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Since its inception, Health Technology Assessment (HTA) has typically determined the value of a technology by collecting information derived from randomized clinical trials (RCTs), in line with the principles of evidence-based medicine (EBM). However, data from RCTs did not constitute the sole source of information, as other types of evidence (such as primary qualitative research) have often been utilized. Recent advances in both generating and collecting other types of evidence are broadening the landscape of evidence, adding complexity to the discussion of "robustness of evidence." What are the consequences of these recent developments for the methodology and conduct of HTA, the HTA community, and its ethical commitments? The aim of this article is to explore some ethical challenges that are emerging in the current evolving evidence landscape, particularly changes in evidence generation and collection (e.g., diversification of data sources), and shifting standards of evidence in the field of HTA (e.g., increasing acceptability of evidence that is thought of as lower quality). Our conclusion is that deciding how to best maintain trustworthiness is common to all these issues.

The purpose of this study was to compare the flexural strength, Weibull modulus (reliability), marginal gap, and internal fit (internal gap) of 4 materials for milling or 3-dimensional (3D) printing of definitive and provisional crowns: IPS e.max CAD (IEC), Paradigm MZ100 Block (PMB), Permanent Crown Resin (PCR), and Temporary CB Resin (TCR). Flexural strength was tested by subjecting sectioned milling blocks (IEC and PMB) or 3D-printed bars (PCR and TCR) to a 3-point bending test in a universal testing machine (n = 15 per material). Crowns were milled or 3D printed, and the marginal gap and internal fit were measured using microcomputed tomography (n = 5 per material). The data were analyzed with a t test and compared using analysis of variance (ANOVA) with Tukey post hoc comparisons (α = 0.05). The groups demonstrated the following mean (SD) flexural strength values: IEC, 335.50 (28.97) MPa; PMB, 154.34 (21.03) MPa; PCR, 128.09 (7.30) MPa; and TCR, 126.29 (9.23) MPa. A 1-way ANOVA revealed significant differences in the flexural strengths of sectioned and 3D-printed bars (P < 0.001). The PMB group showed the lowest Weibull modulus (8.77), indicating its poor reliability. The IEC group showed the smallest marginal gap, 53.42 (31.99) μm; this value was significantly smaller than the gap in the TCR group (P < 0.001) but not the PCR or PMB group. The PMB group had the smallest internal fit discrepancy (87.44 [37.60] μm) but was not significantly different from PCR, while TCR had a significantly greater internal fit discrepancy (130.61 [65.16] μm) than IEC, PMB, and PCR (P < 0.001). The occlusal internal fit discrepancies of 3D-printed crowns were significantly greater than those of milled crowns (P < 0.001). There was no statistically significant difference in flexural strength between the 3D-printed definitive (PCR) and provisional (TCR) materials. When the data were combined according to manufacturing method, the marginal gap and internal fit of crowns fabricated with 3D printing were comparable to those of milled crowns, and all mean marginal gaps were within a clinically acceptable limit of less than 120 μm., Competing Interests: No conflicts of interest reported.

Purpose: Defects in the gene encoding selenocysteine insertion sequence binding protein 2, SECISBP2, result in global impaired selenoprotein synthesis manifesting a complex syndrome with characteristic serum thyroid function tests due to impaired thyroid hormone metabolism. Knowledge about this multisystemic defect remains limited., Methods: Genetic and laboratory investigations were performed in affected members from 6 families presenting with short stature and failure to thrive., Results: Four probands presented a complex neurodevelopmental profile, including absent speech, autistic features, and seizures. Pediatric neurological evaluation prompted genetic investigations leading to the identification of SECISBP2 variants before knowing the characteristic thyroid tests in 2 cases. Thyroid hormone treatment improved motor development, whereas speech and intellectual impairments persisted. This defect poses great diagnostic and treatment challenges for clinicians, as illustrated by a case that escaped detection for 20 years because SECISBP2 was not included in the neurodevelopmental genetic panel, and his complex thyroid status prompted antithyroid treatment instead., Conclusion: This syndrome uncovers the role of selenoproteins in humans. The severe neurodevelopmental disabilities manifested in 4 patients with SECISBP2 deficiency highlight an additional phenotype in this multisystem disorder. Early diagnosis and treatment are required, and long-term evaluation will determine the full spectrum of manifestations and the impact of therapy., Competing Interests: Conflict of Interest The authors declare no conflicts of interest, (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Neuropilin-1 (NRP1) is a transmembrane glycoprotein expressed by several cell types including, neurons, endothelial cells (ECs), smooth muscle cells, cardiomyocytes and immune cells comprising macrophages, dendritic cells and T cell subsets. Since NRP1 discovery in 1987 as an adhesion molecule in the frog nervous system, more than 2300 publications on PubMed investigated the function of NRP1 in physiological and pathological contexts. NRP1 has been characterised as a coreceptor for class 3 semaphorins and several members of the vascular endothelial growth factor (VEGF) family. Because the VEGF family is the main regulator of blood and lymphatic vessel growth in addition to promoting neurogenesis, neuronal patterning, neuroprotection and glial growth, the role of NRP1 in these biological processes has been extensively investigated. It is now established that NRP1 promotes the physiological growth of new vessels from pre-existing ones in the process of angiogenesis. Furthermore, several studies have shown that NRP1 mediates signalling pathways regulating pathological vascular growth in ocular neovascular diseases and tumour development. Less defined are the roles of NRP1 in maintaining the function of the quiescent established vasculature in an adult organism. This review will focus on the opposite roles of NRP1 in regulating transforming growth factor β signalling pathways in different cell types, and on the emerging role of endothelial NRP1 as an atheroprotective, anti-inflammatory factor involved in the response of ECs to shear stress., (© 2024 The Author(s).)

Background: The purpose of this study was to evaluate the effect of milling speed on the surface roughness, marginal gap, marginal gap volume, marginal offset, and fracture load of zirconia restorations., Material and Methods: A mandibular molar #30 typodont tooth was digitally scanned and an ideal crown preparation for a zirconia restoration was digitally created. A single master model die of the crown preparation was milled out of a resin material. The master die was scanned, and a final restoration was designed using the bio-copy feature of the typodont tooth. Ten zirconia restorations were milled (CEREC Primemill, Dentsply Sirona) per each of three milling speeds (super-fast, fine, and extra-fine), sintered, and seated on the master die. Surface roughness, marginal gap, marginal gap volume, and marginal offset were measured using a non-contact profilometer. Then, all restorations were cemented to the dies and loaded to failure in a material testing device. Data were analyzed with one-way ANOVA and Tukey's post hoc tests per property (alpha=0.05)., Results: Super-fast milling speed resulted in restorations with statistically significant greater surface roughness and marginal gap volume compared to fine and extra-fine milling speeds. No significant difference in marginal gap, marginal offset, and fracture load were found based on milling speed., Conclusions: Zirconia restorations milled at slower speeds may result in similar or slightly better properties compared to super-fast speed. Key words: Milling speed, properties, zirconia restorations., Competing Interests: Conflicts of interest The authors do not have any financial interest in the companies whose materials are discussed in this manuscript., (Copyright: © 2024 Medicina Oral S.L.)

"Evidence" is a key term in medicine and health services research, including Health Technology Assessment (HTA). Randomized clinical trials (RCTs) have undoubtedly dominated the scene of generating evidence for a long period of time, becoming the hallmark of evidence-based medicine (EBM). However, due to a number of misunderstandings, the lay audience and some researchers have sometimes placed too much trust in RCTs compared to other methods of investigation. One of the principal misunderstandings is to consider RCTs findings as isolated and self-apparent pieces of information. In other words, what has been essentially lacking was the awareness of the value-context of the evidence and, in particular, the value- and theory-ladenness (normativity) of scientific knowledge. This paper aims to emphasize the normativity that exists in the production of scientific knowledge, and in particular in the conduct of RCTs as well as in the performance of HTA. The work is based on some lessons learned from Philosophy of Science and the European project "VALIDATE" (VALues In Doing Assessments of healthcare TEchnologies"). VALIDATE was a three-year EU Erasmus+ strategic partnerships project (2018-2021), in which training in the field of HTA was further optimized by using insights from political science and ethics (in accordance with the recent definition of HTA). Our analysis may reveal useful insights for addressing some challenges that HTA is going to face in the future.

Several rare genetic variations of human XDH have been shown to alter xanthine oxidoreductase (XOR) activity leading to impaired purine catabolism. However, XOR is a multi-functional enzyme that depending upon the environmental conditions also expresses oxidase activity leading to both O 2 ·- and H 2 O 2 and nitrite (NO 2 - ) reductase activity leading to nitric oxide (·NO). Since these products express important, and often diametrically opposite, biological activity, consideration of the impact of XOR mutations in the context of each aspect of the biochemical activity of the enzyme is needed to determine the potential full impact of these variants. Herein, we show that known naturally occurring hXDH mutations do not have a uniform impact upon the biochemical activity of the enzyme in terms of uric acid (UA), reactive oxygen species (ROS) and nitric oxide ·NO formation. We show that the His1221Arg mutant, in the presence of xanthine, increases UA, O 2 ·- and NO generation compared to the WT, whilst the Ile703Val increases UA and ·NO formation, but not O 2 ·- . We speculate that this change in the balance of activity of the enzyme is likely to endow those carrying these mutations with a harmful or protective influence over health that may explain the current equipoise underlying the perceived importance of XDH mutations. We also show that, in presence of inorganic NO 2 - , XOR-driven O 2 ·- production is substantially reduced. We suggest that targeting enzyme activity to enhance the NO 2 - -reductase profile in those carrying such mutations may provide novel therapeutic options, particularly in cardiovascular disease., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Amrita Ahluwalia is a Co-Director of a small start-up Heartbeet Ltd seeking to identify therapeutic opportunities for dietary nitrate., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: The purpose of this study was to compare the optical and mechanical properties of newer ceramic CAD/CAM materials to more established materials on the market., Methods and Materials: The following ceramic materials were tested: lithium disilicate/lithium-aluminum silicate (Tessera, Dentsply/Sirona), lithium disilicate (Initial LiSi Block, GC), IPS e.max CAD, Ivoclar Vivadent), and 4Y polycrystalline stabilized zirconia (IPS e.max ZirCAD MT, Ivoclar Vivadent; Katana STML, Kuraray; YZ ST, VITA). Optical properties (translucency, opalescence) were determined using a dental spectrophotometer on 0.5-, 1.0-, 1.5-, or 2.0-mm specimens. Mechanical properties (flexural strength, flexural modulus, flexural fatigue strength, Weibull modulus, and characteristic strength) were determined with beams undergoing 3-point bend testing. The data were analyzed with multiple analyses of variance and Tukey's post hoc tests (α=0.05)., Results: Significant differences were found between groups based on type of ceramic or property (p<0.05)., Conclusions: In general, the lithium disilicate based-ceramic materials had greater optical properties and lower mechanical properties than the zirconia-based ceramic materials., (©Operative Dentistry, 2023.)

Linear and disturbed flow differentially regulate gene expression, with disturbed flow priming endothelial cells (ECs) for a proinflammatory, atheroprone expression profile and phenotype. Here, we investigated the role of the transmembrane protein neuropilin-1 (NRP1) in ECs exposed to flow using cultured ECs, mice with an endothelium-specific knockout of NRP1, and a mouse model of atherosclerosis. We demonstrated that NRP1 was a constituent of adherens junctions that interacted with VE-cadherin and promoted its association with p120 catenin, stabilizing adherens junctions and inducing cytoskeletal remodeling in alignment with the direction of flow. We also showed that NRP1 interacted with transforming growth factor-β (TGF-β) receptor II (TGFBR2) and reduced the plasma membrane localization of TGFBR2 and TGF-β signaling. NRP1 knockdown increased the abundance of proinflammatory cytokines and adhesion molecules, resulting in increased leukocyte rolling and atherosclerotic plaque size. These findings describe a role for NRP1 in promoting endothelial function and reveal a mechanism by which NRP1 reduction in ECs may contribute to vascular disease by modulating adherens junction signaling and promoting TGF-β signaling and inflammation.

In line with how ethics has developed for the last three centuries, public health ethics has been widely dominated by a deontological as well as a utilitarian approach. The latter is a version of consequentialism, which states that maximizing utility is the primary goal of the majority of individuals or group action, while, on the other hand, virtue ethics, or at least the appeal to virtues, has been largely marginalized. The aim of this article is twofold. Firstly, we aim to highlight the political and ethical nature of public health interventions, often interpreted and presented as mere scientific enterprises. Secondly, we try to highlight the need to integrate or at least recognize the value of appeal to virtues in public health measures. The analysis will reference the Italian COVID-19 vaccination program as a case study. Initially, we will explore the political and ethical nature of any public health measure, using the implementation of the COVID-19 vaccination program in Italy as an example. Subsequently, we will illustrate the deontological approach to ethics, the utilitarian one, and the virtues one, focusing on the dynamic of the agent's perspective. Lastly, we will briefly analyze both the Italian COVID-19 vaccination program and the communication campaign that promoted it.

Background: Conflicting evidence exists on the impact of the COVID-19 pandemic restrictions on preterm birth (PTB) and stillbirth rates. We aimed to evaluate changes in PTB and stillbirth rates before and during the pandemic period and assess the potential effect modification of socioeconomic status (SES)., Methods: Using the linked administrative health databases from Manitoba, Canada, we conducted a cross-sectional study among all pregnant women, comparing 3.5 years pre-pandemic (1 October 2016 to 29 February 2020) to the first year of the pandemic (1 March 2020 to 31 March 2021). We used generalised linear models to assess the quarterly rates of PTB (<37 weeks) and stillbirths. We calculated the predicted trends based on pre-pandemic period data. Finally, we evaluated the PTB and stillbirth rates among lower and higher SES pregnant women (average annual household income) using subgroup analysis and interaction models., Results: We examined 70 931 pregnancies in Manitoba during the study period. The risk of PTB increased by 7.7% (95%CI 1.01 to 1.13) and stillbirths by 33% (95% CI 1.08 to 1.64) during the pandemic period. Following COVID-19 restrictions implemented in March 2020, there were increases in the quarterly rates of both PTB (immediate increase (β 2 )=1.37; p=0.0247) and stillbirths (immediate increase (β 2 )=0.12; p=0.4434). Among the lower income groups, the pandemic restrictions resulted in an immediate relative increase in PTB and stillbirth rates by 20.12% (immediate increase (β 2 )=3.17; p=0.0057) and 27.19% (immediate increase (β 2 )=0.48; p=0.0852). However, over the pandemic, the overall PTB rate significantly decreased as a rebound effect by 0.85% per quarter (p=0.0004), whereas the overall stillbirth rate did not decrease significantly (slope decrease (β 3 ) =-0.01; p=0.8296) compared with the pre-pandemic period. The quarterly rates during the pandemic among the higher income group decreased by 0.39% (p=0.1296) for PTB and increased by 0.07% (p=0.1565) for stillbirth. We observed an effect modification by SES for PTB rates (p=0.047)., Conclusion: While the onset of COVID-19 pandemic restrictions was not associated with significant effects on stillbirth rates, we observed an immediate and rebound effect on PTB rates. The impact of COVID-19 on preterm birth was dependent on SES, with higher influence on families with lower SES. Further studies are needed to detect future trend changes during pandemic waves after 2021 and assess potential underlying mechanisms., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Severe cases of Coronavirus Disease 2019 (COVID-19) that require admission to the Intensive Care Unit (ICU) and mechanical ventilation assistance show a high mortality rate with currently few therapeutic options available. Severe COVID-19 is characterized by a systemic inflammatory condition, also called "cytokine storm", which can lead to various multi-organ complications and ultimately death. Lidocaine, a safe local anesthetic that given intravenously is used to treat arrhythmias, has long been reported to have an anti-inflammatory and pro-homeostatic activity., Methods: We studied the capacity of lidocaine to modulate cytokine secretion of mouse and human myeloid cell lines activated by different cytokines or Toll Like Receptor (TLR) ligands (flagellin (FliC), Lipopolysaccharide (LPS), Polyinosinic:polycytidylic acid (Poly I:C) and N-Palmitoyl-S- [2,3-bis(palmitoyloxy)-(2RS)-propyl]-(R)-cysteinyl-(S)-seryl-(S)-lysyl-(S)-lysyl-(S)-lysyl-(S)-lysine x 3HCl (Pam3Cys-SKKKK)) or by Severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2) infection to epithelial cells. Reporter cell lines were used to study modulation of lidocaine of specific signaling pathways., Results: Lidocaine used in combination with dexamethasone, had an additive effect in the modulation of cellular inflammatory response triggered by Tumoral Necrosis Factor alpha (TNFα), Interleukin 1 beta (IL-1β) as well as different TLR ligands. We also found that lidocaine in combination with dexamethasone modulates the Nuclear factor kappa B (NF-κB) pathway, inflammasome activation as well as interferon gamma receptor (IFNγR) signaling without affecting the type I interferons (Type I IFNs) pathway. Furthermore, we showed that lidocaine and dexamethasone treatment of epithelial cells infected with SARS-CoV-2 modulated the expression of chemokines that contribute to pro-inflammatory effects in severe COVID., Conclusions: We reported for the first time in vitro anti-inflammatory capacity of lidocaine on SARS-CoV-2 triggered immune pathways. These results indicated the potential of lidocaine to treat COVID-19 patients and add tools to the therapeutic options available for these concerning cases., (Copyright © 2022 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

Background: This study investigated the properties (depth of cure, surface hardness, and volumetric shrinkage) of two composite restorative materials when polymerized with a novel "quad" spectrum (PinkWave) light-curing unit (LCU) compared to a tri-spectrum LCU (Valo Grand)., Material and Methods: One Valo Grand LCU was modified to be similar in irradiance to the PinkWave, and a second Valo Grand was utilized at the manufacturer's standard irradiant settings. Depth of cure was evaluated using the scraping technique (ISO 4049). Top and bottom surface hardness and bottom/maximum hardness ratios were determined using a hardness tester. Volumetric shrinkage was determined using a video-imaging device. Additionally, the surface temperature of the light tips of the LCUs was measured using a K-type thermocouple., Results: No significant difference in depth of cure was found with either composite between the PinkWave LCU and the modified Valo Grand LCU at similar irradiance. The unadjusted Valo Grand LCU had slightly less depth of cure. There was no difference in top or bottom surface hardness, bottom/maximum hardness ratios, or volumetric shrinkage between any of the LCU curing modes per composite type. The PinkWave LCU had a significantly greater increase in heat at the tip compared to the modified Valo Grand LCU at similar irradiance and the unadjusted Valo Grand LCU., Conclusions: The new quad-spectrum LCU, PinkWave, had a significant increase in surface temperature without any improvement in the composite properties tested compared to the tri-spectrum LCU, Valo Grand, at similar irradiance. Key words: Light-curing unit, emission spectrum, composite resin, mechanical and physical properties., Competing Interests: Conflicts of interest None declared., (Copyright: © 2022 Medicina Oral S.L.)

Digital therapeutics (DTx) are a subset of digital health which are often coupled with artificial intelligence (A.I.) techniques and machine learning systems. DTx differ from common wellness apps or medication reminder tools in that they require "rigorous" clinical evidence. They are emerging as a new treatment option and are being applied in a variety of areas, including type II diabetes, hypertension, chronic respiratory problems, obesity, insomnia, Alzheimer's disease, various types of dementia or addiction (smoking, alcohol, drugs), anxiety, depression, autism, learning disabilities, and attention deficits. Today, there are roughly 35 to 40 products on the market, 8 of which approved by regulatory agencies. The value of the global DTx market was estimated at USD 1.8 billion in 2018, and it is expected to reach USD 8.9 billion by 2027. Implementing DTx across healthcare systems raises a number of ethical concerns. The present article aims to provide an overview of the main ethical issues pertaining the assessment, implementation, and use of this emerging technology. The final purpose is to support and facilitate an open and transparent deliberation with regard to DTx.

Chronic kidney disease mineral and bone disorder may persist after successful kidney transplantation. Persistent hyperparathyroidism has been identified in up to 80% of patients throughout the first year after kidney transplantation. International guidelines lack strict recommendations about the management of persistent hyperparathyroidism. However, it is associated with adverse graft and patient outcomes, including higher fracture risk and an increased risk of all-cause mortality and allograft loss. Secondary hyperparathyroidism may be treated medically (vitamin D, phosphate binders and calcimimetics) or surgically (parathyroidectomy). Guideline recommendations suggest medical therapy first but do not clarify optimal parathyroid hormone targets or indications and timing of parathyroidectomy. There are no clear guidelines or long-term studies about the impact of hyperparathyroidism therapy. Parathyroidectomy is more effective than medical treatment, although it is associated with increased short-term risks. Ideally parathyroidectomy should be performed before kidney transplantation to prevent persistent hyperparathyroidism and improve graft outcomes. We now propose a roadmap for the management of secondary hyperparathyroidism in patients eligible for kidney transplantation that includes the indications and timing (pre- or post-kidney transplantation) of parathyroidectomy, the evaluation of parathyroid gland size and the integration of parathyroid gland size in the decision-making process by a multidisciplinary team of nephrologists, radiologists and surgeons., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Background: Renal transplantation represents the therapeutic gold standard in patients with end stage renal disease (ESRD). Still the role of pre-transplant dialysis in affecting time to transplantation has yet to be determined. We wanted to verify whether the type of renal replacement therapy (hemodialysis vs. peritoneal dialysis) affects time to transplantation and to identify clinical features related to the longer time to transplantation., Methods: We performed a retrospective single-center observational study on patients who had received a transplant in the Bologna Transplant Unit from 1991 to 2019, described through the analysis of digital transplant list documents for sex, age, body mass index (BMI), blood group, comorbidities, underlying disease, serology, type of dialysis, time to transplantation, Panel Reactive Antibodies (PRA) max, number of preformed anti Human Leukocyte Antigens (HLA) antibodies. A p -value < 0.05 was considered statistically significant., Results: In the 1619 patients analyzed, we observed a significant difference in time to transplant, PRA max and Preformed Antibodies Number between patients who received Hemodialysis (HD) and Peritoneal dialysis (PD). Then we performed a multiple regression analysis with all the considered factors in order to identify features that support these differences. The clinical variables that independently and directly correlate with longer time to transplantation are PRA max ( p < 0.0001), Antibodies number ( p < 0.0001) and HD ( p < 0.0001); though AB blood group ( p < 0.0001), age ( p < 0.003) and PD ( p < 0.0001) inversely correlate with time to transplantation., Conclusions: In our work, PD population received renal transplants in a shorter period of time compared to HD and turned out to be less immunized. Considering immunization, the type of dialysis impacts both on PRA max and on anti HLA antibodies.

We design a "wisdom-of-the-crowds" GRN inference pipeline and couple it to complex network analysis to understand the organizational principles governing gene regulation in long-lived glp-1 /Notch Caenorhabditis elegans . The GRN has three layers (input, core, and output) and is topologically equivalent to bow-tie/hourglass structures prevalent among metabolic networks. To assess the functional importance of structural layers, we screened 80% of regulators and discovered 50 new aging genes, 86% with human orthologues. Genes essential for longevity-including ones involved in insulin-like signaling (ILS)-are at the core, indicating that GRN's structure is predictive of functionality. We used in vivo reporters and a novel functional network covering 5,497 genetic interactions to make mechanistic predictions. We used genetic epistasis to test some of these predictions, uncovering a novel transcriptional regulator, sup-37 , that works alongside DAF-16/FOXO. We present a framework with predictive power that can accelerate discovery in C. elegans and potentially humans., Competing Interests: The authors declare no competing interests., (Crown Copyright © 2021.)

In 2018, the Neurodevelopmental and Psychosocial Interventions Working Group of the Cardiac Neurodevelopmental Outcome Collaborative convened through support from an R13 grant from the National Heart, Lung, and Blood Institute to survey the state of neurodevelopmental and psychosocial intervention research in CHD and to propose a slate of critical questions and investigations required to improve outcomes for this growing population of survivors and their families. Prior research, although limited, suggests that individualised developmental care interventions delivered early in life are beneficial for improving a range of outcomes including feeding, motor and cognitive development, and physiological regulation. Interventions to address self-regulatory, cognitive, and social-emotional challenges have shown promise in other medical populations, yet their applicability and effectiveness for use in individuals with CHD have not been examined. To move this field of research forward, we must strive to better understand the impact of neurodevelopmental and psychosocial intervention within the CHD population including adapting existing interventions for individuals with CHD. We must examine the ways in which dedicated cardiac neurodevelopmental follow-up programmes bolster resilience and support children and families through the myriad transitions inherent to the experience of living with CHD. And, we must ensure that interventions are person-/family-centred, inclusive of individuals from diverse cultural backgrounds as well as those with genetic/medical comorbidities, and proactive in their efforts to include individuals who are at highest risk but who may be traditionally less likely to participate in intervention trials.

Endothelial cells drive the formation of new blood vessels in physiological and pathological contexts such as embryonic development, wound healing, cancer and ocular diseases. Once formed, all vessels of the vasculature system present an endothelial monolayer (the endothelium), lining the luminal wall of the vessels, that regulates gas and nutrient exchange between the circulating blood and tissues, contributing to maintaining tissue and vascular homeostasis. To perform their functions, endothelial cells integrate signalling pathways promoted by growth factors, cytokines, extracellular matrix components and signals from mechanosensory complexes sensing the blood flow. New evidence shows that endothelial cells rely on specific metabolic pathways for distinct cellular functions and that the integration of signalling and metabolic pathways regulates endothelial-dependent processes such as angiogenesis and vascular homeostasis. In this review, we provide an overview of endothelial functions and the recent advances in understanding the role of endothelial signalling and metabolism in physiological processes such as angiogenesis and vascular homeostasis and vascular diseases. Also, we focus on the signalling pathways promoted by the transmembrane protein Neuropilin-1 (NRP1) in endothelial cells, its recently discovered role in regulating mitochondrial function and iron homeostasis and the role of mitochondrial dysfunction and iron in atherosclerosis and neurodegenerative diseases.

Endothelial cells actively maintain an anti-thrombotic environment; loss of this protective function may lead to thrombosis and systemic coagulopathy. The transcription factor ERG is essential to maintain endothelial homeostasis. Here, we show that inducible endothelial ERG deletion (Erg iEC-KO ) in mice is associated with spontaneous thrombosis, hemorrhages and systemic coagulopathy. We find that ERG drives transcription of the anticoagulant thrombomodulin (TM), as shown by reporter assays and chromatin immunoprecipitation. TM expression is regulated by shear stress (SS) via Krüppel-like factor 2 (KLF2). In vitro, ERG regulates TM expression under low SS conditions, by facilitating KLF2 binding to the TM promoter. However, ERG is dispensable for TM expression in high SS conditions. In Erg iEC-KO mice, TM expression is decreased in liver and lung microvasculature exposed to low SS but not in blood vessels exposed to high SS. Our study identifies an endogenous, vascular bed-specific anticoagulant pathway in microvasculature exposed to low SS.

The CellSearch® system which is still considered the gold standard for the enumeration of circulating tumor cells (CTC) utilizes antibodies against the epithelial cell adhesion molecule (EpCAM) for CTC enrichment. Recently, CTC discarded by the CellSearch® system due to their low EpCAM expression have been isolated and analyzed. We here sought to discuss technical and biological issues concerning the isolation and characterization of EpCAM low CTC, highlighting the enormous potential of this subpopulation discarded by CellSearch®, which might instead reveal an unexpected clinical significance in tumor types where CTC enumeration has never been validated for prognostic and predictive purpose., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2019 Chiara Nicolazzo et al.)

Molecular alterations are not randomly distributed in colorectal cancer (CRC), but rather clustered on the basis of primary tumor location underlying the importance of colorectal cancer sidedness. We aimed to investigate whether circulating tumor cells (CTC) characterization might help clarify how different the patterns of dissemination might be relative to the behavior of left- (LCC) compared to right-sided (RCC) cancers. We retrospectively analyzed patients with metastatic CRC who had undergone standard baseline CTC evaluation before starting any first-line systemic treatment. Enumeration of CTC in left- and right-sided tumors were compared. The highest prognostic impact was exerted by CTC in left-sided primary cancer patients, even though the lowest median number of cells was detected in this subgroup of patients. CTC exhibit phenotypic heterogeneity, with a predominant mesenchymal phenotype found in CTC from distal compared to proximal primary tumors. Most CTC in RCC patients exhibited an apoptotic pattern. CTC in left-sided colon cancer patients exhibit a predominant mesenchymal phenotype. This might imply a substantial difference in the biology of proximal and distal cancers, associated with different patterns of tumor cells dissemination. The poor prognosis of right-sided CRC is not determined by the hematogenous dissemination of tumor cells, which appears to be predominantly a passive shedding of non-viable cells. Conversely, the subgroup of poor-prognosis left-sided CRC is reliably identified by the presence of mesenchymal CTC.

Background: Clinical behavior of non-muscle-invasive bladder cancer (NMIBC) is largely unpredictable, and even patients treated according to European Association of Urology recommendations have a heterogeneous prognosis. High-grade T1 (HGT1) bladder cancer is the highest-risk subtype of NMIBC, with an almost 40% rate of recurrence and 20% of progression at 5 years. Nomograms predicting risk of recurrence, progression, and cancer-specific survival (CSS) are not available specifically within HGT1 bladder cancer, and the identification of robust prognostic biomarkers to better guide therapeutic strategies in this subgroup of patients is of paramount importance. Strategies to identify putative biomarkers in liquid biopsies from blood and urine collected from patients with bladder cancer have been intensively studied in the last few years., Subjects, Materials, and Methods: We here report the final analysis of a single-center prospective study aimed to investigate the impact of circulating tumor cells (CTCs) on CSS and overall survival (OS) in 102 patients with HGT1 bladder cancer, in a median follow-up of 63 months., Results: We here demonstrate that the presence of even a single CTC is predictive of shorter CSS and OS, as compared with the standard predictive variables. Points of attention in this multivariable analysis are the long-term follow-up and the adequate number of outcome events., Conclusion: The accurate risk stratification provided by CTCs might be essential for determining the best surveillance strategy for patients after diagnosis. A closer follow-up, an early radical surgery, or even a systemic treatment might be recommended in patients with super-high-risk non-muscle-invasive bladder cancer., Implications for Practice: Circulating tumor cells identify patients with super-high-risk non-muscle-invasive bladder cancer who require closer monitoring for local recurrence and/or progression of disease. This super-high-risk subgroup of patients might also require more aggressive treatment interventions, which should be evaluated in large prospective cohorts., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Background: The heterogeneity of metastatic breast cancer (MBC) necessitates novel biomarkers allowing stratification of patients for treatment selection and drug development. We propose to use the prognostic utility of circulating tumor cells (CTCs) for stratification of patients with stage IV disease., Methods: In a retrospective, pooled analysis of individual patient data from 18 cohorts, including 2436 MBC patients, a CTC threshold of 5 cells per 7.5 ml was used for stratification based on molecular subtypes, disease location, and prior treatments. Patients with ≥ 5 CTCs were classified as Stage IV aggressive , those with < 5 CTCs as Stage IV indolent. Survival was analyzed using Kaplan-Meier curves and the log rank test., Results: For all patients, Stage IV indolent patients had longer median overall survival than those with Stage IV aggressive (36.3 months vs. 16.0 months, P < 0.0001) and similarly for de novo MBC patients (41.4 months Stage IV indolent vs. 18.7 months Stage IV aggressive , p < 0.0001). Moreover, patients with Stage IV indolent disease had significantly longer overall survival across all disease subtypes compared to the aggressive cohort: hormone receptor-positive (44 months vs. 17.3 months, P < 0.0001), HER2-positive (36.7 months vs. 20.4 months, P < 0.0001), and triple negative (23.8 months vs. 9.0 months, P < 0.0001). Similar results were obtained regardless of prior treatment or disease location., Conclusions: We confirm the identification of two subgroups of MBC, Stage IV indolent and Stage IV aggressive , independent of clinical and molecular variables. Thus, CTC count should be considered an important tool for staging of advanced disease and for disease stratification in prospective clinical trials., (Copyright © 2018. Published by Elsevier B.V.)

The transmembrane protein neuropilin-1 (NRP1) promotes vascular endothelial growth factor (VEGF) and extracellular matrix signaling in endothelial cells (ECs). Although it is established that NRP1 is essential for angiogenesis, little is known about its role in EC homeostasis. Here, we report that NRP1 promotes mitochondrial function in ECs by preventing iron accumulation and iron-induced oxidative stress through a VEGF-independent mechanism in non-angiogenic ECs. Furthermore, NRP1-deficient ECs have reduced growth and show the hallmarks of cellular senescence. We show that a subcellular pool of NRP1 localizes in mitochondria and interacts with the mitochondrial transporter ATP-binding cassette B8 (ABCB8). NRP1 loss reduces ABCB8 levels, resulting in iron accumulation, iron-induced mitochondrial superoxide production, and iron-dependent EC senescence. Treatment of NRP1-deficient ECs with the mitochondria-targeted antioxidant compound mitoTEMPO or with the iron chelator deferoxamine restores mitochondrial activity, inhibits superoxide production, and protects from cellular senescence. This finding identifies an unexpected role of NRP1 in EC homeostasis., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)