United Nations University

Telomerase (TERT) activation is a fundamental step in tumorigenesis. By maintaining telomere length, telomerase relieves a main barrier on cellular lifespan, enabling limitless proliferation driven by oncogenes. The recently discovered, highly recurrent mutations in the promoter of TERT are found in over 50 cancer types, and are the most common mutation in many cancers. Transcriptional activation of TERT, via promoter mutation or other mechanisms, is the rate-limiting step in production of active telomerase. Although TERT is expressed in stem cells, it is naturally silenced upon differentiation. Thus, the presence of TERT promoter mutations may shed light on whether a particular tumor arose from a stem cell or more differentiated cell type. It is becoming clear that TERT mutations occur early during cellular transformation, and activate the TERT promoter by recruiting transcription factors that do not normally regulate TERT gene expression. This review highlights the fundamental and widespread role of TERT promoter mutations in tumorigenesis, including recent progress on their mechanism of transcriptional activation. These somatic promoter mutations, along with germline variation in the TERT locus also appear to have significant value as biomarkers of patient outcome. Understanding the precise molecular mechanism of TERT activation by promoter mutation and germline variation may inspire novel cancer cell-specific targeted therapies for a large number of cancer patients.

The advent of the 4th industrial revolution promises significant social and economic opportunities and challenges which demand that governments respond appropriately in supporting the transformation of the society. The purpose of this study is to understand the challenges confronting developing countries in the adoption of digital transformation agendas to leverage the social and economic benefits of the digital-driven industrial revolution 4.0. The research is based on an interpretive case study that uses documents evidence and a review of the literature as its primary method of collecting data. South Africa is used as a single case study of a developing country that has embraced digital transformation as a critical strategy in inclusive growth.

Bone tissue has an astonishing self-healing capacity yet only for non-critical size defects (<6 mm) and clinical intervention is needed for critical-size defects and beyond that along with non-union bone fractures and bone defects larger than critical size represent a major healthcare problem. Autografts are, still, being used as preferred to treat large bone defects. Mostly, due to the presence of living differentiated and progenitor cells, its osteogenic, osteoinductive and osteoconductive properties that allow osteogenesis, vascularization, and provide structural support. Bone tissue engineering strategies have been proposed to overcome the limited supply of grafts. Complete and successful bone regeneration can be influenced by several factors namely: the age of the patient, health, gender and is expected that the ideal scaffold for bone regeneration combines factors such as bioactivity and osteoinductivity. The commercially available products have as their main function the replacement of bone. Moreover, scaffolds still present limitations including poor osteointegration and limited vascularization. The introduction of pores in scaffolds are being used to promote the osteointegration as it allows cell and vessel infiltration. Moreover, combinations with growth factors or coatings have been explored as they can improve the osteoconductive and osteoinductive properties of the scaffold. This review focuses on the bone defects treatments and on the research of scaffolds for bone regeneration. Moreover, it summarizes the latest progress in the development of coatings used in bone tissue engineering. Despite the interesting advances which include the development of hybrid scaffolds, there are still important challenges that need to be addressed in order to fasten translation of scaffolds into the clinical scenario. Finally, we must reflect on the main challenges for bone tissue regeneration. There is a need to achieve a proper mechanical properties to bear the load of movements; have a scaffolds with a structure that fit the bone anatomy.

This paper contributes to the literature on government transparency by addressing the question of what drives the differences in local government levels of transparency. Our main objective is to ascertain whether transparency is mainly driven by the leadership, capacity and other political traits of the local governments themselves -"supply-side determinants"or, rather, if it hinges on social, cultural and/or other local community factors ("demand-side" determinants). We test the hypotheses derived from this theoretical framework using the results of the Municipal Transparency Index which is based on the information disclosed in the local governments' official websites and was applied to all Portuguese municipalities for the first time in 2013. Our findings indicate that municipalities with less financial autonomy, run by male mayors, with a larger number of consecutive terms in office, and smaller margins of victory in local elections display lower levels of transparency. On the demand-side, the unemployment rate and the average age of the municipal population emerge as the best predictors and are both negatively associated with transparency.

BACKGROUND: In all societies, the burden and cost of allergic and chronic respiratory diseases are increasing rapidly. Most economies are struggling to deliver modern health care effectively. There is a need to support the transformation of the health care system into integrated care with organizational health literacy. MAIN BODY: As an example for chronic disease care, MASK (Mobile Airways Sentinel NetworK), a new project of the ARIA (Allergic Rhinitis and its Impact on Asthma) initiative, and POLLAR (Impact of Air POLLution on Asthma and Rhinitis, EIT Health), in collaboration with professional and patient organizations in the field of allergy and airway diseases, are proposing real-life ICPs centred around the patient with rhinitis, and using mHealth to monitor environmental exposure. Three aspects of care pathways are being developed: (i) Patient participation, health literacy and self-care through technology-assisted "patient activation", (ii) Implementation of care pathways by pharmacists and (iii) Next-generation guidelines assessing the recommendations of GRADE guidelines in rhinitis and asthma using real-world evidence (RWE) obtained through mobile technology. The EU and global political agendas are of great importance in supporting the digital transformation of health and care, and MASK has been recognized by DG Santé as a Good Practice in the field of digitally-enabled, integrated, person-centred care. CONCLUSION: In 20 years, ARIA has considerably evolved from the first multimorbidity guideline in respiratory diseases to the digital transformation of health and care with a strong political involvement.

BACKGROUND: Lateralized dysfunction has been suggested in obsessive-compulsive disorder (OCD). However, it is currently unclear whether OCD is characterized by abnormal patterns of brain structural asymmetry. Here we carried out what is by far the largest study of brain structural asymmetry in OCD. METHODS: We studied a collection of 16 pediatric datasets (501 patients with OCD and 439 healthy control subjects), as well as 30 adult datasets (1777 patients and 1654 control subjects) from the OCD Working Group within the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium. Asymmetries of the volumes of subcortical structures, and of measures of regional cortical thickness and surface areas, were assessed based on T1-weighted magnetic resonance imaging scans, using harmonized image analysis and quality control protocols. We investigated possible alterations of brain asymmetry in patients with OCD. We also explored potential associations of asymmetry with specific aspects of the disorder and medication status. RESULTS: In the pediatric datasets, the largest case-control differences were observed for volume asymmetry of the thalamus (more leftward; Cohen's d = 0.19) and the pallidum (less leftward; d = -0.21). Additional analyses suggested putative links between these asymmetry patterns and medication status, OCD severity, or anxiety and depression comorbidities. No significant case-control differences were found in the adult datasets. CONCLUSIONS: The results suggest subtle changes of the average asymmetry of subcortical structures in pediatric OCD, which are not detectable in adults with the disorder. These findings may reflect altered neurodevelopmental processes in OCD.

Smart Governance is one dimension of Smart Cities, it relies on good governance such as open (i.e. transparent), accountable, collaborative (i.e. involving all stakeholders) and participatory (i.e. citizens' participation) principles and on Electronic Government (e-Government). This paper tries to answer the question - “What governance models are being implemented in smart cities?”. To answer this question, six interviews were conducted with people involved in Smart Cities initiatives from Brazil, Singapore, Colombia, Portugal, and Uruguay. The empirical analysis of the interviews shows that Smart Cities and e-Government present a similar evolutionary trajectory, both converging to smart governance. The paper concludes that all the initiatives underlie heavily in technologies and follow the same sort of smart governance model, a mix of collaborative, open and participatory governance. We claim that advanced technologies, innovation and smart governance are essential prerequisites for developing smart, creative, innovative and sustainable cities.

BACKGROUND: By contrast with other southern European people, north Portuguese population registers an especially high prevalence of hypertension and stroke incidence. We designed a cohort study to identify individuals presenting accelerated and premature arterial aging in the Portuguese population. METHOD: Pulse wave velocity (PWV) was measured in randomly sampled population dwellers aged 18-96 years from northern Portugal, and used as a marker of early vascular aging (EVA). Of the 3038 individuals enrolled, 2542 completed the evaluation. RESULTS: Mean PWV value for the entire population was 8.4 m/s (men: 8.6 m/s; women: 8.2 m/s; P < 0.02). The individuals were classified with EVA if their PWV was at least 97.5th percentile of z-score for mean PWV values adjusted for age (using normal European reference values as comparators). The overall prevalence of EVA was 12.5%; 26.1% of individuals below 30 years presented this feature and 40.2% of individuals in that same age strata were placed above the 90th percentile of PWV; and 18.7% of the population exhibited PWV values above 10 m/s, with male predominance (17.2% of men aged 40-49 years had PWV > 10 m/s). Logistic regression models indicated gender differences concerning the risk of developing large artery damage, with women having the same odds of PWV above 10 m/s 10 years later than men. CONCLUSION: The population PWV values were higher than expected in a low cardiovascular risk area (Portugal). High prevalence rates of EVA and noteworthy large artery damage in young ages were found.

BRAF inhibitor (BRAFi) therapy for melanoma patients harboring the V600E mutation is initially highly effective, but almost all patients relapse within a few months. Understanding the molecular mechanisms underpinning BRAFi-based therapy is therefore an important issue. Here we identified a previously unsuspected mechanism of BRAFi resistance driven by elevated Hedgehog (Hh) pathway activation that is observed in a cohort of melanoma patients after vemurafenib treatment. Specifically, we demonstrate that melanoma cell lines, with acquired in vitro-induced vemurafenib resistance, show increased levels of glioma-associated oncogene homolog 1 and 2 (GLI1/GLI2) compared with naïve cells. We also observed these findings in clinical melanoma specimens. Moreover, the increased expression of the transcription factors GLI1/GLI2 was independent of canonical Hh signaling and was instead correlated with the noncanonical Hh pathway, involving TGFβ/SMAD (transforming growth factor-β/Sma- and Mad-related family) signaling. Knockdown of GLI1 and GLI2 restored sensitivity to vemurafenib-resistant cells, an effect associated with both growth arrest and senescence. Treatment of vemurafenib-resistant cells with the GLI1/GLI2 inhibitor Gant61 led to decreased invasion of the melanoma cells in a three-dimensional skin reconstruct model and was associated with a decrease in metalloproteinase (MMP2/MMP9) expression and microphthalmia transcription factor upregulation. Gant61 monotherapy did not alter the drug sensitivity of naïve cells, but could reverse the resistance of melanoma cells chronically treated with vemurafenib. We further noted that alternating dosing schedules of Gant61 and vemurafenib prevented the onset of BRAFi resistance, suggesting that this could be a potential therapeutic strategy for the prevention of therapeutic escape. Our results suggest that targeting the Hh pathway in BRAFi-resistant melanoma may represent a viable therapeutic strategy to restore vemurafenib sensitivity, reducing or even inhibiting the acquired chemoresistance in melanoma patients.

This article explores the determinants of local governments' use of social networking sites . It does so by analysing the relative impact of institutional, political and social determinants , while controlling for the impact of mayors' traits and social characteristics of municipalities on local governments levels of activity on Facebook. Empirically, this article presents a within-case analysis of Portuguese municipalities' activity on social media, aiming to shed light on the strategic use of social media by local governments. A coherent picture associated with politically pro-active local governments emerges from the results: higher levels of social media activity appear in municipalities with more competitive local elections and higher commitment to transparency. Moreover, findings suggest that local governments tend to be concerned with the low levels of voter turnout , potentially resorting to social media as a powerful tool to increase civic engagement and (offline) political participation . Levels of Facebook activity are significantly higher in larger and wealthier municipalities. The results indicate that Facebook official pages of municipalities are part of a larger arsenal of tools to promote political engagement and activity levels signal a propensity to involve citizens pro-actively. • SNS appears to emerge as a mechanism to reinforce other e-government strategies. • SNS is mostly used to inform citizens rather than to promote e-participation. • citizen engagement with the Facebook accounts of local governments is rather limited. • SNS usage is best explained by the social and demographic profile of municipalities. • commitment to transparency emerge as capable of explaining SNS activity. • political incentives, especially local political competition, play an enduring role as determinants of social media activity.

Turbidity and suspended sediment concentration are crucial parameters indicative of water quality, playing pivotal roles in evaluating the well-being of aquatic ecosystems and the effectiveness of water treatment processes. This manuscript provides an in-depth review of various methods and instruments in use for in situ and in-line applications. The exploration of optical instrumentation is central to this review, examining its widespread use and current challenges within standard methods, commercial instruments and scientific research. The study also delves into alternative techniques, such as acoustic and capacitive methods, elucidating their applications, calibration intricacies, and practical considerations. Furthermore, the paper scrutinizes the emerging importance of satellite and aerial imaging processing as a supplementary tool for turbidity monitoring, underscoring its potential to offer comprehensive insights on a larger scale. The review emphasizes the key accomplishments and challenges of the state-of-the-art technologies, providing a comprehensive overview of the current stage of the field and its prospects. and aims to provide valuable insights for researchers, practitioners, and decision-makers involved in environmental monitoring and water facility management, enabling a deeper comprehension of the significance of turbidity and suspended sediment concentration in safeguarding water quality and ecosystem health. • Optical instruments are still the preferred choice for accessing turbidity and SSC. • Acoustic methods remain relevant due to their utilization in aquatic platforms. • Satellite and aerial imaging offer broader insights and higher spatial detail. • Environmental monitoring has been the driver for the recent technological development.

Abstract Additive manufacturing techniques established a new paradigm in the manufacture of composite materials providing a simple solution to build complex, custom designed shapes. In the biomedical field, 3D printing enabled the production of scaffolds with patient-specific requirements, controlling product architecture and microstructure, and have been proposed to regenerate a variety of tissues such as bone, cartilage, or the nervous system. Polymers reinforced with graphene or graphene derivatives have demonstrated potential interest for applications that require electrical and mechanical properties as well as enhanced cell response, presenting increasing interest for applications in the biomedical field. The present review focuses on graphene-based polymer nanocomposites developed for additive manufacturing fabrication, provides an overview of the manufacturing techniques available to reach the different biomedical applications, and summarizes relevant results obtained with 3D printed graphene/polymer scaffolds and biosensors.

Sepsis is the third most common cause of neonatal death, with Group B Streptococcus (GBS) being the leading bacterial agent. The pathogenesis of neonatal septicemia is still unsolved. We described previously that host susceptibility to GBS infection is due to early IL-10 production. In this study, we investigated whether triggering TLR2 to produce IL-10 is a risk factor for neonatal bacterial sepsis. We observed that, in contrast to wild-type (WT) pups, neonatal TLR2-deficient mice were resistant to GBS-induced sepsis. Moreover, if IL-10 signaling were blocked in WT mice, they also were resistant to sepsis. This increased survival rate was due to an efficient recruitment of neutrophils to infected tissues that leads to bacterial clearance, thus preventing the development of sepsis. To confirm that IL-10 produced through TLR2 activation prevents neutrophil recruitment, WT pups were treated with the TLR2 agonist Pam3CSK4 prior to nebulization with the neutrophil chemotactic agent LTB4. Neutrophil recruitment into the neonatal lungs was inhibited in pups treated with Pam3CSK4. However, the migration was restored in Pam3CSK4-treated pups when IL-10 signaling was blocked (either by anti-IL-10R mAb treatment or by using IL-10-deficient mice). Our findings highlight that TLR2-induced IL-10 production is a key event in neonatal susceptibility to bacterial sepsis.

This study compares the incidence, nature, and impact of persistent post-surgical pain after total knee arthroplasty (TKA) and total hip arthroplasty (THA) and investigates differences between these procedures, with the focus on potential presurgical and post-surgical issues that could be related to the distinct persistent post-surgical pain outcomes between these two groups. A consecutive sample of 92 patients was assessed prospectively 24 hours before, 48 hours, and 4-6 months after surgery. The data show that TKA patients had a higher likelihood of developing persistent post-surgical pain, of reporting higher pain levels, and of using more neuropathic descriptors when classifying their pain. In addition, TKA patients more often reported interference from pain on functional domains, including general activity, walking ability, and normal work. Demographic factors, like gender and age, along with presurgical clinical factors like disease onset, existence of medical comorbidities, and other pain problems, may have contributed to these differences, whereas baseline psychologic factors and functionality levels did not seem to exert an influence. Heightened acute post-surgical pain experience among TKA patients could also be related to distinct outcomes for persistent post-surgical pain. Future prospective studies should therefore collect TKA and THA samples wherein patients are homogeneous for demographic and presurgical clinical issues. Overall, these findings contribute to a small but growing body of literature documenting persistent post-surgical pain after major arthroplasty, conducted in different countries and across different health care settings.

PURPOSE: To determine the clinical outcomes of arthroscopic superior capsular reconstruction (ASCR) using either fascia lata autograft or human dermal allograft for irreparable rotator cuff tears (IRCTs). METHODS: A systematic review was performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines by searching the MEDLINE, Embase, and Cochrane Library databases through January 31, 2019. The inclusion criteria were as follows: 5 or more consecutive patients who underwent ASCR for IRCTs; clinical outcome measures reported at a minimum follow-up of 12 months; and magnetic resonance imaging assessment at a minimum follow-up of 6 months. The methodologic quality was evaluated using the Methodological Index for Non-randomized Studies (MINORS). A narrative synthesis of data was performed. Mean outcome improvements were compared with minimal clinically important differences. RESULTS: We identified 7 eligible studies that included 344 shoulders in 338 patients who underwent ASCR for IRCTs (all Level IV studies). The mean MINORS score was 12.3 ± 1.60. Of the 7 studies, 5 had a high risk of bias (MINORS score ≤12): 2 studies using only fascia lata autograft and 3 studies using only human dermal allograft. The mean age of patients ranged from 59.4 to 66.9 years. The mean follow-up time ranged from 12 to 48 months. All studies reported statistically significant and clinically important mean improvements in active elevation (range of means, 28°-56°), the Constant score (range of means, 12-47.1 points), or the American Shoulder and Elbow Surgeons score (range of means, 29.3-56 points). In total, 218 shoulders underwent postoperative magnetic resonance imaging. The graft tear rate reported in studies using fascia lata autograft (181 shoulders) ranged from 5% to 32%, whereas the values reported in studies using human dermal allograft (37 shoulders) ranged from 20% to 75%. CONCLUSIONS: ASCR using either fascia lata autograft or human dermal allograft leads to significant and clinically important improvements in clinical outcomes in IRCT patients at 12 months or later. LEVEL OF EVIDENCE: Level IV, systematic review of Level IV studies.

Water supply is essential to public health, quality of life, environmental protection, economic activity, and sustainable development. In this context, it is imperative to assure the continuous improvement of all processes and practices conducive to guarantee water quality and safety. Water Safety Plans (WSPs) by water utilities are an important public policy tool to accomplish these goals. This manuscript reviews the international evidence of the adoption and implementation of water safety planning and reports the current situation in Portugal, as part of the necessary adjustment of the national legal framework to the publication of the Directive (EU) 2015/1787, October 6th, on water quality for human consumption. The aim is to draw lessons from several successful WSP experiments around the world and extract lessons from these cases when drafting new legislation in Portugal and elsewhere. Findings suggest there are four critical dimensions and key elements of success in developing and implementing WSPs: leadership commitment, technical knowledge, governance, and interagency collaboration.

Iron is essential for mammalian cellular homeostasis. However, in excess, it promotes free radical formation and is associated with aging-related progressive deterioration and with neurodegenerative disorders such as Alzheimer's disease (AD). There are no mechanisms to excrete iron, which makes iron homeostasis a very tightly regulated process at the level of the intestinal absorption. Iron is believed to reach the brain through receptor-mediated endocytosis of iron-bound transferrin by the brain barriers, the blood-cerebrospinal fluid (CSF) barrier, formed by the choroid plexus (CP) epithelial cells and the blood-brain barrier (BBB) formed by the endothelial cells of the brain capillaries. Importantly, the CP epithelial cells are responsible for producing most of the CSF, the fluid that fills the brain ventricles and the subarachnoid space. Recently, the finding that the CP epithelial cells display all the machinery to locally control iron delivery into the CSF may suggest that the general and progressive senescence of the CP may be at the basis of the impairment of regional iron metabolism, iron-mediated toxicity, and the increase in inflammation and oxidative stress that occurs with aging and, particularly, in AD.

OBJECTIVE: The objective of this study was to characterise international trends in the use of psychotropic medication, psychological therapies, and novel therapies used to treat obsessive-compulsive disorder (OCD). METHODS: Researchers in the field of OCD were invited to contribute summary statistics on the characteristics of their samples. Consistency of summary statistics across countries was evaluated. RESULTS: The study surveyed 19 expert centres from 15 countries (Argentina, Australia, Brazil, China, Germany, Greece, India, Italy, Japan, Mexico, Portugal, South Africa, Spain, the United Kingdom, and the United States) providing a total sample of 7,340 participants. Fluoxetine (n = 972; 13.2%) and fluvoxamine (n = 913; 12.4%) were the most commonly used selective serotonin reuptake inhibitor medications. Risperidone (n = 428; 7.3%) and aripiprazole (n = 415; 7.1%) were the most commonly used antipsychotic agents. Neurostimulation techniques such as transcranial magnetic stimulation, deep brain stimulation, gamma knife surgery, and psychosurgery were used in less than 1% of the sample. There was significant variation in the use and accessibility of exposure and response prevention for OCD. CONCLUSIONS: The variation between countries in treatments used for OCD needs further evaluation. Exposure and response prevention is not used as frequently as guidelines suggest and appears difficult to access in most countries. Updated treatment guidelines are recommended.

Administrative burden represents the costs to businesses, citizens and the administration itself of complying with government regulations and procedures. The burden tends to increase with new forms of public governance that rely less on direct decisions and actions undertaken by traditional government bureaucracies, and more on government creating and regulating the environment for other, non-state actors to jointly address public needs. Based on the reviews of research and policy literature, this paper explores administrative burden as a policy problem, presents how Digital Government (DG) could be applied to address this problem, and identifies societal adoption, organizational readiness and other conditions under which DG can be an effective tool for Administrative Burden Reduction (ABR). Finally, the paper tracks ABR to the latest Contextualization stage in the DG evolution, and discusses possible development approaches and technological potential of pursuing ABR through DG.

VAL is a computer based control system and programming language which has been designed specifically for use with industrial robots. In this paper, VAL is described as it is implemented as an integral part of the Unimation PUMA robot. First, the general capabilities of VAL are presented. These include the ability to interactively edit, interpret, debug, execute, and store user programs in an environment that supports concurrent console communication and program execution. Then, the system hardware is described. Next, the various methods of tool point trajectory control which are available in VAL are described. This is followed by a brief description of the VAL language. Special instructions for dynamically modifying position data are described along with instructions for automatically adapting programs based upon sensory information.