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Il ruolo della Commissione nel NGEU si caratterizza per una compresenza di elementi di continuità e di discontinuità. Se il meccanismo della condizionalità ha caratterizzato già gli strumenti di assistenza finanziaria predisposti in risposta alla crisi del debito sovrano, nel caso del NGEU le condizioni di assegnazione e di esborso dei finanziamenti si collegano a obiettivi ampi, quali la trasformazione ecologica e quella digitale, che vanno a indirizzare ex ante le riforme nazionali. Attraverso l'esame della prassi applicativa del primo anno di operatività del dispositivo per la ripresa e la resilienza, il contributo indaga la trasformazione del ruolo di controllo della Commissione

ObjectiveCortical thickness changes dramatically during development and is influenced by adolescent drinking. However, previous findings have been inconsistent and limited by region-of-interest approaches that are underpowered because they do not conform to the underlying heterogeneity from the effects of alcohol.MethodsAdolescents (n=657; 12-22 years at baseline) from the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) who endorsed little to no alcohol use at baseline were assessed with structural MRI and followed longitudinally at four yearly intervals. Seven unique spatially covarying patterns of cortical thickness were obtained from the baseline scans by applying a novel data-driven method called non-negative matrix factorization (NMF). The cortical thickness maps of all participants’ longitudinal scans were projected onto vertex-level cortical patterns to obtain participant-specific coefficients for each pattern. Linear mixed-effects models were fit to each pattern to investigate longitudinal effects of alcohol consumption on cortical thickness.ResultsIn most NMF-derived cortical thickness patterns, the longitudinal rate of decline in no/low drinkers was similar for all age cohorts, among moderate drinkers the decline was faster in the younger cohort and slower in the older cohort, among heavy drinkers the decline was fastest in the younger cohort and slowest in the older cohort (FDR corrected p-values < 0.01).ConclusionsThe NMF method can delineate spatially coordinated patterns of cortical thickness at the vertex level that are unconstrained by anatomical features. Age-appropriate cortical thinning is more rapid in younger adolescent drinkers and slower in older adolescent drinkers.

The benefit of resection of liver metastases depends on primary diseases. Neuroendocrine tumors are associated with favorable prognosis after resection of liver metastases. Gastric cancer has worse tumor biology, and resection of gastric liver metastases should be performed in selected patients. A multidisciplinary approach is well established for colorectal liver metastases (CLMs). Resection remains the only curative treatment of CLM. Chemotherapy and molecular-targeted therapy have improved survival in unresectable metastatic colorectal cancer. Understanding of the following two strategies, conversion therapy and two-stage hepatectomy, are important to make this patient group to be candidates for curative-intent surgery.

Objective To assess the frequency of adverse events associated with periendoscopic management of direct oral anticoagulants (DOACs) in patients undergoing elective GI endoscopy and the efficacy and safety of the British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) recommendations (NCT 02734316). Design Consecutive patients on DOACs scheduled for elective GI endoscopy were prospectively included. The timing of DOAC interruption and resumption before and after the procedures were recorded, along with clinical and procedural data. Procedures were stratified into low-risk and high-risk for GI-related bleeding, and patients into low-risk and high-risk for thromboembolic events. Patients were followed-up for 30 days for major and clinically relevant non-major bleeding events (CRNMB), arterial and venous thromboembolism and death. Results Of 529 patients, 38% and 62% underwent high-risk and low-risk procedures, respectively. There were 45 (8.5%; 95% CI 6.3% to 11.2%) major or CRNMB events and 2 (0.4%; 95% CI 0% to 1.4%) thromboembolic events (transient ischaemic attacks). Overall, the incidence of bleeding events was 1.8% (95% CI 0.7% to 4%) and 19.3% (95% CI 14.1% to 25.4%) in low-risk and high-risk procedures, respectively. For high-risk procedures, the incidence of intraprocedural bleeding was similar in patients who interrupted anticoagulation according to BSG/ESGE guidelines or earlier (10.3%vs10.8%, p=0.99), with a trend for a lower risk as compared with those who stopped anticoagulation later (10.3%vs25%, p=0.07). The incidence of delayed bleeding appeared similar in patients who resumed anticoagulation according to BSG/ESGE guidelines or later (6.6%vs7.7%, p=0.76), but it tended to increase when DOAC was resumed earlier (14.4%vs6.6%, p=0.27). The risk of delayed major bleeding was significantly higher in patients receiving heparin bridging than in non-bridged ones (26.6%vs5.9%, p=0.017). Conclusion High-risk procedures in patients on DOACs are associated with a substantial risk of bleeding, further increased by heparin bridging. Adoption of the BSG/ESGE guidelines in periendoscopic management of DOACs seems to result in a favourable benefit/risk ratio. Trial registration number NCT 02734316; Pre-results.

Approximately 25% of patients with gastroesophageal reflux severe enough to be considered for surgical treatment have dysfunction of esophageal peristalsis in addition to dysfunction of the lower esophageal sphincter. A standard total (i.e., Nissen) fundoplication in these patients may be followed by dysphagia, so many experts recommend a partial fundoplication as an alternative. The goal of this study was to compare the clinical results and changes in esophageal function following laparoscopic total and partial fundoplication. Ninety-three patients with gastroesophageal reflux disease had laparoscopic antireflux operations. Total fundoplication was performed in 50 patients with normal esophageal peristalsis. Partial fundoplication was chosen for 43 patients with severe abnormalities of esophageal peristalsis. The same percentage of patients has resolution of heartburn (93%) and regurgitation (97%) after partial as compared to total fundoplication. Dysphagia developed in four patients (8%) after total fundoplication (one patient required dilatation) and in no patients after partial fundoplication. Both operations produced similar changes in lower esophageal sphincter function, but only partial fundoplication was associated with improvement in esophageal dysfunction. Esophageal acid exposure became normal in 92% of patients after total and in 91% of patients after partial fundoplication. Partial fundoplication improves lower esophageal sphincter pressure and esophageal body function and, in patients with abnormal esophageal peristalsis, it corrects reflux without producing dysphagia. Partial and total fundoplication are both indicated in patients with gastroesophageal reflux disease, and the choice of which procedure to use should be based on each patient"s specific esophageal motor function abnormalities.

Background During the first coronavirus disease 2019 (COVID-19) pandemic wave, an unprecedented number of patients with respiratory failure due to a new, highly contagious virus needed hospitalization and intensive care unit (ICU) admission. The aim of the present study was to describe the communication and visiting policies of Italian intensive care units (ICUs) during the first COVID-19 pandemic wave and national lockdown and compare these data with prepandemic conditions. Methods A national web-based survey was conducted among 290 Italian hospitals. Each ICU (active between February 24 and May 31, 2020) was encouraged to complete an individual questionnaire inquiring the hospital/ICU structure/organization, communication/visiting habits and the role of clinical psychology prior to, and during the first COVID-19 pandemic wave. Results Two hundred and nine ICUs from 154 hospitals (53% of the contacted hospitals) completed the survey (202 adult and 7 pediatric ICUs). Among adult ICUs, 60% were dedicated to COVID-19 patients, 21% were dedicated to patients without COVID-19 and 19% were dedicated to both categories (Mixed). A total of 11,102 adult patients were admitted to the participating ICUs during the study period and only approximately 6% of patients received at least one visit. Communication with family members was guaranteed daily through an increased use of electronic devices and was preferentially addressed to the same family member. Compared to the prepandemic period, clinical psychologists supported physicians more often regarding communication with family members. Fewer patients received at least one visit from family members in COVID and mixed-ICUs than in non-COVID ICUs, l (0 [0–6]%, 0 [0–4]% and 11 [2–25]%, respectively, p Conclusions Visiting policies of Italian ICUs dedicated to adult patients were markedly altered during the first COVID-19 wave. Remote communication was widely adopted as a surrogate for family meetings. New strategies to favor a family-centered approach during the current and future pandemics are warranted.

Metaglidasen is a fibrate-like drug reported as a selective modulator of peroxisome proliferator-activated receptor γ (PPARγ), able to lower plasma glucose levels in the absence of the side effects typically observed with thiazolidinedione antidiabetic agents in current use. Herein we report an improved synthesis of metaglidasen's metabolically active form halofenic acid (R)-2 and that of its enantiomer (S)-2. The activity of the two stereoisomers was carefully examined on PPARα and PPARγ subtypes. As expected, both showed partial agonist activity toward PPARγ; the investigation of PPARα activity, however, led to unexpected results. In particular, (S)-2 was found to act as a partial agonist, whereas (R)-2 behaved as an antagonist. X-ray crystallographic studies with PPARγ were carried out to gain more insight on the molecular-level interactions and to propose a binding mode. Given the adverse effects provoked by fibrate drugs on skeletal muscle function, we also investigated the capacity of (R)-2 and (S)-2 to block conductance of the skeletal muscle membrane chloride channel. The results showed a more beneficial profile for (R)-2, the activity of which on skeletal muscle function, however, should not be overlooked in the ongoing clinical trials studying its long-term effects.

BACKGROUND: Despite the improvements in diagnosis and treatment, colorectal cancer (CRC) is the second cause of cancer deaths in both sexes. Therefore, research in this field remains of great interest. The approval of bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in combination with a fluoropyrimidine-based chemotherapy in the treatment of metastatic CRC has changed the oncology practice in this disease. However, the efficacy of bevacizumab-based treatment, has thus far been rather modest. Efforts are ongoing to understand the better way to combine bevacizumab and chemotherapy, and to identify valid predictive biomarkers of benefit to avoid unnecessary and costly therapy to nonresponder patients. The BRANCH study in high-risk locally advanced rectal cancer patients showed that varying bevacizumab schedule may impact on the feasibility and efficacy of chemo-radiotherapy. METHODS/DESIGN: OBELICS is a multicentre, open-label, randomised phase 3 trial comparing in mCRC patients two treatment arms (1:1): standard concomitant administration of bevacizumab with chemotherapy (mFOLFOX/OXXEL regimen) vs experimental sequential bevacizumab given 4 days before chemotherapy, as first or second treatment line. Primary end point is the objective response rate (ORR) measured according to RECIST criteria. A sample size of 230 patients was calculated allowing reliable assessment in all plausible first-second line case-mix conditions, with a 80% statistical power and 2-sided alpha error of 0.05. Secondary endpoints are progression free-survival (PFS), overall survival (OS), toxicity and quality of life. The evaluation of the potential predictive role of several circulating biomarkers (circulating endothelial cells and progenitors, VEGF and VEGF-R SNPs, cytokines, microRNAs, free circulating DNA) as well as the value of the early [(18)F]-Fluorodeoxyglucose positron emission tomography (FDG-PET) response, are the objectives of the traslational project. DISCUSSION: Overall this study could optimize bevacizumab scheduling in combination with chemotherapy in mCRC patients. Moreover, correlative studies could improve the knowledge of the mechanisms by which bevacizumab enhance chemotherapy effect and could identify early predictors of response. EudraCT Number: 2011-004997-27 TRIAL REGISTRATION: ClinicalTrials.gove number, NCT01718873.

Objective: The objective of this study was to verify a possible correlation between the etiology of uvulopalatal ptosis and decrease in palatopharyngeal muscle tone, due to a reduction of the number of nerve fibers in surgical specimens obtained from snoring patients. Design/setting of the study: We have designed a comparative retrospective, case-control, double-blind, immunohistochemical and histomorphometric study of human uvula innervation in 51 apneic snoring patients who underwent uvulopalatopharyngoplasty (UPPP) and 47 normal subjects collected in a 5-year-long period in the Departments of Otolaryngology of Desio and Forlì Hospital, Italy. Patients: Case study was chosen in patients who underwent UPPP, variably associated with other disobstructive surgical procedures for treatment of obstructive sleep apnea syndrome, classified according to current clinical, polysomnographic, endoscopic, and imaging criteria. Control subjects were recruited at the Institute of Legal Medicine, University of Milan, according to strong inclusion and exclusion criteria. The main outcome measure of the study was the number of nerve fibers in the patients' uvula evaluated histologically and repeated two times by two different people, in all the areas of the specimens. Finally, we correlated the area of the histological section with the number of fibers contained therein. Results: The number of nerve fibers varied from a minimum of 58 to a maximum of 163 in normal subjects. In the snoring patient population, the number of nerve fibers varied from a minimum of 22 to a maximum of 126 (statistically significant difference, p < 0.0001). In conclusion, our results direct toward a clear neurogenetic predisposition to uvulopalatal ptosis, marked ab initio by a lower set of motor nerve fibers, which may be the initial stage of another subsequent morphological and functional abnormality. © 2011 Springer-Verlag.

arct S [1] Fuccio L. Comment on “Self-expandable metal stents for malignant colonic obstruction: data from a retrospective regional SIED-AIGO study” by R. Di Mitri, F. Mocciaro, M. Traina et al. [Digestive and Liver Disease 2014;46:279–82]. Digestive and Liver Disease 2014;46:859–60. [2] Di Mitri R, Mocciaro F, Traina M, et al. Self-expandable stents for malignant colonic obstruction: data from a retrospective regional SIED-AIGO study. Digestive and Liver Disease 2014;46:279–82. [3] Sanoff HK. Therapy for metastatic colorectal cancer in elderly patients and those with a poor performance status; 2014. Uptodate.com. our ts: 7.

OBJECTIVES: To evaluate the short- and long-term efficacy of self-expanding metal stents (SEMSs) in patients with colorectal obstruction and incurable cancer and the related factors that affect outcomes. DESIGN: Retrospective analysis of SEMS placement for incurable colorectal obstruction in a 3-year period. SETTING: Five tertiary care endoscopic centers. PATIENTS AND INTERVENTION: Consecutive patients (N = 201) undergoing stenting for incurable malignant obstruction. MAIN OUTCOME MEASUREMENTS: Clinical and technical success of stenting, complications rate, and factors affecting outcomes. RESULTS: Technical success was achieved in 184 of 201 patients (91.5%) and clinical success occurred in 165 of 184 patients (89.7%; 82.1% of 201 patients). Technical and clinical failures were more frequent in extrinsic and long colorectal stenoses. Overall, 165 patients had normal bowel movements during follow-up (mean [SD], 115.5 [100.3] days; range, 1-500 days), 15 developed complications, 127 had a functioning SEMS at the time of death, and 23 were alive at completion of the study. Twenty-four (11.9%) major complications occurred: 11 migrations, 12 perforations, and 1 reobstruction. Migration of SEMSs was associated with stent diameter less than 25 mm. Bevacizumab therapy increased the risk of perforation by 19.6-fold. Karnofsky performance status of 50 or less was associated with shorter survival and a 3.7-fold higher risk of death within 6 months after the stent was placed. CONCLUSIONS: The use of SEMSs is safe and effective for palliation of incurable malignant colonic obstruction; approximately 75% of patients with SEMSs are able to avoid colostomy.

In the present paper the homogenization problem of periodic composites is investigated, in the case of a Cosserat continuum at the macro-level and a Cauchy continuum at the micro-level. In the framework of a strain-driven approach, the two levels are linked by a kinematic map based on a third order polynomial expansion. The determination of the displacement perturbation fields in the Unit Cell (UC), arising when second or third order polynomial boundary conditions are imposed, is investigated. A new micromechanical approach, based on the decomposition of the perturbation fields in terms of functions which depend on the macroscopic strain components, is proposed. The identification of the linear elastic 2D Cosserat constitutive parameters is performed, by using a Hill-Mandel-type macrohomogeneity condition. The influence of the selection of the UC is analyzed and some critical issues are outlined. Numerical examples referred to a specific composite with cubic symmetry are shown.