As the field of dissemination and implementation science matures, there are a myriad of outcomes, identified in numerous frameworks, that can be considered across individual, organizational, and population levels. This can lead to difficulty in summarizing literature, comparing across studies, and advancing translational science. This manuscript sought to (1) compare, contrast, and integrate the outcomes included in the RE-AIM and Implementation Outcomes Frameworks (IOF) and (2) expand RE-AIM indicators to include relevant IOF dissemination and implementation outcomes. Cross tabular comparisons were made between the constitutive definitions of each construct, across frameworks, to reconcile apparent discrepancies between approaches and to distinguish between implementation outcomes and implementation antecedents. A great deal of consistency was identified across approaches, including adoption , fidelity/implementation (the degree to which an intervention was delivered as intended), organizational maintenance/sustainability , and cost. The IOF construct of penetration was defined as a higher-order construct that may encompass the reach, adoption, and organizational maintenance outcomes within RE-AIM. Within the IOF approach acceptability, appropriateness, and feasibility did not match constitutive definitions of dissemination or implementation but rather reflected theoretical antecedents of implementation outcomes. Integration of the IOF approach across RE-AIM indicators was successfully achieved by expanding the operational definitions of RE-AIM to include antecedents to reach, adoption, implementation, and organizational maintenance. Additional combined metrics were also introduced including penetration, individual level utility, service provider utility, organizational utility, and systemic utility. The expanded RE-AIM indicators move beyond the current approaches described within both the RE-AIM framework and IOF and provides additional planning and evaluation targets that can contribute to the scientific field and increase the translation of evidence into practice. As the field of dissemination and implementation science matures, there are a myriad of outcomes that can be considered across individual, organizational, and population levels –4. The RThe RE-AIM Framework includes 6 dimensions that focus planning and evaluation on balancing internal and external validity to develop intervention approaches that can achieve a public health impact see . The fraConceptualization of the RE-AIM framework has evolved over the past 20 years  to incluThe IOF presents eight implementation outcomes, including: acceptability, adoption, appropriateness, costs, feasibility, fidelity, penetration, and sustainability  4). The. The4). Similar to the RE-AIM framework, the conceptualization of IOF outcomes has also evolved over the 9 years since its first publication , 7. Of nBoth the RE-AIM framework and the IOF have had a significant impact on the field of implementation and dissemination science. RE-AIM provides a systematic planning and evaluation model that is based on individual and organizational outcomes, while the IOF provides conceptual clarity to distinguish between implementation, service, and client outcomes. Yet, there is considerable overlap between the frameworks and, based on the initial goals of the frameworks, key distinctions. This manuscript sought to compare, contrast and integrate dissemination, and implementation science outcomes included in these frameworks and provide working definitions that could extend the current RE-AIM indicators and outcome measurement approach.Cross tabular comparisons were made between the constitutive definitions of the IOF and RE-AIM framework variables see . FramewoFor the purpose of this comparison, we defined “predictors” as constructs that act as precursors to implementation and dissemination of evidence-based interventions. For example, an intervention would need to be perceived as acceptable in order for it to be adopted. Characterization as a predictor was based on the degree to which the construct definition aligned with constitutive definitions of dissemination  and implementation  . The levA great deal of consistency was identified across approaches, including adoption , fidelity/implementation , organizational maintenance/sustainability , and cost. However, cost was more explicitly defined in the IOF as cost of an implementation effort and of any strategies that targeted improvements in implementation whereas the RE-AIM conceptualization of cost focused on implementation and cost-effectiveness. The IOF construct of penetration was defined as a higher-order construct that may encompass the reach, adoption, and sustainability outcomes within RE-AIM. Within the IOF approach there were also a number of constructs that reflect theoretical antecedents of implementation outcomes including acceptability, appropriateness, and feasibility—rather than reflecting the constitutive definitions of dissemination or implementation. Integration of the IOF constructs with the RE-AIM framework was successfully achieved by extending the operational definitions of each RE-AIM dimension using IOF outcomes and antecedents. In addition, adaptation and cost considerations by RE-AIM dimension—both highlighted, but not explicitly included across dissemination and implementation outcomes were included in the expanded indicators; see The IOF constructs of acceptability, appropriateness, and feasibility were included as multi-leveled variables across reach, adoption, implementation, and organizational maintenance. However, the level of application is hypothesized to differ by dimension and temporality of assessment of the construct relative to the initial implementation . Specifically, initial perceptions of intervention acceptability, appropriateness, and feasibility were operationalized as unique antecedents of reach  and adoption . In each of these cases the temporal assessment of these constructs and the potential for predictive validity is hypothesized to be dependent on the initial perceptions of the intervention prior to individual (reach) or organizational (adoption) decisions on engagement or uptake. In contrast, organizational experience—indicating a later temporal assessment following the initial actions of implementation—of acceptability, appropriateness, and feasibility were hypothesized to be antecedents of implementation fidelity  and organizational-level maintenance.Cost specification was also expanded across reach, adoption, implementation, and organizational maintenance outcomes. An overarching consideration included that for most outcomes at least two categories of costs could be assessed—the cost of a dissemination or implementation strategy used to enhance a specific RE-AIM dimension and the cost of completing the activities associated with each dimension. For example, an implementation strategy could include the cost of training staff on the intervention delivery and the cost of implementing the intervention itself. The training costs are distinct from the ongoing operational costs for intervention implementation. In addition to these two costs, specific budget impact assessments  are inclOf note, adaptation was not included in the original operational definitions provided by the IOF and RE-AIM framework. Recently, however, there have been suggestions to advance the consideration of adaptation within the context of implementation . To addrThe final area of expansion of RE-AIM indicators was in the realm of combined metrics. Penetration was operationalized to include the product of reach, adoption, and organizational maintenance to provide an overarching system-based outcome. Other expanded combined metrics focused on determining the utility of an intervention at the participant, service provider, and organizational decision-maker level. In each case, utility was defined as the product of ratings of acceptability, appropriateness, and feasibility. Each of these metrics were further combined as an aggregate rating to produce a measure of systemic utility.This manuscript described the process used to compare, contrast and integrate dissemination and implementation science outcomes included in the RE-AIM framework and the IOF. We used a cross-tabular content analysis to compare between the frameworks which highlighted similarities and key differences. In addition, we integrated IOF within the context of the RE-AIM dimensions which generated an increased depth for a number of constructs and provided additional guidance on the possibility to examine combined metrics-particularly during later stages of scale-up activities. Based on this work we hypothesize that assessment of the expanded RE-AIM outcomes will improve the ability of dissemination and implementation scientists to document key outcomes that reflect the achievement of translating evidence-based interventions that promote public health.The primary distinction between the two frameworks was an inclusion of individual level factors (RE-AIM) and predictors or antecedents of dissemination and implementation outcomes (IOF). The distinctions between these two models is not surprising when considering the rationale for the development of each , 5. The As The newly expanded RE-AIM indicators has the potential to perform well due to its expanded definitions, in regards to assessment within staged research models such as the Pathways to Scale-Up Model (Pathways) , used prThe assessment of cost was increased to move beyond cost of implementation and implementation strategies, cost effectiveness, and budget impact analysis to a more comprehensive assessment across RE-AIM dimensions. This aligns with the importance of a wide range of cost considerations used by policy makers and organizational leaders . The areAdaptation was not explicitly defined in either the RE-AIM Framework or IOF, but is necessary to consider during the implementation of an intervention . AdaptatThe combined metrics proposed for the RE-AIM framework have not been broadly used across the extant public health or dissemination and implementation science literature. It is unclear whether this uptake is based on the lack of applicability of these metrics and/or the difficulty in gathering all the necessary data. Still, the original combined metrics provided an opportunity to consider a single number to assess individual and organizational impact . We propA potential limitation of our expanded RE-AIM approach is that, by including antecedents to dissemination and implementation outcomes we are initiating a shift from an outcome framework to a blended outcome framework and explanatory model . As suchThe expansion to RE-AIM indictors is intended to improve the planning and outcomes related to health-enhancing interventions. However, a potential unintended consequence of this paper is that it is counter to the intuitive nature of the RE-AIM framework . That isThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.KR, SK, GP, and PE equally contributed to the conceptualization of this report, analyzing definitions, compiling cross-tabular comparisons, and manuscript writing. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Analyze and integrate studies that inquire on the benefits of nursing educational interventions to manage post-surgical pain. A systematic search was conducted in the databases of Scopus, Medline (Pubmed), Web of Science, The Cochrane Library, and CINAHL of systematic reviews, randomized clinical trials, and quasi-experimental studies published in English and Spanish until 2018 that analyzed the effectiveness of educational interventions in managing post-surgical pain in adult patients. Twelve studies complied inclusion criteria, of which nine reported less pain in the group receiving the educational intervention. These interventions also helped to diminish the level of anxiety and improved functionality to perform activities of daily life. The level of quality of the studies was medium.Although the review showed that nursing educational interventions could influence on the relief of post-surgical pain, more rigorous studies are necessary, with bigger sample sizes and higher methodological quality, which help to establish the real effectiveness in managing post-surgical patients with pain.  Pain is a serious public health problem of global relevance. The International Association for the Study of Pain defines pain as an unpleasant emotional and sensory experience associated to current or potential tissue damage. By being a subjective experience, its measurement varies according to the person’s perception. Besides,It is known that in the perception of pain, multiple factors influence, such as the type of intervention, age, gender, or the patient’s own expectations, which hinders foreseeing the level of pain patients can experience after surgery. Prior reTo our knowledge, no prior systematic reviews exist that additionally analyze other variables, like the development of daily activities or the vital constants. The objective of this review is to analyze and integrate studies that inquire on the effects of nursing educational interventions on the relief of post-surgical pain. This study conducted a systematic review of randomized clinical trials (RCT), quasi-experimental studies, systematic reviews and meta-analyses that analyzed the effectiveness of educational interventions, conducted during the preoperative and postoperative phases, on the relief and prevention of post-surgical pain. The search included articles published in English and Spanish in the databases of Scopus, Medline (Pubmed), Web of Science, The Cochrane Library, and CINAHL. It included articles to February 2018 to analyze studies reflecting the association between the educational intervention and relief and decrease of post-surgical pain in patients subjected to any type of surgery. Two reviewers performed independently the search and selection of the articles; thereafter, agreeing on the results. This process used the following criteria. Inclusion criteria: 1) Systematic reviews, RCT, quasi-experimental studies, and meta-analyses inquiring on the effectiveness of educational interventions in managing post-surgical pain; 2) Studies published to February 2018 in English or Spanish; and 3) Studies including in their sample a population over 18 years of age. Exclusion criteria: 1) Studies showing very low quality after the evaluation with instruments for their analysis (score < 40% of the instrument’s maximum score); 2) Educational interventions aimed at the relatives; and 3) Studies including in their sample patients with mental pathology. The study followed the principles of the PRISMA Declaration. To analyze the quality of articles potentially eligible, the following instruments were used: Checklist for Systematic Reviews and Research Syntheses from the Joanna Briggs Institute and AMSTAR to evaluate the systematic reviews, the JADAD scale to evaluate the RCT, Joanna Briggs Institute Checklist for Quasi-experimental Studies to evaluate quasi-experimental studies and the Newcastle-Ottawa Scale (NOS) to evaluate the quality of the meta-analyses. The AMSTAR scale has 16 items with four possible responses. The ChecThe initial search in the databases selected found 3 068 articles after eliminating articles duplicated in various databases. After a first review of the titles and abstracts 3055 articles were eliminated because of dealing with themes different from the object of study. Thereafter, 13 articles were reviewed in full text, from which one article was excluded because it had an insufficient score after its quality analysis . FinallyIn relation with the type of study, six of the articles analyzed were controlled randomized trials (CRT),-19 a sysFurthermore, certain heterogeneity was found regarding the types of interventions used in the studies, finding the following interventions: educational interventions based on the delivery of graphic material,,19,22,251 and the State-Trait Anxiety Inventory (STAI)..,18,20,21Regarding the principal results reported in these studies after these interventions, while certain studies found a significant reduction of post-surgical pain after the educational intervention,,15,25 otStudies inquiring on the interference of pain in the activities of daily life found that, after the educational intervention, pain interfered less in the experimental group, which is why these patients had less problems to mobilize, walk, or perform actions, like coughing.,21-23,25In relation to the methodological quality of the studies analyzed, it was found that the six RCT, evaluated with the JADAD scale, obtainedThe results of the studies included in this systematic review do not permit generalizing that the educational interventions aimed at patients for the knowledge of pain and its management to be effective in controlling or reducing post-surgical pain, due to the controversy found in the results. However, the results found show greater pain relief in patients receiving these interventions, as well as lower incidence of pain in performing daily activities after the intervention, like mobilization, walking, or resting. Additionally, educational interventions improve the expectations of patients on post-surgical pain, modify negative preconceptions of opioid analgesics, and improve the use of analgesics during the post-operative period. Regarding prior studies that have only analyzed the association between the educational interventions and relief of post-surgical pain, this review contributes with the analysis of the benefits of the educational interventions to perform daily activities after surgery ,21-23,25Following the line of prior studies, most of the articles analyzed coincide in that the information provided during the educational intervention is an important tool to raise awareness and sensitize patients on the concept of pain and the need for its treatment, producing a behavioral change in patients toward this pain.-18,20,25However, although prior studies show the benefits of the educational interventions, certain studies in this review do not confirm this fact, not finding that the educational intervention presents any repercussion on relieving post-surgical pain or on the interaction of pain in daily activities.,20,22-24The results from this review show that educational interventions carried out by nursing can improve relief of post-surgical pain. In additThe principal strength of this review is that it has followed the recommendations of the PRISMA Declaration and has evaluated the quality of the studies included with different instruments, according to the type of study. The study had mainly two limitations: the first is that of having found few studies with not very high level of rigor and very diverse applied methodology, and the second, is that considering only articles published in Spanish or English in the databases analyzed constitutes a limitation, when excluding possible relevant articles published in other languages. The conclusion of this review is that educational interventions could influence on the relief of post-surgical pain, as well as aid in the development of daily activities, like moving about or breathing. Furthermore, educational interventions improve management of post-surgical anxiety and reduce barriers during the treatment follow up. In spite of the aforementioned, more rigorous studies are necessary, with larger sample sizes and higher methodological quality, which help to learn with certainty the effect of educational interventions in managing post-surgical patients with pain and extract relevant information that permits developing new pre-operative protocols that help to reduce pain and its post-operative complications.


Background: Pacific Small Island Developing States (SIDS) have health care systems with a limited capacity to deal with pandemics, making them especially vulnerable to the economic and social impacts of the coronavirus (COVID-19). This paper examines the introduction, transmission, and incidence of COVID-19 into Pacific SIDS. Methods: Calculate the rate of transmission (the average number of new cases per day between the first recorded case and the most recent day) and connectivity (daily direct flights to the leading airport in each selected island group) using flight history and COVID-19 transmission data. Results: Correlational analyses show that connectivity is positively related with (a) first-case dates and (b) spread rate in Pacific SIDS. Conclusion: Connectivity plays a central role in the spread of COVID-19 in Pacific SIDS. The continued entry of people was a significant factor for spread within countries. Efforts to prevent transmission by closing borders reduced transmission but also created significant economic hardship because many Pacific SIDS rely heavily on tourism and international exchange. The findings highlight the importance of exploring the possibility that the COVID-19 spread rate may be higher than official figures indicate, and present pathways to mitigate socio-economic impacts. The practical implications of the findings reveal the vulnerability of Pacific SIDS to pandemics and the key role of connectivity in the spread of COVID-19 in the Pacific region. The World Health Organization (WHO) declared the coronavirus COVID-19) a pandemic on March 11, 2020. The next day, French Polynesia confirmed the first report of COVID-19 in the Pacific islands 9 a pande,4. By eaTo address the limited capacity of health care in Pacific SIDS, the WHO developed a six-month Pacific Action COVID-19 Preparedness and Response plan to reduce the virus spread and treat infected patients. The plan includes response activities such as screening passengers at major checkpoints, requiring potentially exposed persons to undergo at least 14 days of quarantine, and closing entry to non-residents. It also calls for the deployment of medical resources from better-equipped Pacific Island countries and territories, such Fiji and Guam, to less well-equipped ones .Few studies have examined virus spread in Pacific SIDS during a worldwide pandemic. To understand how COVID-19 reached and spread within Pacific SIDS and other Pacific Island nations, the authors examined connectivity data for five island groups with recorded cases, dates for first reported case, and the rate of in-country transmission. Knowledge concerning virus spread throughout Pacific SIDS can assist government agencies and health organizations identify ways to mitigate spread.To assess the connectivity of Pacific SIDS and other Pacific Island nations with locations that serve as a hub for international travelers, the authors determined the usual number of daily direct flights from Asia, the Americas, and Australasia for the leading hub airport. FlightRadar24 data was collected for flights on 8 April 2020 to determine flights per week, representing the longer-term situation, and for 9 September 2020, which, at the time, represented return to normal scheduling, from Expedia. The data are presented as an average number of flights per day from the region of flight origination. Virus transmission was calculated by determining the average number of new cases per day between the first recorded case and the most recent day for which data were available. The data were drawn from Johns Hopkins University Center for Systems Science and Engineering GitHub repository and online interactive dashboard , which oCorrelational analyses showed that there is a modest positive relationship between first-case dates and connectivity  are at particular risk. For example, in Fiji, tourism accounts for nearly 40% of its gross domestic product (GDP) and approximately 37% (direct and indirect) of all employment . EffortsThe ramifications are rippling through sectors that support the tourism industry, including agriculture, transportation, retail, lodging, food, and recreation. The loss of tourism in Vanuatu, for example, is threatening to reverse 15 years of steady growth. Countries less reliant on tourism may be more resilient, such as Kiribati, Nauru, and Tuvalu. Papua New Guinea is more dependent on mining and petroleum production than tourism. The economies of some Pacific SIDS rely on public trust funds  but these may be at risk if economic-fiscal instability expands . As travTo make matters worse, from 6 April 2020 to 10 April 2020, Cyclone Harold created damage in several Pacific Island nations. It made landfall in Vanuatu as a Category 5 storm, slightly decreased in strength and brushed Fiji, and then increased in strength and struck Tonga during a king tide. These nations reported extensive losses to businesses (including tourist resorts), homes, crops, and communication capacity. Cyclone Harold came while Vanuatu, Fiji, and Tonga were recovering from recent catastrophic storms: Cyclones Pam (2015), Winston (2016), and Gita 2018) [ [18]. CyFishing contributes to Pacific Island economies, and the industry may decline due to restricted connectivity and COVID-19 supply chain disruptions, restrictions on international sales of fresh fish, and boat crew health issues related to the virus. Illicit fishing and the transportation of unlawful cargo by smugglers and poachers may increase as critical personnel are reassigned from policing fisheries to addressing national COVID-19 issues, thereby reducing the likelihood of seizure .Economic aid and assistance provided by other nations can help mitigate adverse economic consequences in Pacific SIDS. Increased international cooperation and public–private partnerships are vital to producing and supplying necessary medical supplies and promoting stability, as are open trade policies . To addrThe study has a few limitations. Because Pacific SIDS and nations around the world had a limited supply of testing kits for COVID-19, the full number of cases may be underreported in the data. The study is correlational, and the full scope of spread may be underrepresented. Nonetheless, the evidence gathered in this paper may support future policies to mitigate the spread of pandemics in the Pacific region.The connectivity-spread rate analysis presented in this paper offers pathways to delay or mitigate the arrival of COVID-19 in Pacific SIDS by reducing connectivity to/from and between/within islands. Measures to reduce connectivity should consider allowing for the appropriate introduction of outside help, reunification of citizens (with appropriate quarantine upon return), and medical evacuations to areas with more suitable medical facilities. Decisions to reduce connectivity should carefully consider ways to mitigate socio-economic harm.The findings also highlight the importance of exploring the possibility that the COVID-19 spread rate may be higher than official figures indicate. Indeed, “highly likely gross under-detection and underreporting of mild or asymptomatic cases inevitably throws severe disease courses calculations and death rates out of context, distorting epidemiologic reality” .While the apparent absence of COVID-19 from a portion of the Pacific Islands region until now gives cautious hope, we should remember that “absence of evidence about a problem does not imply evidence of absence of a problem” . For exaThe practical implications of the findings are twofold. Firstly, they reveal an association between connectivity and the spread of COVID-19 in the Pacific region, and that less connected regions were among the least affected. Secondly, they outline the vulnerability of Pacific nations to pandemics. Such vulnerability results not only from the fragility of health systems on Pacific SIDS that are not well equipped to handle high numbers of patients, but also due to the economic problems as a result of measures to reduce virus transmission, including the closure of country borders and stay-at-home or lockdown mandates. These efforts place the economic systems of Pacific SIDS under substantial distress and can lead to hardships and a worsening of social problems.Addressing how to mitigate social and economic impacts of the outbreak response related to health systems;Identifying non-intended consequences of epidemic control decisions;Providing answers to social dynamics of the outbreak and the related public health response;Identifying the means to address inequalities that may be exacerbated by the epidemic, such as limited access to medical services and treatments, especially among the elderly.Moving forward, there are some pathways which Pacific nations may follow in order to better cope with the prospects of a widespread COVID-19 pandemic. This entails measures aimed at:A pathway to reduce the vulnerability of the region to COVID-19 should also analyze the effects and efficiency of these responses (including resilience factors), democratic governance, multi-level cooperation, the critical gaps and the various exit strategies, with their underlying methodologies and the prospects for regional adaptations. It will also be helpful if Pacific countries develop guidelines and best ‘next practices’ and implement interventions to mitigate impacts and boost well-being.Finally, research on virus outbreak responses across the region and the impacts on human behavior and social dynamics is needed to help guide future responses. These efforts should take into account societal and cultural structures, health system preparedness and resilience, population densities, population risk groups, climate, and pollution.


Unintentional ingestion of fish bones is a common but frequently unrecognized occurrence at the emergency room. Most ingested fish bones pass through the gastrointestinal tract without complications, but approximately 1% may perforate and cause acute abdomen, peritonitis and/or abscesses, requiring emergent surgery.Clinical presentation is non-specific and computed tomography is essential to confirm the diagnosis and guide the surgery.We present a case of gastric perforation by fish bone and discuss the clinical and radiological challenges in the diagnosis of this condition. Unintentional ingestion of fish bones is a common but frequently unrecognized occurrence at the emergency room. Gastrointestinal perforation may occur in 1% of cases and lead to acute abdomen.The non-specific spectrum of presentations and unawareness of episode of ingestion make the diagnosis of this entity a clinical challenge. This entity is often forgotten when establishing a differential diagnosis of acute abdominal pain and may mimic other frequent abdominal emergencies, such as ruptured gastric ulcer, appendicitis or diverticulitis.Computed tomography (CT) is the method of choice to confirm the diagnosis, but some cases may be difficult, requiring a high level of suspicion and familiarity with the presentation of this condition.Surgery is the treatment of choice in most cases, although endoscopic and conservative approaches may be considered in less severe presentations.A previously healthy 57-year-old woman presented to the emergency room with epigastric pain and nausea, without vomiting or fever. Physical evaluation was unremarkable, and she was discharged medicated with omeprazole and sucralfate. Four days later, she returns with persistent epigastric pain, fever and vomiting. Her upper abdomen was tender and painful, and lab work analysis showed elevated inflammatory parameters.Contrast-enhanced CT was performed and revealed a hyperdense linear image with 5 cm in the lesser omentum, with associated inflammatory gastric wall thickening at the antrum, extraluminal gas and increased density and free fluid of perigastric soft tissues Figures -3.The patient went to laparoscopic surgery, and the diagnosis of gastric perforation by a fish bone was confirmed. The patient recovered well from surgery with resolution of symptoms and was discharged five days after admission. Unintentional ingestion of fish bones is common, and most fish bones pass through the gastrointestinal tract within a week, without symptoms or complications ,2. GastrSeveral risk factors for fish bone ingestions have been identified, including use of dental and palatal prosthetics, alcohol and drug abuse, fast eaters, mental retardation, elderly and infants, mostly due to poor mastication and decreased awareness of sharp materials in the food bolus .Clinical diagnosis is challenging because most patients do not recall an episode of fish bone ingestion and may present with a wide spectrum of non-specific clinical manifestations, including abdominal pain, acute abdomen, vomiting, fever, melena and bowel obstruction -3. Also,Conventional radiographs rarely detect fish bones due to their non-metallic nature . UltrasoCT is the most sensitive method and has a key role to detect the presence of fish bone and the site of perforation, to guide surgery. Fish bones appear as a thin, linear, high-density structure with local inflammatory signs of the perforated wall and surrounding fat stranding, and occasionally abscess formation. Fistulization and migration to other organs may also occur, and gastric or duodenal perforation may lead to hepatic abscess, usually in the left hepatic lobe ,5.Free intraperitoneal gas may not always be present because the perforation is caused by progressive erosion of the wall, covered by inflammatory tissue, fibrin and omentum, limiting the amount of free air . PneumopDespite being the first-line method for diagnosis, CT has some limitations. Fish bones are less conspicuous in contrast-enhanced CT and may be mistaken for a small vessel and with CT slice thickness over 3 mm, small fish bones may be overlook due to volume averaging . Non-conLaparoscopic surgery is the treatment of choice if a perforation is diagnosed, to remove the foreign object, drain abscesses and repair the perforation site . If perfFish bone perforation is a clinical and radiological challenging diagnosis that should be considered in the differential diagnosis of acute abdomen, especially in high-risk patients.The non-specific spectrum of presentations and unawareness of episode of ingestion may delay the clinical diagnosis and mimic other entities, such as ruptured gastric ulcer, appendicitis or diverticulitis. CT is the method of choice to confirm the diagnosis and also to exclude other causes of acute abdomen.


Recycled aggregate concrete (RAC) contributes to mitigating the depletion of natural aggregates, alleviating the carbon footprint of concrete construction, and averting the landfilling of colossal amounts of construction and demolition waste. However, complexities in the mixture optimization of RAC due to the variability of recycled aggregates and lack of accuracy in estimating its compressive strength require novel and sophisticated techniques. This paper aims at developing state-of-the-art machine learning models to predict the RAC compressive strength and optimize its mixture design. Results show that the developed models including Gaussian processes, deep learning, and gradient boosting regression achieved robust predictive performance, with the gradient boosting regression trees yielding highest prediction accuracy. Furthermore, a particle swarm optimization coupled with gradient boosting regression trees model was developed to optimize the mixture design of RAC for various compressive strength classes. The hybrid model achieved cost-saving RAC mixture designs with lower environmental footprint for different target compressive strength classes. The model could be further harvested to achieve sustainable concrete with optimal recycled aggregate content, least cost, and least environmental footprint. Portland cement concrete is the most widely used construction material and the most consumed industrial product in the world. However, the more frequent local shortages of natural aggregates (NA) and the enormous environmental footprint caused by its extraction are global concerns regarding the production of Portland cement concrete. The global annual consumption of NA is estimated at 8 to 12 billion tons .2 emissions and beneficiation of CDW in applications with added value. About 75% of construction waste, including concrete and masonry, can be reused in concrete production [Moreover, there has been a growing worldwide shortage of available landfilling sites to dispose of construction and demolition waste (CDW). In Canada, it is estimated that 9 million tons of CDW are produced every year. Despite the vast country, its biggest cities are encountering stern CDW disposal challenges . LikewisHowever, the inclusion of RA in concrete has been reported to reduce the compressive strength . SeveralAlthough there have been multiple studies on the mechanical properties of RAC, more research needs to be devoted to investigating the effects of various parameters on RAC compressive strength, including the variability of RA, the effect of old cement mortar attached to the RA surface, and the crushing process of RA ,13. ConsThe lack of understanding of RAC has resulted in developing new modeling techniques, such as machine learning (ML) algorithms, to predict its mechanical properties. A major advantage of ML methods is that they can capture the underlying mechanisms, despite the lack of information regarding specific parameters. Data driven ML techniques have proven to be successful in the prediction of RAC mechanical properties including the modulus of elasticity and compressive strength ,14,15,16ML techniques have also been employed for mixture design and optimization. Concrete mixture design is the process of selecting the appropriate quantitative proportions of concrete ingredients . From a Accordingly, the present study aims at creating a large and comprehensive experimental dataset from the available studies in the open literature to develop powerful state-of-the-art ML models to predict the compressive strength of RAC. For this purpose, a dataset consisting of 1134 experimental examples of RAC mixture designs with 10 attributes was developed. Moreover, three different novel ML models were developed, and their performance was compared. Gaussian processes (GP), deep learning (DL) and gradient boosting regression trees (GBRT) techniques were employed for the first time to model the compressive strength of RAC. Eventually, an optimization of the RAC mixture design was performed by coupling PSO with the best proposed ML model to develop a hybrid powerful model for optimizing RAC mixture composition for different target ranges of compressive strength at 28 days. The superior accuracy of the proposed models should assist various stakeholders in optimal use of recycled concrete in diverse construction applications.Other studies have employed ML to predict the compressive strength of RAC. For instance, Khademi et al.  used thrIn summary, Khademi et al. , NaderpoAs elaborated on above, there have been various studies on the application of traditional ML techniques to predict the compressive strength of RAC. The present study aims at creating a large and more comprehensive dataset and deploy it with state-of-the-art ML techniques that have not yet been explored for RAC in the open literature. The models presented herein are executed using the Python programming language. Therefore, to utilize these models, the user can simply apply the development steps along with hyperparameters reported in this study. Furthermore, the compressive strength predictive tools developed in this study are further complemented with optimization of the mixture proportions using a coupled PSO-GBRT model. The proposed mixture proportions can be used as a reference guideline for designing eco-friendlier and more economical RAC mixtures in practice.ML refers to a computer’s capacity of analyzing data and learning complex patterns within the data without being rigorously programmed . DependiGP are stochastic processes that generalize the Gaussian probability distribution . In contDL models are multiple-level computational algorithms able to learn complex underlying structures within a database . DL modeRNN is a class of neural networks with an internal loop that allows the algorithm to keep memories from past information, commonly referred to as hidden state ,38. In Rfunction ,40.M represents the number of weak learners which is known as the n_estimators hyperparameter. The loss function represents to what extent the predicted value is close to the output in the dataset using a specific metric. GBRT approaches the best function using the weighting of weak learner models, GBRT algorithm integrates multiple weak learners using a boosting approach in which additional trees are appended in sequence without model parameters being changed. The objective of the gradient boosting is to find the function } ,42. The  follows ,42,43,44s models ,42,43,44The experimental data used in this study was collected from 55 peer-reviewed publications . The colFeature normalization is commonly applied prior to modeling. Although normalization is not required for all ML algorithms, it has been proven to improve the model performance . Linear K-fold cross-validation was used. K-fold cross-validation is a resampling method that splits the data into k number of subsets and keeps one subset for validation, while the other A common practice to assess the performance of ML models is to divide the entire dataset into three different subsets: training, validation and testing. Whilst the learning process is accomplished with the training set, the validation set is used to track the performance of the model, while the testing set serves to assess the extrapolation capabilities of the model by performing it over unseen samples that are not known to the model . Howevertraining . The 5-fHyperparameter tuning is a crucial step in developing robust ML models. Tuning of ML model mitigates over-fitting and thus, enhances the versatility of the model to unseen data . The selGP is a non-parametric model  and thusAccording to the former equation, parameters associated with the considered kernels were tuned as the hyperparametrs of the GP model, including the length scale 1  in the search of an optimal solution, was adopted . The par vectors  were strThis section presents the results of ML modeling of RAC. The three different models outlined earlier were implemented and their prediction performance is discussed herein. Purposefully, the root mean squared error (RMSE), mean absolute error (MAE), and coefficient of determination GP, GRU, and GBRT models were trained using 793 data examples and tested with the remaining 341 data. The final tuned models were executed over five different seed numbers of data split to assess the robustness of the models trained with randomized split of the data for training and the testing sets. The predictive performance of the GP model for the five random seed numbers is summarized in The GRU model attained better performance compared to that of the GP model see . The difThe GBRT model scored superior predictive execution, as indicated in Based on the results discussed above, all developed ML models could predict the compressive strength of RAC with reasonable accuracy. However, the GRU and GBRT models demonstrated higher generalization capacity since their prediction errors for training and testing datasets were highly analogous, in contrast to the GP model. The prediction accuracy for the training dataset in the GP model was very high, while it was quite low for the testing dataset. Thus, the GP model suffers from over-fitting and lack of generalization to new unseen data. Although DL models are recognized to be more accurate on large datasets, the finely tuned GRU model, despite the relatively small dataset, reached outstanding prediction performance with high generalization capacity.A prime goal in ML is to create models that can accurately predict the output for new unseen data never presented to the model, i.e., achieving models that can generalize . ML mode2 emission. High upper limit of RCA was considered in the optimization to ensure maximum replacement of RCA as presented in A PSO was coupled with the GBRT model to optimize the mixture design and predict the compressive strength of RAC, such that the most economic mixture proportion is obtained for a given compressive strength class. The optimization was performed considering the unit costs of materials presented in K-fold cross-validation was used during the tuning process. The results show that the three models successfully captured the underlying principles contributing to the compressive strength of RAC. Furthermore, the diverse nature of the algorithms used herein proves the robustness of ML algorithms for data analysis despite the complexity within the dataset. The comparison of the models’ performance revealed that the GBRT and DL  models had superior predictive performance compared to the GP model in terms of different statistical metrics and performance indicators. Accordingly, the obtained coefficient of determination of the testing set for GBRT, DL, and GP was 0.919, 0.868, and 0.844, respectively. Furthermore, the GBRT model was coupled with PSO to create a hybrid model for optimizing the mixture design of RAC with various compressive strength classes. Accordingly, the GBRT-PSO hybrid model successfully proposed economic mixture designs that fulfill the compressive strength requirement, reduce cost, and mitigate the environmental footprint of concrete production. To further the high potential of the developed ML models, it is proposed to integrate supplementary cementitious materials, such as fly ash and blast furnace slag in the dataset, and to extend the models to also capture durability requirements of RAC in future work.The present study explores deploying state-of-the-art machine learning models to predict the compressive strength of RAC and optimize its mixture design. For this purpose, one of the largest existing experimental datasets, including 1134 mixture design examples and featuring 10 attributes was built from studies in the open literature. Three advanced machine learning models, including Gaussian processes (GP), deep learning (DL), and gradient boosting regression trees (GBRT) were tuned, trained, and tested using the dataset. To guarantee that the developed models were able to generalize the compressive strength of RAC,


Community health workers (CHWs) are an important cadre of the global health workforce as they are involved in providing health services at the community level. However, evidence on the role of CHWs in delivering interventions for non-communicable diseases (NCDs) in Uganda is limited. This study, therefore, assessed the involvement of CHWs in the prevention and control of NCDs in Wakiso District, Uganda with a focus on their knowledge, attitudes and practices, as well as community perceptions.A cross-sectional study using mixed methods was conducted which involved a structured questionnaire among 485 CHWs, and 6 focus group discussions (FGDs) among community members. The study assessed knowledge, perceptions including the importance of the various risk factors, and the current involvement of CHWs in NCDs, including the challenges they faced. Quantitative data were analysed in STATA version 13.0 while thematic analysis was used for the qualitative data.The majority of CHWs (75.3%) correctly defined what NCDs are. Among CHWs who knew examples of NCDs (87.4%), the majority mentioned high blood pressure (77.1%), diabetes (73.4%) and cancer (63.0%). Many CHWs said that healthy diet (86.2%), physical activity (77.7%), avoiding smoking/tobacco use (70.9%), and limiting alcohol consumption (63.7%) were very important to prevent NCDs. Although more than half of the CHWs (63.1%) reported being involved in NCDs activities, only 20.9 and 20.6% had participated in community mobilisation and referral of patients respectively. The majority of CHWs (80.1%) who were involved in NCDs prevention and control reported challenges including inadequate knowledge (58.4%), lack of training (37.6%), and negative community perception towards NCDs (35.1%). From the FGDs, community members were concerned that CHWs did not have enough training on NCDs hence lacked enough information. Therefore, the community did not have much confidence in them regarding NCDs, hence rarely consulted them concerning these diseases.Despite CHWs having some knowledge on NCDs and their risk factors, their involvement in the prevention and control of the diseases was low. Through enhanced training and community engagement, CHWs can contribute to the prevention and control of NCDs, including health education and community mobilisation.The online version contains supplementary material available at 10.1186/s12992-020-00653-5. The increased burden of non-communicable diseases (NCDs) and related mortality is a major public health issue especially among low-and middle-income countries (LMICs) , 2. AbouCommunity health workers (CHWs) are acknowledged as an important part of the public health workforce globally and are mobilised to provide basic health care at the community level . CHWs arTo address the gaps in human resources for health regarding NCDs, mobilisation of CHWs seems promising , 14. EviDespite other countries having established the role of CHWs in NCDs prevention and control –22, evidLuganda) by Research Assistants among CHWs to establish their knowledge, attitudes and involvement in the prevention and control of NCDs, and had four sections. The first section comprised of questions on demographic characteristics of participants such as age, gender, level of education, and whether they were involved in integrated community case management (iCCM) of childhood illnesses. The second section assessed knowledge of CHWs on NCDs, including whether they could correctly define NCDs or knew examples of such diseases, as well as if they thought the illnesses could be prevented and/or treated. The third section explored perceptions of CHWs towards NCDs particularly how they rated the importance of the following risks factors: smoking/tobacco use, alcohol consumption, physical inactivity, and unhealthy diet using a Likert scale . Attitudes towards NCDs were determined using a Likert scale . This section also explored the potential role that CHWs can play in the prevention and control of NCDs in the community. The fourth section assessed the current involvement of CHWs in the prevention and control of NCDs, including any challenges they faced while doing so. CHWs practices such as community mobilisation; early detection; screening; referral of patients to health facilities; and supporting adherence to treatment were examined. The study assessed the following challenges among CHWs regarding their involvement in the prevention and control of NCDs: low knowledge; lack of training on NCDs; poor community perception towards NCDs; and lack of support from health workers.The study was cross-sectional and involved mixed methods of data collection, with the quantitative and qualitative data collected concurrently. The quantitative component of the study involved administering a structured questionnaire in the local language  were conducted among community members to obtain their views on the involvement of CHWs in the prevention and control of NCDs. The major themes explored in the FGDs were potential involvement of CHWs in NCDs, the involvement of CHWs in NCDs prevention and control at the time, challenges faced / could be faced by community members while seeking services from CHWs on NCDs, and how the involvement of CHWs in NCDs could be improved. These FGDs were also conducted in the local language and audio recorded in a field office located in the study area.The study was conducted in Busiro South health sub-district in Wakiso district, which is comprised of Kajjansi, Kasanje and Katabi town councils, and Bussi sub-county. This health sub-district was involved in the research due to having both rural and peri-urban populations. In addition, Busiro South neighbours Entebbe Municipality (a predominantly urban setting) and other rural areas in the district. Given that many health sub-districts across the country are composed of both rural and peri-urban communities, the findings from this study site can be generalisable to similar settings. According to the 2014 national census, the four administrative units had the following population: Kajjansi , Kasanje 30,276), Katabi , and Bussi   would need to be kept confidential. You may tell your personal condition to a CHW but then you find the entire village knows about it. This may prevent us from going to them to seek support on NCDs.” Participant 3, Female FGD 1The challenges faced by the CHWs were also emphasised by some community members. Although FGD participants agreed that CHWs were to an extent involved in the prevention and control of NCDs, most of them said that health education regarding NCDs was limited as their focus was on other health concerns such as water, sanitation and hygiene.Our study assessed the involvement of CHWs in NCDs prevention and control, and community perceptions about their role in Wakiso District, Uganda. CHWs are integral to addressing accessibility challenges and the human resource shortfall in health service delivery in Uganda and elsewhere. Although the study findings revealed that most CHWs were knowledgeable about the different types of NCDs and preventive measures through lifestyle modification, their role in the prevention and management of these diseases was minimal. From the findings, it is evident that CHWs knew that they had a potential role to play in NCDs prevention and control. However, this potential, as well as existing roles of CHWs, were impeded by health system challenges including lack of training, inadequate support from health workers, and community members’ perceptions about their capability to deliver NCDs services. Our findings reinforce existing literature on the importance of CHWs’ contribution in addressing the growing burden of NCDs , 24, 31.The majority of CHWs were aware of the common NCDs, which is consistent with a recent study conducted in Eastern Uganda where CHWs highlighted that diabetes, cancer and high blood pressure were common NCDs . The higNot only were the CHWs aware of the different NCDs, but the majority also knew about how to prevent them, reflecting fundamental knowledge about these diseases. Many CHWs accurately indicated major lifestyle preventive measures such as healthy diet, avoiding smoking / using tobacco products, regular physical activity, and limiting alcohol consumption as ways of preventing NCDs. These lifestyle preventive measures can be enhanced in the population through health promotion which CHWs can contribute to. Importantly, the attitudes of CHWs around the importance of NCDs risk factors buttress the point that not only were they aware of NCDs but also had nuanced knowledge about these diseases. Specifically, the lifestyle-related risk factors were considered very important by the majority of CHWs. These risk factors, which were historically associated with high-resource settings, are now becoming pervasive even among low-resource African communities  such as The attitudes of CHWs in our study further reflected the current practices in the country where the majority of the population are not sufficiently carrying out measures to prevent NCDs. For example, a high rate of alcohol consumption and low intake of fruits and vegetables in Uganda have been reported in a related study . It has Almost all the CHWs perceived themselves as having a role to play in the prevention and control of NCDs. This finding is a strong indication of CHWs’ commitment and willingness to promoting general health and wellbeing at the community level. This agreed with a recent Ugandan study which revealed that CHWs were keen to support with cardiovascular disease prevention . The potAlthough over half of the CHWs reported being currently involved in NCDs prevention and control, specific activities related to mobilising community members, providing referrals to health facilities, screening and early detection of NCDs, and supporting adherence to treatment was low. The role of CHWs in community mobilisation for NCD services also emerged from the FGDs. A recent community-based train-the-trainer programme reported the successful use of CHWs to promote behavioural change towards the control of chronic respiratory diseases in Uganda . A systeOur study identified challenges concerning CHWs’ involvement in NCDs control such as inadequate knowledge, lack of training, lack of support from health workers and negative perceptions of community members towards the diseases. It also emerged from the FGDs that community health education by CHWs on NCDs was minimal probably due to limited knowledge. Similar challenges have been highlighted in relation to the work of CHWs in Uganda , 23, 33.The current focus of CHWs on infectious diseases , and inaA strength of our study was that it involved both quantitative and qualitative data which enabled triangulation of findings. In addition, the study not only obtained information from CHWs but also community members who are the recipients of their services. Another strength of the study was that it involved all CHWs in a health sub-district hence the findings can relate to similar settings in the country.Despite CHWs having some knowledge on NCDs and their risk factors, their involvement in the prevention and control of the diseases was limited. Through enhanced training, supervisory support and community engagement, CHWs can contribute to the prevention and control of NCDs, including through health education, community mobilisation, screening and referral of patients to health facilities. While carrying out these roles, CHWs would greatly contribute to primary health care for NCDs at the community level and benefit the broader health system.Additional file 1: Study questionnaire.


The development of crack patterns is a serious problem affecting the durability of orthopedic implants and the prognosis of patients. This issue has gained considerable attention in the medical community in recent years. This literature focuses on the five primary aspects relevant to the evaluation of the surface cracking patterns, i.e., inappropriate use, design flaws, inconsistent elastic modulus, allergic reaction, poor compatibility, and anti-corrosiveness. The hope is that increased understanding will open doors to optimize fabrication for biomedical applications. The latest technological issues and potential capabilities of implants that combine absorbable materials and shape memory alloys are also discussed. This article will act as a roadmap to be employed in the realm of orthopedic. Fatigue crack growth and the challenges associated with materials must be recognized to help make new implant technologies viable for wider clinical adoption. This review presents a summary of recent findings on the fatigue mechanisms and fracture of implant in the initial period after surgery. We propose solutions to common problems. The recognition of essential complications and technical problems related to various approaches and material choices while satisfying clinical requirements is crucial. Additional investigation will be needed to surmount these challenges and reduce the likelihood of fatigue crack growth after implantation. Fatigue crack growth and fracture of orthopedic implants are commonly attributed to the progressive damage under the condition of periodic and intermittent stress load . A sharpImplant failure is usually caused by a network of cracks in the fixation that join and intersect. This network is also referred to as a cracking pattern or as river marks, similar to the branches and small tributaries of a river on a floodplain, as depicted in In terms of biomechanical behavior, the potential hazards of the surrounding soft tissue, blood supply, and severe bone defect play a critical role in the propagation and development of cracks, and their importance has been demonstrated by numerous studies ,19. DuriThe analysis of crack growth draws on many fields of science, including the biomechanical effect, fracture mechanics, image analysis, and materials engineering . DespiteHowever, these alloys can suffer drastic loss of fatigue endurance through severe notch sensitivity effect caused by notches or stress raisers ,31. In aGiven the gravity of this possibility, it is essential to determine specific factors that contribute to and are associated with fatigue crack growth. In the present paper, we discuss state-of-the-art knowledge on fatigue crack growth and fracture modes of orthopedic implants. The work is both a review of the rationale of fatigue crack growth and the state of knowledge about material properties in vivo. We also focus on the properties of materials. Our aim is to examine a number of possible materials innovations for orthopedic, and to provide insights useful in clinical practice and implant design that may speed up the development of new products.Currently, internal fixation still does not match the anatomy of human skeleton perfectly . To remeA sandwich of two different metals can induce a continuous micro-current  . A similBesides, in the case of the implants with unstable fixation, scratch and friction damage of the oxide film have been detected at the interface, which could explain why galvanic corrosion occurred . DependiIt is extensively known that the hole structure is the weakest link of the fixation . If the According to the work by Lin et al., the modification of screw hole structures can improve the fatigue strength of plate effectively by removing the threads at the tension side and increasing the crest radii of the threads  6]. It . It 6]. Design flaws are a key reason for fatigue crack growth in internal fixation . Take thFor the treatment of fracture, blood supply and stability are prerequisites for fracture union, and the axial interfragmentary motorization can expedite the course of bone remodeling ,55. HoweIn the case of middle and distal tibia fracture, the intramedullary nail ought to be implanted into the distal side of cancellous bone below the isthmus. However, the distal portion of intramedullary nail is usually difficult to anchor depending on open cancellous bone . It meanThe strength of fracture healing is, as a rule, supposed to manifest a negative correlation with the elastic Young’s modulus of the implant. The stiffness of metallic implant is an order of magnitude greater than that of cortical bone in general . For insCompared with normal bone tissue, the moduli mismatch is more serious in osteoporosis with anticipated high rates of implant crack growth and failure. Thus, some novel implants with ultra-low elastic modulus like Ti-24Nb-4Zr-7.9Sn (42 GPa) , Ti-24NbIn the near future, it seems likely that patented technologies, combining an absorbable exterior metal and a flexible interior material, could come to a future implant as a function of the elastic properties of the construct. For such a device, this elastic artefact needs not to be removed, even if it is non-absorbable. On the one hand, the promising custom-made implant has little effect on recipients and lowers the incidence of re-fracture considerably owing to the favorable stability and flexibility. In particular, interior fixation can even become an auxiliary navigator at time of re-fracture if applied in PFNA-II  or Gamma-3 (third-generation gamma nail). On the other hand, the exterior can facilitate the process of fracture healing theoretically by releasing metal ions, such as magnesium and titanium ion.Sustaining multiaxial loading, including tension, compression, bending, and torsion, is one prime challenge of implants which also must survive in a very corrosive medium in vivo  . SubjectCompound interactions, like ion exchange or adsorption of proteins, determine the quality and stability of the bone-implant-interface . These rGenerally, the surface will experience four different corrosion phases, namely immunity, active metal dissolution, passivity, and transpassive metal dissolution . The surTitanium and its alloys form a very stable oxide layer in quasi-physiological environments bestowing them with exceptional biocompatibility as compared to other metal implant materials . PittingHypersensitivity to implanted metal device is considered as a type IV hypersensitivity, which is a delayed-type hypersensitivity (DTH) mediated by T lymphocytes . It is aIt has been estimated that failure rate of implantation in patients with metallic allergy is almost three times greater than that in the general population . Cadosh Thyssen et al. explicitly indicated the diagnostic criteria for metal-allergy-associated dermatitis after orthopedic implantation: (1) Eczematous dermatitis in operation region confirmed as allergic rash by histological examination; (2) Positive patch test . In thisThe current study has verified that nickel ion is a potential sensitization factor . With thIt has been reported that allergy to alloys is more common for pure metal, which may be related to an over-representation of the compound undesirable reaction caused by alloy . The epiTraditional materials of internal fixation are mainly concerned with metal materials, which can promote the early fracture healing. However, the implantation is indeed traumatic for patient, and prone to induce stress shelter. A second procedure, without doubt, will impose suffering and economic burdens on patients. Recent trends in product offerings have been to accelerate the development of polymer materials  and absorbable inorganic materials (biodegradable ceramics) ,104,105.Micro-cracks are observed not only for reliable fixation of normal strength but also in the unloaded state . As reflAssuming that the innovations mentioned above can be implemented, the ideal rehabilitation would be based on the absorption rate of internal fixation to adjust the level of activity, which would avoid stress shelter effect and maintain a balance between absorption of implant and bone reconstruction. It also would promote the early fracture healing as a result of releasing growth factors. Despite the gradual degradation, the strength of plate would not decrease at various stages of loading, and stress concentrations would be transferred to the remodeling bone. This scenario has great scientific potential and practical significance. For non-absorbable fixation, the implant should be removed after fracture healing in principle, unless the patient is elderly and in poor health.Given the lack of specific understanding and consensus, previous investigations on fatigue crack propagation in internal fixation were relatively scattered and imperfect. The current experimental conditions are unable to mimic exactly what happens in the human body to implant due to the great internal complexity. The stress conditions and internal environment of implant vary from place to place in vivo. Therefore, at present, how to perfect a fixation device remains a major challenge for fixation design and processing technology. In this review, the possible causes of fatigue crack growth in actual application of implant were elaborated scientifically from the perspectives of underlying crack propagation mechanisms, inappropriate use, design flaws, elastic modulus, biocompatibility, corrosion resistance, and metal allergy. In this way, clinicians, manufacturers, and researchers can better understand the future development of internal fixation devices, and acquire a relevant theoretical basis for further studies on fatigue crack growth.


The ability of this class of molecules to regulate cell proliferation was first recognized in the model organism Drosophila and the fruit fly genetic model and continues to provide insight into the molecular mechanism by which this family of adapter molecules regulates both normal development and disease associated with corruption of their proper regulation and function.Tribbles pseudokinases represent a sub-branch of the CAMK (CaThe Tribbles (Trib) family of pseudokinase proteins regulate cell growth, proliferation, and differentiation during normal development and in response to environmental stress. Mutations in human Trib isoforms  have been associated with metabolic disease and linked to leukemia and the formation of solid tumors, including melanomas, hepatomas, and lung cancers. Drosophila Tribbles (Trbl) was the first identified member of this sub-family of pseudokinases and shares a conserved structure and similar functions to bind and direct the degradation of key mediators of cell growth and proliferation. Common Trib targets include Akt kinase , C/EBP (CAAT/enhancer binding protein) transcription factors, and Cdc25 phosphatases, leading to the notion that Trib family members stand athwart multiple pathways modulating their growth-promoting activities. Recent work using the Drosophila model has provided important insights into novel facets of conserved Tribbles functions in stem cell quiescence, tissue regeneration, metabolism connected to insulin signaling, and tumor formation linked to the Hippo signaling pathway. Here we highlight some of these recent studies and discuss their implications for understanding the complex roles Tribs play in cancers and disease pathologies. For example, it might be expected that mutagenesis of the COP1 site in Trbl would disrupt the proteasome binding and degradation of Cdc25, resulting in a failure to block that pathway, however this same mutant may result in a stabilized version of Trbl that simultaneously is more effective at binding MEK kinase to regulate that signaling pathway. Alternatively, the inability of a COP1-mutated tail to interact with its intramolecular binding site the N-lobe could destabilize the protein, leading to its degradation. Thus, despite the attractive minimalism of model organisms, interpreting the results of manipulating a multi-faceted protein like Trbl, should be conducted with caution.The selected examples of recent Drosophila Tribbles research presented in this review show the continued relevance of the fruit fly model to understanding the conserved role of the Trib gene family in tumor formation and growth. The fly can now brag of models for colorectal, brain, and lung cancers and offers genetically enhanced approaches to developing personalized therapies and to drug discovery . Recentl


In recent years, the presence in the environment of chemical compounds with thyroid-disrupting effects is progressively increased. This phenomenon has risen concern for human health as the preservation of thyroid system homeostasis is essential for fetal development and for maintaining psychological and physiological wellbeing. An increasing number of studies explored the role of different classes of toxicants in the occurrence and severity of thyroid diseases, but large epidemiological studies are limited and only a few animal or in vitro studies have attempted to identify the mechanisms of chemical action. Recently, epigenetic changes such as alteration of methylation status or modification of non-coding RNAs have been suggested as correlated to possible deleterious effects leading to different thyroid disorders in susceptible individuals. This review aims to analyze the epigenetic alterations putatively induced by chemical exposures and involved in the onset of frequent thyroid diseases such as thyroid cancer, autoimmune thyroiditis and disruption of fetal thyroid homeostasis.  A continuous release of chemicals into the environment represents a growing risk for all living organisms exposed in different ways to an ever-increasing variety of products. Numerous chemicals are suspected to be associated with various, and often severe, health problems in humans. A class of compounds that have more recently raised concern in society as a possible serious threat to health are the endocrine-disrupting chemicals (EDCs). An endocrine-disrupting compound has been defined by the U.S. Environmental Protection Agency (EPA) as “an exogenous agent that interferes with synthesis, secretion, transport, metabolism, binding action, or elimination of natural blood-borne hormones that are present in the body and are responsible for homeostasis, reproduction, and developmental process.” . EDCs inSome EDCs are believed to specifically exert thyroid-disrupting effects . ThyroidTHs are essential for normal growth and development of the fetus. The fetus relies exclusively on maternal THs ,15, sincThus, maternal exposure to compounds with thyroid-disrupting properties during pregnancy can affect not only the health of the mother but also the child before and after delivery, possibly resulting in fetal disease. Indeed, even small changes in TH levels of pregnant woman were shown to cause deleterious effects in the fetus ,24,25,26Although Kim’s paper observed an alteration of methylation status for only two placental genes, a deep modification of methylation patterns in placenta is probably an important and wider effect at least as a consequence of POP exposure. Accordingly, decreased methylation of long interspersed element-1  and increased methylation of imprinted IGF2 and H19  genes in placenta were found after prenatal exposure to POPs .Thyroid cancer (TC) is the most frequently diagnosed malignancy of the endocrine system . Thyroid2, sulfur, and chlorine compounds) or other potential thyroid disruptors contained in waters such as fluorine, sulfur, and selenium, could be responsible for the higher incidence of thyroid tumors in volcanic areas. Another widespread contaminant of drinking water is nitrate largely used as fertilized and therefore particularly abundant in agricultural areas. Several studies reported the association between nitrate ingestion and increase of thyroid tumor risk [Carcinogenicity of certain chemical compounds is well established. However, there is a paucity of epidemiological evidence on the relationship between exposure to environmental contaminants and risk of thyroid cancer due to the reduced number of extensive epidemiological studies exploring the outcomes following exposure to chemicals whose negative effects on thyroid function were experimentally reported . The onlmor risk ,57. As tmor risk . It has been hypothesized that thyroid homeostasis disruption could be at the base of the carcinogenesis process triggered by the environmental pollutants . The strExploiting a completely different mechanism, thyroid-disrupting compounds such as PBDEs and polycyclic aromatic hydrocarbons (PAHs), can promote tumor development and progression by upregulating the cytochrome-P450 enzymes, which leads to the production of elevated levels of reactive oxygen species (ROS) and oxidative stress, and in turn can foster tumorigenic processes ,66,67,68More recently, epigenetic mechanisms were suggested to have a critical action in thyroid tumorigenesis. As for the most part of tumors, also thyroid tumors exhibit DNA methylation alterations. The first DNA methylation studies in thyroid cancer assessed the DNA methylation status of promoter regions of specific candidate genes. By this approach, aberrant methylation was identified for PTEN (phosphatase and tension homologue), a fundamental tumor suppressor gene , and BRANitrate exposition with the consequent NO overproduction could represent of the causes of alterations in methylation levels: NO treatment on cancer cell lines was shown to induce alteration of methylation patterns although the epigenetic effects through DNA methylation were diverse and contradictory in different lines . A recenMoreover, NO can affect another class of epigenetic modifications that were found to be associated with the insurgence and aggressiveness of tumors: modifications of the histone tails ,80,81. AImportant epigenetic players in thyroid tumorigenesis processes are also microRNAs (miRNAs). miRNAs are small endogenous RNA sequences able to post-transcriptionally regulate gene expression and involved in the modulation of the vast majority of cellular processes, namely proliferation, development, differentiation and even tumorigenesis . MoreoveIn TC, a decrease in the expression of DICER, a crucial player in miRNA biosynthesis, was associated with the occurrence of malignant thyroid tissues, as compared with normal thyroid tissues and benign thyroid lesions. Decreased DICER expression was also correlated with important features suggestive of tumor aggressiveness such as the presence of the BRAFV600E mutation and of the RET/PTC1 rearrangement ,89. FurtmiR-181, a miRNA characterized as oncogene in prostate, ovary, and stomach cancers, was further identified as upregulated in thyroid neoplastic lesions in several investigations ,97. In pAdditionally, miRNAs were observed to be responsive to numerous environmental agents, many of which are also known for their action as EDCs. BPA and metal-rich particulate matter determined a higher miR-222 amount, while miR-146 levels were increased by BPA and reduced by Cd ,100,101.There is another class of non-coding RNAs whose deregulation has recently been demonstrated to participate in cancer progression and is increasingly considered as an important toxicological response to xenobiotics: the long non-coding RNAs (lncRNAs) . lncRNAsThe Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) is a lncRNA overexpressed in different forms of thyroid carcinoma and its repression in MTC-derived cell line negatively affected cell proliferation and invasion ,110. FurAs for MALAT1, also the Homeobox transcript antisense RNA (HOTAIR) lncRNA is upregulated in human TC cells. HOTAIR overexpression correlated with metastasis and poor prognosis of TC patients , whereasBy contrast with MALAT1 and HOTAIR, the lncRNA Growth Arrest-Specific 5 (Gas5) was significantly downregulated in both PTC tissues and PTC cell lines ,115. A lFinally, H19 is a characteristic lncRNA able to act as oncogene in several cancer types and exhibiting a higher expression both in thyroid tumors and in TC cells ,119. In Hashimoto and Graves’ diseases (respectively HT and GD) are the most common forms of autoimmune thyroid disease (AITD), and are characterized by an inflammatory state of the thyroid gland with lymphocytic infiltration and auto reactivity against thyroglobulin, thyroid peroxidase and thyroid stimulating hormone receptor (TSH-R) . Even thAmong environmental factors able to trigger autoimmune thyroiditis in susceptible individuals, influencing the incidence or the progression of the pathologies, excessive dietary iodide, selenium deficiency, stress, certain drugs, some infectious diseases are considered to be of utmost importance . In addiPeople resident in areas surrounding a petrochemical complex displayed a higher risk to develop HT and increased level of anti-thyroid antibodies compared to residents in a control area . Signs oA higher prevalence of primary hypothyroidism, anti-microsomal thyroid and anti-thyroglobulin antibodies (Tg-Ab) were reported in workers from a factory producing polyhalogenated biphenyls (PBB) and PBB oxides . MoreoveA limited number of epidemiological studies correlated PBDE exposure with the presence of markers of a subclinical stage of AITD. A significant association between TPO-Ab and BDE-209 was found among women in a population of workers in a deca-BDE manufacturing plant . AlthougOverall, these results firmly supported the contribution of environmental pollutants to thyroid autoimmunity, albeit their mechanisms of action are yet to be fully established. Epigenetic mechanisms may exert an important role in AITD. The involvement of epigenetic mechanisms and, in particular, of methylation status alteration, in autoimmune diseases has been acknowledged since the end of the last century when chemical inhibition of DNA methylation in mouse CD4+ T cells was shown to induce the presentation of self-antigens and cause a lupus-like syndrome . A growiBesides the effects of EDCs on methylation of placental tissues, studies carried out mainly on animal models showed that EDCs may interfere at the global body level on methylation affecting both DNMT expression and on the level of ten-eleven translocation methyl cytosine dioxygenase (TET) that is the enzyme responsible of the active removal of methyl group ,78. The During the last few years an impressive number of microRNAs have been identified as differentially expressed in thyroid tissue, serum and peripheral blood mononuclear cells of AITD patients with respect to healthy subjects, clearly indicating the involvement of these regulators in the onset and progression of AITD. The potential role of miRNAs in autoimmune thyroiditis is not an unexpected phenomenon, as miRNAs are well-established regulators of T cell activation, proliferation and cytokine production and are deregulated in several autoimmune diseases with both, anti- and pro-inflammatory functions ,152. In Other studies underlined the importance of miRNAs as markers of treatment response ,161,162.A number of miRNAs involved also in the pathogenesis of HT disease have been described. Mir-142, which is highly expressed in HT patient serum, controlled the expression of Claudine (CLDN1), a tight junction protein downregulated in various autoimmune diseases . IntraceAlthough for miRNAs, such as for methylation, a direct link among chemical exposure, miRNA alterations and AITD onset or progression has not yet been reported, some considerations can be noted. We have previously described the role played in thyroid tumor by the signaling pathway of NF-κB, a transcription factor that is affected by several toxicants and is activated in ATC wherein in turn it induces the overexpression of miR-146. NF-κB signaling pathway is also a major regulator of innate and adaptive immune responses . Hence, Although direct and indirect evidence points to epigenetic changes as one of the likely mechanisms underlying the adverse health outcome of EDCs exposure, there is currently no clear link between EDC-induced epigenetic changes and a specific thyroid disease. Several reasons are at the root of this failure: first of all the limited number of studies that extensively investigate the consequence of exposures to environmental levels of EDCs in humans. Furthermore, experimental studies in animal models or in vitro studies on cell cultures to identify possible mechanisms of action for chemicals are sporadic and frequently give inconsistent results if compared with human studies. Other problems are related with the particular nature of the thyroid system. For definition, most EDCs can interfere with thyroid homeostasis, however the TH alterations possibly caused by EDC interference might appear insignificant compared to the wide reference range that characterizes TH levels. This can be of relevance particularly in small studies where the health consequences caused by even minor alterations in TH homeostasis risk being misinterpreted. Large studies are also necessary to deeply understand the impact of EDCs on epigenetics and, in turn, the influence of epigenetic mechanisms on endocrine function, keeping in mind that alterations of the thyroid homeostasis can be the other way around, affecting epigenetic signature . In this review, starting from an analysis of the epigenetic modifications associated with a specific thyroid disease and from an overview of the EDCs implicated in triggering these diseases, we attempted to summarize the sparse experimental evidence supporting the involvement of epigenetic mechanisms in EDC-induced thyroid diseases. A limitation of this topic is that rarely are thyroid alteration caused by EDC exposure and epigenetic changes observed as a consequence of EDC exposure part of the same study or performed in the same cohort or even in the same kind of tissues or cells. However, some epigenetic mechanisms appear conserved in different EDC-triggered thyroid diseases. This is true not only for global modification such as DNA methylation that is deeply affected by EDC exposure, but also for more specific mechanisms. One example is miR-146, one of the most consistently upregulated miRNAs in PTC, FTC and ATC, which also displayed the most significant upregulation in thyroid tissues of GD patients. Other important signatures are represented by the overexpression of the maternally imprinted lncRNA H19 as a consequence of its demethylation in placental tissues, and the overexpression of this lncRNA in thyroid tumors wherein can act as an oncogene. These observations, suggesting a possible scenario where chemical exposure induces epigenetic modifications that can lead to different disease outcomes depending on the time and length of exposure and/or the genetic susceptibility, reinforce the importance of an integrated view of the relationship between EDC exposure, genetic and epigenetic mechanisms, and health alterations.Overall, our review supports the hypothesis that epigenetic mechanisms could play an important role in determining thyroid diseases in response to environmental contaminants. A complex and often interconnected network of epigenetic modifications can be activated by a large number of widespread environmental contaminants. However, our analysis also clearly shows that further research in this field is still necessary to fully elucidate the relationships linking pollutants, epigenetic mechanisms and diseases pathogenesis and eventually to be able to exploit this knowledge for the development of new classes of diagnostic and prognostic disease tools.


Coronary stents belong to the most commonly implanted devices worldwide. A number of different types of stent exist, with very different mechanical and biochemical characteristics that influence their interactions with vascular tissues. Inappropriate inflammatory reactions are the major cause of the two major complications that follow implantation of stents in a percentage as high as 5–20%. It is therefore important to understand these reactions and how different they are among different generations of stents. With several million implantations per year, coronary artery stents are among the most commonly used devices for the treatment of a disease that still represents the major cause of mortality and morbidity worldwide . As compThus, while the multifactorial nature of stent failure is acknowledged , the preWith the constant development of newer device types, the incidence and pattern of their short- and long-term complications have also changed . As compSecond-generation DES were developed explicitly to address these issues of biocompatibility. They feature a thinner strut platform with streamlined strut geometries to decrease prothrombotic fibrin deposition and a thromboresistant polymer as well as different (possibly less toxic) drugs such as everolimus, biolimus, or zotarolimus, which do not inhibit endothelial cell adhesion as compared to tacrolimus . Of impoMeta-analysis studies confirmed a lower target-lesion revascularization and incidence of stent thrombosis with newer-generation devices as compared to 1st generation DES and BMS ,27. The Restenosis is defined as the reduction in lumen size of an artery after intra-arterial intervention. While restenosis prior to the advent of coronary stents was mostly caused by recoil, in-stent restenosis is a response-to-injury process caused by formation of a tissue called neointima. For BMS, the theory postulated that this neointima is mostly composed of fibrotic tissue with a gradual and progressive onset over months, which led to the concept that in-stent restenosis is a benign phenomenon. In contrast, reports on the presentation of restenosis have consistently shown—without differences between BMS and DES—that more than 50% of the patients with in-stent restenosis present with unstable angina and myocardial infarction . The iniThe cytokines involved in these processes include IL-1, IL-6, and TNF-alpha . This caA number of potential therapies have attempted to address or reduce the incidence of restenosis. Based on the concept that oxidative stress may play an important regulatory role in inflammatory states , a numbThe pathophysiology of in-stent thrombosis is complex and multifactorial, and the vascular responses to stent implantation are only one of the players . An incoAs described above, local and systemic inflammation promote neointimal proliferation, resulting in the pathogenesis of in-stent restenosis. More importantly, chronic low-grade inflammation is also felt to play a primary role in the pathogenesis of stent thrombosis ,46,47,48The histology underlying these phenomena has been investigated in several studies . EosinopThe above processes may also lead to a direct activation of the coagulation cascade and platelet activation. An analysis of thrombus composition in the PRESTIGE cooperation  provides important insights into the pathological processes leading to thrombus formation. In this study, a total of 253 thrombus specimens were analyzed, the majority (68.8%) from cases of late stent thrombosis. Histology showed leukocyte infiltration, neutrophil extracellular traps and eosinophils, with a higher incidence in late stent thromboses of DES . In the While the subsequent development of bioresorbable polymers does not seem to have been associated with additional advantages as compared to the antithrombotic fluoropolymer ,57,58, tp = 0.018), even though lesions in BMS had a thinner cap [The chronic inflammation and endothelial dysfunction discussed above as causes of restenosis may also induce late de novo neoatherosclerosis. In a recent imaging study, lipid neointima was shown in 40% of the cases of in-stent restenosis, calcific lesions were reported in a similar incidence, and thin-cap fibroatheromas was observed in up to 15%. The frequency of these forms of neoatherosclerosis was significantly greater with DES than BMS  may in part be proportionally more important in these devices . AlthougIn terms of prevention, statins have been shown in small studies to stabilize neointima and prevent the appearance of neoatherosclerosis . In contPercutaneous coronary interventions cause mechanical injury and vascular inflammation which, along with the presence of a foreign body and the biochemical processes triggered by the polymer and the drug eluted by the stent, cause complex interactions between endothelial cells, smooth muscle cells, platelets, and inflammatory cells including neutrophils, monocytes, and lymphocytes. The activation of signaling cascades leads to repair and vascular healing but also adverse arterial remodeling, neointimal proliferation, and restenosis. Although effectively reduced after the introduction of DES, restenosis, and thrombosis remain important issues with important clinical implications. While the current generations of DES appear to have reached an innovation plateau that allows safe treatment of complex anatomies, future generations of devices, with a better mechanical profile and improved biocompatibility are still awaited.


Lactobacillales were isolated from the International Space Station and commercial resupply vehicle, and whole-genome sequences (WGS) were generated. WGS would permit the characterization of these potentially pathogenic bacteria that have been adapting to the extreme conditions of the space environment.Nineteen strains from the order  Lactobacillales were isolated from the International Space Station and commercial resupply vehicle, and whole-genome sequences (WGS) were generated. WGS would permit the characterization of these potentially pathogenic bacteria that have been adapting to the extreme conditions of the space environment.Nineteen strains from the order  Lactobacillales consists of Gram stain-positive, facultative anaerobes validly described by Ludwig et al.  surfaces were Enterococcus faecalis, Enterococcus faecium, and Aerococcus urinaeequi . The versions described in this paper are the first versions.This WGS project has been deposited at DDBJ/ENA/GenBank, and the accession numbers are given in


In the last few years, research on the central control of energy homeostasis has been unveiling the crucial role of glial cells, providing us a repository of new molecular targets to design therapeutic treatments for metabolic diseases. Among the glial cells involved in the regulation of food intake, energy expenditure, and glucose homeostasis, tanycytes are in the spotlight due to their privileged position within the brain and their wide spectrum of functions. As specialized ependymoglial cells whose cell bodies form the wall of the third ventricle, tanycytes extend their long processes within hypothalamic areas involved in metabolic control and reach close proximity with blood vessels through their end feet. Tanycytes are consequently considered an interface between the periphery, the cerebrospinal fluid (CSF), and the brain parenchyma. In this strategic position, tanycytes are able to regulate the access of metabolic information into the mediobasal hypothalamus by 1) transporting nutrients and hormones toward metabolic neuronal circuits, 2) sensing the metabolic information, and 3) appropriately releasing cytokines, nutritional metabolites, and/or gliotransmitters to modulate the activity of hypothalamic neurons. Conversely, tanycytes also control brain → periphery exchanges by regulating the secretion of key metabolic neurohormones, such as corticotropin-releasing hormone and thyrotropin-releasing hormone, in the portal vessels of the median eminence  by different mechanisms, including calcium signaling, metabolic shift, and/or changes in functional properties. This review highlights the need for more detailed analysis about metabolic and signaling pathways activated by nutrient sensing in tanycytes, as well as functional studies connecting tanycyte nutrient sensing with hypothalamic functions in physiological and pathological context. First, signaling pathways involved in tanycyte glucose sensing are further detailed by Salgado et al.. Hypothalamic tanycytes express several proteins involved in the glucose sensing mechanisms, in particular glucokinase and its regulator glucokinase regulatory protein (GKRP). Described in the liver, GKRP binds glucokinase and holds it inactive in the nucleus when glucose levels are low, which allows its rapid export and activation when glucose concentration rises. Hypothalamic tanycytes display an inverse dynamic in response to glucose: a rise in glucose levels drives nuclear compartmentalization of glucokinase. The authors reveal here that this differential glucokinase subcellular localization in tanycytes relies, at least in part, on the relative expression between glucokinase and GKRP and the regulation of GKRP expression and/or activity in tanycytes. Secondly, the impact of tanycyte glucose sensing on neuronal functions and physiology is reported in a functional study by Palma-Chavez et al.. The authors describe the role of the tanycyte endocannabinoid system in the modulation of arcuate neurons. The deletion of 2-arachidonoylglycerol-producing enzyme, diacylglycerol lipase-alpha (DAGLα), in tanycytes altered the usual response to CSF glucose in terms of neuropeptides produced by arcuate neurons.Yoo et al. who report undetectable expression of leptin receptor in tanycytes as well as a tanycyte-independent regulation of some hypothalamic neuronal functions modulated by leptin signaling. Changes in cell signaling and gene expression observed in tanycytes in response to leptin are proposed to result from indirect regulations.In addition to nutrients, recent studies have reported that tanycytes actively transport and sense metabolic hormones, such as leptin or ghrelin. A contrasting view is presented here by Rodríguez-Rodríguez et al. review here the control of thyrotropin-releasing hormone release, involved in the regulation of energy expenditure through the control of basal metabolic rate and thermogenesis. Tanycytes express a repertoire of proteins involved in transport, sensing, and metabolism of thyroid hormones necessary to coordinately control the activity of the hypothalamic–pituitary–thyroid axis. Alterations in energy balance regulate the expression and activity of these proteins, making median eminence tanycytes a pivot for thyroid-related regulation of energy balance.By projecting their endfeet in contact with fenestrated vessels in the external zone of the median eminence, tanycytes also control the release of neurohormones into the hypothalamic-hypophyseal portal system. Langlet). Tanycytes are characterized by their own molecular signature, which is mostly associated with their diverse physiological functions, and the detection of variations in nutrient/hormone levels leads to adequate modulation of their genetic profile in order to adapt tanycyte functions and to finally regulate energy homeostasis.This adaptability to the metabolic state is a key feature for tanycytes in the regulation of energy balance. It partly relies on an accurate regulation of gene expression profiles in different tanycyte subpopulations (Overall, significant advances have been achieved in the understanding of tanycyte functions in the regulation of energy homeostasis. This Research Topic puts new evidence on the table, points out the current controversies in this field, highlight the missing parts, and, we hope, will encourage researchers to consider tanycytes to solve the puzzle of hypothalamic control of energy balance.FL, JS, and MG-R wrote the paper and critically revised the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.