the Lumipulse automated platform (Fujirebio). Participants completed a digital cognitive assessment with Altoida’s research medical device. The device evaluates cognitive and functional impairment based on motoric and augmented reality tasks that simulate activities of daily living. These tasks evaluate multi‐modal features, including micro‐movements, micro‐errors, speed, reaction times, or navigation trajectories, which are used to train specific machine‐learning models, termed Digital Neuro Signature (DNS). The DNS‐MCI algorithm identifies cognitively normal individuals from those presenting with cognitive impairment. We compared DNS‐MCI scores across study groups and explored correlations with core AD biomarkers. Result DNS‐MCI scores were significantly lower in individuals presenting with MCI compared with SCD (p&lt;0.05; Figure 1A). Participants who were Aβ+ based on the Aβ42/40 ratio (cut‐off ≤0.062) showed significantly lower DNS‐MCI scores compared with those who were Aβ‐ (p&lt;0.001 for the whole sample; and p&lt;0.05 for the SCD subsample (Figure 1B)). DNS‐MCI scores showed significant modest correlations with Aβ42/40, ptau‐181/Aβ42, ptau‐181 and t‐tau biomarkers (Figure 2). Conclusion Digital biomarkers identified differences in cognitive performance between MCI/SCD and Aβ+/Aβ‐ participants in a cohort with cognitive complaints seeking medical advice. DNS‐MCI scores correlated with core CSF AD biomarkers. This work has received support from the Alzheimer’s Drug Discovery Foundation (grant #GDADB‐201906‐2018897) to Ioannis Tarnanas .

Forty patients with irritable bowel syndrome were randomly allocated to treatment with octylonium bromide (20 mg TID) or cimetropium bromide (50 mg BID) in a double-blind trial lasting for six weeks. Drugs were taken before meals, according to a double-blind schedule. Clinical evaluations were made of digestive and other symptoms, objective findings (pain at palpation, contracted colon, tympanites), and overall effectiveness of treatment. Statistically significant decreases in severity of abdominal pain and subjective scores for bowel habits were obtained in both groups. The only statistically significant differences between treatments were in nondigestive symptoms (asthenia, palpitations, tremor, headache, etc.), which improved more in the cimetropium bromide group. No severe side effects were observed in either treatment group.

ABSTRACT Objectives and study: There is a large interobserver variability in evaluating mucosal lesions of inflammatory bowel disease (IBD), especially in pediatric patients. This multicenter prospective observational study aims to evaluate interobserver agreement (IOA) among pediatric endoscopists in assigning validated IBD endoscopic scores in children. Methods: Fifteen videos of follow‐up ileocolonoscopies in children with IBD were recorded and selected as cases. Eleven pediatric endoscopists from different centers blindly evaluated all videos and calculated scores: either Ulcerative Colitis Endoscopic Index of Severity (UCEIS) or Simple Endoscopic Score for Crohn Disease (SES‐CD). Scores from all reviewers were compared in order to calculate IOA for general videos and specific sections. Scores from an expert adult reader were used to calculate possible reviewer's characteristics affecting scores’ reliability. Results: Intraclass correlation was 0.298 (95% confidence interval [CI]: 0.13–0.55) for ulcerative colitis (UC) and 0.266 (0.11–0.52) for Crohn disease (CD). When a disease activity categorization was adopted (remission, mild, moderate, severe activity) Fleiss kappa coefficient was 0.408 (0.29–0.53) for UC and 0.552 (0.43–0.73) for CD. When stratified by item, vascular pattern of UC was the most reliable item IC: 0.624 (0.321–0.854). In multivariable analysis, none of the reviewer's characteristics affected the readers’ errors. Conclusions: This multicenter study shows low agreement among pediatric endoscopists in evaluating endoscopic scores in children with IBD. By using disease activity categorization, agreement slightly increased, mostly for CD. All readers showed a low‐grade concordance with the expert adult gastroenterologist's evaluations. Future‐specific training programs should be considered to increase IOA in using IBD endoscopic activity scores.

Twenty-two chronic acoholic patients were assessed by neurologic examination and muscle biopsy. The patients manifested proximal muscular weakness to a variable extent. One case presented as an acute bout of myopathy, according to the Manual Muscle Test, MMT. The most prominent histologic feature observed was muscle atrophy (95.3%) better evidenced through the ATPase stain with the predominance of type II A fibers (71.4%). Lack of the mosaic pattern (type grouping) seen in 76% of the cases and an important mitochondrial proliferation with intrasarcoplasmatic lipid accumulation in 63% of the patients. In case of acute presentation of muscle weakness the. pathological substrate is quite different, i.e. presence of myositis mainly interstitial characterized by lymphoplasmocytic infiltrate and several spots of necrosis like Zencker degeneration. Based on histologic criteria, our data suggest that: the main determinant of muscle weakness seen in chronic alcoholic patients is neurogenic in origin (alcoholic polineuropathy); the direct toxic action of ethanol under the skeletal muscle is closely related to the mitochondrial metabolism; the so-called acute alcoholic myopathy has probably viral etiology.

The ileal protrusion into the lumen of the large intestine was studied in 9 patients (8 adults and 1 girl), 6 females and 3 males, all Brazilians and Caucasians. One of the patients resulted to have no disease, whereas in the others was confirmed the suspected diverticulosis, non specific ulcerative colitis, polyposis, regional ileitis or tuberculosis. In all cases the papillary and bilabial types of the termination of the ileum was documented by endoscopic photography, justifying the change of the expression "Bauhin's ileocecal valve" to that of "eminentia ilealis". Even in cases (one with regional ileitis and the other with tuberculosis) in which the disease altered the eminentia ilealis, it was possible to recognize the ileal papilla. Endoscopy confirmed direct, in vivo observations of ileal papilla, excluding the influence of the surgical procedure (incision and exteriorization in cases of cecostomy) in the morphological aspect of the normal eminentia ilealis.

Emollients play an important role in the management of atopic dermatitis (AD). The aim of this study was to evaluate the efficacy and the “steroid-sparing” activity of an emollient cream (Xanthena® cream) in patients with mild to moderate AD. Patients were asked to apply twice a day for 7 days a cream containing hydrocortisone butyrate on the lesionai skin and then to apply Xanthena® cream only on the left side of affected areas. During the 2-month study period, the use of the corticosteroid cream was resumed in case of flare-up in any side. The results obtained show significant differences of both the total severity score and the intensity of each symptom and sign of AD between the skin areas treated with Xanthena® cream and the control areas (P&lt;0.05); a relevant reduction of steroid requirement was also noted in correlation with the use of this emollient cream (P&lt;0.05). A significant improvement was observed even after the first month of therapy for most symptoms, except for excoriations/fissuring, oozing/crusting and burning which improved only at 2 months. Treatment was well-tolerated by the majority of patients; adverse local reactions, mostly transient and of mild intensity, were observed in 7% of cases.

In behavioral and psychiatric research, data consisting of a per-subject proportion of "successes" and "failures" over a finite number of trials often arise. This kind of clustered binary data are usually non-normally distributed, which can cause issues with parameter estimation and predictions if the usual general linear model is applied and sample size is small. Here we studied the performances of some of the available analytic methods applicable to the analysis of proportion data; namely linear regression, Poisson regression, beta-binomial regression and Generalized Linear Mixed Models (GLMMs). We report the conclusions from a simulation study evaluating power and Type I error rates of these models in scenarios akin to those met by behavioral researchers and differing in sample size, cluster size and fixed effects parameters; plus, we describe results from the application of these methods on data from two real behavioral experiments. Our results show that, while GLMMs and beta-binomial regression are powerful instruments for the analysis of clustered binary outcomes, linear approximation can still provide reliable hypothesis testing in this context. Poisson regression, on the other hand, can suffer heavily from model misspecification when used to model proportion data. We conclude providing some guidelines for the choice of appropriate analytical instruments, sample and cluster size depending on the conditions of the experiment.

1. Helicobacter pylori (formerly Campylobacter pylori) is now recognized as an etiological factor in gastritis and duodenal ulcers and probably also gastric ulcers. Eradication of the bacteria is fundamental to avoid ulcer relapse. Although bismuth salts have been shown to be effective for treatment, they are not commercially available in Brazil. 2. We report an attempt to treat patients with Helicobacter pylori-associated gastritis with ampicillin (1000 mg twice daily for one month) and compare the results with the conventional treatment used in Brazil (ranitidine, 300 mg daily for one month) and with a combination of the two drugs. We studied 44 patients with histologically confirmed gastritis and with Helicobacter pylori, who were examined at the beginning and after one month of treatment. 3. Ampicillin associated with ranitidine was better than ampicillin or ranitidine alone for the treatment of gastritis. Although ampicillin may be more efficient in patients with lower acid output we did not find a statistically significant difference between these two groups (ampicillin vs drug combination), perhaps owing to the small number of patients studied. When ampicillin was combined with ranitidine there was 25% normalization of the histological picture of the gastric mucosa. 4. We conclude that ampicillin in combination with ranitidine may be a useful treatment for Helicobacter pylori-associated gastritis.

Shannon entropy is being increasingly used in biomedical research as an index of complexity and information content in sequences of symbols, e.g. languages, amino acid sequences, DNA methylation patterns and animal vocalizations. Yet, distributional properties of information entropy as a random variable have seldom been the object of study, leading to researchers mainly using linear models or simulation-based analytical approach to assess differences in information content, when entropy is measured repeatedly in different experimental conditions. Here a method to perform inference on entropy in such conditions is proposed. Building on results coming from studies in the field of Bayesian entropy estimation, a symmetric Dirichlet-multinomial regression model, able to deal efficiently with the issue of mean entropy estimation, is formulated. Through a simulation study the model is shown to outperform linear modeling in a vast range of scenarios and to have promising statistical properties. As a practical example, the method is applied to a data set coming from a real experiment on animal communication.

Shannon entropy is being increasingly used in biomedical research as an index of complexity and information content in sequences of symbols, e.g. languages, amino acid sequences, DNA methylation patterns and animal vocalizations. Yet, distributional properties of information entropy as a random variable have seldom been the object of study, leading to researchers mainly using linear models or simulation-based analytical approach to assess differences in information content, when entropy is measured repeatedly in different experimental conditions. Here a method to perform inference on entropy in such conditions is proposed. Building on results coming from studies in the field of Bayesian entropy estimation, a symmetric Dirichlet-multinomial regression model, able to deal efficiently with the issue of mean entropy estimation, is formulated. Through a simulation study the model is shown to outperform linear modeling in a vast range of scenarios and to have promising statistical properties. As a practical example, the method is applied to a data set coming from a real experiment on animal communication.

Purpose or ObjectiveThis study aimed to evaluate suitability of 4DCT and VMAT planning for lung patients with irregular breathing.Prior 4DCT studies advise caution when imaging such patients, but no studies have evaluated dosimetric quality of treatment.Locally these patients currently receive 3DCT and conformal planning.

Background: Hydroxyurea (HU) is the recommended first line therapy in high risk polycythemia vera (PV) based on the results of PVSG protocol 08. In this prospective observational study, HU was more effective in reducing the rate of thrombotic events in 51 patients in comparison with historical controls treated with phlebotomy (PHL) alone. Since then, very few studies confirmed these results. Recently, a propensity score analysis of patients enrolled in the ECLAP trial documented superiority of HU in reducing thrombosis compared to PHL only. HU was compared to Interferon (IFN) in three recent randomized controlled trials in PV; unfortunately, primary end-point of these trials was not the reduction of vascular complications but only hematological response, which is not deemed a valid surrogate of vascular events. Aims: We performed a meta-analysis to determine the absolute risk of thrombosis, bleeding, acute myelogenous leukemia (AML) and myelofibrosis (MF) in contemporary patients (2008–2018) under HU treatment. Methods: We searched for relevant articles or abstracts in the following databases: Medline, EMBASE, clinicaltrials.gov, WHO International Clinical Trials Registry, LILACS. Sixteen out of 429 published studies reporting number of events using WHO diagnostic classification for PV, met the criteria of our study protocol (registered in PROSPERO; number CRD42018117814). Through a random effect logistic model, incidences, study heterogeneity and effects of confounders were estimated for each outcome at different follow-ups. Results: Events were collected in 3,236 PV patients, during a mean follow-up ranging from 0.3 to 12.4 years. Thrombosis: Overall major thrombosis incidence (n = 469) was about 3% per year, obtained by pooling event rates from each study. In meta-regression analysis accounting for study-specific confounders such as median age, antithrombotic therapy, cardio-vascular risk factors and history of thrombosis, a slightly lower estimate of 2.8%.was found. This rate did not change over follow-up time, as shown by a comparison between a logistic and a negative binomial model, and depended on age. Annual estimates of major thrombosis in patients with a median age of 60, 70 and 80 years were 1.6%, 3.6% and 6.8% respectively. This incidence is approximately 10-fold higher than the one estimated in the general population. Bleeding: Based on 88 events over 1,485 patients, bleeding pooled incidence was 1% per year, independently of follow-up duration and antithrombotic therapy, as shown by meta-regression. Hematological transformations and mortality: Annual rate of AML (n = 63) was fairly constant over time and the cumulative 10-year incidence was about 4% (0.4% patients/year). In contrast, rate of evolution into MF (n = 157), as predicted by meta-regression, increased steeply after 5 years of follow-up. In the 0–5/5–10 years of follow-up the average annual rate of MF evolution was 1.0% and 5.1% respectively. Mortality (n = 522) followed a similar pattern as MF. Estimates were 2.4%, 12.6% and 56.2% at 1, 5 and 10 years respectively. Summary/Conclusion: The results of this meta-analysis can be a valid reference for patient communication and counseling, and also constitute a help for sample size calculations in future comparative clinical trials adopting hard efficacy endpoints (thrombosis) in selected populations.

Vinte e dois pacientes alcoolatras cronicos foram submetidos a exame clinico neurologico e biopsia muscular. Eles apresentavam graus variaveis de fraqueza muscular proximal (cinturas escapular e pelvica), tendo um deles evoluido com quadro agudo de miopatia (avaliacao pelo 'Manual Muscle Test', MMT). A principal alteracao histologica observada e melhor evidenciada pela coloracao da ATPase: atrofia muscular (95,3%), predominando nas fibras do tipo II A (71,4%) e, em 76% dos casos, alteracao da imagem em mosaico a custa de agrupamentos de fibras musculares de mesmo tipo histoquimico ('type-grouping'). Secundariamente, em 63% dos casos, observa-se proliferacao mitocondrial e consequente acumulo lipidico intra-sarcoplasmatico. No caso de instalacao aguda da fraqueza muscular, o substrato anatomo-patologico e completamente diferente: presenca de mlosite, predominantemente intersticial, caracterizada por infiltrado linfoplasmocitario e numerosas imagens de necrose tipo degeneracao cerea de Zencker. Baseando-se em criterios histologicos, nossos dados sugerem que: a principal genese da fraqueza muscular observada em pacientes alcoolatras cronicos tem natureza neurogenica (polineuropatia alcoolica); a atuacao toxica direta do etanol sobre o musculo esqueletico esta intimamente relacionada ao metabolismo mitocondrial; a chamada miopatia aguda alcoolica tenha etiologia inflamatoria, do tipo viral.

Abstract Background The aim of mucosal healing (MH) as a therapeutic target in paediatric inflammatory bowel diseases (IBD) has emphasised the role of the endoscopy. There is a great variability in evaluating mucosal lesions among different operators, especially in paediatric patients. This multicentre prospective study aims to evaluate the interobserver agreement among paediatric endoscopists in using validated endoscopic scores of IBD in children. Methods Fifteen videos of follow-up ileocolonoscopies in children with IBD (8 ulcerative colitis –UC-, 7 Crohn’s disease –CD-) were selected from 3 different referral sites in Italy. Eleven paediatric endoscopists from different centres were asked to evaluate all videos as independent and blinded readers. The scoring systems used were ulcerative colitis Endoscopic Index of Severity (UCEIS) for UC and simple endoscopic score for Crohn’s disease (SES-CD) for CD. Kappa statistics and intraclass correlation coefficients were used to measure agreement. Furthermore, an experienced adult gastroenterologist evaluated the same videos and scores them. His results were compared with paediatric endoscopists’ findings. Results The median age of the participants was 40 (interquartile range: 6) with a median experience of 12 (14) years in centres with a median number of 140 (230) of paediatric IBDs. Intercluster correlation agreement was 0.298 (95% CI: 0.13–0.55) for UC and 0.266 (0.11–0.52) for CD. When a disease activity categorisation was adopted (remission, moderate, mild and severe) Fleiss’ kappa coefficient was 0.408 (0.29–0.53) for UC and 0.552 (0.43–0.73) for CD (Figure 1). When stratified for item vascular pattern of UC was the most reliable item IC: 0.624 (0.321–0.854). The comparison between paediatric and expert gastroenterologist’s scores is shown in Figure 2. In the multivariate analysis none of the reviewer characteristic affected the readers’ errors. Conclusion This pilot multicentre study shows that there is a low level of agreement among paediatric endoscopists in evaluating children with IBDs. Agreement improved after using a disease activity categorisation, with better results for CD. Regardless to experience, all readers showed a low-grade accordance with adult gastroenterologist. According to these findings, the use of scoring systems should be implemented for all paediatric endoscopists. Future specific training programs should be considered to pursue this goal.

Reply: We would like to thank Dr Monachesi and coworkers for their interest in our recent study on the analytical performance of antitissue transglutaminase (atTG) chemiluminescence immunoassay and the enzyme-linked immunosorbent assay to monitor children with celiac disease after the start of gluten-free diet (1). The group of Ancona strengthens our findings in this setting, showing a similarly slow trend to normalization of atTG measured by another commercially available immunoassay (fluorescence enzyme immunoassay). Furthermore, in agreement with our results, they find that younger age at diagnosis, male sex, and lower baseline atTG are predictors of earlier atTG normalization. We definitely agree with their suggestion to use the same analytical technique for the diagnosis and the follow-up of children with celiac disease on gluten-free diet, and we believe this issue should be taken into account in the future societal guidelines on the follow-up of these patients.

The usefulness of coloscopy in the diagnosis of inflammatory disease of the large intestine is discussed. A nosological classification was obtained in 440/493 instances of inflammation noted in over 3000 coloscopies-on the basis of the clinical, radiological, endoscopic and histological findings. The endoscopic picture for each disease is described, with particular reference to the main features upon which correct differential diagnosis and classification depend. Coloscopy is virtually indispensable in obtaining a complete clinical study of inflammatory diseases of the colon.

On the basis of the usual macroscopic pathological descriptions, the possibility of characterizing endoscopically the various types of polypous proliferations in the large intestine is examined. The endoscopic parameters considered are described together with the histopathological findings incases of polyps observed over a period of 6 months. Comparison between presumed diagnosis formulated at coloscopic examination and final histological diagnosis shows a concordance of 80%. The usefulness of being able to give some indication regarding the type of nature of the polyps as early as endoscopy is stressed.