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In the upcoming decades, the incidence and mortality rates of cancer are expected to rise globally, with colorectal and prostate cancers among the most prevalent types. Despite advancements in molecular targeted therapy, platinum-based chemotherapies remain the cornerstone of treatment, especially for colorectal and prostate cancer, with oxaliplatin and cisplatin being extremely effective due to their DNA-targeting capabilities. In our pursuit of new platinum-based chemotherapeutics that are potentially less toxic and more effective, we have explored the combination of the Pt-binding groups of the diaminocyclohexane ring used in oxaliplatin, with the stable amino-pyrimidine hemicurcumin moiety. This new derivative exhibit improved stability in physiological conditions and increased solubility in aqueous media, demonstrating promising effects on cell proliferation of both colorectal and prostate cells. We report herein the complete synthesis and chemical characterization in solution of the new derivative [(1R,2R)-N1-(3-(4-((E)-2-(2-Amino-6-methylpyrimidin-4-yl)vinyl)-2-methoxyphenoxy) propyl) cyclohexane-1,2-diamine] (MPYD). Our analysis includes an examination of its acid-base equilibria, speciation and stability in physiological conditions. The synthesis and in situ formation of Pt(II) complexes were investigated by nuclear magnetic resonance spectroscopy, while density functional theory calculations were employed to elucidate the chemical structure in solution. Results on the biological activity were obtained through cell viability assays on different colorectal and prostate cell lines (HCT116, HT29, PC3 and LNCaP)., 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 © 2024. Published by Elsevier Inc.)

Background: Red blood cell transfusion can cause fluid overload. We evaluated the interaction between heart failure (HF) at baseline and transfusion strategy on outcomes in acute myocardial infarction (AMI)., Methods: We used data from the randomized REALITY trial. HF was defined as history of HF or Killip class > 1 at randomization. Primary outcome was major adverse cardiovascular events (MACE): composite of all-cause death, nonrecurrent AMI, stroke, or emergency revascularization prompted by ischemia at 30 days., Results: Among 658 randomized patients, 311 (47.3%) had HF. Patients with HF had higher rates of MACE at 30 days and 1 year and higher rates of nonfatal new-onset HF. There was no interaction between HF and effect of randomized assignment on the primary outcome or nonfatal new-onset HF. A liberal transfusion strategy was associated with increased all-cause death at 30 days and at 1 year in patients with HF (P interaction  = 0.009 and P = 0.049, respectively). The main numerical difference in cause of death between restrictive and liberal strategies was death by HF at 30 days (4 vs 11)., Conclusions: HF is frequent in patients with AMI and anemia and is associated with higher risk of MACE (including all-cause death) and nonfatal new-onset HF. Although there was no interaction of HF with effect of transfusion strategy on MACE, a liberal transfusion strategy was associated with higher all-cause death that appears driven by a higher risk of early death caused by HF., Clinical Trial Registration: NCT02648113., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Autoantibodies directed against the GluA3 subunit (anti-GluA3 hIgGs) of AMPA receptors have been identified in 20%-25% of patients with frontotemporal lobar degeneration (FTLD). Data from patients and in vitro/ex vivo pre-clinical studies indicate that anti-GluA3 hIgGs negatively affect glutamatergic neurotransmission. However, whether and how the chronic presence of anti-GluA3 hIgGs triggers synaptic dysfunctions and the appearance of FTLD-related neuropathological and behavioural signature has not been clarified yet. To address this question, we developed and characterized a pre-clinical mouse model of passive immunization with anti-GluA3 hIgGs purified from patients. In parallel, we clinically compared FTLD patients who were positive for anti-GluA3 hIgGs to negative ones. Clinical data showed that the presence of anti-GluA3 hIgGs defined a subgroup of patients with distinct clinical features. In the preclinical model, anti-GluA3 hIgGs administration led to accumulation of phospho-tau in the postsynaptic fraction and dendritic spine loss in the prefrontal cortex. Remarkably, the preclinical model exhibited behavioural disturbances that mostly reflected the deficits proper of patients positive for anti-GluA3 hIgGs. Of note, anti-GluA3 hIgGs-mediated alterations were rescued in the animal model by enhancing glutamatergic neurotransmission with a positive allosteric modulator of AMPA receptors. Overall, our study clarified the contribution of anti-GluA3 autoantibodies to central nervous system symptoms and pathology and identified a specific subgroup of FTLD patients. Our findings will be instrumental in the development of a therapeutic personalised medicine strategy for patients positive for anti-GluA3 hIgGs., 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 © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Converging evidence points to impairments of the predictive function exerted by the cerebellum as one of the causes of the social cognition deficits observed in patients with cerebellar disorders., Objective: We tested the neurorestorative effects of cerebellar transcranial direct current stimulation (ctDCS) on the use of contextual expectations to interpret actions occurring in ambiguous sensory sceneries in a sample of adolescents and young adults with congenital, non-progressive cerebellar malformation (CM)., Methods: We administered an action prediction task in which, in an implicit-learning phase, the probability of co-occurrence between actions and contextual elements was manipulated to form either strongly or moderately informative expectations. Subsequently, in a testing phase, we probed the use of these contextual expectations for predicting ambiguous (i.e., temporally occluded) actions. In a sham-controlled, within-subject design, participants received anodic or sham ctDCS during the task., Results: Anodic ctDCS, compared to sham, improved patients' ability to use contextual expectations to predict the unfolding of actions embedded in moderately, but not strongly, informative contexts., Conclusions: These findings corroborate the role of the cerebellum in using previously learned contextual associations to predict social events and document the efficacy of ctDCS to boost social prediction in patients with congenital cerebellar malformation. The study encourages the further exploration of ctDCS as a neurorestorative tool for the neurorehabilitation of social cognition abilities in neurological, neuropsychiatric, and neurodevelopmental disorders featured by macro- or micro-structural alterations of the cerebellum., 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 © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Transfusions are extremely frequent after cardiac surgery, and they have a considerable economic burden and impact on outcomes. Optimal patient blood management could play a fundamental role in reducing the rate of transfusion and Jehovah's Witnesses (JW) represent the ideal surrogate study population. This meta-analysis compares outcomes of JWs and non-JWs' patients undergoing cardiac surgery, assessing the safety of a bloodless cardiac surgery. A scoping review was conducted using a search strategy for studies assessing outcomes of JW undergoing cardiac surgery. The primary outcome was perioperative mortality, and a random-effects meta-analysis was performed. Ten studies were included in our meta-analysis, involving 780 JW patients refusing any type of transfusion ("JW") and 1182 patients accepting transfusion if needed ("non-JW"). 86% of non-JW patients received at least 1 transfusion. There was no significant difference in terms of perioperative mortality (OR 0.91; 95% CI 0.55-1.52; p = 0.72). The volume blood loss was significantly less in the JW (p = 0.001), while the rate of reoperation for bleeding was also lower, but not statistically significative, in the JW (p = 0.16). Both preoperative and postoperative hemoglobin and hematocrit were significantly higher in the JW. Therefore, we concluded that bloodless cardiac surgery is safe and early outcomes are similar between JW and non-JW patients: optimal patient blood management is fundamental in guarantying these results. Further studies are needed to assess if a limitation of transfusion could have a positive long-term impact on outcomes., 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 Elsevier Inc. All rights reserved.)

Background: Mitral valve-in-valve (ViV) is associated with suboptimal hemodynamics and rare left ventricular outflow tract (LVOT) obstruction., Objectives: This study aimed to determine whether device position and asymmetry are associated with these outcomes., Methods: Patients undergoing SAPIEN 3 (Edwards Lifesciences) mitral ViV included in the VIVID (Valve-in-Valve International Data) Registry were studied. Clinical endpoints are reported according to Mitral Valve Academic Research Consortium definitions. Residual mitral valve stenosis was defined as mean gradient ≥5 mm Hg. Depth of implantation (percentage of transcatheter heart valve [THV] atrial to the bioprosthesis ring) and asymmetry (ratio of 2 measures of THV height) were evaluated., Results: A total of 222 patients meeting the criteria for optimal core lab evaluation were studied (age 74 ± 11.6 years; 61.9% female; STS score = 8.3 ± 7.1). Mean asymmetry was 6.2% ± 4.4%. Mean depth of implantation was 19.0% ± 10.3% atrial. Residual stenosis was common (50%; mean gradient 5.0 ± 2.6 mm Hg). LVOT obstruction occurred in 7 cases (3.2%). Implantation depth was not a predictor of residual stenosis (OR: 1.19 [95% CI: 0.92-1.55]; P = 0.184), but more atrial implantation was protective against LVOT obstruction (0.7% vs 7.1%; P = 0.009; per 10% atrial, OR: 0.48 [95% CI: 0.24-0.98]; P = 0.044). Asymmetry was found to be an independent predictor of residual stenosis (per 10% increase, OR: 2.30 [95% CI: 1.10-4.82]; P = 0.027)., Conclusions: Valve stenosis is common after mitral ViV. Asymmetry was associated with residual stenosis. Depth of implantation on its own was not associated with residual stenosis but was associated with LVOT obstruction. Technical considerations to reduce postdeployment THV asymmetry should be considered., Competing Interests: Funding Support and Author Disclosures Dr Whisenant is a consultant for Edwards Lifesciences. Dr Unbehaun is a proctor for Edwards Lifesciences. Dr Erlebach has received speaker honoraria from Medtronic and Abbott; and is a proctor for Abbott. Dr Guerrero has received institutional research grant support from Edwards Lifesciences. Dr Bruschi is a consultant for Abbott. Dr Rudolph has received speaker honoraria from Edwards Lifesciences; and is a proctor for Edwards Lifesciences. Dr Andreas is a consultant for Edwards Lifesciences, Abbott, Medtronic, Boston Scientific, Zoll, and AbbVie; and has received institutional research grants from Edwards Lifesciences, Abbott, Medtronic, and LSI. Dr Dvir is a consultant for Edwards Lifesciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Cigarette smoking is a modifiable risk factor associated with formation and rupture of intracranial aneurysms (IAs). Cytochrome P450 2A6 (CYP2A6) is the main enzyme implied in catabolism of nicotine and xenobiotics, giving rise to oxidative stress products. Our study investigated the associations between specific single-nucleotide polymorphisms (SNPs) in the CYP2A6 gene and the presence of sporadic IAs in a cluster of Italian patients, as well as their rupture regarding cigarette smoking habit., Methods: Three hundred and thirty-one Italian patients with sporadic IAs were recruited in a single institution. We recorded data on clinical onset with subarachnoid hemorrhage (SAH) and smoking habit. Genetic analysis was performed with a standard procedure on peripheral blood samples: CYP2A6 ∗1B2, CYP2A6 ∗2, and CYP2A6 ∗14 SNPs were analyzed in the study group along with 150 healthy control subjects. Statistical analysis was conducted according to genetic association study guidelines., Results: In the patient cohort, the frequency of aSAH was significantly higher in current smokers (P < 0.001; OR=17.45), regardless of the pattern of CYP2A6 SNPs. There was a correlation between IA rupture and cigarette smoking in patients with the heterozygous CYP2A6 ∗1B2 allele (P < 0.001; OR=15.47). All patients carrying the heterozygous CYP2A6 ∗14 allele had an aSAH event (100%), regardless of smoking habit, although this correlation was not statistically significant (P = 1)., Conclusions: According to our findings, a cigarette smoker carrying a fully active CYP2A6 enzyme (heterozygous ∗1B2 allele) may have an increased risk of IA rupture compared to those with functionally less active variants: further investigation on a larger sample is needed to verify this result. The role of the heterozygous CYP2A6 ∗14 allele in aSAH is yet to be clarified., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Thoracic endovascular aortic repair (TEVAR) has become a standard treatment for acute and chronic thoracic aorta diseases. We analyzed long-term outcomes and risk factors of TEVAR procedures according to the aortic pathology., Methods: Demographics, indications, technical details, and outcomes of patients undergoing TEVAR procedures in our institutions were prospectively collected and retrospectively analyzed. Overall survival was determined using Kaplan-Meier methods while log-rank tests were used to compare the survival between groups. Cox regression analysis was used to identify risk factors., Results: Between June 2002 and April 2020, 116 patients underwent TEVAR for different thoracic aorta diseases. Among them, 47 patients (41%) underwent TEVAR for aneurysmatic aortic disease, 26 (22%) for type-B aortic dissection, 23 (20%) for penetrating aortic ulcer, 11 (9%) after previous type-A dissection treatment, and 9 (8%) for traumatic aortic injury. Patients with posttraumatic aortic injury were younger (P < 0.01) with less hypertension (P < 0.01), diabetes (P < 0.01), and prior cardiac surgery (P < 0.01). Survival was different based on indication for TEVAR (log rank 0.024). Patients after previous type-A dissection treatment had the worst survival rate (50% at 5 years) while survival for aneurysmatic aortic disease was 55% at 5 years. No late death occurred in the traumatic group. Cox-regression model identified independent predictors for mortality: age (hazard ratio [HR]: 1.05, 95% confidence interval [CI]: 1.01-1.09, P = 0.006), male gender (HR: 3.2, 95% CI: 1.1-9.2, P = 0.028), moderate chronic obstructive pulmonary disease (HR: 2.1, 95% CI: 1.02-4.55, P = 0.043), previous cardiac surgery (HR: 2.1, 95% CI: 1.008-4.5, P = 0.048), and treatment indication for aneurysm (HR: 2.6, 95% CI: 1.2-5.2, P = 0.008)., Conclusions: TEVAR is a safe and effective procedure with excellent long-term results in case of traumatic aortic injury. The overall long-term survival is affected by aortic pathology, associated comorbidities, gender, and previous cardiac surgery., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Thoracic endovascular aortic repair (TEVAR) has been the favored approach for the treatment of type B aortic dissection (TBAD). To obtain an adequate proximal landing zone, coverage of the left subclavian artery (LSA) will often be necessary. The occurrence of possible neurologic complications has continued to be debated. We investigated the management of the LSA in patients with TBAD undergoing endovascular repair., Methods: We searched the PubMed and MEDLINE databases to October 2020 for studies of TEVAR for TBAD. Data on the study design, demographics, endograft details, LSA coverage and revascularization, mortality, complications, and follow-up were extracted and analyzed. The effects of LSA coverage and revascularization on neurologic complications and outcomes were investigated., Results: A total of 26 reports (24 retrospective and 2 prospective) were deemed eligible for our study. A total of 1483 patients (mean age, 56.9 ± 6.2 years) had undergone TEVAR for acute (n = 932; 62.9%), subacute (n = 36; 2.4%), or chronic (n = 515; 34.7%) TBAD, with a success rate of 97.8% and hospital mortality of 4.9%. The LSA origin had been covered for 707 patients (47.7%), and 326 had undergone LSA revascularization (surgical, n = 96; endovascular, n = 170; unspecified or not reported, n = 60). LSA revascularization was concomitant for 68.1% of cases, after TEVAR for 1.8%, and not reported for 30.1%. Of 1146 patients, 10 (0.9%) had experienced left arm claudication, and the overall stroke rate was 3.3% (2.7% for the LSA group and 1% for the uncovered LSA group; P = .0815). Of the patients with stroke and a covered LSA, 1% (2 of 203) had undergone LSA revascularization and 4.8% (5 of 105) had not (P = .0478). Twenty-six patients (1.9%) had developed paraplegia: 0.7% (3 of 433) with a covered LSA, 1.4% (7 of 491) with an uncovered LSA (P = .3508), and not reported for 16 patients. Endoleak was present in 138 patients (13.4%) at a mean follow-up of 32.1 ± 25.6 months., Conclusions: Our review has shown that LSA coverage during endovascular repair for complicated TBAD will does not significantly increase the risk of neurologic complications; however, revascularization of the LSA should be always recommended., (Copyright © 2022. Published by Elsevier Inc.)

Antarctica has been affected directly and indirectly by human pressure for more than two centuries and recently plastic pollution has been recognized as a further potential threat for its unique biodiversity. Global long-range transport as well as local input from anthropogenic activities are potential sources of plastic pollution in both terrestrial and marine Antarctic territories. The present study evaluated the presence of microplastics in specimens of the Antarctic whelk Neobuccinum eatoni, a key species in benthic communities of the Ross Sea, one of the largest marine protected areas worldwide. To this aim, a thermo-oxidative extraction method was applied for microplastic isolation and quantification, and polymer identification was performed by manual μ-FTIR spectroscopy. Textile (semi-)synthetic or composite microfibers (length range: 0.8-5.7 mm) were found in 27.3% of whelk specimens, suggesting a low risk of bioaccumulation along Antarctic benthic food webs in the Ross Sea. Their polymer composition (of polyethylene terephthalate and cellulose-polyamide composites) matched those of outdoor technical clothing in use by the personnel of the Italian "Mario Zucchelli" station near Terra Nova Bay in the Ross Sea. Such findings indicate that sewage from base stations may act as potential local sources of textile microplastic fibers in this remote environment. More in-depth monitoring studies aiming at defining the extent of microplastic contamination related to such sources in Antarctica are encouraged., 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 © 2022 Elsevier Inc. All rights reserved.)

Objective: Dissection of the carotid artery (CaAD) may result in aneurysm formation. The present study was undertaken to evaluate the time of onset of post-dissection extracranial carotid artery aneurysms (ECAA) following CaAD, and to analyse independent risk factors for the development of these aneurysms., Methods: From four European stroke centres, 360 patients with extracranial CaAD were included. The time between the estimated dissection onset and aneurysm formation was analysed, and the clinical risk factors increasing the probability of aneurysm were assessed., Results: The median duration of follow up was 5.2 months (range 0 - 24 months). A total of 75 post-dissection ECAAs were identified in 70 patients (19.4%, 95% confidence interval [CI] 15.7 - 23.8). In 52 of 70 (74%) patients, the ECAA was diagnosed at the initial clinical work up of CaAD diagnosis, with the median estimated time of dissection onset to ECAA diagnosis being six days (interquartile range [IQR] 0 - 25). In the remaining 18 (26%) patients who had normal carotid arteries at the initial imaging, the aneurysm diagnosis was made a median of 6.2 months (189 days) from the original imaging (IQR 128 - 198). A Cox proportional hazards model showed that both multiple artery dissections (hazard ratio [HR] 2.58, 95% CI 1.54 - 4.33) and arterial tortuosity (HR 1.79, 95% CI 1.08 - 2.95) were associated with presence of ipsilateral ECAA., Conclusion: This post hoc cohort analysis showed substantially delayed development of ipsilateral ECAA in patients with CaAD, months after baseline. Multiple dissections and arterial tortuosity are associated with the presence of ECAA and can be used in future prediction models of ECAA development in patients with CaAD., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Toxic aggregates of α-synuclein (αsyn) are considered key drivers of Parkinson's disease (PD) pathology. In early PD, αsyn induces synaptic dysfunction also modulating the glutamatergic neurotransmission. However, a more detailed understanding of the molecular mechanisms underlying αsyn-triggered synaptic failure is required to design novel therapeutic interventions. Here, we described the role of Rabphilin-3A (Rph3A) as novel target to counteract αsyn-induced synaptic loss in PD. Rph3A is a synaptic protein interacting with αsyn and involved in stabilizing dendritic spines and in promoting the synaptic retention of NMDA-type glutamate receptors. We found that in vivo intrastriatal injection of αsyn-preformed fibrils in mice induces the early loss of striatal synapses associated with decreased synaptic levels of Rph3A and impaired Rph3A/NMDA receptors interaction. Modulating Rph3A striatal expression or interfering with the Rph3A/αsyn complex with a small molecule prevented dendritic spine loss and rescued associated early motor defects in αsyn-injected mice. Notably, the same experimental approaches prevented αsyn-induced synaptic loss in vitro in primary hippocampal neurons. Overall, these findings indicate that approaches aimed at restoring Rph3A synaptic functions can slow down the early synaptic detrimental effects of αsyn aggregates in PD., Competing Interests: Conflicts of interest The authors declare no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Postthrombotic syndrome (PTS) is a long-term complication after deep vein thrombosis (DVT) and can affect quality of life (QoL). Pathogenesis is not fully understood but inadequate anticoagulant therapy with vitamin K antagonists is a known risk factor for the development of PTS., Objectives: To compare the prevalence of PTS after acute DVT and the long-term QoL following DVT between patients treated with edoxaban or warfarin., Methods: We performed a long-term follow-up study in a subset of patients with DVT who participated in the Hokusai-VTE trial between 2010 and 2012 (NCT00986154). Primary outcome was the prevalence of PTS, defined by the Villalta score. The secondary outcome was QoL, assessed by validated disease-specific (VEINES-QOL) and generic health-related (SF-36) questionnaires., Results: Between 2017 and 2020, 316 patients were enrolled in 26 centers in eight countries, of which 168 (53%) patients had been assigned to edoxaban and 148 (47%) to warfarin during the Hokusai-VTE trial. Clinical, demographic, and thrombus-specific characteristics were comparable for both groups. Mean (SD) time since randomization in the Hokusai-VTE trial was 7.0 (1.0) years. PTS was diagnosed in 85 (51%) patients treated with edoxaban and 62 (42%) patients treated with warfarin (adjusted odds ratio 1.6, 95% CI 1.0-2.6). Mean differences in QoL scores between treatment groups were not clinically relevant., Conclusion: Contrary to our hypothesis, the prevalence of PTS tended to be higher in patients treated with edoxaban compared with warfarin. No differences in QoL were observed. Further research is warranted to unravel the role of anticoagulant therapy on development of PTS., Competing Interests: J.B.W. reports personal fees and other from Bayer HealthCare, personal fees and other from Boehringer. Ingelheim, personal fees and other from BMS/Pfizer, personal fees and other from CSL Behring, personal fees and other personal fees and other from Daiichi Sankyo, personal fees and other from LEO Pharma, outside the submitted work. F.C. reports grants from BMS/Pfizer, personal fees and other from Bayer HealthCare, personal fees and other from AstraZeneka, personal fees and other from MSD, personal fees and other from GSK, other from Janssen, personal fees and other from Novartis, outside the submitted work. M.C. reports personal fees from Bayer HealthCare, personal fees from Boehringer Ingelheim, personal fees from Bristol‐Myers Squib, personal fees from CSL Behring, personal fees from Daiichi Sankyo, personal fees from Pfizer, personal fees from Portola, personal fees from Sanquin Blood Supply, outside the submitted work. W.G. reports grants and other from Bayer HealthCare, grants and other from Pfizer, other from Novartis, other from Amgen, other from Principia, from Sanofi, other from MSD, other from Sobi, outside the submitted work. K. Meijer receives other from Bayer HealthCare, other from Uniqure, other from Alexion, other from Octapharma, outside the submitted work. S.M. reports grants from GSK, grants from BMS/Pfizer, grants from Aspen, grants from Daiichi Sankyo, grants from Bayer HealthCare, grants from Boehringer Ingelheim, grants from Sanofi, grants from Portola, outside the submitted work. M.A.S.P. reports honoraria from Bayer, Pfizer, and Leo Pharma. O.S. reports grants from Daiichi‐Sankyo, during the conduct of the study; grants, personal fees, and nonfinancial support from Bayer HealthCare, grants, personal fees and nonfinancial support from BMS, personal fees and non‐financial support from Pfizer, grants, personal fees and non‐financial support from Boehringer Ingelheim, grants and personal fees from MSD, personal fees from Chiesi, grants and personal fees from Boston Scientifics, outside the submitted work. S.M.S. reports receiving consulting fees from Bayer and Boehringer Ingelheim, and lecture fees from Bayer, Boehringer Ingelheim, and Bristol‐Myers Squibb–Pfizer. P.V. reports grants and personal fees from Bayer HealthCare, grants and personal fees from Boehringer Ingelheim, grants and personal fees from BMS/Pfizer, personal fees from Daiichi Sankyo, personal fees from LEO Pharma, personal fees from Anthos therapeutics, personal fees from Portola Pharmaceuticals/Alexion, outside the submitted work. M.G., M.S., and Y.L. report being an employee of Daiichi‐Sankyo. No other potential conflict of interest with relation to this study were reported., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Nuclear Magnetic Resonance (NMR) based metabolomic analysis of whole saliva has provided potential diagnostic biomarkers for numerous human diseases contributing to a better understanding of their mechanisms. However, a comprehensive interpretation of the significance of metabolites in whole, parotid, and submandibular/sublingual saliva subtypes is still missing. Precision and reproducibility of sample preparation is an essential step. Here, we present a simple and efficient protocol for saliva 1 H-NMR metabolic profiling. This procedure has been specifically designed and optimized for the identification and quantification of low concentration metabolites (as low as 1.1 μM) and is suitable for all the saliva subtypes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Long-term sequelae of acute pulmonary embolism (PE) include decreased quality of life (QoL). Evidence suggests that adequacy of initial anticoagulant treatment in the acute phase of venous thrombosis has a key impact on late postthrombotic complications. We hypothesize that patients with acute PE treated with edoxaban for acute PE experience have improved QoL compared to those treated with warfarin., Methods: Patients with PE who participated in the Hokusai-VTE trial were contacted between June 2017 and September 2020 for a single long-term follow-up visit. Main outcomes were the generic and disease-specific QoL measured by the 36-Item Short Form Health Survey (SF-36) and Pulmonary Embolism Quality of Life questionnaire., Results: We included 251 patients from 26 centers in eight countries, of which 129 (51%) had been assigned to edoxaban and 122 (49%) to warfarin. Patient- and thrombus-specific characteristics were similar in both groups. Mean time since randomization in the Hokusai-VTE trial was 7.0 years (standard deviation, 1.0). No relevant or statistical differences were observed in the QoL for patients treated with edoxaban compared to patients treated with warfarin. The mean difference between patients treated with edoxaban and patients with PE treated with warfarin was 0.8 (95% confidence interval [CI]. -1.6 to 3.2) for the SF-36 summary mental score and 1.6 (95% CI, -0.9 to 4.1) for summary physical score., Conclusion: Our findings indicate that patients with an index PE treated with edoxaban or warfarin have a similar long-term QoL. Since our study was a follow-up study from a well-controlled clinical trial setting, future studies should be designed in a daily clinical practice setting. We suggest a longitudinal design for investigation of changes in QoL over time., (© 2021 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Background: Cardiac injury has been reported in up to 30% of coronavirus disease 2019 (COVID-19) patients. However, cardiac injury is defined mainly by troponin elevation without description of associated structural abnormalities and its time course has not been studied., Research Question: What are the ECG and echocardiographic abnormalities as well as their time course in critically ill COVID-19 patients?, Study Design and Methods: The cardiac function of 43 consecutive COVID-19 patients admitted to two ICUs was assessed prospectively and repeatedly, combining ECG, cardiac biomarker, and transthoracic echocardiographic analyses from ICU admission to ICU discharge or death or to a maximum follow-up of 14 days. Cardiac injury was defined by troponin elevation and newly diagnosed ECG or echocardiographic abnormalities, or both., Results: At baseline, 49% of patients demonstrated a cardiac injury, and 70% of patients experienced cardiac injury within the first 14 days of ICU stay, with a median time of occurrence of 3 days (range, 0-7 days). The most frequent abnormalities were ECG or echocardiographic signs, or both, of left ventricular (LV) abnormalities (87% of patients with cardiac injury), right ventricular (RV) systolic dysfunction (47%), pericardial effusion (43%), new-onset atrial arrhythmias (33%), LV relaxation impairment (33%), and LV systolic dysfunction (13%). Between baseline and day 14, the incidence of pericardial effusion and of new-onset atrial arrhythmias increased and the incidence of ECG or echocardiographic signs, or both, of LV abnormalities as well as the incidence of LV relaxation impairment remained stable, whereas the incidence of RV and LV systolic dysfunction decreased., Interpretation: Cardiac injury is common and early in critically ill COVID-19 patients. ECG or echocardiographic signs, or both, of LV abnormalities were the most frequent abnormalities, and patients with cardiac injury experienced more RV than LV systolic dysfunction., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Silicon oxide (SiO 2 ) nanostructures (SiO 2 NS) are increasingly being incorporated into an array of products, notably in the food, pharmaceutical, medical industries and in water treatment systems. Amorphous SiO 2 NS have low toxicity, however, due to their great versatility, superficial modifications can be made and these altered structures require toxicological investigation. In this study, SiO 2 NS were synthetized and amine-functionalized with the molecules (3-aminopropyl)triethoxysilane (APTMS) and 3-[2-(2-aminoethylamino)ethylamino]propyltrimethoxysilane (AEAEAPTMS), named SiO 2 NS@1 and SiO 2 NS@3, respectively. The bare SiO 2 NS, SiO 2 NS@1 and SiO 2 NS@3 samples were characterized and the influence of the culture medium used in the toxicological assays was also evaluated. The effect of amine functionalization of SiO 2 NS was investigated through acute and chronic toxicity assays with Daphnia magna. Modifications to ultrastructures of the intestine and eggs of these organisms were observed in TEM and SEM analysis. The toxicity was influenced by the surface modifications and a possible Trojan horse effect was highlighted, particularly in the case of chronic exposure. Exposure to all NSs promoted alterations in the microvilli and mitochondria of the D. magna intestine and some damage to egg cells was also observed. The results demonstrate the importance of carrying out a full characterization of these materials, since surface modifications can enhance their toxic potential., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Complete atrioventricular block (AVB3) may be an urgent potentially lifethreatening situation. Our objective was to describe the routine management of AVB 3, with emphasis on the organizational aspects., Methods: From September 2019 to November 2019, a prospective national survey including 28 questions was electronically sent to 100 physicians (Google Form)., Results: The answers were collected from 93 physicians (response rate 93%). Permanent pacemaker implantation during weekends and nights (after 8PM) is possible for 49% of the operators (<5 times a year), for 15% (>5 times a year), impossible for 36% of the operators. For AVB3 nonresponsive to isoproterenol occurring during the night, a temporary pacing lead (TPL) is implanted by: the on-site medical staff on-duty (27%), the on-call interventional cardiologist (21%), the on-call electrophysiologist (19%), a permanent pacemaker is implanted by the electrophysiologist (12%), the strategy is not standardized (15%). An externalized active fixation lead (AFL) for AVB3 has already been implanted by 50% of the operators. 80 (86%) have already observed a dislocation of the TPL, a cardiac perforation already occurred in 57 (61%), a groin hematoma in 35 (38%), and this technique was proscribed for 4% of the operators., Conclusion: Our survey shows important disparities in terms of management of AVB3 among the different centers. An externalized AFL with a reusable generator was used by half of the centers., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

The COVID-19 pandemic has affected all Sub-Saharan economies through a multitude of impact channels. The study determines the medium-term macroeconomic outcomes of the pandemic on the Kenyan economy and links the results with a detailed food security and nutrition microsimulation module. It thus evaluates the effectiveness of the adopted government measures to reduce the negative outcomes on food security and to enable economic recovery at aggregate, sectoral and household levels. Through income support measures, the food sector and food demand partially recover. However, 1.3% of households still fall below calorie intake thresholds, many of which are in rural areas. Results also indicate that the state of food security in Kenya remains vulnerable to the evolution of the pandemic abroad., Competing Interests: 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., (© 2021 The Authors.)

Background: Electrical cardioversion is the first-line rhythm control therapy for symptomatic persistent atrial fibrillation (AF). Contemporary use of biphasic shock waveforms and anterior-posterior positioning of defibrillation electrodes have improved cardioversion efficacy; however, it remains unsuccessful in >10% of patients., Objective: The purpose of this study was to assess the efficacy of applying active compression on defibrillation electrodes during AF cardioversion., Methods: We performed a bicenter randomized study including patients referred for persistent AF cardioversion. Elective external cardioversion was performed by a standardized step-up protocol with increasing biphasic shock energy (50-100-150-200 J). Patients were randomly assigned to standard anterior-posterior defibrillation or to defibrillation with active compression applied over the anterior electrode. If sinus rhythm was not achieved at 200 J, a single crossover shock (200 J) was applied. Defibrillation threshold, total delivered energy, number of shocks, and success rate were compared between groups., Results: We included 100 patients, 50 in each group. In the active compression group, defibrillation threshold was lower (103.1 ± 49.9 J vs 130.4 ± 47.7 J; P = .008), as well as total delivered energy (203 ± 173.3 J vs 309 ± 213.5 J; P = .0076) and number of shocks (2.2 ± 1.1 vs 2.9 ± 1.2; P = .0033), and cardioversion was more often successful (48 of 50 patients [96%] vs 42 of 50 patients [84%]; P = .0455) than that in the standard anterior-posterior group. Crossover from the compression group to the standard group was not successful (0 of 2 patients), whereas crossover from the standard group to the compression group was successful in 50% of patients (4 of 8)., Conclusion: Active compression applied to the anterior defibrillation electrode is more effective for persistent AF cardioversion than standard anterior-posterior cardioversion, with lower defibrillation threshold and higher success rate., (Copyright © 2020 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

The 25R-NBOH family is a group of thermally labile compounds that are relevant for forensic sciences and traditionally analyzed by GC-MS after derivatization - a step that is time consuming in a routine work. In this paper, the use of short analytical columns (4 and 10 m) showed to decrease compound degradation in the GC oven during chromatographic separation and to allow the analysis of non-derivatized 25R-NBOH compounds by GC-MS. A shorter column demanded a higher gas flow rate, and both factors decreased residence time of the analytes in the column and their degradation. The inlet temperature (250° C or 280°C) did not impact the response of 25R-NBOH. A 25R-NBOH fragmentation pathway by electron ionization was also presented for the first time. The GC-MS method with a 4 m column was successfully applied to other compounds of forensic interest, and it can be tested in the analysis of biological samples in toxicological investigations., 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 © 2020 Elsevier B.V. All rights reserved.)

Protease-activated receptor 1 (PAR1) is a G protein-coupled receptor (GPCR), whose activation requires a proteolytic cleavage in the extracellular domain exposing a tethered ligand, which binds to the same receptor thus stimulating Gα q/11 -, Gα i/o - and Gα 12-13 proteins. PAR1, activated by serine proteases and matrix metalloproteases, plays multifaceted roles in neuroinflammation and neurodegeneration, in stroke, brain trauma, Alzheimer's diseases, and Parkinson's disease (PD). Substantia nigra pars compacta (SNpc) is among areas with highest PAR1 expression, but current evidence on its roles herein is restricted to mechanisms controlling dopaminergic (DAergic) neurons survival, with controversial data showing PAR1 either fostering or counteracting degeneration in PD models. Since PAR1 functions on SNpc DAergic neurons activity are unknown, we investigated if PAR1 affects glutamatergic transmission in this neuronal population. We analyzed PAR1's effects on NMDARs and AMPARs by patch-clamp recordings from DAergic neurons from mouse midbrain slices. Then, we explored subunit composition of PAR1-sensitive NMDARs, with selective antagonists, and mechanisms underlying PAR1-induced NMDARs modulation, by quantifying NMDARs surface expression. PAR1 activation inhibits synaptic NMDARs in SNpc DAergic neurons, without affecting AMPARs. PAR1-sensitive NMDARs contain GluN2B/GluN2D subunits. Moreover, PAR1-mediated NMDARs hypofunction is reliant on NMDARs internalization, as PAR1 stimulation increases NMDARs intracellular levels and pharmacological limitation of NMDARs endocytosis prevents PAR1-induced NMDARs inhibition. We reveal that PAR1 regulates glutamatergic transmission in midbrain DAergic cells. This might have implications in brain's DA-dependent functions and in neurological/psychiatric diseases linked to DAergic dysfunctions., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Curcumin metal complexes showed widespread applications in medicine and can be exploited as a lead structure for developing new tracers for nuclear medicine application. Herein, the synthesis, chemical characterization and radiolabelling with gallium-68 and scandium-44 of two new targeting vectors based on curcumin scaffolds and linked to the chelators 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA) and 1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-methylperhydro-1,4-diazepine (AAZTA) are reported. Synthesis of the precursors could be achieved with a 13% and 11% yield and radiolabelling generally afforded rapid incorporation under mild conditions (>95%). Stability in physiological media (~75% after 2 h in human blood for [ 68 Ga]Ga-/[ 44 Sc]Sc-AAZTA-PC21 and ~60% for [ 68 Ga]Ga-NODAGA-C21, respectively) are generally enhanced if compared to the previously radiolabelled analogues. MS n fragmentation experiments showed high stability of the AAZTA-PC21 structure mainly due to the pyrazole derivatization of the curcumin keto-enol moiety and a more feasible radiolabelling was noticed both with gallium-68 and scandium-44 mainly due to the AAZTA-chelator properties. [ 68 Ga]Ga-NODAGA-C21 showed the most favorable lipophilicity value (logD = 1.3). Due to these findings, both compounds appear to be promising candidates for the imaging of colorectal cancer, but further studies such as in vitro uptake and in vivo biodistribution experiments are needed., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2019. Published by Elsevier Inc.)

A selection of historical textile fragments from the Venetian art dealer Moisè Michelangelo Guggenheim collection, ranging from XV to XVIII century, has been investigated by means of non-invasive techniques in order to reveal the coloring materials. Imaging was preliminarily used to visually investigate the selected artwork fragments in order to investigate their structure and conservation conditions; Fiber Optics Reflectance Spectroscopy (FORS) allowed recognizing the main natural dyestuffs, such as indigotin and anthraquinones-based compounds, except the yellow ones, difficultly identifiable when using this non-invasive technique. Collected spectroscopic data have been also elaborated by using a clustering algorithm that permitted to group collected spectra on the basis of similar properties and evidencing their inflection point wavelength as the most influencing feature., (Copyright © 2018 Elsevier B.V. All rights reserved.)

This case illustrates the evolution of right ventricular (RV) 3-dimensional (3D) area strain during pregnancy in a patient with repaired Tetralogy of Fallot. The report highlights impairment in RV function with pregnancy, suggesting the importance of prepregnancy RV systolic function assessment, especially using 3D echocardiography., (Copyright © 2018 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Acinetobacter baumannii has been identified by the WHO as a high priority pathogen. It can be resistant to multiple antibiotics and colistin sulphate is often used as a last-resort treatment. However, the potentially severe side-effects of colistin are well documented and this study compared the bactericidal and anti-biofilm activity of two synthetic nature-inspired antimicrobial peptides, bicarinalin and BP100, with colistin. The minimum bactericidal concentration (MBC) against planktonic A. baumannii was approximately 0.5 μg/ml for colistin sulphate and ∼4 μg/ml for bicarinalin and BP100. A. baumannii commonly occurs as a biofilm and biofilm removal assay results highlighted that both bicarinalin and BP100 had significantly greater potential than colistin. Atomic force microscopy (AFM) showed dramatic changes in A. baumannii cell size and surface conformity when treated with peptide concentrations at and above the MBC. Scanning electron microscopy (SEM) visualised the reduction of biofilm coverage and cell surface changes as peptide concentration increased. Liposome assays revealed that these peptides most likely act as pore-forming agents in the membrane. Bicarinalin and BP100 may be effective therapeutic alternatives to colistin against A. baumannii infections but further research is required to assess if they elicit cytotoxicity issues in patients., (Copyright © 2018 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

Intrinsic foot muscles (IFM) are a crucial component within the human foot. Investigating their functioning can help understand healthy and pathological behaviour of foot and ankle, fundamental for everyday activities. Recording muscle activation from IFM has been attempted with invasive techniques, mainly investigating single muscles. Here we present a novel methodology, to investigate the feasibility of recording physiological surface EMG (sEMG) non-invasively and quantify patterns of activation across the whole plantar region of the foot. sEMG were recorded with a 13 × 5 array from the sole of the foot (n = 25) during two-foot stance, two-foot tiptoe and anterior/posterior sways. Physiological features of sEMG were analysed. During anterior/posterior epochs within the sway task, sEMG patterns were analysed in terms of signal amplitude (intensity) and structure (Sample Entropy) distribution, by evaluating the centre of gravity (CoG) of each topographical map. Results suggest signals are physiological and not affected by loading. Both amplitude and sample entropy CoG coordinates were grouped in one region and overlapped, suggesting that the region with highest amplitude corresponds with the most predictable signal. Therefore, both spatial and temporal features of IFM activation may be recorded non-invasively, providing opportunity for more detailed investigation of IFM function in healthy and patient populations., (Copyright © 2018. Published by Elsevier Ltd.)