Search

Lipopeptides (LPs) are secondary metabolites produced by a diversity of bacteria and fungi. Their unique chemical structure comprises both a peptide and a lipid moiety. LPs are of major biotechnological interest owing to their emulsification, antitumor, immunomodulatory, and antimicrobial activities. To date, these versatile compounds have been applied across multiple industries, from pharmaceuticals through to food processing, cosmetics, agriculture, heavy metal, and hydrocarbon bioremediation. The variety of LP structures and the diversity of the environments from which LP-producing microorganisms have been isolated suggest important functions in their natural environment. However, our understanding of the ecological role of LPs is limited. In this review, the mode of action and the role of LPs in motility, antimicrobial activity, heavy metals removal and biofilm formation are addressed. We include discussion on the need to characterise LPs from a diversity of microorganisms, with a focus on taxa inhabiting ‘extreme’ environments. We introduce the use of computational target fishing and molecular dynamics simulations as powerful tools to investigate the process of interaction between LPs and cell membranes. Together, these advances will provide new understanding of the mechanism of action of novel LPs, providing greater insights into the roles of LPs in the natural environment.

The temperature of cities increases due to the UHI phenomenon and climate change. Among the mitigation strategies, high solar reflectance materials make an important contribution, in particular ceramic materials on which studies have shown that the functionalization of the ceramic engobe allows to increase solar reflectance (SR). This study attempted to improve the SR of ceramic tiles, starting from studies correlating the heat treatment temperatures of glass-ceramic frits with SR, because frit is fundamental for the preparation of an engobe, which plays, as some studies have shown, an increasingly important role in solar reflectance. Five glass-ceramic frits have been analysed: four of these are commercial frits, while one has been obtained and optimized experimentally.

Enhanced recovery after surgery (ERAS) guidelines are evidence-based recommendations designed to improve patient outcomes and reduce complications after surgery. Although the ERAS guidelines focus primarily on surgical procedures, many of the principles could be applied also to therapeutic endoscopy as well. An extensive literature research on Embase and PubMed was thus made to reviewed articles regarding ERAS protocols applied to therapeutic endoscopy, organized by specific endoscopic field. Out of 214 papers, only 6 were relevant to the topic. Few studies explored in real life and in trial setting the hypothesized significance of ERAS principles applied to endoscopic procedures, mostly retrospective, not even covering the entire field of therapeutic endoscopy. This field of knowledge appears neglected so far by scientific community and endoscopic organizations. We believe that endoscopy units could benefit anyway from developing and implementing structured enhanced recovery pathways for their patients, therefore we subsequently created and suggested a simply and easily applicable, Enhanced Recovery protocol After Therapeutic Endoscopy which include preoperative preparation, anesthesia and sedation, nausea and vomiting (PONV) prophylaxis, and postoperative care., Competing Interests: Conflicts of Interest For all the authors none were declared., (Copyright © 2023. Published by Elsevier Ltd.)

Background: The safety and efficacy of minimally invasive radical antegrade modular pancreatosplenectomy (MI-RAMPS) remain to be established in pancreatic cancer (PDAC) METHODS: Eighty-five open (O)-RAMPS were compared to 93 MI-RAMPS. The entropy balance matching approach was used to compare the two cohorts, eliminating the selection bias. Three models were created. Model 1 made O-RAMPS equal to the MI-RAMPS cohort (i.e., compared the two procedures for resectable PDAC); model 2 made MI-RAMPS equal to O-RAMPS (i.e., compared the two procedures for borderline-resectable PDAC); model 3, compared robotic and laparoscopic RAMPS., Results: O-RAMPS and MI-RAMPS showed "non-small" differences for BMI, comorbidity, back pain, tumor size, vascular resection, anterior or posterior RAMPS, multi-visceral resection, stump management, grading, and neoadjuvant therapy. Before reweighting, O-RAMPS had fewer clinically relevant postoperative pancreatic fistulae (CR-POPF) (20.0% vs. 40.9%; p = 0.003), while MI-RAMPS had a higher mean of lymph nodes (25.7 vs. 31.7; p = 0.011). In model 1, MI-RAMPS and O-RAMPS achieved similar results. In model 2, O-RAMPS was associated with lower comprehensive complication index scores (MD = 11.2; p = 0.038), and CR-POPF rates (OR = 0.2; p = 0.001). In model 3, robotic-RAMPS had a higher probability of negative resection margins., Conclusion: In patients with anatomically resectable PDAC, MI-RAMPS is feasible and as safe as O-RAMPS., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Despite second-line transplant(SLT) for recurrent hepatocellular carcinoma(rHCC) leads to the longest survival after recurrence(SAR), its real applicability has never been reported. The aim was to compare the SAR of SLT versus repeated hepatectomy and thermoablation(CUR group)., Methods: Patients were enrolled from the Italian register HE.RC.O.LE.S. between 2008 and 2021. Two groups were created: CUR versus SLT. A propensity score matching (PSM) was run to balance the groups., Results: 743 patients were enrolled, CUR = 611 and SLT = 132. Median age at recurrence was 71(IQR 6575) years old and 60(IQR 53-64, p < 0.001) for CUR and SLT respectively. After PSM, median SAR for CUR was 43 months(95%CI = 37 - 93) and not reached for SLT(p < 0.001). SLT patients gained a survival benefit of 9.4 months if compared with CUR. MilanCriteria(MC)-In patients were 82.7% of the CUR group. SLT(HR 0.386, 95%CI = 0.23 - 0.63, p < 0.001) and the MELD score(HR 1.169, 95%CI = 1.07 - 1.27, p < 0.001) were the only predictors of mortality. In case of MC-Out, the only predictor of mortality was the number of nodules at recurrence(HR 1.45, 95%CI= 1.09 - 1.93, p = 0.011)., Conclusion: It emerged an important transplant under referral in favour of repeated hepatectomy or thermoablation. In patients with MC-Out relapse, the benefit of SLT over CUR was not observed., Competing Interests: Conflict of interest None., (Copyright © 2023 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Hypomyelinating Leukodystrophy 22 (HLD22) is caused by a stoploss mutation in CLDN11. To study the molecular mechanisms underlying HLD22, human induced pluripotent stem cells (hiPSCs) were generated from patient fibroblasts carrying the stop-loss mutation in CLDN11., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background & Aims: In chronic HBV infection, elevated reactive oxygen species levels derived from dysfunctional mitochondria can cause increased protein oxidation and DNA damage in exhausted virus-specific CD8 T cells. The aim of this study was to understand how these defects are mechanistically interconnected to further elucidate T cell exhaustion pathogenesis and, doing so, to devise novel T cell-based therapies., Methods: DNA damage and repair mechanisms, including parylation, CD38 expression, and telomere length were studied in HBV-specific CD8 T cells from chronic HBV patients. Correction of intracellular signalling alterations and improvement of antiviral T cell functions by the NAD precursor nicotinamide mononucleotide and by CD38 inhibition was assessed., Results: Elevated DNA damage was associated with defective DNA repair processes, including NAD-dependent parylation, in HBV-specific CD8 cells of chronic HBV patients. NAD depletion was indicated by the overexpression of CD38, the major NAD consumer, and by the significant improvement of DNA repair mechanisms, and mitochondrial and proteostasis functions by NAD supplementation, which could also improve the HBV-specific antiviral CD8 T cell function., Conclusions: Our study delineates a model of CD8 T cell exhaustion whereby multiple interconnected intracellular defects, including telomere shortening, are causally related to NAD depletion suggesting similarities between T cell exhaustion and cell senescence. Correction of these deregulated intracellular functions by NAD supplementation can also restore antiviral CD8 T cell activity and thus represents a promising potential therapeutic strategy for chronic HBV infection., Impact and Implications: Correction of HBV-specific CD8 T cell dysfunction is believed to represent a rational strategy to cure chronic HBV infection, which however requires a deep understanding of HBV immune pathogenesis to identify the most important targets for functional T cell reconstitution strategies. This study identifies a central role played by NAD depletion in the intracellular vicious circle that maintains CD8 T cell exhaustion, showing that its replenishment can correct impaired intracellular mechanisms and reconstitute efficient antiviral CD8 T cell function, with implications for the design of novel immune anti-HBV therapies. As these intracellular defects are likely shared with other chronic virus infections where CD8 exhaustion can affect virus clearance, these results can likely also be of pathogenetic relevance for other infection models., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: The study measures trends in the profile of patients with chronic hepatitis B virus linked to care in Italy., Methods: A cross-sectional, multicenter, observational cohort (PITER cohort) of consecutive patients with hepatitis B surface antigen (HBsAg) over the period 2019-2021 from 46 centers was evaluated. The reference was the MASTER cohort collected over the years 2012-2015. Standard statistical methods were used., Results: The PITER cohort enrolled 4583 patients, of whom 21.8% were non-Italian natives. Compared with those in MASTER, the patients were older and more often female. The prevalence of hepatitis B e antigen (HBeAg) declined (7.2% vs 12.3; P <0.0001) and that of anti-hepatitis D virus (HDV) remained stable (9.3% vs 8.3%). In both cohorts, about 25% of the patients had cirrhosis, and those in the PITER cohort were older. HBeAg-positive was 5.0% vs 12.6% (P <0.0001) and anti-HDV positive 24.8% vs 17.5% (P <0.0017). In the logistic model, the variables associated with cirrhosis were anti-HDV-positive (odds ratio = 10.08; confidence interval 7.63-13.43), age, sex, and body mass index; the likelihood of cirrhosis was reduced by 40% in the PITER cohort. Among non-Italians, 12.3% were HBeAg-positive (vs 23.4% in the MASTER cohort; P <0.0001), and 12.3% were anti-HDV-positive (vs 11.1%). Overall, the adherence to the European Association for the Study of the Liver recommendations for antiviral treatment increased over time., Conclusion: Chronic hepatitis B virus infection appears to be in the process of becoming under control in Italy; however, HDV infection is still a health concern in patients with cirrhosis and in migrants., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

We aimed to identify features associated with different disease trajectories in Alzheimer's disease (AD)-related primary progressive aphasia (PPA). We considered 23 patients diagnosed with AD-related PPA. All patients underwent neuropsychological evaluation, 18 F-Fluorodeoxyglucose-PET brain scan, CSF biomarkers measurement and APOE genotype analysis at baseline and underwent neurological follow-up for a mean time of 3 years. Patients who progressed to total loss of speech (TLoS + ) had greater impairment in writing and higher t-tau concentration as compared to TLoS - patients. Patients who progressed to loss of functional autonomy (LoFA + ) had greater impairment in single-word comprehension as compared to patients who maintained autonomy in self-care. Furthermore, 18 F-FDG-PET SPM analyses revealed different brain metabolic patterns between TLoS + and TLoS - and between LoFA + and LoFA - . In conclusion, linguistic profile, CSF t-tau and brain metabolic pattern might be useful tools to predict progression to total loss of speech and loss of functional autonomy in AD-related PPA patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Benchmark analysis for open liver surgery for cirrhotic patients with hepatocellular carcinoma (HCC) is still undefined., Methods: Patients were identified from the Italian national registry HE.RC.O.LE.S. The Achievable Benchmark of Care (ABC) method was employed to identify the benchmarks. The outcomes assessed were the rate of complications, major comorbidities, post-operative ascites (POA), post-hepatectomy liver failure (PHLF), 90-day mortality. Benchmarking was stratified for surgical complexity (CP1, CP2 and CP3)., Results: A total of 978 of 2698 patients fulfilled the inclusion criteria. 431 (44.1%) patients were treated with CP1 procedures, 239 (24.4%) with CP2 and 308 (31.5%) with CP3 procedures. Patients submitted to CP1 had a worse underlying liver function, while the tumor burden was more severe in CP3 cases. The ABC for complications (13.1%, 19.2% and 28.1% for CP1, CP2 and CP3 respectively), major complications (7.6%, 11.1%, 12.5%) and 90-day mortality (0%, 3.3%, 3.6%) increased with the surgical difficulty, but not POA (4.4%, 3.3% and 2.6% respectively) and PHLF (0% for all groups)., Conclusion: We propose benchmarks for open liver resections in HCC cirrhotic patients, stratified for surgical complexity. The difference between the benchmark values and the results obtained during everyday practice reflects the room for potential growth, with the aim to encourage constant improvement among liver surgeons., (Copyright © 2022 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: We aimed to evaluate, in a large Western cohort, perioperative and long-term oncological outcomes of salvage hepatectomy (SH) for recurrent hepatocellular carcinoma (rHCC) after primary hepatectomy (PH) or locoregional treatments., Methods: Data were collected from the Hepatocarcinoma Recurrence on the Liver Study Group (He.RC.O.Le.S.) Italian Registry. After 1:1 propensity score-matched analysis (PSM), two groups were compared: the PH group (patients submitted to resection for a first HCC) and the SH group (patients resected for intrahepatic rHCC after previous HCC-related treatments)., Results: 2689 patients were enrolled. PH included 2339 patients, SH 350. After PSM, 263 patients were selected in each group with major resected nodule median size, intraoperative blood loss and minimally invasive approach significantly lower in the SH group. Long-term outcomes were compared, with no difference in OS and DFS. Univariate and multivariate analyses revealed only microvascular invasion as an independent prognostic factor for OS., Conclusion: SH proved to be equivalent to PH in terms of safety, feasibility and long-term outcomes, consistent with data gathered from East Asia. In the awaiting of reliable treatment-allocating algorithms for rHCC, SH appears to be a suitable alternative in patients fit for surgery, regardless of the previous therapeutic modality implemented., (Copyright © 2022 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Centenarians are the best example of successful aging, reaching extreme longevity escaping age-related diseases. Genome sequencing studies provided evidence for genetic factors linked to heathy long life, including genes related to age-dependent diseases. HTT (Huntingtin) gene is linked to Huntington's Disease, but also associated to longevity in capuchins and mice. HTT Intermediate alleles (IAs) are defined as CAG repeat expansion between 27 and 35. According to recent data IAs might increase Alzheimer's Disease risk, but also might have a neuroprotective effect and can confer an advantage in brain development. Here, we investigated, for the first time, the possible implication of HTT IAs in extreme longevity and their possible association in cognitive decline. We analysed the distribution of IAs in Italian Centenarians (n = 143) and compared with pathological controls with cognitive decline (n = 232, including 80 Alzheimer's Disease, 78 Frontotemporal Dementia and 74 Subjective Cognitive Decline patients) and healthy controls (n = 104). Our data show a statistically significant higher frequency of IAs in Centenarians with respect to pathological controls with cognitive decline (p = .031; OR = 2.3097 95% CI 1.0591 to 5.0371), with a percentage of 11.2 respect to 5.4 respectively. The highest presence of IAs in Centenarians confirms and extends in humans a possible implication of HTT gene in exceptional lifespan and in brain development with a neuroprotective effect., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The default mode (DMN) and the salience (SN) networks show functional hypo-connectivity in Alzheimer's disease (AD) and the behavioral variant of frontotemporal dementia (bvFTD), respectively, along with patterns of hyper-connectivity. We tested the clinical and neurobiological effects of noninvasive stimulation over these networks in 45 patients (AD and bvFTD) who received either anodal (target network: DMN in AD, SN in bvFTD) or cathodal stimulation (target network: SN in AD, DMN in bvFTD). We evaluated changes in clinical, cognitive, functional and structural connectivity, and perfusion measures. In both patient groups, cathodal stimulation was followed by behavioral improvement, whereas anodal stimulation led to cognitive improvement. Neither functional connectivity nor perfusion showed significant effects. A significant interaction between DMN and SN functional connectivity changes and stimulation protocol was reported in AD. These results suggest a protocol-dependent response, whereby the protocols studied show divergent effects on cognitive and clinical measures, along with a divergent modulatory pattern of connectivity in AD., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: We investigated the clinical impact of the newly defined metabolic-associated fatty liver disease (MAFLD) in patients undergoing hepatectomy for HCC (MAFLD-HCC) comparing the characteristics and outcomes of patients with MAFLD-HCC to viral- and alcoholic-related HCC (HCV-HCC, HBV-HCC, A-HCC)., Methods: A retrospective analysis of patients included in the He.RC.O.Le.S. Group registry was performed. The characteristics, short- and long-term outcomes of 1315 patients included were compared according to the study group before and after an exact propensity score match (PSM)., Results: Among the whole study population, 264 (20.1%) had MAFLD-HCC, 205 (15.6%) had HBV-HCC, 671 (51.0%) had HCV-HCC and 175 (13.3%) had A-HCC. MAFLD-HCC patients had higher BMI (p < 0.001), Charlson Comorbidities Index (p < 0.001), size of tumour (p < 0.001), and presence of cirrhosis (p < 0.001). After PSM, the 90-day mortality and severe morbidity rates were 5.9% and 7.1% in MAFLD-HCC, 2.3% and 7.1% in HBV-HCC, 3.5% and 11.7% in HCV-HCC, and 1.2% and 8.2% in A-HCC (p = 0.061 and p = 0.447, respectively). The 5-year OS and RFS rates were 54.4% and 37.1% in MAFLD-HCC, 64.9% and 32.2% in HBV-HCC, 53.4% and 24.7% in HCV-HCC and 62.0% and 37.8% in A-HCC (p = 0.345 and p = 0.389, respectively). Cirrhosis, multiple tumours, size and satellitosis seems to be the independent predictors of OS., Conclusion: Hepatectomy for MAFLD-HCC seems to have a higher but acceptable operative risk. However, long-term outcomes seems to be related to clinical and pathological factors rather than aetiological risk factors., Competing Interests: Declaration of competing interest The Authors declare that there are no conflicts of interest., (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Dysphagia is common in Parkinson's disease (PD). The effects of antiparkinsonian drugs on dysphagia are controversial. Several treatments for dysphagia are available but there is no consensus on their efficacy in PD., Objective: To conduct a systematic review of the literature and to define consensus statements on the treatment of dysphagia in PD and related nutritional management., Methods: A multinational group of experts in the field of neurogenic dysphagia and/or Parkinson's disease conducted a systematic evaluation of the literature and reported the results according to PRISMA guidelines. The evidence from the retrieved studies was analyzed and discussed in a consensus conference organized in Pavia, Italy, and the consensus statements were drafted. The final version of statements was subsequently achieved by e-mail consensus., Results: The literature review retrieved 64 papers on treatment and nutrition of patients with PD and dysphagia, mainly of Class IV quality. Based on the literature and expert opinion in cases where the evidence was limited or lacking, 26 statements were developed., Conclusions: The statements developed by the Consensus panel provide a guidance for a multi-disciplinary treatment of dysphagia in patients with PD, involving neurologists, otorhinolaryngologists, gastroenterologists, phoniatricians, speech-language pathologists, dieticians, and clinical nutritionists., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

The study of enzymes from extremophiles arouses interest in Protein Science because of the amazing solutions these proteins adopt to cope with extreme conditions. Recently solved, the structure of the psychrophilic acyl aminoacyl peptidase from Sporosarcina psychrophila (SpAAP) pinpoints a mechanism of dimerization unusual for this class of enzymes. The quaternary structure of SpAAP relies on a domain-swapping mechanism involving the N-terminal A1 helix. The A1 helix is conserved among homologous mesophilic and psychrophilic proteins and its deletion causes the formation of a monomeric enzyme, which is inactive and prone to aggregate. Here, we investigate the dimerization mechanism of SpAAP through the analysis of chimeric heterodimers where a protomer lacking the A1 helix combines with a protomer carrying the inactivated catalytic site. Our results indicate that the two active sites are independent, and that a single A1 helix is sufficient to partially recover the quaternary structure and the activity of chimeric heterodimers. Since catalytically competent protomers are unstable and inactive unless they dimerize, SpAAP reveals as an "obligomer" for both structural and functional reasons., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: The SARS-CoV-2 pandemic has had a huge impact on healthcare systems, resulting in many routine diagnostic procedures either being halted or postponed., Aims: To evaluate whether the diagnoses of colorectal, gastric and pancreatic cancers have been impacted by the SARS-CoV-2 pandemic in Italy., Methods: A survey designed to collect the number of histologically-proven diagnoses of the three cancers in gastroenterology services across Italy from January 1 to October 31 in 2017-2020. Non-parametric ANOVA for repeated measurements was applied to compare distributions by years and macro-areas., Results: Compared to 2019, in 2020 gastric cancer diagnoses decreased by 15.9%, CRC by 11.9% and pancreatic by 9.9%. CRC distributions showed significant differences between all years, stomach cancer between 2018 and 2020 and 2019-2020, and pancreatic cancer only between 2017 and 2019. The 2019-2020 comparison showed fewer CRC diagnoses in the North (-13.7%), Center (-16.5%) and South (-4.1%), fewer stomach cancers in the North (-19.0%) and South (-9.4%), and fewer pancreatic cancers in the North (-14.1%) and Center (-4.7%), with an increase in the South (+12.3%). Distributions of CRC and gastric cancer were significantly different between all years in the North., Conclusions: This survey highlights the concerning effects of the COVID-19 pandemic on the diagnostic yield of gastroenterology services for stomach, colorectal and pancreatic cancers in Italy., Competing Interests: Declaration of Competing Interest The authors of the manuscript and the researchers involved in the study declare no conflict of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Management of recurrence after surgery for hepatocellular carcinoma (rHCC) is still a debate. The aim was to compare the Survival after Recurrence (SAR) of curative (surgery or thermoablation) versus palliative (TACE or Sorafenib) treatments for patients with rHCC., Methods: This is a multicentric Italian study, which collected data between 2007 and 2018 from 16 centers. Selected patients were then divided according to treatment allocation in Curative (CUR) or Palliative (PAL) Group. Inverse Probability Weighting (IPW) was used to weight the groups., Results: 1,560 patients were evaluated, of which 421 experienced recurrence and were then eligible: 156 in CUR group and 256 in PAL group. Tumor burden and liver function were weighted by IPW, and two pseudo-population were obtained (CUR = 397.5 and PAL = 415.38). SAR rates at 1, 3 and 5 years were respectively 98.3%, 76.7%, 63.8% for CUR and 91.7%, 64.2% and 48.9% for PAL (p = 0.007). Median DFS was 43 months (95%CI = 32-74) for CUR group, while it was 23 months (95%CI = 18-27) for PAL (p = 0.017). Being treated by palliative approach (HR = 1.75; 95%CI = 1.14-2.67; p = 0.01) and having a median size of the recurrent nodule>5 cm (HR = 1.875; 95%CI = 1.22-2.86; p = 0.004) were the only predictors of mortality after recurrence, while time to recurrence was the only protective factor (HR = 0.616; 95%CI = 0.54-0.69; p<0.001)., Conclusion: Curative approaches may guarantee long-term survival in case of recurrence., (Copyright © 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background & Aims: In chronic HBV infection, mitochondrial functions and proteostasis are dysregulated in exhausted HBV-specific CD8 T cells. To better characterise the potential involvement of deregulated protein degradation mechanisms in T cell exhaustion, we analysed lysosome-mediated autophagy in HBV-specific CD8 T cells. Bioactive compounds able to simultaneously target both mitochondrial functions and proteostasis were tested to identify optimal combination strategies to reconstitute efficient antiviral CD8 T cell responses in patients with chronic HBV infection., Methods: Lysosome-mediated degradation pathways were analysed by flow cytometry in virus-specific CD8 T cells from patients with chronic HBV infection. Mitochondrial function, intracellular proteostasis, and cytokine production were evaluated in HBV-peptide-stimulated T cell cultures, in the presence or absence of the polyphenols resveratrol (RSV) and oleuropein (OLE) and their metabolites, either alone or in combination with other bioactive compounds., Results: HBV-specific CD8 T cells from patients with CHB showed impaired autophagic flux. RSV and OLE elicited a significant improvement in mitochondrial, proteostasis and antiviral functions in CD8 T cells. Cytokine production was also enhanced by synthetic metabolites, which correspond to those generated by RSV and OLE metabolism in vivo, suggesting that these polyphenols may also display an effect after transformation in vivo. Moreover, polyphenolic compounds improved the T cell revitalising effect of mitochondria-targeted antioxidants and of programmed cell death protein 1/programmed cell death ligand 1 blockade., Conclusions: Simultaneously targeting multiple altered intracellular pathways with the combination of mitochondria-targeted antioxidants and natural polyphenols may represent a promising immune reconstitution strategy for the treatment of chronic HBV infection., Lay Summary: In chronic hepatitis B, antiviral T lymphocytes are deeply impaired, with many altered intracellular functions. In vitro exposure to polyphenols, such as resveratrol and oleuropein, can correct some of the deregulated intracellular pathways and improve antiviral T cell function. This effect can be further strengthened by the association of polyphenols with antioxidant compounds in a significant proportion of patients. Thus, the combination of antioxidants and natural polyphenols represents a promising strategy for chronic hepatitis B therapy., Competing Interests: Conflicts of interest CF received grants from Gilead and AbbVie. He is a consultant for Gilead, AbbVie, Vir Biotechnology, Arrowhead, Transgene, and Bristol Myers Squibb. PL is an advisor and speaker bureau for Gilead, Roche, Bristol Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Arrowhead, Alnylam, Spring Bank, Janssen, and EIGER. AL is consultant for MYR Pharmaceuticals and Gilead. MM is an advisory board for AbbVie. The other authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

It has been theorized that hemispheric dominance and more segregated information processing have evolved to overcome long conduction delays through the corpus callosum (transcallosal conduction delay - TCD) but that this may still impact behavioral performance, mostly in tasks requiring high timing accuracy. Nevertheless, a thorough understanding of the temporal features of interhemispheric communication is lacking. Here, we aimed to assess the relationship between TCD and behavioral performance with a noninvasive directional cortical measure of TCD obtained from transcranial magnetic stimulation (TMS)-evoked potentials (TEPs) in the motor system. Twenty-one healthy right-handed subjects were tested. TEPs were recorded during an ipsilateral silent period (iSP) paradigm and integrated with diffusion tensor imaging (DTI) and an in-phase bimanual thumb-opposition task. Linear mixed models were applied to test relationships between measures. We found TEP indexes of transcallosal communication at ∼15 ms both after primary motor cortex stimulation (M1-P15) and after dorsal premotor cortex stimulation (dPMC-P15). Both M1-and dPMC-P15 were predicted by mean diffusivity in the callosal body. Moreover, M1-P15 was positively related to iSP. Importantly, M1-P15 latency was linked to bimanual coordination with direction-dependent effects, so that asymmetric TCD was the best predictor of bimanual coordination. Our findings support the idea that transcallosal timing in signal transmission is essential for interhemispheric communication and can impact the final behavioral outcome. However, they challenge the view that a short conduction delay is always beneficial. Rather, they suggest that the effect of the conduction delay may depend on the direction of information flow., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2021. Published by Elsevier Inc.)

Brain vascular damage accumulate in aging and often manifest as white matter hyperintensities (WMHs) on MRI. Despite increased interest in automated methods to segment WMHs, a gold standard has not been achieved and their longitudinal reproducibility has been poorly investigated. The aim of present work is to evaluate accuracy and reproducibility of two freely available segmentation algorithms. A harmonized MRI protocol was implemented in 3T-scanners across 13 European sites, each scanning five volunteers twice (test-retest) using 2D-FLAIR. Automated segmentation was performed using Lesion segmentation tool algorithms (LST): the Lesion growth algorithm (LGA) in SPM8 and 12 and the Lesion prediction algorithm (LPA). To assess reproducibility, we applied the LST longitudinal pipeline to the LGA and LPA outputs for both the test and retest scans. We evaluated volumetric and spatial accuracy comparing LGA and LPA with manual tracing, and for reproducibility the test versus retest. Median volume difference between automated WMH and manual segmentations (mL) was -0.22[IQR = 0.50] for LGA-SPM8, -0.12[0.57] for LGA-SPM12, -0.09[0.53] for LPA, while the spatial accuracy (Dice Coefficient) was 0.29[0.31], 0.33[0.26] and 0.41[0.23], respectively. The reproducibility analysis showed a median reproducibility error of 20%[IQR = 41] for LGA-SPM8, 14% [31] for LGA-SPM12 and 10% [27] with the LPA cross-sectional pipeline. Applying the LST longitudinal pipeline, the reproducibility errors were considerably reduced (LGA: 0%[IQR = 0], p < 0.001; LPA: 0% [3], p < 0.001) compared to those derived using the cross-sectional algorithms. The DC using the longitudinal pipeline was excellent (median = 1) for LGA [IQR = 0] and LPA [0.02]. LST algorithms showed moderate accuracy and good reproducibility. Therefore, it can be used as a reliable cross-sectional and longitudinal tool in multi-site studies., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Chronically HBV infected subjects are more than 260 million worldwide; cirrhosis and liver cancer represent possible outcomes which affect around 700,000 patients per year. Both innate and adaptive immune responses are necessary for viral control and both have been shown to be defective in chronic patients. Metabolic remodeling is an essential process in T cell biology, particularly for T cell activation, differentiation and survival. Cellular metabolism relies on the conversion of nutrients into energy to support intracellular processes, and to generate fundamental intermediate components for cell proliferation and growth. Adaptive immune responses are the central mechanisms for the resolution of primary human infections leading to the activation of pathogen-specific B and T cell functions. In chronic HBV infection the anti-viral immune response fails to contain the virus and leads to persistent hepatic tissue damage which may finally result in liver cirrhosis and cancer. This T cell failure is associated with metabolic alterations suggesting that control of nutrient uptake and intracellular utilization as well as correct regulation of intracellular metabolic pathways are strategic for T cell differentiation during persistent chronic infections. This review will discuss some of the main features of the T cell metabolic processes which are relevant to the generation of an efficient antiviral response, with specific focus on their clinical relevance in chronic HBV infection in the perspective of possible strategies to correct deregulated metabolic pathways underlying T cell dysfunction of chronic HBV patients., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

We aimed to detail language profiles, brain metabolic patterns and proportion of Alzheimer's disease biomarkers in a cohort of patients with mixed primary progressive aphasia (mPPA). We considered 58 patients with PPA: 10 with non-fluent/agrammatic variant (nfvPPA), 16 with semantic variant (svPPA), 21 with logopenic variant (lvPPA) and 9 with mPPA. Patients with mPPA were further classified as 4 nf/lvPPA (with prevailing features for nfvPPA and lvPPA) and 5 s/lvPPA (with prevailing features for svPPA and lvPPA). Nf/lvPPA patients were characterized by higher proportion of Naming impairment compared to nfvPPA and more frequent Grammatical Errors and Phonologic Errors than lvPPA. S/lvPPA had higher proportion of impairment in Sentences Repetition compared to svPPA and in Single-word Comprehension compared to lvPPA. 100% of nf/lvPPA and 40% of s/lvPPA had Aβ positive biomarkers. Brain hypometabolic pattern in Nf/lvPPA was consistent with lvPPA, while s/lvPPA had a brain metabolism resembling svPPA. We concluded that nf/lvPPA patients might be considered as PPA variant due to Alzheimer's disease and s/lvPPA group mainly included patients with svPPA., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Amyloid and tau pathological accumulation should be considered for Alzheimer's disease (AD) definition and before subjects' enrollment in disease-modifying trials. Although age, APOEε4, and sex influence cerebrospinal fluid (CSF) biomarker levels, none of these variables are considered by current normality/abnormality cutoffs. Using baseline CSF data from 2 independent cohorts (PharmaCOG/European Alzheimer's Disease Neuroimaging Initiative and Alzheimer's Disease Neuroimaging Initiative), we investigated the effect of age, APOEε4 status, and sex on CSF Aβ42/P-tau distribution and cutoff extraction by applying mixture models with covariates. The Aβ42/P-tau distribution revealed the presence of 3 subgroups (AD-like, intermediate, control-like) and 2 cutoffs. The identification of the intermediate subgroup and of the higher cutoff was APOEε4 dependent in both cohorts. APOE-specific classification (higher cutoff for APOEε4+, lower cutoff for APOEε4-) showed higher diagnostic accuracy in identifying MCI due to AD compared to single Aβ42 and Aβ42/P-tau cutoffs. APOEε4 influences amyloid and tau CSF markers and AD progression in MCI patients supporting i) the use of APOE-specific cutoffs to identify MCI due to AD and ii) the utility of considering APOE genotype for early AD diagnosis., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: The aims of the study were to test the diagnostic accuracy of integrated evaluation of dynamic myocardial computed tomography perfusion (CTP) on top of coronary computed tomography angiography (cCTA) plus fractional flow reserve computed tomography derived (FFR CT ) by using a whole-heart coverage computed tomography (CT) scanner as compared with clinically indicated invasive coronary angiography (ICA) and invasive fractional flow reserve (FFR)., Background: Recently, new techniques such as dynamic stress computed tomography perfusion (stress-CTP) emerged as potential strategies to combine anatomical and functional evaluation in a one-shot scan. However, previous experiences with this technique were associated with high radiation exposure., Methods: Eighty-five consecutive symptomatic patients scheduled for ICA were prospectively enrolled. All patients underwent rest cCTA followed by stress dynamic CTP with a whole-heart coverage CT scanner (Revolution CT, GE Healthcare, Milwaukee, Wisconsin). FFR CT was also measured by using the rest cCTA dataset. The diagnostic accuracy to detect functionally significant coronary artery disease (CAD) in a vessel-based model of cCTA alone, cCTA+FFR CT , cCTA+CTP, or cCTA+FFR CT +CTP were assessed and compared by using ICA and invasive FFR as reference. The overall effective dose of dynamic CTP was also measured., Results: The prevalence of obstructive CAD and functionally significant CAD was 77% and 57%, respectively. The sensitivity and specificity of cCTA alone, cCTA+FFR CT , and cCTA+CTP were 83% and 66%, 86% and 75%, and 73% and 86%, respectively. Both the addition of FFR CT and CTP improves the area under the curve (AUC: 0.876 and 0.878, respectively) as compared with cCTA alone (0.826; p < 0.05). The sequential strategy of cCTA+FFR CT +CTP showed the highest AUC (0.919; p < 0.05) as compared with all other strategies. The mean effective radiation dose (ED) for cCTA and stress CTP was 2.8 ± 1.2 mSv and 5.3 ± 0.7 mSv, respectively., Conclusions: The addition of dynamic stress CTP on top of cCTA and FFR CT provides additional diagnostic accuracy with acceptable radiation exposure., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The growing demand for bariatric surgery has been accompanied by an expensive technological evolution and the need to contain healthcare costs and to increase the quality of care. The enhanced recovery after surgery (ERAS) protocols applied to the bariatric setting can be the answer to all these different issues., Objectives: Feasibility and safety of ERAS protocol in a single, high-volume bariatric center., Setting: Humanitas Research Hospital, Rozzano MI, Italy., Methods: Our ERAS bariatric protocol is based on the following 3 steps: (1) preoperative: optimization of all co-morbidities, counseling patients and family with information and education, and shortening fasting times (clear fluids up to 2 hr and solids up to 4 hr before induction of anesthesia); (2) intraoperative: premedication, parallel team work, awake patient positioning, standardized multimodal anesthesia and analgesia, noninvasive monitoring, video-laryngoscopy in reverse Trendelenburg position, short-acting anesthetic agents, and standardized laparoscopic surgery avoiding the nasogastric tube, catheter, and drain; and (3) postoperative: analgesia, early mobilization, early oral fluid, thromboprophylaxis, discharge planning, and follow-up telephone call. Clinical pathways were established and outcomes were retrospectively collected., Results: Comparison between conventional care and ERAS protocol reveals a reduction of the length of hospital stay (from 4.7 to 2.1 d) and a low morbidity rate. From July 2015 to July 2018, a total of 2400 consecutive patients underwent primary or revisional bariatric surgery (2122 sleeve gastrectomies and 278 Roux-en-Y gastric bypasses [RYGB]). Mean body mass index was 44.9 kg/m 2 , mean age was 41.9 years, and the male to female ratio was 1:2.5. Total mean operative time was 85 minutes, with a surgical time of 65 minutes and an anesthesiologic/patient induction time of 4 minutes. Early complication rate was 3.5% with no perioperative mortality. Mean hospital stay was 2.1 days and the rate of readmission was .9%., Conclusions: This study demonstrates that our ERAS protocol is safe, feasible, and efficient. Patient preparation and multidisciplinary/parallel team work are crucial points., (Copyright © 2019 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to compare the diagnostic accuracy of coronary computed tomography angiography (cCTA) with that of cCTA+fractional flow reserve derived from cCTA datasets (FFR CT ) and that of cCTA+static stress-computed tomography perfusion (stress-CTP) in detecting functionally significant coronary artery lesions using invasive coronary angiography (ICA) plus invasive FFR as the reference standard., Background: FFR CT and static stress-CTP are new techniques that combine anatomy and functional evaluation to improve assessment of coronary artery disease (CAD) using cCTA., Methods: A total of 147 consecutive symptomatic patients scheduled for clinically indicated ICA+invasive FFR were evaluated with cCTA, FFR CT , and stress-CTP., Results: Vessel-based and patient-based sensitivity, specificity, and negative predictive values, and positive predictive values, and accuracy rates of cCTA were 99%, 76%, 100%, 61%, 82%, and 95%, 54%, 94%, 63%, 73%, respectively. cCTA+FFR CT showed vessel-based and patient-based sensitivity, specificity, and negative predictive values, and positive predictive values and accuracy rates of 88%, 94%, 95%, 84%, 92%, and 90%, 85%, 92%, 83%, 87%, respectively. Finally, cCTA+stress-CTP showed vessel-based and patient-based sensitivity, specificity, and negative predictive values, and positive predictive values and accuracy rates of 92%, 95%, 97%, 87%, 94% and 98%, 87%, 99%, 86%, 92%, respectively. Both FFR CT and stress-CTP significantly improved specificity and positive predictive values compared to those of cCTA alone. The area under the curve to detect flow-limiting stenoses of cCTA, cCTA+FFR CT , and cCTA+CTP were 0.89, 0.93, 0.92, and 0.90, 0.94, and 0.93 in a vessel-based and patient-based model, respectively, with significant additional values for both cCTA+FFR CT and cCTA+CTP versus cCTA alone (p < 0.001) but no differences between cCTA+FFR CT versus cCTA+CTP., Conclusions: FFR CT and stress-CTP in addition to cCTA are valid and comparable tools to evaluate the functional relevance of CAD., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The goal of this study was to evaluate the diagnostic accuracy of stress computed tomography myocardial perfusion (CTP) for the detection of functionally significant coronary artery disease (CAD) by using invasive coronary angiography (ICA) plus invasive fractional flow reserve (FFR) as the reference standard in consecutive intermediate- to high-risk symptomatic patients., Background: Stress CTP recently emerged as a potential strategy to combine the anatomic and functional evaluation of CAD in a single scan., Methods: A total of 100 consecutive symptomatic patients scheduled for ICA were prospectively enrolled. All patients underwent rest coronary computed tomography angiography (CTA) followed by stress static CTP with a whole-heart coverage CT scanner (Revolution CT, GE Healthcare, Milwaukee, Wisconsin). Diagnostic accuracy and overall effective dose were assessed and compared versus those of ICA and invasive FFR., Results: The prevalence of obstructive CAD and functionally significant CAD were 69% and 44%, respectively. Coronary CTA alone demonstrated a per-vessel and per-patient sensitivity, specificity, negative predictive value, positive predictive value, and accuracy of 98%, 76%, 99%, 63%, and 83% and of 98%, 54%, 96%, 68%, and 76%, respectively. Combining coronary CTA with stress CTP, per-vessel and per-patient sensitivity, specificity, negative predictive value, positive predictive value, and accuracy were 91%, 94%, 96%, 86%, and 93% and 98%, 83%, 98%, 86%, and 91%, with a significant improvement in specificity, positive predictive value, and accuracy in both models. The mean effective dose for coronary CTA and stress CTP were 2.8 ± 1.4 mSv and 2.5 ± 1.1 mSv., Conclusions: The inclusion of stress CTP for the evaluation of patients with an intermediate to high risk for CAD is feasible and improved the diagnostic performance of coronary CTA for detecting functionally significant CAD., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

A few studies reported functional abnormalities at rest in borderline personality disorder (BPD), but their relationship with clinical aspect is unclear. We aimed to assess functional connectivity (FC) in BPD patients and its association with BPD clinical features. Twenty-one BPD patients and 14 healthy controls (HC) underwent a multidimensional assessment and resting-state fMRI. Independent component analysis was performed to identify three resting-state networks: default mode network (DMN), salience network (SN), and executive control network (ECN). FC differences between BPD and HC were assessed with voxel-wise two-sample t-tests. Additionally, we investigated the mean FC within each network and the relationship between connectivity measures and BPD clinical features. Patients showed significant lower mean FC in the DMN and SN, while, at the local level, a cluster of lower functional connectivity emerged in the posterior cingulate cortex of the DMN. The DMN connectivity was positively correlated with the anger-state intensity and expression, while the SN connectivity was positively correlated with metacognitive abilities and a negative correlation emerged with the interpersonal aggression. The dysfunctional connectivity within these networks might explain clinical features of BPD patients., (Copyright © 2018. Published by Elsevier B.V.)

Background: Coronary computed tomography angiography (cCTA) has limited diagnostic accuracy in patients with intermediate to high pre-test likelihood of coronary artery disease (CAD) that may have large amounts of coronary calcium. Stress computed tomography myocardial perfusion (CTP) has emerged as a valuable strategy, combining anatomical and functional assessment of CAD. Purpose of the study is to evaluate the diagnostic accuracy of combining coronary artery imaging and myocardial perfusion in a single stress dataset versus invasive coronary angiography (ICA) and invasive fractional flow reserve (FFR) as reference standard., Methods: One-hundred-thirty consecutive symptomatic patients (age: 65 ± 9 years; men: 70%) scheduled for clinically indicated ICA plus invasive FFR were prospectively enrolled. cCTA + CTP were simultaneously evaluated in a single stress-dataset by blinded readers and compared to ICA and invasive FFR findings., Results: CTP was successfully performed in all patients. The most common artifacts observed in the stress dataset for coronary artery imaging were blooming effect and motion effect related. Overall evaluability of coronary arteries by using cCTA stress dataset was 93%. In a vessel and patient-based model, stress cCTA + stress CTP showed sensitivity, specificity, negative predictive value, positive predictive value and diagnostic accuracy of 93%, 94%, 97%, 85%, 94%, and 98%, 86%, 98%, 85%, 92%, respectively. The overall effective dose (ED) of stress protocol acquisition alone was 2.5 ± 1.1 mSv., Conclusions: Simultaneous evaluation of coronary arteries and myocardial perfusion with single stress acquisition is feasible and it has diagnostic accuracy and low ED to identify functionally significant stenosis in patients with intermediate to high risk for CAD., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Recent studies demonstrated a significant improvement in the diagnostic performance of coronary CT angiography (CCTA) for the evaluation of in-stent restenosis (ISR). However, coronary stent assessment is still challenging, especially because of beam-hardening artifacts due to metallic stent struts and high atherosclerotic burden of non-stented segments. Adenosine-stress myocardial perfusion assessed by CT (CTP) recently demonstrated to be a feasible and accurate tool for evaluating the functional significance of coronary stenoses in patients with suspected coronary artery disease (CAD). Yet, scarce data are available on the performance of CTP in patients with previous stent implantation., Aim of the Study: We aim to assess the diagnostic performance of CCTA alone, CTP alone and CCTA plus CTP performed with a new scanner generation using quantitative invasive coronary angiography (ICA) and invasive fractional flow reserve (FFR) as standard of reference., Methods: We will enroll 300 consecutive patients with previous stent implantation, referred for non-emergent and clinically indicated invasive coronary angiography (ICA) due to suspected ISR or progression of CAD in native coronary segments. All patients will be subjected to stress myocardial CTP and a rest CCTA. The first 150 subjects will undergo static CTP scan, while the following 150 patients will undergo dynamic CTP scan. Measurement of invasive FFR will be performed during ICA when clinically indicated., Results: The primary study end points will be: 1) assessment of the diagnostic performance (diagnostic rate, sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy) of CCTA, CTP, combined CCTA-CTP and concordant CCTA-CTP vs. ICA as standard of reference in a territory-based and patient-based analysis; 2) assessment of sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy of CCTA, CTP, combined CCTA-CTP and concordant CCTA-CTP vs. invasive FFR as standard of reference in a territory-based analysis., Conclusions: The ADVANTAGE study aims to provide an answer to the intriguing question whether the combined anatomical and functional assessment with CCTA plus CTP may have higher diagnostic performance as compared to CCTA alone in identifying stented patients with significant ISR or CAD progression., (Copyright © 2018. Published by Elsevier Inc.)

HBV-specific T cells play a key role in antiviral protection and failure to control HBV is associated with severely dysfunctional T cell responses. Therefore, functional T cell reconstitution represents a potential way to treat chronically infected patients. The growing understanding of the dysregulated transcriptional/epigenetic and metabolic programs underlying T cell exhaustion allows to envisage functional T cell reconstitution strategies based on the combined/sequential use of compounds able to induce decline of antigen load, checkpoint modulation, metabolic and epigenetic reprogramming with possible boosting of functionally restored responses by specific vaccines., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Aims: Despite the lack of evidence that assessing the global cardiovascular risk leads to a decreased incidence of cardiovascular events, accurate patient profiling is paramount in preventive medicine. An excess of visceral fat (VF) is associated with an enhanced cardiovascular risk; importantly, VF is quantifiable rapidly, cheaply and safely by ultrasound, which makes it suitable for use in clinical practice. In the present study, we aimed to evaluate if US-measured VF (USVF) could be a better predictor of glucose homeostasis and cardiovascular risk than simple anthropometric measures., Methods and Results: One-hundred sixty-two patients attending a Metabolic Disorders Clinic underwent a cross-sectional study for which USVF, anthropometric measures, a standard oral glucose tolerance test (OGTT), and calculation of cardiovascular Framingham score and vascular age were obtained. USVF was directly correlated with fasting and 2-h plasma glucose (respectively: r = 0.26, p < 0.001; r = 0.28, p < 0.0001), fasting and 2-h plasma insulin (for both: r = 0.41, p < 0.0001), homeostatic model assessment of insulin resistance (HOMA-IR; r = 0.42, p < 0.0001), cardiovascular Framingham score (r = 0.44 p < 0.0001) and vascular age (r = 0.30 p < 0.001). In receiver operator characteristic curves USVF had good diagnostic abilities for type 2 diabetes mellitus, fatty liver and metabolic syndrome, in both genders. At multivariate analysis, body mass index (BMI) outperformed USVF in the prediction of HOMA-IR; neverthless, USVF, not BMI, was an independent predictor of cardiovascular risk. Finally, models including USVF were the most parssimonious to predict Framingham score, vascular age and HOMA-IR., Conclusion: In overweight and obese subjects, USVF could usefully complement other parameters for cardiovascular risk stratification., (Copyright © 2018. Published by Elsevier B.V.)

Introduction: The present study investigated the utility of fluorine-18 ( 18 F) fluoro-2-deoxy-d-glucose ( 18 F-FDG) positron emission tomography/computed tomography (PET/CT) in assessing bone marrow involvement (BMI) compared with bone marrow biopsy (BMB) in newly diagnosed pediatric Hodgkin lymphoma (HL)., Patients and Methods: A total of 224 pediatric patients with HL underwent 18 F-FDG PET/CT at staging. BMB or follow-up imaging was used as the standard of reference for the evaluation of BMI., Results: 18 F-FDG PET/CT was negative for BMI in 193 cases. Of the 193 patients, the findings for 16 were originally reported as doubtful and later interpreted as negative for BMI, with negative findings on follow-up imaging and BMB. At BMB, 1 of the 16 patients (6.25%) had BMI. Of the 193 patients, 192 (99.48%) had negative BMB findings. Thus, the 18 F-FDG PET/CT findings were truly negative for 192 patients and falsely negative for 1 patient for BMI., Conclusion: 18 F-FDG PET/CT showed high diagnostic performance in the evaluation of BMI in pediatric HL. Thus, BMB should be ideally reserved for patients presenting with doubtful 18 F-FDG PET/CT findings for BMI., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The molecular underpinnings associated to first episode psychosis (FEP) remains to be elucidated, but compelling evidence supported an association of FEP with blood alterations in biomarkers related to immune system, growth factors and metabolism regulators. Many of these studies have not been already confirmed in larger samples or have not considered the FEP diagnostic subgroups. In order to identify biochemical signatures of FEP, the serum levels of the growth factors BDNF and VEGF, the immune regulators IL-1RA, IL-6, IL-10 and IL-17, RANTES/CCL5, MIP-1b/CCL4, IL-8 and the metabolic regulators C-peptide, ghrelin, GIP, GLP-1, glucagon, insulin, leptin, PAI-1, resistin and visfatin were analysed in 260 subjects collected in the GET UP project. The results indicated an increase of MIP-1b/CCL4, VEGF, IL-6 and PAI-1, while IL-17, ghrelin, glucagon and GLP-1 were decreased in the whole sample of FEP patients (p < 0.01 for all markers except for PAI-1 p < 0.05). No differences were evidenced for these markers among the diagnostic groups that constitute the FEP sample, whereas IL-8 is increased only in patients with a diagnosis of affective psychosis. The principal component analysis (PCA) and variable importance analysis (VIA) indicated that MIP-1b/CCL4, ghrelin, glucagon, VEGF and GLP-1 were the variables mostly altered in FEP patients. On the contrary, none of the analysed markers nor a combination of them can discriminate between FEP diagnostic subgroups. These data evidence a profile of immune and metabolic alterations in FEP patients, providing new information on the molecular mechanism associated to the psychosis onset for the development of preventive strategies and innovative treatment targets., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background & Aims: Vesatolimod (GS-9620) is an oral agonist of toll-like receptor 7, an activator of innate and adaptive immune responses. Herein the safety and efficacy of vesatolimod is assessed after once-weekly treatment in patients with chronic hepatitis B (CHB) infection suppressed on oral antiviral treatment., Methods: In a phase II, double-blind, randomized, placebo (PBO)-controlled study, 162 patients stratified by hepatitis B surface antigen (HBsAg) levels and serum hepatitis B e antigen (HBeAg) status were randomized 1:3:3:3 to once-weekly oral PBO or vesatolimod (1-, 2-, or 4-mg doses) for 4, 8 or 12 weeks per cohort. Efficacy was assessed by change in baseline HBsAg (log 10 IU/ml) at the primary endpoint (Week 24). Safety assessments included adverse events (AE) and laboratory abnormality monitoring. Pharmacodynamic assessments included peripheral cytokine level quantification and interferon-stimulated gene (ISG) mRNA expression evaluation., Results: The majority of patients were male (76%) and HBeAg-negative (79%) at baseline. Most (41-80%) experienced ≥1 AE during the study with the majority of AEs mild or moderate in severity. No significant declines in HBsAg were observed at the primary (Week 24) or secondary endpoints (Weeks 4, 8, 12, and 48). ISG15 induction was dose-dependent and consistent after repeat dosing, returning closer to baseline by one week after treatment at all dose levels; no patient demonstrated significant serum interferon alpha (IFNα) expression at any timepoint evaluated. Multivariate analyses showed that ≥2-fold ISG15 induction is associated with 2- or 4-mg vesatolimod dose and female sex., Conclusions: Vesatolimod was safe and well-tolerated in patients with CHB, demonstrating consistent dose-dependent pharmacodynamic induction of ISG15 without significant systemic induction of IFNα expression or related symptoms. However, no significant HBsAg declines were observed., Lay Summary: In a phase II study, vesatolimod, an oral, once-weekly, experimental immune-activating drug for the treatment of hepatitis B virus (HBV), is safe and well-tolerated in chronic HBV patients who are virally suppressed on oral antiviral treatment. Despite demonstrating on-target biomarker responses in patients, no significant declines in hepatitis B surface antigen were observed. Clinical Trial Number: GS-US-283-1059; NCT 02166047., (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Differential diagnosis of atypical parkinsonian disorders, i.e. dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP) or corticobasal syndrome (CBS) still remains problematic. Furthermore, DLB may overlap with Alzheimer's disease (AD) in the early stages of disease., Objective: To determine whether transcranial magnetic stimulation (TMS) can be used to classify atypical parkinsonian disorders and AD., Methods: A paired-pulse TMS multi-paradigm approach assessing multiple intracortical circuits, as short interval intracortical inhibition-facilitation and short latency afferent inhibition, was used to model a decision tree analysis and determine diagnostic accuracy in classifying different neurodegenerative disorders., Results: We observed a significant impairment in short latency afferent inhibition in AD and DLB and a significant impairment in short interval intracortical inhibition-facilitation in DLB, PSP and CBS patients. These parameters were used to model a decision tree analysis which yielded an overall diagnostic accuracy of 88.3%, with 90.5% for AD, 85.2% for DLB, 76.0% for CBS-PSP, and 94.9% for healthy controls., Conclusions: The assessment of intracortical connectivity with TMS may aid in the differential diagnosis of AD and the atypical parkinsonian disorders., (Copyright © 2017 Elsevier Inc. All rights reserved.)