Among livestock species, cattle are crucially important for the meat and milk production industry. Cows can be affected by different pathologies, such as mastitis, endometritis and lameness, which can negatively affect either food production or reproductive efficiency. The use of mesenchymal stromal cells (MSCs) is a valuable tool both in the treatment of various medical conditions and in the application of reproductive biotechnologies. This review provides an update on state-of-the-art applications of bovine MSCs to clinical treatments and reproductive biotechnologies.Attention on mesenchymal stromal cells (MSCs) research has increased in the last decade mainly due to the promising results about their plasticity, self-renewal, differentiation potential, immune modulatory and anti-inflammatory properties that have made stem cell therapy more clinically attractive. Furthermore, MSCs can be easily isolated and expanded to be used for autologous or allogenic therapy following the administration of either freshly isolated or previously cryopreserved cells. The scientific literature on the use of stromal cells in the treatment of several animal health conditions is currently available. Although MSCs are not as widely used for clinical treatments in cows as for companion and sport animals, they have the potential to be employed to improve productivity in the cattle industry. This review provides an update on state-of-the-art applications of bovine MSCs to clinical treatments and reproductive biotechnologies. Research into stem cells has been very active over the past decade. Due to the increasing number of studies, several breakthroughs have been achieved in this field, and stem cell therapy has gained ground as a modality of regenerative medicine. Mesenchymal stromal cells (MSCs) are present in different body tissues and are characterised as able to adhere to plastic, express specific surface antigens and possess multipotent differentiation potential . FurtherBovine MCSs have been isolated and characterised  from difThe potential of MSCs for cell-based therapies has originally been based on their typical characteristics, which include the multipotentiality to differentiate in vitro into mesodermal-derived lineages, particularly osteogenic, chondrogenic and adipogenic cells . FurtherThe immunomodulatory activity of MSCs depends on direct cell-to-cell contact and on contact-independent paracrine signalling, with the production of soluble factors regulating proliferation, differentiation, migration and apoptosis of several immune cells . The redAutologous MSCs therapy implies cell isolation and expansion to achieve therapeutic doses. Consequently, there is a lag time between their collection and use, threatening the effectiveness of the treatment. In addition, critical parameters for MSCs isolation include donor variability, tissue of origin, amount of tissue and culture conditions . On the Although in veterinary medicine, cell therapies are mainly focused on pets, regenerative medicine applications also involve farm animals, not only for their importance as a food source  but alsoSo far, MSCs have been used in many experimental instances to treat various diseases in different animal species. Orthopaedic diseases were the primary field of regenerative veterinary medicine, and then the focus rapidly expanded to other areas. Dogs and horses were the species in which stem cell-based therapies were commonly used to treat different diseases of various organ systems, while for cats, they were used for renal, respiratory and inflammatory pathologies . Bovine The major obstacles in livestock species are related to a minor interest in treating clinical conditions in these animals compared to pets and the higher maintenance costs in comparison with other animal models . LaboratAlthough many studies have been published for animal MSCs, it is still not easy to evaluate the efficacy of MSC-based therapies because of the different sources of MSCs and variations in manufacturing processes, inconsistent characterisation and measure of potency, inappropriate controls and a lack of experimental power . MSCs haIn the last years, the application of regenerative medicine to skin lesions has been a focus for both human and veterinary medicine. The physiological healing process of cutaneous wounds is a well-orchestrated complex of molecular and biological activities. Even so, a chronic lesion can develop when the normal process fails. The regenerative potential of stromal cells has also been widely recognised for skin lesion repair . Recent Even if the exact functions of stromal cells in wound healing have not yet been completely elucidated, they are involved in the removal of dead cells and necrotic tissue, angiogenesis, reduction in scar tissue formation, contraction of the wound and induction of re-epithelisation . ConsequThe first report of a case study in which autologous BM-derived MSCs were used to treat a chronic ulcer in a heifer dates back to 2012 . A 2-yeaAnother clinical study of the same research group concerns the successful treatment of an interdigital chronic ulcerative wound in a 6-year-old cross-bred Jersey cow . The aniIn the last clinical trial , a bull Despite the lack of controls and large-scale randomised studies and clinical trials, the promising results obtained from the applications of autologous BM-MSCs confirmed the potential of MSC-based therapy for treating chronic nonhealing wounds in bovines.A weak immunogenicity and a vasculogenic effect are favourable properties for wound healing capacity. Bovine BM-MSCs are the most well-characterised cells, and recently their immunomodulatory properties  and proaIn the dairy industry, mastitis is a common problem, which implicates costs to treat the disease, and since antimicrobials are the standard therapy, this increases the possibility of developing antimicrobial resistance. Hence, alternative therapies are required.The mammary gland contains stromal cells and precursors with high regenerative potential, which apparently are maintained during the productive life of dairy cows. The presence of such cells opens new research perspectives regarding the physiological mechanisms concerned with milk secretion and the possibility of enhancing or prolonging dairy cow production . The preS. aureus, a mastitis-causing pathogen, by reducing about 30% of relative bacterial growth [On the other hand, less research is available for MSCs and bovine mammary glands. As summarised in l growth . The mecl growth .S. aureus clinical mastitis in order to evaluate the safety and efficacy of an allogenic MSC-based therapy [Dairy cows were experimentally infected to induce  therapy . Bovine  therapy . A simil therapy . On days therapy . With th therapy ,69. Both therapy . Treated therapy ,69. Fina therapy . Milk pH therapy . Moreove therapy .In the last 50 years, the selection in the dairy industry has led to an improvement in average milk production by a single cow. However, the selection for milk yield has caused some unfavourable effects, such as a decrease in fertility. Despite an improvement in cow fertility in the last two decades, as a consequence of selection for fertility traits in breeding programmes and improvement in animal nutrition and comfort, reproductive performance is not optimal yet . ReproduThe endometrium is characterised by an elevated and constant regeneration, and mesenchymal progenitor cells have also been identified in the cow endometrium . ProgeniOther pathologies, which can lead to considerable economic loss, are those involving the ovaries. Ovarian dysfunctions in dairy cattle have a high incidence and are responsible for a reduction in reproductive performance. The two major ovarian causes of infertility in dairy cows are inactive ovaries and ovarian cysts ,134. ChaThe first successful nuclear transfer (NT) dates back to 1952, when the nucleus from an early tadpole embryo was transferred into an enucleated frog egg . Then, iFirstly, it was demonstrated that bovine BM-MSCs had developmental totipotency after NT  and wereAnother context of research into cells includes their ability to incorporate exogenous DNA for the production of transgenic animals. Bovine MSCs were transfected with pBC1-anti-CD3 vector, and while those derived from WJ were more sensitive to treatments, AT-MSCs showed a better response to transfection .Bovine MSCs have also been used for in vitro embryo production. The traditional coculture system of bovine embryos with granulosa cells was less efficient than coculture with AT-MSCs . In addiAnother application of MSCs is to produce germinal cells after differentiation. The in vitro production of germ cell lineages is a new intriguing strategy for obtaining gametes in order to treat infertility, disseminate the genetics of elite animals and preserve endangered species . The in The development of stem cell technologies in species other than bovine can be seen as a useful background for developing and deepening similar advancements in livestock. MSC characteristics make them appealing for their potential in clinical applications, and the lack of ethical concern is the other factor that makes them ideal for laboratory studies. As for humans , for sucThe bovine model could be advantageous for the size and physiology when compared with traditional laboratory animals. In cattle, MSCs have been isolated from different tissues, and their pluripotency has been demonstrated, but there is still a lack of clinical applications and studies comparing MSCs from different sources to suggest which one is the best choice for cell therapy or for which specific pathology. The studies presented are promising for the possible applications of MSCs both in veterinary medicine and the livestock industry. However, more studies are required to develop bovine-specific protocols, and further investigation is needed to evaluate clinical responses after cell therapy applications. Attitudes in the livestock industry have shifted towards the preservation of the commercial viability of individual animals with high genetic value, leading, in turn, to an increase in medical expenditure to keep those animals healthy . MSCs tr


Latin America and the Caribbean (LAC) are among those regions most affected by the COVID-19 pandemic worldwide. The COVID-19 pandemic has strained health systems in the region. In this context of severe healthcare resource constraints, there is a need for systematic priority-setting to support decision-making which ensures the best use of resources while considering the needs of the most vulnerable groups. The aim of this paper was to provide a critical description and analysis of how health systems considered priority-setting in the COVID-19 response and preparedness plans of a sample of 14 LAC countries; and to identify the associated research gaps.A documentary analysis of COVID-19 preparedness and response plans was performed in a sample of 14 countries in the LAC region. We assessed the degree to which the documented priority-setting processes adhered to established quality indicators of effective priority-setting included in the Kapiriri and Martin framework. We conducted a descriptive analysis of the degree to which the reports addressed the quality parameters for each individual country, as well as a cross-country comparison to explore whether parameters varied according to independent variables.While all plans were led and supported by the national governments, most included only a limited number of quality indicators for effective priority-setting. There was no systematic pattern between the number of quality indicators and the country’s health system and political contexts; however, the countries that had the least number of quality indicators tended to be economically disadvantaged.This study adds to the literature by providing the first descriptive analysis of the inclusion of priority-setting during a pandemic, using the case of COVID-19 response and preparedness plans in the LAC region. The analysis found that despite the strong evidence of political will and stakeholder participation, none of the plans presented a clear priority-setting process, or used a formal priority-setting framework, to define interventions, populations, geographical regions, healthcare setting or resources prioritized. There is need for case studies that analyse how priority-setting actually occurred during the COVID-19 pandemic and the degree to which the implementation reflected the plans and the parameters of effective priority-setting, as well as the impact of the prioritization processes on population health, with a focus on the most vulnerable groups.The online version contains supplementary material available at 10.1186/s12961-022-00861-y. Latin America and the Caribbean (LAC) stand among those regions most affected by the COVID-19 pandemic, exceeding the average number of reported cases and deaths globally and in other regions, including Europe and North America . As of 6The pandemic has had very high social and economic costs for the region by increasing population poverty and socioeconomic inequalities. It has also exposed the weaknesses of the health and social protection systems, which have mainly impacted the most vulnerable populations. The preparedness of countries in LAC has also been undermined by political factors. For example, some political leaders have repeatedly minimized the threat of COVID-19 by not transparently communicating accurate data regarding the number of deaths and infections within their countries .The COVID-19 emergency has strained health systems and shifted critical health resources from routine programmes towards containing the spread of the pandemic and treating those that fall seriously ill , 12. In The COVID-19 context provides a unique scenario to study and understand whether and how priority-setting was undertaken in a sample of LAC during pandemic times. As part of a global study,Analysis for this paper is based on a review of COVID-19 response and preparedness planning documents . KapirirFourteen of the 33 LAC countries were sampled for maximum variation with respect to the following: regional representation ; economic status , a technique which uses the dependencies between the variables to represent it in a more tractable, lower-dimensional form, without losing too much information, was performed . PCAR isA total of 14 national COVID-19 preparedness and response plans were included in this study . Of the 14, 12 plans were in the form of a single national COVID-19 pandemic, while for two countries (Chile and Mexico), several documents collectively comprised the countries’ COVID-19 pandemic plan. All documents were published between February 2020 and July 2020.The study sample included four low- to middle-income countries , seven upper- to middle-income countries  and three high-income countries . The countries were at different stages of the COVID-19 pandemic at the time of retrieval.In what follows, we describe results organized according to the five domains of priority-setting, as identified in Kapiriri and Martin’s framework, including priority-setting context, prerequisites, priority-setting process, implementation and outcomes/impact. For each domain, and related parameters, we describe the number of countries that included the parameter in their reports, provide a snapshot of their content, and present a cross-country comparison Fig. .Fig. 1CoThe framework identifies five relevant contextual factors: the social, economic, cultural, political and health system contexts. While the reviewed COVID-19 plans did not describe the contexts in detail, the government webpages and the literature were used to obtain the additional information on the priority-setting context. We discuss some of the relevant contextual factors below.High inequality rates characterize the sociopolitical context of the region. In the last 6 years, many countries have suffered from political and social instability, in particular Ecuador, Peru, Chile, Bolivia, Colombia and Brazil , 28. TheAll the health systems of the sampled countries have a mix of public and private financing, and 13 are considered as having universal health coverage (UHC).The framework identifies four prerequisites for effective priority-setting: political will, availability of a legitimate priority-setting institution, incentives for compliance, and human and financial resources. While the plans discussed political will and resources, and identified the committees that developed the plans, there was neither explicit discussion of the legitimacy and capacity of the committees or priority-setting institutions, nor identification of (dis)incentives for compliance. We discuss the parameters that were presented below.political will, all the countries provided a response and preparedness plan led by their governments, often with participation of different governmental and social institutions . Ten out of 14 countries  created COVID-19 task forces, inter-ministerial committees or governmental commissions responsible for advising the government and designing the implementation of different interventions.In relation to Although all the countries we sampled had national pandemic influenza plans, only Panama and the Bahamas made an explicit reference that the COVID-19 plan incorporated some of the institutional legacies of previous coordination structures established to respond to the influenza pandemic.This parameter assesses the availability (or lack) of financial, material and human resources to implement the identified priorities. Apart from Bolivia, all countries’ plans discussed resources relevant to managing COVID-19, identifying PPE and other infection prevention and control (IPC) materials as well as the need for laboratory equipment and specimen transportation Fig. . HoweverSince most of the committees that were involved in developing the plans were appointed by the country’s governments, their legitimacy could be inferred by virtue of their appointment. However, it was not possible to assess the committees’ capacity to set priorities and whether there was an increase in the public’s confidence in the institution.The priority-setting process domain assesses whether the stipulated prioritization process was based on an explicit guiding tool/method/framework, was evidence-based and was fair. Fairness was assessed based on whether the plan articulated explicit priority-setting criteria (including equity considerations), stakeholder involvement, a publicity strategy, and mechanisms for appeals and revisions. Although none of the plans presented clear priority-setting process/tool/methods, several explicitly mentioned the incorporation of the WHO recommendations. For example, the Dominican Republic, Honduras and Panama used the WHO strategy of planning according to three pandemic phases and four scenarios—which do not incorporate priority-setting.prioritizing the sustenance of routine essential services, Mexico’s plan explicitly mentioned the necessity and importance of the continuity of maternal and child healthcare essential services, providing a plan to ensure it. In Chile, a planning document established that from the 85 diseases already prioritized through a national health benefits package called Universal Access with Explicit Guarantees (AUGE by the acronym in Spanish), only a subset of those diseases  would keep their priority status during the pandemic.In relation to stakeholder participation, all plans were led by the ministries of health , and many plans identified intersectoral committees. Commonly identified sectors included agriculture, transportation, education, tourism and finance. Additional stakeholders included medical associations and colleges, representatives of the public and private healthcare institutions, insurance companies, and journalists and media groups. Three plans  explicitly indicated that the public was represented or that public values had been considered for the development or implementation of the plan.In relation to Some countries included representatives of WHO in the task forces/commissions/committees coordinating the COVID-19 response plan.All the country plans were in some way (and to a varied extent) “evidence-informed”. Countries used various forms of evidence, for example, epidemiological data, lessons learnt from previous outbreaks or evidence on effective interventions. Many countries made explicit mention of using WHO pandemic planning guidelines , and three countries specifically adopted the WHO planning strategy according to three pandemic phases and four scenarios .explicit priority-setting principles and/or criteria. In this plan, the identified criteria included disease transmissibility, geographical spread, clinical severity of the disease, population vulnerability, and availability of preventive measures such as vaccines and possible treatments.Only the COVID-19 response and preparedness plan of Brazil articulated equity as a priority-setting criterion, including whether equity was considered when identifying programmes that should be sustained during the pandemic, and noting strategies proposed to provide healthcare services to vulnerable populations  identified vulnerable populations and explicitly prioritized them in the COVID-19 planning. The vulnerable populations included people with disabilities , immigrants, and sexual and gender minorities (Mexico). Only the Mexico and Chile plans considered the continuity of services for pregnant women and young infants, or people with particular diseases, respectively.publicly available, and recommends the presence of mechanisms for publicizing, appealing and revising the decisions as well as mechanisms for enforcing the three prior conditions. While nine plans included a section on communication, this was mainly risk communication, oriented towards health education and not information about priority-setting decisions. However, all the countries developed webpages to communicate decisions and to provide citizens information about the unfolding pandemic. While there were no clear appeals or revisions mechanisms, five plans  mentioned that the established commissions/task forces would periodically review additional emerging national and/or international evidence and use it to revise their plans and activities. Some countries tasked certain stakeholders  with the role of evaluating or supervising compliance with the plan .In addition to the priority-setting criteria and equity considerations, the Kapiriri and Martin framework requires that priority-setting decisions and their rationales be made Mechanisms for appealing the decisions were only considered in the preparedness and response plan for Peru, which highlighted that laws could be revised and decisions might change according to the dynamic epidemiological conditions. Enforcement mechanisms to ensure that the process adhered to the above conditions were not articulated. However, some plans  articulated mechanisms for ensuring that the decisions were implemented. These mostly referred to the proclamation of laws that enforced the compliance with lockdowns, social distancing and restrictions on gatherings and public transportation.There were no discussions about the efficiency of the prioritization process or the reduction in public dissensions.degree to which resources were allocated according to the priorities, reduction in resource wastage, improved accountability and reducing corruption, increased stakeholder understanding of priority-setting and strengthening of the priority-setting institutes.This domain assesses the Some countries specified the need for reallocation of resources (monetary and others) from less prioritized areas to high-priority areas .While several plans included budget estimates for the pandemic priorities, only Peru’s plan talked about aiming to improve internal accountability/reduce corruption by supporting transparency in the management of resources and accountability.The other parameters were not discussed in the reviewed documents.impact on institutional goals and objectives, impact on health policy and practice, impact on population health, impact on reducing inequalities, fair financial contribution, increased public confidence in the health sector, responsive healthcare system, improved financial and political accountability, increased investment in the health sector and strengthening of the healthcare system.This domain has the following parameters: All these parameters could not effectively be assessed from the information in the planning documents. However, some of the plans indicated that they would mobilize additional resources for financing the plan, and the need to strengthen the healthcare system to respond to the pandemic. Since these parameters can only be effectively assessed after the plans are implemented, interviews with decision makers and implementers to evaluate the degree to which these parameters were actually achieved.The PCAR enabled us to identify patterns between countries in relation to the number of parameters contained within their plans. According to the Wright mapping, all the sampled country plans included only a few parameters (the red box). When assessing which country plans identified the various parameters (side A of the figure), the countries at the top of the figure are those whose plans identified the greatest number of parameters (including those that were least likely to be found in the other plans). When assessing the likelihood that the parameters were found in the plans (side B of the figure), parameters above zero  were the least likely to be found in the reviewed plans, while those below zero (e.g. stakeholder engagement) were more likely to be found in the reviewed plans.Based on this analysis, three groups of countries were identified. The plans from the first group of countries  contained the highest number (9–11) of parameters. Those from the second group  contained 7–8 parameters, and the plans from the third and last group (Bolivia and Haiti) had the lowest number (six) of parameters. Fig. . There wWHO warns that when priority-setting “is not explicitly done, with a transparent discussion on priority-setting criteria and a joint examination of the evidence, then it will be done in an ad hoc, implicit way”.7Hence, this study provides the first descriptive analysis of whether and how COVID-19 response and preparedness plans in the LAC region included priority-setting. The analysis, based on Kapiriri and Martin’s  frameworResponse and preparedness plans in all 14 countries included in this analysis were led by the country’s government. In 10 of these countries, specific COVID-19 task forces, inter-ministerial committees, or governmental commissions were created to coordinate some activities of the plan and/or to advise government. Most plans also acknowledged the participation of civil society actors such as scientific societies and clinical experts.Despite the strong evidence of political will and stakeholder participation, none of the plans presented a clear priority-setting process, or used a formal priority-setting framework, to define interventions, populations, geographical regions, healthcare setting or resources prioritized. Likewise, most plans did not present explicit guiding criteria or principles for priority-setting. Although the plans of Brazil and Bolivia mentioned some criteria, they included no systematic discussion or application of the criteria in the prioritization process. In this respect, the plans deviate from the WHO and the IACHR recommendations.All the reviewed plans (except Bolivia) identified availability/scarcity of various resources that were deemed relevant to managing the COVID-19 pandemic. This is consistent with the priority-setting literature, which emphasizes the need for explicit identification of both priorities and resources . The ideOne approach to incorporating equity considerations is by prioritizing vulnerable populations . Our fin8According to the IACHR resolutions on the Pandemic and Human Rights in the Americas of 10 April 2020, and Human Rights of Persons with COVID-19 of 27 July 2020, the rights of certain people or groups, such as indigenous peoples, persons deprived of liberty, people living with HIV/AIDS, and women, among others, may be at special risk during the pandemic. Indeed, some studies in the United States and Latin America have indicated that in vulnerable communities and regions with a higher rate of poverty, unemployment or informal employment, or where ethnic minorities live, there is a higher prevalence of COVID-19 and a higher risk of mortality, regardless of age and the existence of comorbidities –51. ThisThe purpose of the PCAR cross-country comparison was to assess the degree to which the priority-setting quality parameters in the reviewed plans reflected particular health system organization, pandemic experiences and socioeconomic status. Although the differences between the countries were not substantial, the findings that more lower- and middle-income countries tended to have a smaller number of quality parameters in their plans, and three of them lacked UHC , highlight a possible link between priority-setting, economic status and the type of health system. While these linkages may not be clear, some of the literature alludes to the weaknesses in priority-setting infrastructure in contexts with weak health infrastructure and limited resources .The study findings should be interpreted with caution for the following reasons: First, the response and preparedness plans reviewed were published at different stages of the global and national COVID-19 pandemic. The comprehensiveness of the plans may have been affected by this temporal difference. Second, for two countries (Chile and Mexico), we included several government documents that formed part of the national response plan, as opposed to a single document. While this approach could have led to favourable comparisons with the countries, the cross-country comparison did not indicate any additional advantage for the two countries. Third, basing the analysis on government documents may have introduced governmental bias. However, governments led the pandemic response efforts in most of the countries.Explicit priority-setting is critical to improving the quality of COVID-19 pandemic preparedness and response. Since most LAC countries lacked explicit reference to the parameters of effective priority-setting, incentivizing the study and use of priority-setting frameworks in the LAC region should be encouraged. Countries in the region are unlikely to deliver equitable healthcare services during disease pandemics, especially for marginalized communities, without explicit priority-setting processes. Those processes must reflect the parameters of effective priority-setting, as discussed in this paper. The Pan American Health Organization and the Center for Global Health Development could support these countries in instituting and strengthening their priority-setting mechanisms.This study highlights the need for case studies on the formulation, implementation and evaluation of public policies (beyond priority-setting) in the face of health emergencies, based on the experience of the COVID-19 pandemic.Integrating priority-setting in the pandemic plans is an initial step to implementing systematic priority-setting. However, since the plans may, due to various contextual factors, not be implemented, there is need for cases studies that describe how priority-setting was actually implemented during the COVID-19 pandemic in the LAC and how the implementation compared to what was planned. Such case study will begin to unpack the relevant local and global contextual factors that impact priority-setting, which will contribute to the health policy and priority-setting literature.To the best of our knowledge, this is the first paper that systematically analyses the inclusion of priority-setting in COVID-19 pandemic plans in the LAC. Based on the analysis using the parameters for effective priority-setting in Kapiriri and Martin’s  frameworSince systematic priority-setting is critical to improving the quality of COVID-19 (and future) pandemic preparedness and response, LAC should be supported to better integrate the parameters of effective priority-setting in the pandemic plans and their implementation. The Pan American Health Organization and the Center for Global Health Development could support these countries in instituting and strengthening their priority-setting mechanisms. There should be concurrent efforts to integrate evaluation of actual priority-setting in order to understand the actual impact of the prioritization process on population health, but more specifically on the most vulnerable populations in this region.Additional file 1. Documents reviewed in each country.


The ablation mechanism and performance of carbon fiber (CF)-reinforced poly aryl ether ketone (PAEK) thermoplastic composites were studied in this paper. The results show that the ablation damaged area is controlled by the irradiation energy, while the mass loss rate is controlled by the irradiation power density. In the ablation center, the PAEK resin and CFs underwent decomposition and sublimation in an anaerobic environment. In the transition zone, the resin experienced decomposition and remelting in an aerobic environment, and massive char leaves were present in the cross section. In the heat-affected zone, only remelting of the resin was observed. The fusion and decomposition of the resin caused delamination and pores in the composites. Moreover, oxygen appeared crucial to the ablation morphology of CFs. In an aerobic environment, a regular cross section formed, while in an anaerobic environment, a cortex–core structure formed. The cortex–core structure of CF inside the ablation pit was caused by the inhomogeneity of fibers along the radial direction and the residual carbon layer generated by resin decomposition in an anoxic environment. The description of the ablation mechanism presented in this study broadens our understanding of damage evolution in thermoplastic composites subjected to high-energy CW laser irradiation. Carbon fiber (CF)-reinforced polymer composites (CFRPCs) have become important structural materials in the aeronautic industry because of their outstanding properties, such as high specific stiffness, strength-to-weight ratio, and low thermal expansion coefficient ,2,3. RecCurrently, research on laser damage to resin matrix composites mainly focuses on the physical damage and ablation behavior of the material. At the physical level, it was found that laser shock can cause composite delamination. Regarding the ablation behavior, researchers analyzed the decomposition and sublimation reactions that occurred in the composites and discussed the influencing factors. Ecault et al.  quantifiIn summary, the ablation mechanism of CFRPCs under laser irradiation has been extensively studied in experiments and simulations. However, the above literature was primarily focused on traditional thermoset matrix composites. With the gradual improvement of the properties of high-performance thermoplastic (TP) matrix materials, thermoplastic composites (TPCs) are expected to be widely used in next-generation aircraft, owing to their high toughness, outstanding damage tolerance, and recoverability ,19,20,212, and the resin content of the prepreg was 37 wt%. Moreover, the nominal ply thickness of the prepreg was 0.15 mm. The thermophysical properties of the CF and PAEK-L resin are presented in 7s . Second, the welded preform was placed in a combination die for hot pressing and cured by the process shown in The CFRTPCs were prepared from CF -reinforced poly(aryl ether ketone) (PAEK-L) unidirectional prepreg provided by Heilongjiang Yingchuang New Materials Co., Ltd. Jiamusi, China The areal density of the CF was 149 g/mThe laser ablation experimental system is shown in The changes in laser power (samples 1–4), irradiation time (samples 4–7), and spot diameter  had different effects on the damage of CF/PAEK, as shown in The relationship between damaged area and mass loss rate of CF/PAEK on one hand and spot diameter on the other is shown in In summary, the ablation damaged area is controlled by the irradiation energy, while the mass loss rate is controlled by the power density. According to the above conclusions, different damage effects can be achieved by adjusting the laser parameters. For example, the smallest spot diameter and highest laser power should be chosen to destroy internal electronic components and equipment. In contrast, a high laser power and large spot diameter are more suitable for structural destruction owing to the larger damaged area.The ablation behavior and its mechanism are significant issues in laser damage assessment. As shown in During the preparation of CF, a slight cortex–core structure of the precursor fiber formed due to double diffusion in the coagulation bath, which further intensified during the subsequent carbonization. The cortex was densely arranged and aligned along the axial direction with fewer defects, while the core was disordered, with a large number of pores ,35,36. TAccording to the above analysis, the ablation mechanism of CF/PAEK under CW laser irradiation can be summarized as follows see .When a high-energy CW laser irradiates the surface of the CF/PAEK laminate, the temperature in the spot center increases rapidly, causing the PAEK resin and the CFs to decompose and sublimate instantly. According to the temperature distribution, the ablation area can be divided into three regions: ablation center, transition zone, and heat-affected zone. The ablation center is directly irradiated by the laser, showing the fastest heating rate and the highest temperature . The PAEK resin first decomposes to produce small molecular gaseous products. When the temperature continues to rise above the sublimation temperature of the CF, the CFs sublimate into gas. Since the laser energy has a Gaussian distribution, a V-shaped ablation pit is formed. Due to the rapid formation of abundant gaseous products, a positive vapor pressure is formed, which prevents external air from entering the ablation pit. Therefore, the PAEK resin decomposes and leaves a thin residual carbon layer on the surface of CFs. Meanwhile, the CFs sublimates and forms a needle-like structure owing to the inhomogeneity of the fibers along the radial direction. Therefore, the unique cylinder nested cone structure of CF forms.2 [The temperature in the transition region is between the decomposition temperature of the PAEK resin and the sublimation temperature of CF. In the presence of air, the PAEK resin and the CFs on the surface layer are oxidized to gaseous products such as CO and CO2 . In contThe temperature in the heat-affected zone is between the melting temperature and the decomposition temperature of the PAEK resin. The PAEK resin undergoes physical changes associated with remelting and solidification during heating and cooling, while the CFs do not change in this temperature range. The PAEK resin flows locally under gravity in the molten state, leaving cavities in several areas after solidification. Since most resin remains in the interlaminate, and no gas decomposition product is generated, there is no delamination in the heat-affected zone. Therefore, the damage mechanism in this region is only thermophysical melting of the PAEK resin, which is different from that observed for the thermoset resin.The above mechanism shows that the ablation behavior of thermoplastic composites is obviously different from that of thermosetting composites in some respects. Compared with thermoset resins, CF/PAEK formed a molten layer during the laser ablation process, which protected the material from further oxidation and damage. This property enables the composite structures to maintain high residual strength after laser ablation, thus showing good laser damage resistance.This paper concentrated on the ablation mechanism and performance of CF/PAEK thermoplastic composites subjected to CW laser irradiation. The effects of laser power, irradiation time, and spot diameter on the ablation damaged area and mass loss rate of CF/PAEK thermoplastic composites were discussed. The results showed that the ablation damaged area is controlled by the irradiation energy, while the mass loss rate is controlled by the power density. The morphology and composition of the ablated composite were characterized to reveal the ablation mechanism. According to the temperature distribution, the ablation area was divided into three regions: ablation center, transition zone, and heat-affected zone. The formation mechanism of the unique cylinder nested cone ablation morphology of CF was explained.The ablation mechanism presented in this study can deepen our understanding of the damage evolution of CF/PAEK subjected to high-energy CW laser irradiation. Moreover, this work lays the foundation for subsequent research on CF/PAEK damage tolerance after laser ablation. The residual strength of the damaged laminate can be tested, and the strain response of the laminate during laser ablation can be tested in situ. In addition, research about the development of laser ablation-resistant coatings and protective effects is meaningful.


Abiotic stress is an important factor affecting the normal growth and development of plants and crop yield. To reduce the impact of abiotic adversity on cotton growth and development, the material basis of cotton resistance and its physiological functions are analyzed at the molecular level. At the same time, the use of genetic engineering methods to recombine resistance genes has become a hot spot in cotton resistance research. This paper provides an overviews of the resistance mechanism of cotton against the threat of non-biological adversity, as well as the research progress of osmoregulation-related genes, protein-acting genes, and transcription regulatory factor genes in recent years, and outlines the explored gene resources in cotton resistance genetic engineering, with the aim to provide ideas and reference bases for future research on cotton resistance. Cotton is an important cash crop and occupies an important position in the industrial and agricultural economy of the country . Cotton Abiotic stress mainly includes environmental factors that cause adverse effects such as extreme temperature, drought, salinity and alkali and low temperature usually cause a series of physiological and biochemical reactions in plants to adapt the adverse environment. These factors influence the development and growth of plants in addition to their morphological, physiological, biochemical and molecular processes . Plant rThe response pathway of cotton to abiotic stress can be roughly divided into four stages, ① the perception phase, the cotton senses the signal of abiotic adversity; ② the abiotic adversity signal is transmitted after the transmission stage; the reaction stage; the signal initiates a series of downstream molecular reactions ④ Expression stage; induces the expression of resistance-associated genes after going through the above four phases, cotton shows a specific response and resistance to the threat of non-biological adversity . This paNon-biotic stress mainly includes drought, salinity-alkaline, polar temperature, soil nutrient deficiency and other unhealthy environmental conditions . The nor2 and the decrease in photosynthesis in Loss of crop production due to drought ranked first among all non-plant related pressures, and second among crop-related pressures. Drought can cause severe dehydration of plant cells; the normal cell membrane structure is destroyed, resulting in excessive closure of gas pores, which affects the absorption and uptake of CO2+ K+, Mg2+, P3, and Mn4+ in the leaves and roots of cotton seedlings, leading to nutritional imbalance of cotton . High temperature stress (40°C during the day and 32° at night) reduced the rate of seed germination  isthe main cause of difference in nitrogen efficiency . Under t enzymes . Nitroge enzymes .In recent years, the shortage of global water resources, soil salinity, frequent extreme weather conditions and so on, the demand for cotton side-effect resistance is getting higher and higher. Cotton breeding not only focuses on improving yield, quality and resistance to diseases and insects, but also pays increased attention to resistance to abiotic stress and efficient use of soil nutrients . ExploreResearch on cotton resistance started late, however has progressed rapidly in recent years. At home and abroad, the collection, assessment and verification of cotton resistant germplasm resources on the non-biotic resistance of cotton  such as Cotton is recognized a salt and drought-resistant crop, and is the “pioneer crop” for desalination beach soil. It is an important source for increasing cotton acreage in the future to alleviate the conflict between grain and cotton and to utilize the reclaimed land. Selecting and breeding to salt-tolerant and drought-resistant cotton varieties to improve the adaptability of cotton to a salt-tolerant environment is one of the important ways to reduce the damage of salt-tolerant soils and to develop and utilize salt-tolerant land resources such as coastal beach . The selConductivity is an important indicator of cell membrane stability and fluidity and identifies the cold resistance of seedlings. The results showed that under low temperature stress, young cotton seedling electrical conductivity enzyme activity of peroxidants and soluble sugars increased, and root activity decreased, while young cotton seedling electrical conductivity and root activity decreased less in low temperature resistant varieties . The conThere were significant differences in nutrient uptake and availability between different cotton lines. Selecting the screening index of the combination and digging up nutrition and beneficial strains can improve the absorption and utilization efficiency of nutrients, improve the utilization rate of seed resources, reduce resources, protect the environment, and achieve sustainable agricultural development. By determining the height, dry weight and total nitrogen content of cotton plants , the seeMolecular markers of important characteristic genes of cotton mainly concentrated on the screening of molecular markers such as yield and its constitutive factors, fiber quality traits, resistance to rot and wilt. There is less research on abiotic stress resistance, mainly focusing on QTL screening of drought resistance and salinity resistance traits.2 to isolate the population. QTL screening for drought resistance was performed by observing the water loss capacity of leaves of cotton after 6 h of natural water loss. A QTL site was discovered on chromosome #16 that controls leaf water loss. The additive effect can explain the phenotypic variation of 12.2% [Lu Mian 97−8 × (12)] F2 isolated groups, and obtained data on the impact of constraints on cotton seed yield and plant height in each reproductive period by detecting the restraint index and coefficient, and then screened 7 plant heights in term of site drought resistance, with a contribution rate of 4.5%, 19–19.66%, including 4 plant heights QTL in bud phase, 1 plant height in flowering stage, and 2 plant heights in growth phase. Plant heights of different periods were distributed to different linkage groups, indicating that the same traits are controlled by different loci genes, and plant heights of different reproductive stages are controlled by different genes  genetically modified cotton at different development periods, and after long-term drought stress during the flowering period, the yield of single seed cotton of GM strains is significantly higher than that of wild-type controls. Compared to the large-scale production and use of insect-resistant genetically modified cotton, the genetic engineering of cotton against abiotic stress has made some progress, however it is still in the experimental and research stage, and there is still some distance to commercial application. Compared with the production requirements, research progress needs to be further accelerated.The gene’s stress response to stress is mainly manifested in the control of its own genetic material and epigenetic regulation under the influence of DNA methylation, RNA disruption or histone modification. There have been many studies on the inverse correlation of stress resistance non- living cotton and the analysis of its energy, which can be divided into two types: one is the functional factor which can enhance the ability of plants to adapt to adverse environments after induced expression by stress, such as r stress , such asentified , and theentified  introducGossypium Hirsutum L.) is currently used. Among them, there are about 30 factors of reverse conversion of cotton resistance the energy properties of which have been preliminarily defined (Transcription factor (TF), also known as trans-acting factors, are a type of protein molecules that can specifically bind to cis-acting elements in the promoter region of eukaryotic genes to ensure that the target gene is expressed at a specific intensity at a specific time and place . Under t defined .GhDREB -gene from cotton into wheat, and functional analysis showed the following: under drought, high salinity and freezing stress, transgenic plants accumulated a large amount of soluble sugar and the content of chlorophyllin increased significantly compared with the control, but the plant phenotype did not change much  belongs to the AP2/ERBP family of transcription factors and contains the AP2/ERBP domain . The cisnge much  isolatedstructed . The polin vitro and in model organisms.NAC transcription factors are a special type of transcription factors found in plants. Their common feature is the approximately 150 amino acid long NAC domain with a high degree of protection at the N-terminus, while the C-terminus is a highly variable transcriptional regulatory region. The results indicated that NAC transcription factor played an important role in plant resistance to drought and high salt stress through direct or inducible transcription factor and the expression of drought and high salt stress. It was found that rice tolerance to drought, high salinity and low temperature was increased when rice was overgrown in the vegetative growth stage. Although the cultivars with abiotic stress resistance of cotton were selected, their development was slow compared to the research results of high yield, good quality and diseases and insect resistance. There is still a long way to go to meet the commercial need for stress resistant varieties mainly the following aspects of the problem.(1)Lack of systematic identification and screening of cotton superior resistance to reverse germplasm resources. For a long time, there have been studies on yield, quality and disease and insect resistance in cotton breeding, but less research on non-biotic stress. Although the researchers have performed relevant work on the screening criteria of cotton resistance and identification of germplasm resources with resistance to resistance, the materials come from different sources of cotton, such as local varieties, extended varieties, introduced materials, and distant hybrid materials. Identification criteria and results from different antagonistic/sensory laboratory resources need to be integrated.(2)Under tagging of deficiency and resistance elements is closely related, which limits the process of culturing new material aided by under tagging. Molecular markers were used to aid in the selection and polymerization of cotton. Research has mainly focused on improving of fiber quality and disease resistance of cotton. So far, i only preliminary studies of QTL mapping related to drought and salt tolerance have been performed in abiotic stresses , but the(3)The lack of an important value of anti-inverse factor. Although Kronn has a large number of inverse correlation factors of cotton resistance, they are mainly some stress response factors and transfer factors, and few of them have any real value. In meantime, the resistance mechanism also needs to be further elucidated. In addition, in the current cloning of cotton resistance to inverse factor, many in the drought resistance, salt resistance, and cold resistance, high temperature resistance, cotton nutrition efficient use of the target factor is not much.(4)The theory of seed breeding and the method of sub-design must be thoroughly studied. In the past 10 years, the technology of seed breeding and seed breeding has been highly appreciated, and through the technology of gene transformation a batch of cotton materials with a wide cultivars has been created However, there is a need to do more research on the theory and method of organic combination of seed splitting breeding technology and conventional breeding technology, and the fruit of biomass technology should be used in cotton peanut production.Compared with the progress of research on resistance of rice, corn, wheat and other food crops, research on resistance of cotton is relatively stagnant, and there is still a certain gap in resistance breeding. In order to better use the research results of molecular biology in the practice of cotton resistance breeding as soon as possible, and speed up the process of cotton resistance breeding, future research, will be conducted based on the exploration and evaluation of excellent resources, the main effect of resistance QTL and the cloning of excellent key resistance genes, using MAS technology (marker assisted selection) and transgenic technology to polymerize resistance genes to achieve the analysis of resistance genes. Sub-design and breeding, to breed high-yielding, -quality, multi-resistant, and widely suitable new varieties of cotton (series). It is recommended to focus on the following aspects of work.(1)The identification and evaluation of resistant gene-type varieties of cotton are carried out systematically. Through extensive collection of cotton resource materials from different sources, resistance biology identification of germplasm resources and analysis of genetic mechanism of target traits are carried out. Complete and clarify the resistance evaluation indicators under the threat of different adversities, combine the evaluation indicators with field trails, systematically and comprehensively identify and assess resistance gene varieties for cotton, and provide excellent resistance germplasm resources and gene sources for crop breeding practices as soon as possible.(2)A batch of molecular markers of important resistance traits from cotton QTL were screened and used to aid in the selection of target traits. It is difficult to identify the resilience of different materials on large scale using morphological and physiological indicators. Molecular marker technology has been widely used in various studies of cotton to discover molecular markers closely linked to the characteristic target genes of resistance, and use MAS technology to conduct large-scale screening of the characteristic target genes to find marker resources to provide the design and future breeding of related resistance characteristic molecules.(3)Explore anti-reverse heterogeneity resources and create new anti-reverse materials. Using omics and other techniques and biological information methods, cotton varieties that contain excellent resistance genes are being studied, and resistance-related genes are discovered and cloned. Functional verification of key genes for resistance is obtained, and their mechanism of action is clarified. Make full use of the research into other crop resistances, direct endogenous and exogenous resistance-genes to human cotton receptors, and create new transgenic materials containing excellent resistance genes to provide excellent genetic resources and target materials for resistance breeding.(4)Strengthening the combination of basic research and seed breeding and strengthening multidisciplinary cooperation. Although a number of resistance related genes and resistance related transcription factors have been discovered, the endogenous or exogenous resistance related genes have been successfully transferred into cotton using genetic engineering, and the transformation materials with a significantly improved phase table have been obtained. However this work is limited to laboratory research and has not yet been applied to breeding practice. So far, the new varieties with improved non biotic resistance have not been used in production. Each step of cotton resistance breeding involves many scientific researches, such as developing new cotton varieties with high yield, quality, multi-resistance as well as high efficiency and utilization of nutrients through comprehensive assessment.SS and LW: conceptualization, writing original draft, and writing review and editing. Both authors contributed to the article and approved the submitted version.


Critically ill patients often require complex clinical care by highly trained staff within a specialized intensive care unit (ICU) with advanced equipment. There are currently limited data on the costs of critical care in low-and middle-income countries (LMICs). This study aims to investigate the direct-medical costs of key infectious disease  patients admitted to ICU in a hospital in Ho Chi Minh City (HCMC), Vietnam, and explores how the costs and cost drivers can vary between the different diseases.We calculated the direct medical costs for patients requiring critical care for tetanus, dengue and sepsis. Costing data (stratified into different cost categories) were extracted from the bills of patients hospitalized to the adult ICU with a dengue, sepsis and tetanus diagnosis that were enrolled in three studies conducted at the Hospital for Tropical Diseases in HCMC from January 2017 to December 2019. The costs were considered from the health sector perspective. The total sample size in this study was 342 patients.ICU care was associated with significant direct medical costs. For patients that did not require mechanical ventilation, the median total ICU cost per patient varied between US$64.40 and US$675 for the different diseases. The costs were higher for patients that required mechanical ventilation, with the median total ICU cost per patient for the different diseases varying between US$2,590 and US$4,250. The main cost drivers varied according to disease and associated severity.This study demonstrates the notable cost of ICU care in Vietnam and in similar LMIC settings. Future studies are needed to further evaluate the costs and economic burden incurred by ICU patients. The data also highlight the importance of evaluating novel critical care interventions that could reduce the costs of ICU care. Critically ill patients require complex clinical care by highly trained staff, often within a specialized intensive care unit (ICU) with advanced equipment. The provision of high-quality critical care in low-and middle-income countries (LMICs) is challenging due to the burden these requirements place on infrastructure, healthcare expenditure and human resources –3. FurthThe requirement for high numbers of specialized staff and advanced medical equipment means that critical care is one of the most expensive types of hospital-based care globally. In the United States (US), ICU costs have been estimated to account for around 13 to 39% of the total hospital costs nationally . The daiSimilar to other LMICs, the healthcare system in Vietnam has limited human resources, infrastructure and technology to provide quality health care and critical care . A recenImproving knowledge of costs of critical care is important for evaluating the cost-effectiveness of new interventions and for better resource utilization. However, there is currently limited information available related to the health care cost of hospitalized patients who need critical care, particularly for those with infectious diseases. particularly the out-of-pocket costs. Although, social health insurance has been shown to decrease the out-of-pocket costs of patients , 22, thePoorer groups of the population will be most at risk of the negative consequences of these out-of-pocket costs generating socio-economic difficulties and exacerbating equity and accessibility issues , 26.Limited information related to the cost of critical care illness, particularly for infectious diseases, has been reported in Vietnam. It is important to understand the potential significance of these costs and the degree the costs may vary according to disease and associated severity. This study aims to investigate the direct medical cost  in the context of critical care for key infectious diseases  in a referral hospital in HCMC, Vietnam, explore how the costs and cost drivers can vary and investigate the patients' out-of-pocket costs in the context of the national health insurance program. We focus on these key diseases due to their notable burden in this setting and the availability of data for them.We calculated the direct medical costs for patients requiring critical care for tetanus, dengue and sepsis. Costing data, extracted from the bills of patients hospitalized to adult ICU in the Hospital for Tropical Diseases in HCMC from January 2017 to December 2019 were retrieved from three different studies of tetanus, dengue and sepsis that have been conducted in the hospital . We also reported the ICU costs stratified by key cost categories. Moreover, the daily cost of ICU was calculated by dividing the total direct medical costs incurred in ICU by the length of stay in ICU. The costs were stratified based on whether the patient needed mechanical ventilation, as a proxy for the severity of the cases . As therDue to the highly skewed data, we reported the median and interquartile range for the costs and cost categories. For patients covered by the national health insurance program, we estimated the proportion of the total ICU cost that was covered by the program and the remaining cost that would be covered by the patient (out-of-pocket cost). This was based on information from the patients' bill which included the total ICU cost and the amount reimbursed by the health insurance program. It should be noted that only insurance information related to the national health insurance program was available for this study and the potential contribution from private medical insurance was not considered.The costs reported in different years were adjusted for inflation using Vietnam Gross Domestic Product deflator rates  and thenThe primary studies from which this sample was drawn were approved by the Oxford Tropical Research Ethics Committee and Hospital for Tropical Diseases Ethics Committee and patients gave written informed consent for their medical bills to be obtained.The collected baseline information is summarized in The costs across the different diseases and severity status are summarized in The key drivers of ICU costs also differed across the diseases and the severity of the cases . For patThe total direct medical cost is highly influenced by the duration of ICU stay. We therefore also calculated the average daily ICU costs across the different diseases. For patients not requiring mechanical ventilation, the daily cost of sepsis was the most expensive ), followed by dengue ) and tetanus ). For the patients requiring mechanical ventilation, the median daily cost of dengue was the most expensive with a median of US$406 , followed by sepsis with a median of US$213  and tetanus with a median of US$109 . As with the total cost, the key drivers for the daily costs differed across the diseases and the severity of the cases. For the patients not requiring mechanical ventilation, the most expensive cost categories were ICU bed charges for patients with tetanus, laboratory costs for those with dengue and medication costs for patients with sepsis. In contrast, for patients requiring mechanical ventilation, costs related to medication were consistently the most expensive daily cost category . The dif5, US$160For the patients who did not require mechanical ventilation, the usage and cost of antibiotics in the ICU was relatively limited in patients with dengue and tetanus but as expected, for patients with sepsis was considerably higher with a median of US$172  . In contAmong our sample, 70% of the patients with dengue and sepsis were covered by the national health insurance program   35). Fo. Fo35). This study focused on the direct medical costs incurred by infectious disease patients staying in the ICU of a tertiary hospital in HCMC. We found that ICU care is associated with significant direct medical costs, particularly for patients requiring mechanical ventilation and that the disease and associated severity are the main cost drivers of ICU care. The total cost was also highly influenced by the duration of ICU stay, with a longer stay associated with more severe disease and the possibility of complications and hospital-acquired infections.This study demonstrates the notable cost of ICU care in Vietnam and similar LMIC settings and highlights the importance of evaluating novel critical care interventions that could reduce the costs of ICU care in such settings . The specific costs we estimated will be useful for the evaluation of interventions to control the specific diseases investigated, including not only critical care interventions but also population level interventions. For example, in the case of dengue, it could be used within the economic evaluation of vaccines or Wolbachia deployments. In tetanus, this data could be used in the justification of strengthening vaccination programs, particularly of at at-risk groups. Similarly, this data could be used in the evaluation of novel vaccines for causes of sepsis. Furthermore, as the main cost drivers of ICU care were found to be disease and associated severity, our results imply that general critical care cost estimates can be misleading/inaccurate when evaluating a particular disease. This variation in cost drivers needs to be considered when comparing the results of different costing studies. Finally, this data highlights the vital need for future studies to further evaluate the costs and economic burden incurred by ICU patients in LMIC settings. This should include further examination of the implications of these critical care costs on different aspects of society, such as healthcare affordability, patients' attitudes and equity.The median ICU length of stay in this study (13 days) was longer than reported in other studies in Southeast Asia  , 36, 37.In general, medication costs were the main cost driver for patients irrespective of mechanical ventilation requirement. Not surprisingly, with the exception of sepsis cases, for patients not requiring ventilation, the costs related to antibiotics were trivial in the case of dengue  and tetanus (where inexpensive antibiotics are first-line treatment). However, the costs for antibiotics were significant for all sampled patients requiring mechanical ventilation. This is likely due to ventilator-associated respiratory infections, other hospital-acquired infections and possible diagnostic uncertainty in severe patients necessitating empiric antibiotic therapy , 36, 38.There are limited costing studies in Vietnam to compare these estimates to. Our total hospital admission cost estimate for non-ventilated dengue patients that needed the ICU (US$150) was similar to previous estimates regarding the cost of hospitalized dengue patients in Vietnam (which ranged from US$46-153 – 2019 prices) . Note thThis study used the available data from previous trials conducted at the Hospital for Tropical Diseases in HCMC. Although it did not follow any established protocol the bottom-up approach employed is commonly used and generally believed to be the preferred methodology for such a costing because it values each cost component for the individual patients .The direct medical cost estimates of ICU care in our study were significantly lower than those for Thailand, Malaysia and China, with corresponding medians of US$2,716, US$5,207 and US$18,889 per ICU stay, respectively –16. ThesImportantly, the total direct medical cost associated with ICU care for non-ventilated and ventilated patients in our study was 1.9 and 19.1 times higher than Vietnam's annual average per capita health care spending in 2018 , respectively . Hence, The national health insurance program in Vietnam aims to support financing and access of health care services, and to reduce patients' out-of-pocket healthcare costs, particularly for the poor and vulnerable populations. For those within our sample covered by the national health insurance program, the median proportion of their total ICU costs covered by the program was 76.4% . Despite this high level of coverage, the remaining portion of the costs that patients paid was equivalent to a mean of US$142.4 and US$877.4 for non-ventilated patients and ventilated patients, respectively . These mFurther investigation of strategies to lower ICU costs is needed, particularly in low-resource settings such as Vietnam. This will require the consideration of multiple aspects of healthcare, including medical research/innovations, collaboration with other actors/stakeholders (such as equipment manufacturers and training programs), as well as monitoring and assessment. The use of management frameworks/theory [such as Vuong et al. ] could hThis study used a sample of ICU patients' medical bills that were retrieved from three different studies at the Hospital for Tropical Diseases in HCMC  and that the main cost drivers of ICU care depend on the disease and associated severity, would be robust to this.The cost data estimates calculated within this paper were based directly on the charges from the patients' hospital bills and the costs related to the staff time were assumed to be captured by the charges for the different services. However, these charges do not necessarily reflect the economic value of the resources utilized for their care –47. In oTo conclude, ICU care in the Hospital for Tropical Diseases in HCMC results in substantial direct medical costs, particularly for patients requiring mechanical ventilation. The main cost drivers of ICU care depend on the disease and associated severity. Understanding the burden of ICU cost is crucial for informing and supporting decision-making, particularly in LMIC, such as Vietnam. Further studies are needed to fully evaluate the costs and economic burden incurred by ICU patients. Understanding the main drivers cost in ICU is important for policymakers and hospital managers and will be vital for the evaluation of novel interventions/technology to improve critical care in LMICs.The data analyzed in this study are available on reasonable request. Requests to access the datasets should be directed to TH, hungtm@oucru.org.The primary studies involving human participants were reviewed and approved by the Hospital for Tropical Disease (Ho Chi Minh City) Ethics Committee and Oxford Tropical Research Ethics Committee. The patients/participants provided their written informed consent to participate in this study.OUCRU inclusive authorship list in Vietnam : Dang Phuong Thao, Dang Trung Kien, Doan Bui Xuan Thy, Dong Huu Khanh Trinh, Du Hong Duc, Ronald Geskus, Ho Bich Hai, Ho Quang Chanh, Ho Van Hien, Huynh Trung Trieu, Evelyne Kestelyn, Le Dinh Van Khoa, Le Thanh Phuong, Luu Hoai Bao Tran, Luu Phuoc An, Angela Mcbride, Nguyen Lam Vuong, Nguyen Quang Huy, Nguyen Than Ha Quyen, Nguyen Thanh Ngoc, Nguyen Thi Giang, Nguyen Thi Le Thanh, Nguyen Thi Phuong Dung, Nguyen Thi Phuong Thao, Ninh Thi Thanh Van, Phan Nguyen Quoc Khanh, Phung Khanh Lam, Phung Tran Huy Nhat, Guy Thwaites, Tran Minh Duc, Jennifer Ilo Van Nuil, Vu Ngo Thanh Huyen, Hospital for Tropical Diseases, Ho Chi Minh City : Cao Thi Tam, Duong Bich Thuy, Ha Thi Hai Duong, Ho Dang Trung Nghia, Le Buu Chau, Le Mau Toan, Le Ngoc Minh Thu, Le Thi Mai Thao, Luong Thi Hue Tai, Nguyen Hoan Phu, Nguyen Quoc Viet, Nguyen Thanh Nguyen, Nguyen Thi Kim Anh, Nguyen Van Thanh Duoc, Pham Kieu Nguyet Oanh, Phan Thi Hong Van, Phan Tu Qui, Phan Vinh Tho, Truong Thi Phuong Thao. University of Oxford : Natasha Ali, David Clifton, Mike English, Shadi Ghiasi, Heloise Greeff, Jannis Hagenah, Ping Lu, Jacob McKnight, Chris Paton, Tingting Zhu Imperial College London : Pantelis Georgiou, Bernard Hernandez Perez, Kerri Hill-Cawthorne, Alison Holmes, Stefan Karolcik, Damien Ming, Nicolas Moser, Jesus Rodriguez Manzano King's College London : Liane Canas, Alberto Gomez, Hamideh Kerdegari, Marc Modat, Reza Razavi, Miguel Xochicale University of Ulm : Walter Karlen The University of Melbourne : Linda Denehy, Thomas Rollinson Mahidol Oxford Tropical Medicine Research Unit (MORU) : Luigi Pisani, Marcus Schultz.TH and HT conceived the study. TH entered, cleaned the data, and wrote the first draft of the paper. NV, LY, AM, VD, HL, NP, CT, HD, BN, and NVVC collected and contributed the data for the analysis. All authors contributed to the content and writing of the paper, read and approve the final of manuscript.This study was supported by the Wellcome Trust VITAL project grant 217650/Z/19/Z. The primary studies from which the sample was taken from were supported by a Wellcome Trust fellowship (107367/Z/15/Z) to CT, a Wellcome Trust Ph.D. Fellowship award 203905/Z/16/Z to AM and funding from the OUCRU Wellcome Trust core grant 106680/B/14/Z. HCT acknowledges funding from the MRC Centre for Global Infectious Disease Analysis (reference MR/R015600/1), jointly funded by the UK Medical Research Council (MRC) and the UK Foreign, Commonwealth & Development Office (FCDO), under the MRC/FCDO Concordat agreement and is also part of the EDCTP2 programme supported by the European Union. Funders have no roles in study design, collection, analysis, and decision to publish or preparation of the manuscript. For the purpose of open access, the author has applied a ‘Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising from this submission.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Atherosclerosis remains the leading cause of cardiovascular diseases and represents a primary public health challenge. This chronic state may lead to a number of life-threatening conditions, such as myocardial infarction and stroke. Lipid metabolism alterations and inflammation remain at the forefront of the pathogenesis of atherosclerotic cardiovascular disease, but the overall mechanism is not yet fully understood. Recently, significant effects of trained immunity on atherosclerotic plaque formation and development have been reported. An increased reaction to restimulation with the same stimulator is a hallmark of the trained innate immune response. The impact of trained immunity is a prominent factor in both acute and chronic coronary syndrome, which we outline in this review. Atherosclerosis represents a primary public health challenge and the leading cause of cardiovascular diseases (CVD) . ScientiIn this review, we will discuss the mechanisms of trained immunity, to atherosclerotic cardiovascular disease (ASCVD), in the context of the global pandemic.Host immune responses are classically divided into innate and adaptive immune systems, which are often described as the opposite types of the host response. Although they differ in their mechanisms of action, the synergy between them is indispensable for a fully effective immune response . The innThe innate immune response is dominated by germline-encoded pattern recognition molecules. The adaptive response is based primarily on antigen-specific receptors expressed on the surface of T and B lymphocytes . These aUntil a few years ago, it was thought that only an adaptive immunity could build up immunological memory . HoweverIn fact, trained immunity provides protection against secondary infection through mechanisms independent of T/B cell adaptive responses . TrainedThe most important receptors for this review include toll-like receptors (TLRs) and NOD-like receptors (NLRs). TLRs represent the family of transmembrane or cytosolic receptors. All TLRs are expressed in the heart . The relTrained immunity, as mentioned above, is mediated by epigenetic and metabolic reprogramming. It is present in both mature cells and their bone marrow progenitors . This inTrained immunity has a protective function as a host response to repeated infections, but it can also lead to chronic inflammation and, thus, to various diseases . RecentlThe development of ASCVD is generally believed to be fueled by the persistence of low-grade vascular inflammation and the permanent hyperactivation of the innate immune system . Both inRecent studies suggest that the innate immune system cells, after a short stimulation with microbiological products or endogenous atherogenic stimuli, can develop a long-lasting proinflammatory phenotype . Other iAcute coronary syndrome (ACS) is one of the clinical presentations of coronary artery disease (CAD). Chronic coronary syndromes (CCS) and ACS have different clinical consequences and distinct pathophysiology . While CScientists widely agree upon an inflammatory origin of ACS, where the local immune response plays a key role. Various triggering factors influence the state of the vessel’s endothelial cells. Chronic damage of the endothelium by hyperlipidemia, shear stress, and a low-grade inflammatory state with its mediators are those which result in its dysfunction . This leAn atherosclerotic plaque rupture is followed by an exposition of endothelial collagen and the formation of a thrombus within an occlusion of a coronary artery, thus, being the direct cause of ACS . In the There are several features of atherosclerotic plaques that trigger their instability and rupture. A thin layer of a fibrous cap covers a thick lipid core containing foam cells, matrix metalloproteinases, calcium, and cellular debris. The layer of smooth muscle tissue underneath the plaque is relatively diminished. By performing angiographic detection, it is possible to overlook an unstable atherosclerotic plaque, which may result in thrombosis later . In thisSeveral recent studies have presented new data on the inherence of an innate immune system of the heart muscle that reduces its tissue impairment as it controls its own homeostatic state. This phenomenon is founded on the disturbing balance between pro- and anti-inflammatory cells and biochemical substances. Inflammatory cytokines and chemokines that promote inflammation and contribute to the regulation of monocyte infiltration are generated by macrophages . The athIL-1ß is an essential cytokine expressed by many cells, including macrophages, NK cells, monocytes, and neutrophils. IL-1ß signaling in atherosclerosis pathogenesis includes increasing endothelial permeability and, also, the increased adhesion of lymphocytes and neutrophils to the endothelium . MoreoveThe role of reactive oxygen species (ROS) in the pathogenesis of atherosclerosis has been confirmed by many laboratories, both in experimental animals and in humans . The oxiProatherogenic risk factors lead to endothelial dysfunction and, consequently, to increased exposure to the adhesion proteins  that facilitate the activation of monocytes and their adhesion to the dysfunctional area . Along wMany scientists agree upon the significance of scavenger receptors (SR), as well as Toll-like receptors (TLRs), appearing to have been providing a mediating role as a component of an intrinsic immunological response due to stress factors. SRs play a key role in the phagocytosis of oxidized LDL (oxLDL) by foam cells, while the Toll-like receptors are involved in plaque formation . These r/- and TLR6-/- had a lesser risk of thrombotic events than those without such a phenotype. Therefore, oxLDL remains a valid risk factor for vascular inflammation and thrombosis [Furthermore, the dysfunction of endothelium enables LDL to interweave the vessel wall, resulting in its oxidation to a minimally modified LDL (mmLDL), as well as immunogenic oxLDL. Not only are these forms of lipoproteins found in atherosclerotic plaques, but they may also be found on the surfaces of cells, as well as in the circulation of patients with CAD. Within the role of innate immunity, mmLDL is internalized into atherosclerotic plaque via TLR4, resulting in the formation of foamy macrophages. TLR4s are found to be expressed more intensively in the peripheral blood mononuclear cells (PBMCs) of patients with severe CAD . On the rombosis .Despite the undoubted contribution of the plasmatic factors to coagulation, the innate immunity system also responds to inflammatory processes ongoing in blood vessels. It should be stressed that chronic, or even singular, episodes of an inflammatory process generate a great risk of thrombotic events, including the pathophysiology of CAD. In fact, several studies have revealed that there is a correlation between high levels of anti-oxLDL immunoglobulin M (IgM) antibodies and a lower risk of CAD . Many stThere are many benefits of trained immunity; however, it also plays a major role in the pathogenesis of ASCVD. The proinflammatory microenvironment in the vascular wall that promotes atherosclerotic plaque formation is formed from a complex interaction between endothelial cells, smooth muscle cells, and circulating immune cells . In the Foam cells, a type of macrophages located on the walls of blood vessels, absorb various substances involved in plaque growth . In the Additionally, PRRs are activated by danger-associated molecular patterns, including heat shock proteins (HSP) and the High Mobility Group Box 1 protein (HMGB1). DAMPs could accumulate in atherosclerotic plaque . It has Recently, monocytes M1 and the M2-phenotype have been shown to use different metabolic pathways during activation ,81. In sStress, both acute and chronic, is linked with an elevated risk of ASCVD and even with the acceleration of atherosclerotic lesions in animal models . RecentlUnder insulin resistance, peripheral macrophages acquire an anti-inflammatory M2-like phenotype characterized by the increased expression of M2 markers and a decreased secretion of proinflammatory factors after the stimulation . LikewisObesity induces metabolic inflammation, a chronic low-grade inflammatory condition characterized by elevated systemic levels of proinflammatory markers and insulin resistance. Obesity can affect innate immunity through the dysregulation of NK cells, an increased number of marrow cells in the adipose tissue, and the expression of ACE2 by adipocytes . In animNotably, modified LDL levels may be used for the identification of patients with acute coronary syndrome . StatinsProprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors are the group of drugs that, besides lowering LDL concentrations, are proven to have numerous pleiotropic effects, including an anti-atherosclerotic effect, the stabilisation of atherosclerotic plaque, and the ability to affect the course of bacterial infections . As prevThere is only limited evidence that comes from research directly linking trained immunity to ASCVD. Our literature review highlights the aspects of knowledge that has the potential to advance our understanding of trained immunity and the pathogenesis of atherosclerosis. Although it is widely accepted that atherosclerosis is associated with chronic low-grade sterile inflammatory processes of the vascular wall, the precise mechanisms remain elusive. Further studies investigating the effect of epigenetic changes on the modification of innate immune cells in the context of atherosclerosis are relevant. A better understanding of those mechanisms is essential for ASCVD prevention and for creating novel therapeutic goals, which would be used in primary cardiovascular prevention.


Minimally invasive endodontic access cavities have gained popularity in academic discussions for their clinical applications in recent years. Although some studies showed an improved fracture resistance of endodontically-treated teeth accessed with a minimally invasive access cavity design, the resulting effectiveness and efficiency of subsequent root canal treatment procedures may be impaired. Aspects that may be impaired are canal detection and negotiation, chemomechanical debridement of the root canal system, quality of the obturation. These are potentially complicated by the increased incidence of procedural mishaps and compromised aesthetic outcomes. In addition, the inherent flaws presented in the methodology of some in vitro studies and the lack of a universal classification system are also of concern. This literature review aims to present a comprehensive overview of the development of the minimally invasive endodontic access cavity and summarise the currently available from a clinical context. However, with the potential risks of procedural impairment, the use of MIECs is yet to be recommended universally. Proper training and armamentarium such as OM and heat-treated NiTi instruments may be prerequisites of clinical application.•A universal classification system and consistent methodologies in future studies are required to validate the use of MIECs.The contemporary practice of endodontics and restorative dentistry has shifted to preserving tooth structure. Minimally invasive endodontics refers to a concept that advocates the preservation of as much natural tooth structure as possible by downsizing the preparation of the access cavity, the taper of prepared canals, and the prepared apical size . This chMinimally invasive endodontic access cavities (MIECs) have been described as openings to gain access to the root canal system, which aim to preserve sound tooth structure. Common approaches to the preparation of MIEC are known as: (i) contracted access, (ii) "ninja" access, and (iii) "truss" access , 4. AdvoThis literature review aims to summarise the advantages and disadvantages of MIEC based on the currently available evidence.A structured literature search was performed involving electronic searches on PubMed (covering the time frame from 1966 to 2020), EMBASE (1947 to 2020), and Web of Science (1956 to 2020). Search terms applied were  AND ("access cavity" OR "access cavities") AND . The abstracts of the articles obtained were reviewed independently by 2 reviewers. Articles included were limited to those written in English. After the removal of duplicates, 20 articles were retrieved. Additional articles were identified by reviewing the reference section of studies identified for the full-text review. A total of 44 studies were included for the review session on MIEC.The importance of access cavity has been well validated as one of the key steps towards successful non-surgical root canal treatment. An adequately prepared access cavity facilitates the performance of subsequent clinical steps, including the detection of the canal orifice, chemomechanical debridement, obturation of the root canal, and reducing the chance of iatrogenic damage . One of Non-surgical root canal treatment is a predictable treatment modality for preserving the natural dentition. Studies reported that the ETT fared similar survival rates to the implant-supported crowns, while the longevity of ETT appeared superior to the fixed dental prostheses . HoweverThe access cavity preparation has been shown to contribute to the loss of tooth structure during non-surgical root canal treatment . An exceThe concept of MIEC underlies the development of the conservative endodontic access cavity (CEC). All defective restorations and caries are removed before the preparation of CEC, as in the TEC , 19. HowIn addition to a more constrained occlusal outline in the CEC than TEC, the CEC also preserves part of the pulp chamber roof and pericervical dentine (PCD), the tooth substance 4 mm above and 4 mm apical to the alveolar bone crest . PreservTaking the conservative approach to a greater extent, an ultraconservative endodontic access cavity (UEC), also known as "ninja" access, was further proposed -4. The UAccess cavity designs that employ minimally invasive principles are gaining popularity among clinicians . A surveTo date, there is a lack of a universal classification system for the different designs of MIEC. For example, the definitions of CEC and UEC lack clear mutual exclusiveness thus may overlap in meaning. Current terms used in the literature (and their abbreviations) such as "conservative", "contracted", and "ultraconservative" do not offer precise quantitative categorisation. Their usage is often empirical and not surprisingly may have been used interchangeably by some. It may be confusing to understand the exact extension and features of the access cavity designs adopted in the studies , 25. ApaSeveral authors have proposed the classifications based on the anatomical landmarks projecting to the occlusal surface, design principles, and the percentage of the volume of tooth structure removal. Based on the micro-CT evaluation, Eaton et al.  proposedThe proposed classification and quantitative measurement method aim to facilitate future research studies on the different types of access cavities using standardised measures . HoweverThe availability of nickel-titanium (NiTi) engine-driven instruments, OM, ultrasonic instruments and CBCT has made the MIEC approach potentially feasible in clinical endodontics , 56, 58.In general, small-sized tip and long-shank burs could be used to enhance visibility and preservation of tooth structure , 19. In Traditional step-down or step-back instrumentation techniques commonly use GG burs and Peeso reamers for coronal flaring to establish straight-line access . Both GGSome authors stressed the importance to use the NiTi files that have undergone thermal treatment in MIEC , 52, 53.The use of an OM is indispensable when performing MIEC, which is supported by the majority of studies utilising OM when comparing the effects between TEC and MIEC , 54-58. Ultrasonic instruments are also important adjuncts in the preparation of MIEC as they enable effective debridement, precise and selective removal of the obstructions such as pulp stone, and direct visual examination of the pulp chamber floor, significantly improving the ability of the operators to detect extra canals . PlotinoWhile the effect of MIEC on the fracture resistance of ETT remains debatable, a few possible drawbacks caused by an inadequately extended access opening were mentioned in the literature , 52, 55.(i)The ability of canal detection and negotiation , 31, 56;(ii)The quality of chemomechanical preparation, obturation and post-endodontic restoration , 47, 55;(iii)Increased iatrogenic mishaps , 53, 55;(iv)Negative effects on the aesthetic outcome , 55, 75;(v)Prolonged treatment time , 40, 52.in vitro study, Reeh et al. (1989)   showed tIn order to reproduce the actual clinical scenario, a few recent studies have tested their experimental specimens in the presence of post-endodontic restorations and continued to demonstrate the superiority of the fracture resistance of ETT prepared with CEC in both the premolars and molars when compared to TEC , 24. In In summary, there are no studies investigating the effects of CEC on the fracture resistance of ETT in the anterior teeth, while the fracture resistance of ETT in the posterior teeth accessed with CEC were found either comparable to or better than those accessed with TEC , 43. A rThe mode of failure was also investigated in many studies. It is well accepted that a catastrophic failure of ETT often leads to extraction, while a more favourable and restorable fracture pattern yields a better chance for tooth survival . Cuspal in vivo condition by subjecting the experimental specimens to thermocycling in order to mimic the thermal alterations in the oral cavity  and RECIPROC Blue R25 , using the TEC for comparison . It was Root canal obturation using the single cone and warm vertical compaction technique in teeth prepared with CEC might result in an increased number of voids, as shown by a study performed on the mandibular incisors . The sinThe role of quality of the coronal restoration towards successful root canal treatment outcome has been emphasised in the literature . One stuIn the anterior teeth, MIEC is usually created from the incisal edge to partial deroofing of the pulp chamber, leaving the pulp horns intact. As a result, the ability to completely remove pulp remnants from the pulp chamber and adequate placement of the intracoronal bleaching agent into the constricted access cavity is hindered . AdditioMarchesan et al.  addresseSeveral authors have reported significantly longer canal preparation time for teeth accessed with the CEC or UEC , 40, 52.ex vivo, limiting their clinical application to coronally intact teeth requiring root canal treatment due to pulpal or periapical pathology, such as those secondary to orthodontic movement, luxation injuries without crown fractures and dens evaginatus, etc. Meanwhile, most teeth requiring root canal treatment are either carious or previously restored, making the clinical application of the MIEC on such teeth worthy of further research.Until now, most studies have been performed on intact teeth The ability of MIEC to identify cracks might also be hindered owing to the reduced illumination in smaller access cavities and areas of undercuts, such as those beneath the preserved pulp horns. In addition, vital or necrotic pulp tissue remnants and debris may also obscure the presence of cracks and indiscriminately takes up methylene blue staining used for crack detection.in vivo than ex vivo studies. Besides, most of the previous studies were conducted on the CEC. Thus, this review focuses largely on the CEC, necessitating due caution before directly comparing the performance of various MIEC designs.The authors anticipate that procedural challenges, such as canal location, instrumentation and disinfection, are likely to be greater for the teeth studied in the The authors suggested that a few clinical approaches may be adopted in MIEC to overcome the problems in chemomechanical debridement of the root canal system, which include:1.Increase the concentration of the disinfectant used as irrigant;2.The use of irrigant agitation techniques;3.Increase the time spent on chemical disinfection;4.The use of heat-treated NiTi files with improved flexibility and fatigue resistance;5.The placement of calcium hydroxide as intracanal medicament;6.The use of the retrograde surgical tip to access and debride the areas beneath the pulp horns; and,7.The use of an operating microscope.Although the importance of preserving tooth structure appears self-evident, it can be concluded from this literature review that the complete transition to MIEC has yet to be validated. Therefore, the application of MIEC in clinical practice requires critical consideration by weighing the risks and benefits of the TEC and MIEC. Furthermore, the currently available evidence is insufficient to support the use of MIEC indiscriminately in routine endodontic practice.