The Ukraine war has led to a severe global food crisis due to complex supply disruptions and price increases of agricultural inputs. Countries of the Middle East have been directly affected because of their high dependence on food imports from Russia and Ukraine. Furthermore, this food crisis comes at times of high baseline vulnerability due to the compound impacts of COVID-19, repeated food shocks, and weakened states due to political-economic difficulties. This paper provides a detailed analysis of the food-related vulnerability of Middle Eastern countries in the wake of the Ukraine war. It contextualizes the varying impacts of this crisis in the region, and highlights country-level response strategies. The analysis shows a concerning and deepened crisis in the case of highly exposed and politically fragile countries with weakened food sectors; e.g., Lebanon, Sudan, and Yemen. Political-economic instabilities, limited domestic agriculture, and the lack of reliable grain reserves have aggravated the current food crisis in some countries. At the same time, indigenous short-term responses related to regional aid and cooperation have emerged, particularly in the Gulf countries, which have witnessed soaring revenues from higher energy prices. Alongside more regional frameworks for collaboration on food security, future action to mitigate such food crises should include the strengthening of local sustainable agriculture, storage capacities, and grain procurement strategies from international suppliers. The Ukraine war marks a new era in international diplomatic and economic relations, with major anticipated reconfigurations of trade flows. Not only are the direct disruptions to production in violence-ridden areas a matter of concern, but the war has also been accompanied by sanctions and boycotts causing major value-chain disruptions. In fact, although the effects take time, trade has always been part of the collateral damage of wars, with significant associated costs , 2. FurtThe long-term consequences for energy trade with Europe after the Ukraine war has been a key subject of debate. However, in the short term, the war has already resulted in serious food security concerns for highly vulnerable regions . It has The complexity of the food crisis caused by the Ukraine war necessitates detailed assessments of regional vulnerabilities. The Middle East is considered to be one of the worst-hit regions since several countries in the region are listed among the countries most dependent on agri-food commodities from Ukraine and Russia; e.g., in order of dependence, Turkey, Egypt, Sudan, Tunisia, Morocco, and Saudi Arabia . Other rThere is so far no knowledge regarding the impacts of the Ukraine war within the context of repeated shocks from COVID-19 and economic or political crises in the Middle East. To address this, this paper aims to provide a more detailed analysis of the vulnerability of the Middle East to food insecurity in the aftermath of the Ukraine war. It contextualizes this food crisis within country-level vulnerabilities and recent political-economic shocks. This paper’s analysis focuses on access aspects to food in the wake of the Ukraine crisis, with an emphasis on stable crops. Through identifying high-risk countries and possible mitigation strategies, this paper shows the impacts of the food security crisis on Middle Eastern countries, and how these impacts happen at different speeds. It also illustrates indigenous adaptation pathways using intraregional cooperation mechanisms. While this paper focuses on access to stable crops, it does not tackle nutrition and dietary aspects; for example, it does not look into horticultural produce and animal-source food which are also imported into the Middle East.In 2022, many developing countries, particularly those in Africa and the Middle East, have been shaken by the impacts of the COVID-19 pandemic. In this year, it is estimated – before the Ukraine war – that around 44 million people in 38 countries are threatened by hunger . BesidesMeanwhile, the negative impacts of the COVID-19 crisis on food security in Middle Eastern countries have been well-documented in the academic literature. COVID-19 has resulted in serious disruptions to the food value chain, with grain export restrictions during the pandemic, together with locusts destroying crops and causing price hikes, and food insecurity across many regions including parts of the Middle East . CountriPrior to COVID-19 and the current Ukraine-related crisis, the Middle East had only recently emerged from years of recurrent food shocks. Early this century, Middle Eastern countries suffered from unreliable imports and began investing in reserves and the acquisition of foreign agricultural land , 31. MorIn order to assess and contextualize the food-related vulnerabilities of Middle Eastern countries in the wake of the Ukraine water, the analysis in this paper is carried out in two steps. Firstly, the relative level of vulnerability to supply risks from Ukraine and Russia is determined. For this, trade data obtained from UN Comtrade are initially used  to determine the biggest importers from Russia and Ukraine in key food commodity categories, and also to determine dependence levels of Middle Eastern countries on imports from Russia and Ukraine in some important food commodity categories. Later, in order to categorize the vulnerability of Middle Eastern countries, the dependence indicators are combined with data from the Global Food Security Index (GFSI) published by the Economist. The GFSI is a composite index using indicators in four categories: affordability, availability, quality and safety, and natural resources and resilience. In our analysis, the data provided by the GFSI on the baseline vulnerability of Middle Eastern countries to increased risks due to the Ukraine war, together with the dependence indicators, allow information to be extracted on which Middle Eastern countries are particularly vulnerable during this crisis.Secondly, using the categorization of Middle Eastern countries in terms of relative vulnerability related to the food insecurity crisis caused by the Ukraine war, a country-level case analysis is carried out. For this, the paper uses the recent academic literature, announcements from international organizations, and media reports on country-level adaptation measures in order to present the vulnerability contexts at the country level. As for academic literature on the impacts of the Ukraine crisis on food security in the Middle East, this study does not present a full literature review due to the lack of studies on this recent topic. For example, a scopus-based search was conducted in January 2023 using the keywords “food security” and “Ukraine” in either in the title, abstract or keywords of the publications, together with any of the following keywords: Middle East, MENA, North Africa or the country name see . The resIn order to determine the vulnerability of Middle Eastern countries to the current shock related to the Ukraine war, one needs to assess the relative importance of any potential disruptions in the components of the food value chain related to Ukraine and Russia. Firstly, the importance of food trade between Russia, Ukraine, and the Middle East can be shown using key categories of food commodities. While the value of food exports from Russia and Ukraine to some countries might be relatively small, imports from Ukraine and Russia can still be high in terms of total imports. The group of moderately vulnerable countries contains some Mediterranean countries with relative resilience and varying levels of dependence on imports from Ukraine and Russia. The level of dependence on Ukraine’s agricultural exports matters more since it has become a main war area. This can divide Group 2 countries into two subgroups, with Algeria, Jordan, and Turkey forming the first group with “manageable” pressures, since their dependence levels are not very high and rather skewed toward Russia rather than Ukraine. In this category, Algeria has a concerning (more than 20%) dependence on Russia only in the category of oils and fats. As a result of the Ukraine war, Algeria has suffered from double-digit inflation, particularly hitting food staples whose prices were liberalized in 2021 through the removal of food and energy subsidies . HoweverIn Jordan, some limited level of dependence exists, mostly on Russia regarding cereals and oils, but it can be mitigated for this small-sized country (ca. 10 million inhabitants). Jordan has also mitigated past crises related to COVID-19 or the bans imposed by some countries on the exports of agri-food products. For example, in 2020, Romania banned wheat exports, thus triggering supply chain concerns across the Middle East . AlthougSimilarly, in Turkey, dependence on cereals, the milling industry or fats and oil is strongly in favor of Russia. Particularly in cereals, Turkey–Russia trade flows are vitally important for Turkey, since Russia accounted for more 50% of the import value of cereals to Turkey in the last 5 years . So far,Both Egypt and Tunisia exhibit high dependence on Russia and Ukraine for the import of cereals, oil seeds (in the case of Egypt) and fats and oil see . The higThere are important impacts and long-term implications for Tunisia and Egypt. For Tunisia, there are compounded impacts from COVID-19, recent political turmoils, and the Ukraine war. The rising costs of food imports, fuel, and fertilizers will weigh heavily on the Tunisian economy. Since food subsidies are substantial, the higher costs could add 1.5 billion USD to the subsidy bill . This coEgypt has been exploring long-term reorientation through new sources such as India . While IThe three countries share a relatively high import dependence but also a fragile political-economic context. One can argue that if it were not for political instability and associated economic troubles, Lebanon, Libya and Sudan would have been much better positioned to deal with any repercussions of the Ukraine war. For example, Libya is a resource-rich (considerable oil reserves) and small-sized country, which has been suffering from the aftermath of the 2011 Arab Spring. Similar to the carbon economies of the GCC, Libya has an arid climate with no significant domestic production see . It has Lebanon has for a long time been one of the countries with the highest GDP per capita levels among non-carbon exporting countries in the Middle East. In recent years, Lebanon has suffered from political conflicts leading to a serious economic crisis including high inflation rates and a strong devaluation of the national currency, thus causing food insecurity . In the Similarly, to Lebanon, international aid is a prominent short-term strategy for Sudan, which faces a serious hunger crisis, as food prices has been rising since 2021 due to domestic inflation, the dismantling of all forms of wheat subsidies in early 2022, and the fallout from the Ukraine war . Sudan’sYemen has been one of the most publicized cases of a food insecurity emergency getting worse as a result of the Ukraine war. This is due to the compounded impacts of the current civil war since late 2014, the COVID-19 crisis and the dependence on cereal imports provided through international aid . The civqat) have left Yemen’s agricultural sector quite weak , and thus spiking food prices; e.g., ca. 20% food inflation in Egypt in 2010–2011 . In the (1) Existence of food subsidy or social security programs: Food subsidy systems or special programs providing food stamps for the most vulnerable have softened some of the impacts of the price hikes for vulnerable groups. However, in the Middle East, some countries  have recently abandoned food subsidies, or have been unable to continue them due to political or economic difficulties. At the same time, the increased costs associated with these programs have caused fiscal difficulties, particularly in large countries such as Egypt.(2) Cereal reserves and storage capacity: Although strategic grain reserves can be costly, some Middle Eastern countries have invested in such reserves in the aftermath of food crises in the last two decades , 31. Cou(3) Relative political-economic stability: Many of the most vulnerable countries in the current crisis are suffering from political conflicts and fragility . Although this paper did not include Syria and Iraq in the analysis due to data availability, there are reports of similar food insecurities induced by the Ukraine war , 58. Pol(4) Baseline vulnerability to the COVID-19 pandemic: In some Middle Eastern countries such as Tunisia and Lebanon, the COVID-19 pandemic has greatly affected the states’ capacity to weather the current crisis, either due to reduced state revenues or aggravated food insecurities , 62. In (5) Liquidity through additional revenues: In oil- and/or gas-exporting countries, the increase in carbon fuel prices after the Ukraine invasion meant additional revenues that can be used in the mitigation of the food crisis; e.g., in Algeria, Libya, or generally in the GCC countries. It is, however, not yet clear whether the additional revenues will be offset by the declining energy demand due to the global economic downturn.(6) Existence of climatic aggravators: Recent dry spells, prolonged droughts and harvest failures can weaken the ability of local agriculture to provide food, as some narrative evidence from Sudan and Lebanon indicates , 63, 75.With regard to responses in the Middle East, The Ukraine war has unleashed a complex global food crisis with supply interruptions and rising costs of key agricultural inputs such as fuel, transport and fertilizers. Together with the climate-related impacts and the baseline vulnerabilities related to COVID-19 and various conflicts, many countries in the global South are paying a high price for basic food commodities such as cereals and cooking oil. To better understand the reach of such compounded food crises, the Middle East serves as an illustrative case related to a high dependence on food imports from Russia and Ukraine and a very difficult political-economic context. Even prior to COVID-19 and the current Ukraine-related crisis, Middle Eastern countries have suffered from repeated food shocks that have caused or exacerbated political crises and state collapse, and many of these countries were hard-hit by the food-related spillovers of the COVID-19 crisis. However, despite the importance of food imports from Russia and Ukraine for the region, not all Middle Eastern countries will be highly exposed to the food crisis in the wake of the Ukraine war.Moderately vulnerable countries such as Algeria, Jordan and Turkey face “manageable” pressures due to lower levels of dependence, availability of alternative production domestically, or well-functioning food sectors. They also demonstrate the importance of food diplomacy in these countries in order to maintain the flow of vital cereals, e.g., Algeria with France, Turkey with Russia, or Jordan with Romania. Within the same group of moderately vulnerable countries, Egypt and Tunisia stand out as facing more exposure due to high dependence rates. However, Egypt and Tunisia have ramped up their food storage capacities in the past years and invested in expanding wheat infrastructure. Tunisia has had rather stable but fluctuating imports from Ukraine. In both cases, the exposure to the Ukraine-related food crisis is complicated by growing populations (Egypt), COVID-19 turbulence, and an increase in internal political conflicts (Tunisia). Some immediate exit strategies relied on securing additional funds  for satisfying the soaring costs of food subsidies while re-orienting the food import strategies toward new sources in Asia. Later, the release of some shipments from Ukraine helped lower the supply pressure although economic difficulties and high food prices persisted.The case of the group of highly vulnerable countries  will prove quite concerning. While one would expect countries such as Libya to funnel some of their (increased) oil revenues toward mitigating the new crisis, Lebanon, Sudan and Yemen will be relying on international cooperation in the short and medium term, including shipments under the BSGI. These countries illustrate how political-economic instability is aggravating the food crisis in the Middle East in the wake of the Ukraine war. Political-economic stability is one of six vulnerability determinants identified by this paper, which can be examined in the future through case studies that are more detailed. However, state responses can still play an important role in deciding the outcomes of the current crisis. Alongside classic responses such as trade controls, supply diversification, public support, and aid, this paper has argued that the relatively comfortable position of Arab Gulf countries will play a crucial role in mitigating some of the impacts on the Middle East through regional cooperation and aid-related food security and fiscal stability. With regard to future food security strategies, the Ukraine war has highlighted the importance of both domestic, regional and international resilience and adaptation measures. Enhancing local capacities in the areas of storage or the procurement of food supplies  will be important for mitigating future shocks. As previous crises have also shown , local agriculture remains an important food security tool in some Middle Eastern countries, but it should be securitized using sustainability and efficiency criteria (particularly the issues of water availability and use efficiency). While special aid programs from the international community toward the most vulnerable and conflict-ridden communities in the Middle East is essential for overcoming the current food crises, strengthening regional frameworks for collaboration on food security has emerged as an interesting long-term pathway for the Middle East region.https://comtrade.un.org.Publicly available datasets were analyzed in this study. This data can be found here: UN Comtrade Database The author confirms being the sole contributor of this work and has approved it for publication.


Melatonin is a well-known animal hormone with relevant and multiple cellular and hormonal roles. Its discovery in plants in 1995 has led to a great diversity of molecular and physiological studies that have been showing its multiple actions also in plants. Its roles as a biostimulator and modulator agent of responses to abiotic and biotic stresses have been widely studied. This review raises the possible use of melatonin as a natural safener in herbicide treatments. Existing studies have shown excellent co-acting qualities between both the following agents: herbicide and melatonin. The presence of melatonin reduces the damage caused by the herbicide in the crop and enhances the stress antioxidant response of plants. In this area, a similar role is suggested in the co-action between fungicides and melatonin, where a synergistic response has been demonstrated in some cases. The possible reduction in the fungicide doses is proposed as an eco-friendly advance in the use of these pesticides in certain crops. Finally, future research and applied actions of melatonin on these pest control agents are suggested. Safeners are chemical compounds used to reduce the harmful effects of herbicides on crop plants and are applied alongside the herbicide. Safeners, also known as herbicide antidotes, are usually presented in mixed formulations of herbicide and safener . GeneralAs for the way the safeners act, today we know that these compounds mainly act by inducing the degradation of the herbicide in the tissues of the crop plant. The active degradation of the herbicide to non-harmful compounds causes less cellular and physiological damage, so the safeners protect the plant from excessive exposure to the herbicide. The rate of herbicide degradation is intimately related to crop selectivity and weed control. Thus, if the rate of degradation to inactive forms of the herbicide in the crop is very slow, then damage will occur. On the other hand, if detoxification is too fast in weeds, then the weed control effect of the herbicide is reduced or lost. Therefore, with the added safener, the herbicide is metabolized more quickly and, as a result, the threshold that would cause visible damage to crops is not reached ,3,4. TheIn some cases, the safener has been proven to act as an activator or inactivator of the herbicide. Some safeners can perform the activation of the initial compound in the form of a pro-herbicide, generating the active form of the herbicide in the plant tissues  . A partiIn this review, we analyze the results published so far to be able to consider melatonin as a possible natural plant safener. The properties of melatonin as a biostimulating agent in stressful conditions and its possibilities as a safener against treatments with herbicides, fungicides, and other pesticides are presented. Its possible use in crops is proposed with important considerations in its application.N-acetyl-5-methoxytryptamine) was discovered in 1958 in the pineal gland of a cow by Lerner et al. and then in humans, elucidating its chemical structure [Melatonin  and also nitrogen (RNS), in vitro and at the cellular level ,50,51,52The role of melatonin as a protector in biological systems has been widely demonstrated. In animal cells, melatonin reduces oxidative stress against drugs, toxins, and heavy metals . MoreoveButafenacil is an herbicide used to control annual and perennial broad-leaved weeds that inhibits the protoporphyrinogen IX oxidase enzyme involved in chlorophyll biosynthesis, provoking a massive accumulation of chlorophyll precursors and generating dangerous singlet oxygen molecules and membrane lipid peroxidation, leading to cellular death . In the Paraquat, also dimethyl viologen  is a broad-spectrum herbicide that blocks the process of photosynthesis at the photosystem I level, generating excessive ROS production with critical damage . Pea plaIpomoea batatas) crops to control yellow nutsedge (Cyperus esculentus) weeds is bentazone -one 2,2-dioxide), a post-emergence contact diazinone herbicide (inhibits Photosystem II action at D1 protein level) used to control annual weeds in a variety of crops [A potential herbicide used in sweet potato , which acts by inhibiting fungal mitosis, also provokes pesticide-induced phytotoxicity, causing severe oxidative stress in treated plants. Co-treatments with exogenous melatonin alleviated ROS production and lipid peroxidation. Moreover, a modulation of the ASC-GSH cycle by melatonin occurs, increasing ASC, GSH, and antioxidative enzyme levels, improving the detoxification capacity of the plant cells and metabolizing fungicide with minimal collateral damage. According to the authors, melatonin makes plants “cleverer” to withstand phytotoxic stressful conditions [Phytophthora sp. are one of the most devastating diseases. In a study of tobacco black shank (P. nicotianae) using ethylicin and melatonin co-treatments, both compounds induced the inhibition of the hyphal growth, the reduction of the cell viability, and the suppression of the virulence of P. nicotianae. Moreover, melatonin and ethylicin shared the same metabolic targets, interfering amino acid metabolism, overexpressing apoptosis-inducing factor, and dysregulating the virulence-related genes. The authors proposed that tobacco black shank caused by P. nicotianae can be successfully controlled using the combination of ethylicin and melatonin as an eco-friendly alternative for the control of the oomycetic diseases [P. infestans, melatonin inhibited mycelial growth and increased stress tolerance, attenuating the potato late blight symptoms. In the use of the fungicide Infinito® (a mixed combination of fluopicolide and propamocarb), synergistic antifungal effects of melatonin with fungicides were described, suggesting that melatonin could reduce the dose of fungicide and improve the efficacy of the fungicide against late potato blight [Ethylicin (S-ethylethanethiosulfonate) is a biofungicide with broad spectrum activity, mainly used in oomycete disease control. In agriculture, pathogenic oomycetes such as diseases . In a sio blight .A general scheme is proposed , where tThere are not many examples in which the possible role of melatonin as a natural safener has been studied. However, studies carried out clearly show the excellent possibilities of melatonin in reducing the damage caused by the herbicide in the crop, activating anti-oxidative defenses, reducing oxidative stress, and presenting a greater tolerance to the herbicide. That is, melatonin behaves as a usual safener, but with greater protective skills and without the prejudice of the use of synthetic substances in addition to the herbicide, thus being a clear biological bet. In the case of the fungicides tested, very positive results have been observed, verifying not only the individual and joint efficacy of melatonin and fungicide in the control of plant disease, but also finding a synergistic action between both, which allows a lower dosage of the artificial fungicide, which is always preferable for using ecological pest control. The analyzed studies provide evidence for the adequate role of melatonin as safener and can serve as a proposal for its possible applications in agricultural and biotechnological areas.However, there are many studies to be carried out in this context, such as the following: (i) given the breadth of herbicides used, studies should be performed in categories, verifying the role as a safener of melatonin in each case; (ii) provide quantitative data on the capacity of melatonin to reduce crop damage; (iii) possibilities of decrease in the applied dose of herbicides, with the consequent environmental benefit; (iv) improvement in the rate of detoxification of the herbicide, destination, and toxicity of the by-products; (v) study the great synergistic possibilities between melatonin and fungicides as a possible eco-friendly tool in the fight of fungal pests; (vi) extend the studies to other pesticides, such as insecticides, etc.Finally, we should not overlook the possible effects of melatonin treatments on crops. Although melatonin is a safe molecule in humans (no intoxication or serious side effects have been reported), its excessive presence in treated crops could have unintended consequences. Several aspects of the application of melatonin in agriculture have been previously discussed, analyzing its pros and cons and giving a series of tips to stimulate research in the field of health and the environment related to melatonin ,79. In b


In order to scientifically evaluate the characteristics and impact outcomes of transportation carbon emissions, this paper uses the panel statistics of 286 cities to measure transportation carbon emissions and analyze their spatial correlation characteristics. Afterwards, primarily based on the current research, a system of indicators for the impact factors of transportation carbon emissions was established. After that, ordinary least squares regression, geographically weighted regression, and multiscale geographically weighted regression models were used to evaluate and analyze the data, and the outcomes of the multiscale geographically weighted regression model were selected to analyze the spatial heterogeneity of the elements influencing transportation carbon emissions. The effects exhibit that: (1) The spatial characteristics of China’s transportation carbon emissions demonstrate that emissions are high in the east, low in the west, high in the north, and low in the south, with high-value areas concentrated in the central cities of Beijing-Tianjin-Hebei, the Yangtze River Delta, the Guangdong-Hong Kong-Macao region, and the Chengdu-Chongqing regions, and the low values concentrated in the Western Sichuan region, Yunnan, Guizhou, Qinghai, and Gansu. (2) The spatial heterogeneity of transportation carbon emissions is on the rise, but the patten of local agglomeration is obvious, showing a clear high-high clustering, and the spatial distribution of high-high agglomeration and low-low agglomeration is positively correlated, with high-high agglomeration concentrated in the eastern region and low-low agglomeration concentrated in the western region. (3) The effects of three variables—namely, GDP per capita, vehicle ownership, and road mileage—have a predominantly positive effect on transportation carbon emissions within the study area, while another three variables—namely, constant term, population density, and number of people employed in transportation industry—have different mechanisms of influence in different regions. Constant term, vehicle ownership, and road mileage have greater impacts on transportation carbon emissions. As a fundamental and pioneering industry in the development of various sectors and an important energy-consuming and carbon-emitting industry, the transportation industry is in an important period for achieving a transition to low-carbon options and fulfilling international carbon emission reduction commitments. Transportation carbon emissions involve many aspects of society, including the economy, technology, and policy and is an important research object for many subjects, such as the environment, transportation, the economy, etc. ,2. It isCurrently, macroscopic studies related to transportation carbon emissions have focused on emission characteristics and driving factors. Studies have shown that transportation carbon emissions are mainly influenced by the following human factors: population ,4,5,6, aIn summary, we have explored the influencing factors on transportation carbon emission differences and their spatial variation patterns using panel data of Chinese cities. Our research results can provide practical references for the differentiation of transportation carbon emission reduction policies in different regions, which is important for achieving emission reduction targets, accelerating supply-side reform, and speeding up the construction of an ecological civilization.2 emission factors to obtain carbon emissions. Due to the diversity of regions and the incompleteness of statistics in China, it is difficult to obtain the energy consumption of each urban transportation sector. Therefore, a “bottom-up” algorithm was used to calculate the transportation carbon emissions for each province and city in China, mainly including freight and passenger transportation. According to the literature, the microscopic model of freight transportation carbon emissions is as follows:The existing literature summarizes two relatively well-established methods for calculating transportation carbon emissions: a top-down approach based on energy end-consumption ,17 and aThe passenger transportation carbon emission model is as follows:Spatial autocorrelation of transportation carbon emissions refers to the potential dependency between the transportation carbon emissions of different cities and can be divided into global spatial autocorrelation and local spatial autocorrelation.(1)Global spatial autocorrelationThe global Moran’s I index is generally used to reflect global spatial autocorrelation and takes on a value in the range of . Positive values indicate positive spatial correlation (high-high aggregation or low-low aggregation), negative values indicate negative spatial correlation (high-low aggregation), and a value of 0 indicates that the variables are independent within the study space. The global Moran’s I index is calculated using the following formula:(2)Local spatial autocorrelationLocal Moran’s I index and LISA aggregation maps are used to measure and analyze the local spatial autocorrelation of transportation carbon emissions, and the local Moran’s I index is calculated as follows:As different regions have different development characteristics of transportation carbon emissions, this paper uses Geographically Weighted Regression (GWR) models and Multiscale Geographically Weighted Regression (MGWR) models, which are improved on the basis of GWR models, to compare with Ordinary Least Squares (OLS) models. By comparing the fit and explanatory power of the two types of models, the spatial variation of the factors affecting transportation carbon emissions are explored.(1)Ordinary Least SquaresOrdinary least squares regression is a common linear regression and global estimation model which uses the following equation:(2)Geographically Weighted RegressionThe geographically weighted regression model is an improved model based on a linear regression model with the addition of parameters reflecting differences in geographic location to differentiate the variables at a local scale. Its regression equation is as follows:(3)Multiscale Geographically Weighted RegressionThe multiscale geographically weighted regression model finds the most appropriate bandwidth for each variable through stepwise regression, thus better demonstrating the scale of action and spatial characteristics of each variable ,25,26,27Unlike the geographically weighted regression model, all regression parameters of the multiscale geographically weighted regression model are solved by local regression, which accounts for the different bandwidths of different variables. In the solution process, multiscale geographically weighted regression still uses the bandwidth selection and kernel function selection rules of the geo-weighted regression. In most cases, the AICc criterion is chosen for the general bandwidth, while the quadratic kernel function is chosen for the kernel function. In addition, the solution process for geographically weighted regression is a weighted least squares estimation, while multiscale geographically weighted regression is similar to a generalized additive model with the following expressions:We chose to use geographically weighted regression as the preliminary estimate for a multiscale geographically weighted regression, and then solved for the difference between the predicted and true values to obtain the initialized residuals The initialized residuals are added to In the measurement of transportation carbon emissions, data on the holdings of different means of transportation were obtained from the statistical yearbooks of each city in previous years, the China Automobile Industry Yearbook, the China Economic and Social Development Statistical Database, and Social Development Statistical Bulletin. Carbon emission coefficients and the average fuel consumption of various energy sources were obtained from IPCC 2006 and the Guidelines for the Preparation of Provincial Greenhouse Gas Inventory. Mileage data were obtained from the China Urban Statistical Yearbook and the annual reports of urban transportation development in previous years. The energy consumption per unit of each transportation means is shown in According to the measurement method detailed in From the spatial distribution of transportation carbon emissions in the three characteristic years, the spatial characteristics of China’s transportation carbon emissions show that emissions are high in the east, low in the west, high in the north, and low in the south, and these characteristics are stable. In terms of regional characteristics, the areas with high-value transportation carbon emissions are mainly concentrated in the central cities of the Beijing-Tianjin-Hebei region, the Yangtze River Delta, the Guangdong-Hong Kong-Macao region, and the Chengdu-Chongqing regions, and the low values are mainly concentrated in the Western Sichuan region, Yunnan, Guizhou, Qinghai, Gansu, and other regions. In terms of city characteristics, Shanghai, Chongqing, Tianjin, Suzhou, Shijiazhuang, Tangshan, Wuhan, Chengdu, and Ordos are stably ranked in the top ten with regard to emissions. From the temporal changes in spatial distribution, the transportation carbon emissions in Eastern Inner Mongolia and Central Xinjiang show faster growth, and the transportation carbon emissions in the Beijing-Tianjin-Hebei region have a trend of regional spread growth.The Moran’s I index was used to examine the transportation carbon emissions from the period 2009–2019, and Moran’s scatter plots were plotted, producing the results shown in p-values, it can be seen that at a significance level of 0.1, transportation carbon emissions from the period 2009–2019 show a more significant positive spatial correlation, i.e., areas with higher transportation carbon emissions tend to have one or more neighboring cities that also have higher carbon emissions (high-high positive correlation), while cities with low transportation carbon emissions also have at least one city with low transportation carbon emissions adjacent to them (low-low positive correlation). The global Moran’s I index value has remained stable at around 0.3 for 11 years, indicating a long-term stable, positive spatial correlation for transportation carbon emissions at a municipal scale in China. The number of samples located in the L-H and H-L quadrants accounted for 14%, 16%, and 19% of the total in 2009, 2014, and 2019, respectively. These results indicate that the spatial heterogeneity (discrete distribution pattern) of transportation carbon emissions showed an increasing trend during the study period, but in general, the spatial correlation of transportation carbon emissions at the local scale was high, and the local clustering pattern was significant.According to the test results, the global Moran’s I index values for each year were greater than 0. Combined with the A characteristic annual transportation carbon emission LISA map was drawn based on the results of local Moran’s I calculation, and the results are shown in As can be seen in The index system of transportation carbon emission influence factors was mainly constructed using four elements: population, economy, science and technology, and transportation industry development. In terms of population, population density and the proportion of urban population were selected as indicators. In terms of economy, the following three indicators were selected: GDP per capita, the proportion of added value of tertiary industry, and GDP growth rate. In terms of science and technology, indicators related to energy use, such as energy technology and transportation energy intensity, were selected. In terms of transportation industry development, indicators such as road mileage, vehicle ownership, passenger transportation structure, freight transportation structure, and the number of employees in the transportation industry were selected ,29,30,312, adjusted R2, sum of squares of residuals, and AICc—to compare and analyze the fitting effects of ordinary least squares regression, geographically weighted regression, and multiscale geographically weighted regression models  of each variable to reflect the differences between the action scales of different variables, the optimal bandwidth of each variable is the optimal action scale of each variable, and the AICc values of each variable are shown in p < 0.05 test was performed on all variables with the results of the model. According to the test results, the variables with a small number of test sample points were screened out, and the variables with a larger number of test sample points were further analyzed. Thus, we finally selected Intercept, PD, Agdp, NC, ROAD, and NTP for further analysis:(1)The spatial distribution of the constant terms was visualized, and the resulting images are shown in The (2)The spatial distribution of the coefficients of population density indicators was visualized, and the resulting images are shown in (3)The results of visualizing the spatial distribution of GDP per capita indicator coefficients are displayed in (4)The spatial distribution of road mileage indicator coefficients is visualized, and the results are shown in (5)The spatial distribution of car ownership index coefficients was visualized, and the resulting images are shown in (6)The spatial distribution of the index coefficient of the number of employees in the transportation industry was visualized, and the resulting images are shown in This paper extends the macro-level study of transportation carbon emissions from national and provincial scales to city scales, and on this basis, the conclusions regarding the spatial and temporal variation characteristics of transportation carbon emissions are more reasonable. In addition, this paper used a multiscale geographically weighted regression model to analyze the influencing factors of transportation carbon emissions, which can accurately calculate the scale of action of each influencing factor, and the carbon emission reduction strategy of transportation industry based on this can be more targeted. Nevertheless, due to the limited data and research conditions, we selected the influencing factors of transportation carbon emissions from four dimensions: population, economy, technology, and transportation industry development, and the indicators were selected macroscopically, lacking further analysis of microscopic deep-level factors, such as individual awareness of low-carbon travel, and consideration of the influence of urban spatial structure and urban public transportation system on urban transportation carbon emissions. In addition, although multiscale geographically weighted regression makes up for the shortcomings of the traditional global regression model, it still has a strong linearity assumption. With the increasing maturity of machine learning and deep learning methods, the linearity assumption of the model should be further relaxed in the future, while exploring the impact of interaction effects among variables on transportation carbon emissions.(1)China’s transportation carbon emissions showed the spatial characteristics of high emissions in the east, low emissions in the west, high emissions in the north, and low emissions in the south, and these characteristics were stable throughout the time period studied. At a local scale, transportation carbon emissions have a high spatial correlation and a clear pattern of local aggregation. The L-L agglomeration area is mainly due to the low level of overall regional socio-economic development and insufficient transportation infrastructure. Additionally, the H-H agglomeration area has close economic interactions within the area; the economic development of cities within the H-L agglomeration area varies greatly. We should focus on promoting transportation carbon emission reduction in H-H agglomeration regions, such as some cities in the Beijing-Tianjin-Hebei region and some cities in the Yangtze River Delta, and thus effectively reduce total transportation carbon emissions. As the central cities are closely linked to the surrounding, non-central cities, policies should be jointly formulated for such regions to promote regional transportation emission reduction linkage: for example, by designing a cross-regional, low-carbon, multimodal transportation system to cater for the interaction between regional human and logistical flows.(2)Location, population density, GDP per capita, car ownership, road mileage, and the number of employees in the transportation industry are the major factors influencing transportation carbon emissions. The impact of car ownership is low, which indicates that the spatial variation of transportation carbon emissions with car ownership is significant. The impact of the number of employees in the transportation industry is similar to that of the regional or district scale. The impacts of the other variables were similar to those on the global scale in a certain characteristic year, which indicates that there is little spatial heterogeneity in the effects of the above factors on transportation carbon emissions. Based on the differences in coefficients, differences in the growth mechanisms of carbon emissions in different cities can be identified, and thus targeted measures can be proposed. For example, the GDP per capita in Northwest China showed a stronger positive influence on transportation carbon emissions, reflecting the stronger coupling between urban economic development and transportation in Northwest China, which indicates that there should be a focus on promoting the low-carbon transformation of transportation in this region. Additionally, the degree of influence of car ownership on transportation carbon emissions showed an enhanced trend over the time period, and this trend was especially obvious in Southwest and Northwest China, reflecting the more intensive use of small cars in these cities. Indirectly, this indicates that urban public transportation is not attractive enough, so the development of public transportation should be increased to promote the green transformation of urban transportation.We measured the transportation carbon emissions based on the panel data of 286 cities in China, analyzed the spatial autocorrelation characteristics of transportation carbon emissions on the basis of the spatial interaction theory, and analyzed the spatial heterogeneity characteristics of transportation carbon emission influencing factors using the MGWR model considering multiscale effects. Based on this analysis, we came to the following conclusions:


M = 205.53, SD = 164.99. As part of the plan of care, the duration and frequency of therapy both had similar means (~M = 3.60) and standard deviations (~SD = 1.65). There was a significant variance of hours during (SD = 139.54) and outside of therapy (SD = 130.06). The results of this study, together with other emerging evidence, can assist practitioners in prescribing dosages dependent on the setting, the pediatric client, and their current functional status.Constraint Induced Movement Therapy (CIMT) utilizes a behavioral approach to neurorehabilitation involving constraint of an unaffected upper extremity which forces the use of the affected extremity. There is substantial evidence supporting the effectiveness of CIMT among both children and adults. The purpose of this study was to explore the frequency, intensity, and duration parameters across the published clinical outcomes related to pediatric CIMT (pCIMT) among children and youth populations. A content analysis approach was used to search the following databases Google Scholar, OT seeker, American Occupational Therapy Association special interest section, Medline, EbscoHost, and Cinhal. A total of 141 studies were identified via the initial search, with 51 studies meeting inclusion criteria. The findings revealed that 100% of the studies included restraint of the non-affected upper extremity, 73% incorporated repetitive task-oriented training, but less than half prescribed home practice strategies. Further, only 34% of the studies reviewed included all three components of CIMT. Outpatient hospital clinics and home-based settings were the most utilized settings for research studies. The mean minutes per session was  Constraint-induced movement therapy (CIMT) has been ubiquitous in the physical medicine practitioner’s repertoire since its inception in the 1990s. Taub et al. [In the late 1990s pediatric CIMT (pCIMT) was introduced into neurorehabilitation by multiple teams of researchers and therapists . Hoare eRehabilitation specialists  have used various types of constraints for the unaffected upper extremity, including mitts, gloves, slings, splints, and casts. In addition, treatment settings for individualized and group therapy sessions have included the home, outpatient clinics, and specialized intensive therapy camps .As CIMT and pCIMT continued to evolve over time with varying model types, a uniform terminology was necessary to clarify categories for knowledge translation, recommendations, and for future research.Signature CIMT (sCIMT) is Taub’s original model developed for adults with hemiparesis following stroke. This involves restraint of the well-functioning upper limb for 90% of waking hours for at least two weeks and the addition of intensive training of the involved upper limb for several hours per day ,6;Modified constraint-induced movement therapy (mCIMT), like the signature model, contains restraint and intensive training. However, mCIMT varies parameters of restraint used for the well-functioning upper limb ; the type of structured training ; the program duration (hours per day) and length (number of weeks); and the location, context, and provider of training  ,6;Forced use therapy involves restraint of the well-functioning upper limb but no specific structured training is provided. Forced use is related to, but not considered CIMT ,6;Ramey et al.  proposedModified pCIMT has been differentiated from traditional pCIMT only in the dosage by reducing the number of systematic trainings per day (intensity) and modifying the number of consecutive days of the restraint applied to the non or less impaired UE .Eliasson et al.  further Duration of pCIMT varies. As a part of their systematic review, Hoare et al.  reportedA plethora of existing research demonstrates pCIMT as an effective and safe intervention for children and youth. A thorough systematic review of 36 studies conducted by Hoare et al. [Content analysis of literature has become a recent trend in the rehabilitation sciences and medicine . AnalyseExploring more recent pCIMT scholarship, Deluca et al.  demonstrThe primary aim of this study was to explore common frequency, intensity, and duration parameters of published clinical outcomes related to pCIMT among children and youth populations. A secondary aim of this study was to inform rehabilitation practitioners of settings where pCIMT is occurring to guide future planning for program development in diverse practice settings. This study was conducted between 2017 and 2019, compliments the more recently published literature mentioned above (that was not available during data collection), and adds evidence of appropriate forms and parameters of pCIMT.This study was not deemed as research that involved human subjects and was approved by the Human Subjects Committee at Rocky Mountain University of Health Professions protocol #2022-38. As a part of the study methodology, authors operationalized key terms as part of the study. Pediatric Constraint Induced Movement Therapy (pCIMT) was defined as an intervention for children (from age one up to age 21) in which the unaffected upper extremity was restricted, and the affected upper extremity was principally used during therapeutic activities. The foundational components of pCIMT included repetitive, task-oriented training (consisting of shaping or repetitive task practice), home practice strategies , and constraint of the non-affected limb (restraint of the less impaired UE to encourage the use of the more affected UE during tasks) ,14. An oIntervention frequency was defined as the number of treatment sessions undergone by the patient that included pCIMT as the sole intervention or one of a few interventions as part of a given session . Intervep = 0.05)); (4) the interventions in the study could consist of any of the three main components of CIMT, but required the third component of the constraint of the less impaired limb to be present; and (5) the study had to report at least one of the following aspects related to the intervention being tested, the number of treatment sessions, session frequency per week, duration of the treatment plan, and/or the total hours spent on the intervention. Systematic reviews and meta syntheses studies were excluded as they had insufficient information related to parameters of dosage in method sections of the individual studies included.For an article to be included in the study, it had to meet the following inclusion criteria: (1) the study population had to consist of children that were one to 21 years of age; (2) studies published outside of the years between 2002 and 2019 were omitted; (3) the study design had to be quantitative empirical studies consisting of randomized control trials, quasi-experimental, pre-posttest measures, and report positive intervention outcomes  data of the three components of dosage  across the 51 outcomes studies were analyzed see . Data weM = 23.92  and outside of therapy (SD = 130.06) is notable  was refer to .The distribution of settings where pCIMT occurred revealed outpatient hospital clinics and home-based settings were the most utilized settings for research studies. This is not surprising as applying and wearing a restraint in these settings would likely have been most confident and controlled  for the researchers refer to .Most of the studies reviewed used designs that can be categorized as level II , specifiThe primary aim of this study was to explore common frequency, intensity, and duration parameters of published clinical outcomes related to pCIMT among children and youth populations. A secondary aim of this study was to inform rehabilitation practitioners regarding settings where pCIMT is occurring to guide planning for future program development in diverse practice settings.This study’s results differed from those of Hoare et al.  in severM = 4.94) and the number of weeks per plan of care (M = 3.61). This alignment is helpful for clinicians implementing the intervention in non-research settings or focus.Furthermore, comparing the dosage findings from this study to those of Deluca et al.  and RameMuch like a systematic review, the findings from this content analysis provide a comprehensive resource for clinicians regarding the status of pCIMT dosage, which may be useful for some clinicians who lack resources  focused on pCIMT.Moreover, this study provided additional information related to the intervention setting, which is helpful to rehabilitation professionals in deciding if pCIMT may be an intervention that could be successfully delivered in their own setting. The findings provide clinicians with crucial points of dialog and clinical reasoning when establishing dosage within their practices or in novel settings, e.g., school-based contexts, early intervention/homes, and emerging practice settings, like summer day camps, where dosage may be further controlled.In addition, this study provides researchers with information related to the fidelity of CIMT intervention. A method to enhance intervention of pCIMT within an experimental group would be to ensure implementation of home practice strategies by parents and caregivers.This content analysis of dosage parameters within pCIMT contained the following limitations. The study was conducted between 2017 and 2019 and newer literature emerged on the topic of dosage and pCIMT  that wasThe purpose of this content analysis was to identify and explore the dosage parameters of pCIMT. The results brought up as many questions as answers and opened the doorway for further analysis of dosage outcomes. For increased value of future research, skilled therapists who are practicing pCIMT need to be documenting and participating in research to create a standardized evidence-based protocol for pCIMT implementation. Comparison of outcomes from research implementing traditional pCIMT and modified pCIMT may help therapists better understand the role of the components of pCIMT. Further research that documents the outcome measures used and each participant’s manual ability and gross motor function to develop a patient profile that may be more responsive to the intensive nature of pCIMT is warranted.Rehabilitation specialists and providers who implement pCIMT into practice need to be aware of effective parameters of pCIMT. Currently, there is no standardized protocol for implementing pCIMT; therefore, providers may fall into habitual, and possibly ineffective, routines when providing pCIMT. The results of this study, together with other emerging evidence, can assist practitioners in prescribing dosages dependent on the setting, the pediatric client, and their current functional status. However, rehabilitation specialists should be thinking more about dosage and what constitutes an efficacious and ultimately an effective dosage in pCIMT; thus, more research is warranted.


In this study, the genetic relationship and the population structure of western Mediterranean basin native sheep breeds are investigated, analyzing Maghrebian, Central Italian, and Venetian sheep with a highly informative microsatellite markers panel. The phylogeographical analysis, between breeds’ differentiation level (Wright’s fixation index), gene flow, ancestral relatedness measured by molecular coancestry, genetic distances, divergence times estimates and structure analyses, were revealed based on the assessment of 975 genotyped animals. The results unveiled the past introduction and migration history of sheep in the occidental Mediterranean basin since the early Neolithic. Our findings provided a scenario of three westward sheep migration phases fitting properly to the westward Neolithic expansion argued by zooarcheological, historical and human genetic studies. Ovis aries (O. a.)were domesticated from a unique wild species, the Asiatic mouflon Ovis orientalis gmelinii named Ovis gmelinii (O. g.), in the region between Northern Zagros to Southeastern Anatolia ). The relative dating of the analyzed breeds’ divergence, forming the second westward sheep migration phase, is very informative because these dates should roughly correspond to the following zooarcheological, ancient climatic change and textile evolution dates. In fact, on the basis of archeological and written prehistoric sources [O. a. longipes in the southern Mediterranean rim. In fact, Grömer and Saliari [The second migration phase is represented, in the present study, by the divergence and then the westward migration of the woolly and fat-tailed sheep, the BAR, from the domestication center during the 6th millennium. This divergence was started in the 7th millennium, which revealed the divergence time between the BAR and APP (6943 years ago,  sources ,125, the sources ,126,127, sources . This pr sources ,129, is  sources  emphasiz sources ,129 ment sources  mentione sources ,86,125.  sources ,129,131. sources . The mis Saliari  mentioneOvis platyra aegyptiaca, was largely depicted between 3002 and 2644 B.P. in Egyptian monuments [During the same period and in parallel to the evolution from the hairy to woolly sheep, and induced as well by the drying climate change, an evolution from thin- to fat-tailed occurred in the Fertile Crescent . Archeolonuments . This faonuments . Babelononuments  mentioneonuments ,135. Unfonuments .The fat deposition in the tail is considered as an adaptive response of sheep to fluctuant environment conditions and is a valuable energy reserve for the animal during migration and food scarcity ,137. ThiThe second migration phase of these evolved woolly and/or fat-tailed sheep, following the same westward direction from the Middle East, would took a sea way and presented a slower and narrower expansion compared to the first migration phase involving both Neolithic human populations and their livestock, who settled and established their coastal farming enclaves around the Mediterranean Basin . In factThe westward migration wave aspect, which corresponded to the second migration wave reintroducing fat-tailed sheep in the western Mediterranean basin, caused the final divergence between the fat-tailed BAR and the thin-tailed QFO 1440 years ago . This diThe local western Mediterranean gene flow aspect between already installed and more or less evolved and selected woolly Mediterranean breeds. This west Mediterranean breeds’ gene flow finalized the genetic makeup of the present day northern and southern Mediterranean shores’ sheep breeds. This intensive gene flow is strongly related to the wide exchange and trades of finer woolly sheep starting in the Roman period and continues into the medieval period under the merinization process ,123. TheThe third migration phase was highlighted in the present study by the most recent divergence time between the analyzed breeds occurring in the common area between 2000 to 900 years ago . This ph2 phylogenetic tree of the 11 analyzed sheep breeds in the occidental Mediterranean basin using the GPT method [In light of these high congruencies between our genetic results and the zooarcheological and historical findings, it is worth speculating that three phases of westward sheep migration, dating from the early Neolithic to the medieval period, shaped the genome of both Mediterranean coasts’ sheep. This tri-phase westward migration was illustrated in T method  (Figure T method ,138, matT method ,32 and gT method ,33.The aim of the present study is to investigate the expansion of the western Mediterranean sheep by analyzing native sheep breeds that did not undergo the effect of the strong modern human selection practiced in the last two centuries. A molecular characterization, using microsatellite markers, was successfully used in highlighting the phylogeographic patterns and the divergence times, starting from the early Neolithic to the medieval period, of the westward sheep migration from the domestication center to North Africa and South Europe. The genetic results, strongly supported by systematic classification, zooarcheological, historical and climatic data, contributed to the reconstruction of the history of the westward domestication center sheep migration by the assumption of the three phases’ migration scenario. We highlighted that the current analyzed western Mediterranean breeds were the result of the miscegenation of three migration phases. The first phase, introducing the first ancestral hairy sheep, would have been miscegenated with the second phase of migration sheep. This last more evolved sheep diverged in the Fertile Crescent, after a long selection which looked for desired secondary products and adaptability, leading to the woolly and the fat-tailed sheep that migrated westward. The third migration phase corresponded, in addition to the last introduction of the fat-tailed sheep in the Islamic conquest, to the recent exchange of installed and locally evolved occidental Mediterranean breeds. The miscegenation of these three migration phases shaped the mosaic genome of the westward Mediterranean breeds. Our results perfectly reflected the Neolithic, prehistoric and historic sheep migrations. They contribute to a better visualization of the domestic sheep’s genetic background, since its domestication, as well as the effort that the Neolithic and prehistoric sheep breeders have provided, leads to a productive and well adapted sheep. These sheep, which survived and resisted the extreme cooling and drying climatic events, the fire activity and the desertification that happened during the last postglacial period, were the origin of the native sheep breeds. It is worth emphasizing that these native breeds, with their precious genetic reservoir, deserve to be preserved from the dilution and the intensive selection pressure of productive traits highly practiced during the last two centuries, under the modernization and the production standardization process of breeding.


She was submitted to cardiac magnetic resonance  and 2, w It is essentially caused by two mechanisms: the impact of the hypertrophied septum in the left ventricle free wall, generally with interposition of the hypertrophied papillary muscle, and anomalous insertion of the hypertrophied anterolateral papillary muscle directly in an anterior elongated mitral leaflet.Another more rare obstructive mechanism is that resulting from impedance to flow in the middle of the left ventricular cavity, called mid-ventricular obstruction, a distinct phenotype of hypertrophic cardiomyopathy, occurring in approximately 10% of patients.The diagnosis of mid-ventricular obstruction is considered when there is a mid-ventricular gradient estimated at 30mmHg. Obliteration is caused by marked septal hypertrophy, resulting in contact with the hypercontractile left ventricle free wall, and not by systolic anterior motion of the mitral valve anterior leaflet.,5,6 Moreover, the formation of apical aneurysms is more frequent in this subtype of hypertrophic cardiomyopathy.Patients with mid-ventricular obstruction tend to present many symptoms - dyspnea is the most common, and have increased risk of progressive heart failure and death (sudden death and arrhythmic events), according to studies in this population.The initial treatment of this condition is usually conservative. The interventions are reserved for cases of persistent symptoms after initiating drug therapy.After assessing the images, discussing the case, and establishing the obstruction mechanism, she initiated on beta blocker, with appropriate initial response. It was decided to carry on drug therapy, with strict clinical follow-up, due to the risk of complications associated with the disease.


Alterations in the human microbiota have been linked to carcinogenesis in several cancers. To date, few studies have addressed the role of the microbiota in cholangiocarcinoma (CCA). Our work aims to update the knowledge about the role of the microbiota in the CCA microenvironment, and to highlight possible novel insights for the development of new diagnostic, prognostic, or even therapeutic strategies. We thus conducted a review of the literature. In recent years, great progress has been made in understanding the pathogenesis, the clinical and histological behavior, and the molecular profile of CCA. Much evidence suggests that the bile microbiota plays an essential role in biliary diseases, including CCA. Some studies have demonstrated that alterations in the qualitative and quantitative composition of the intestinal commensal bacteria lead to overall cancer susceptibility through various pathways. Other studies suggest that the gut microbiota plays a role in the pathogenesis and/or progression of CCA. The clinical implications are far-reaching, and the role of the microbiota in the CCA microenvironment may lead to considering the exciting implications of implementing therapeutic strategies that target the microbiota-immune system axis. Cholangiocarcinoma (CCA) is a group of rare epithelial cell malignancies, arising from the cholangiocellular epithelium, which are mostly adenocarcinomas .CCA has always been considered a rare disease, accounting for less than 1% of all human cancers and about 10–15% of all primary liver cancers. However, in recent decades, the overall incidence has increased worldwide . It is uClonorchis Sinensis and Opisthorcis Viverrini), especially in some countries  [Some conditions are well-known risk factors for the development of CCA. Choledochal cysts , inflammatory bowel disease (IBD), primary sclerosing cholangitis (PSC), and chronic liver disease are strongly associated with CCA incidence and progression, as well as liver flukes  ,4. All thailand) . The inchailand) ,7. HowevCCA is divided into three subtypes according to its anatomical site of origin: intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA) CCA. iCCAs arise above the second-order bile ducts, whereas pCCA and dCCA respectively arise above and below the confluence between the common bile duct and the cystic duct; pCCA and dCCA can also be grouped under the term “extrahepatic” (eCCA). In terms of frequency, iCCAs account for 10–20% of CCAs, while 50% are pCCA and 30–40% are eCCA .The different classification of CCA during the past years may have influenced its correct estimation of prevalence and incidence. Notwithstanding the methodological problems in obtaining and processing data, the global incidence of CCA has increased worldwide in recent decades . In the Interestingly, iCCA has shown a stable rate in recent years in countries where a decrease in alcohol-related chronic liver disease and cirrhosis has been observed. In contrast, the same form of CCA has shown an increasing rate in European and American countries where alcohol consumption, hepatitis C virus (HCV) infection, obesity, and metabolic-dysfunction-associated fatty liver disease (MAFLD) have increased ,9.The landscape of risk factors for CCA is complex and constantly evolving; indeed, in recent years, new risk factors have been recognized in addition to the known ones. Of the established risk factors, some are common to all types of CCA, such as chronic biliary diseases, while others are more specifically associated with certain subtypes that follow a specific geographic distribution .Chronic biliary disorders represent well-known risk factors for all types of CCA, as chronic biliary inflammation and, eventually, biliary stasis are the pathophysiologic mechanisms.One of the major causes of chronic biliary disease in the Western world is PSC, a rare idiopathic, immune-mediated chronic cholestatic liver disease characterized by inflammation of the intra- and extrahepatic biliary tree with progressive fibrosis, biliary strictures, and consequent progressive liver failure . PSC is A well-established correlation between biliary cysts and CCA has also been reported . Bile duIntrahepatic biliary lithiasis is strongly associated with iCCA , especiaChronic viral infections, especially hepatitis B and C virus , are risk factors for the development of CCA, with a stronger association with iCCA  and withSimilarly, a positive association between MAFLD and nonalcoholic steatohepatitis (NASH) and CCA has been suggested, especially in relation with iCAA, and even in the not-yet cirrhotic stage . FinallyOpisthorchis Viverrini and Clonorchis Sinensis, are the most common risk factor for the development of CCA in Asia [Parasitic infections, particularly  in Asia ; for thi in Asia . Liver f in Asia . Chronic in Asia .To date, there is very little information on inherited predisposing genetic risk factors for CCA . OverallInterestingly, however, the predominant genomic CCA alterations are associated with epigenetic processes . DeregulInsulin-resistant patients have a higher overall cancer risk due to the mitogenic effect of insulin, which enhances a signaling pathway that activates the transcription of molecules involved in the cell cycle and proliferation . InsulinRegarding obesity, data on its association with the occurrence of CCA are conflicting and inconsistent . SeveralProspective studies are needed to better investigate obesity as a risk factor for CCA. Given the increasing prevalence of cardiovascular disease in Western countries and the fact that metabolic disorders are increasingly associated with primary liver cancer , a possiMetabolism of alcohol by hepatic microsomes generates reactive oxygen and nitrogen species by lipid peroxidation, leading to the excretion of carcinogenic compounds  via bile, which causes DNA alterations.Chronic alcohol abuse is identified as an independent risk factor for CCA, particularly for iCCA  , whereasTobacco smoking increases cancer risk worldwide through the direct and indirect carcinogenic effects of its toxic metabolites such as benzene and N-nitrosamines. Specifically, concerning CCA, these metabolites can either directly attack the epithelia of bile ducts or indirectly damage the DNA of gallbladder cells ,55. AlthVery few studies have addressed epidemiologic differences in CCA among racial groups. Saha et al. examined trends in CCA incidence in the United States between 1973 and 2012 and reported that CCA incidence rates were 30% higher in Hispanics and Asians than in non-Hispanics and Caucasians . SimilarRecently, a link between asbestos exposure and CCA has been demonstrated in several case-control and cohort studies ,59.TheseExposure to certain toxic substances has been consistently associated with the occurrence of CCA . ThorotrThe microbiota is a nonpathogenic microbial community living within the human body . The intGenerally, in the case of disruption of the intestinal barrier, the liver and bile ducts, which are physiologically sterile, can be exposed to the gut microbiota through the gut-liver axis, which is the major anatomical and physiological link between the gastrointestinal tract and the bile ducts and liver, passing through the systemic circulation . AlteratClostridia, which are responsible for the conversion of primary to secondary bile acids that return to the liver through the entero-hepatic circulation. This indirect role of vancomycin in the biotransformation process may influence the composition of bile acids and underlie its effect on disease progression [This is particularly the case for IBD patients, for whom intestinal barrier dysfunction and chronic inflammation are both triggers for the initiation and progression of tumor growth . Alteratgression .Propionibacterium, for example, might induce apoptosis of colorectal cells through the production of short-chain fatty acids, while bacteria such as Escherichia coli and Helicobacter spp, which contain LPS, appear to be associated with the development of HCC [Recently, a role of the gut microbiota in cancer pathophysiology has also been observed, with both anti-tumorigenic and pro-tumorigenic effects. Among the species in the gut microbiota, t of HCC . With ret of HCC .Opisthorchis Viverrini infection has been widely shown to be a risk factor for CCA. This infection is responsible for an alteration of the gut microbiota, and several clinical reports have observed an increase in Helicobacter spp in stool samples from these patients. In particular, overexpression of the Helicobacter genes CagA and CagE have been observed. The two gene-derived proteins migrate across the plasma membrane and cause phosphorylation of sarcoma family kinases, which may serve as transduction signals to promote fibrosis and inflammation of the bile ducts [Helicobacter spp CagA+ express antiapoptotic factor bcl-2 more strongly and activate mitogen-activated protein kinase and nuclear factor-kappa B (NF-kB) signaling pathway, leading to further proliferation of bile duct cancer cells [Helicobacter spp., including H. Pylori, H. Bilis, and H. Hepaticus. These samples also showed a strong inflammatory infiltrate and increased Ki67, indicating active cell mitosis [As previously mentioned, differences in gut microbiota composition have been observed in the development and progression of various cancers, due to the potentially carcinogenic effect of the inflammatory response resulting from bacterial translocation ,78. In tle ducts . In vitrer cells . These d mitosis ,81.Another hypothesis of a pathogenetic link between microbiota and CCA is related to myeloid-derived suppressor cells (MDSCs), which are immature myeloid cells with morphologic and phenotypic features of neutrophils (PMN-MDSC) and monocytes (M-MDSC), with different chemotaxis processes. Recently, the role of PMN-MDSC in the etiopathogenesis and progression of CCA has been described , as thesTo date, the most accurate data on the interaction between the biliary tract and gut microbiota in CCA pathogenesis come from studies in animal models showing that a disruption in the intestinal barrier leads to an accumulation of bacteria and LPS in the portal circulation and then in the liver and the biliary tree, resulting in hepatic and biliary recruitment of immunosuppressive cells , such asFaecalibacterium, Klebsiella, Ruminococcus Gnavus group, Lactobacillus, Dorea, Veillonella, Burkholderia Caballeronia Paraburkholderia, Citrobacter) that appears to have high accuracy in discriminating patients with CCA or HCC from healthy controls. The authors found that CCA patients had higher alpha-diversity (a measure of the diversity of the microbiota in a single sample) than HCC patients, while HCC patients had lower alpha-diversity compared with controls. Beta-diversity  was then assessed between the three groups: patients with CCA showed differences in microbiota profile compared to the other two groups, while HCC and control patients did not show significant differences, suggesting a similar bacterial distribution in the latter two groups. Based on these data, the authors finally extracted the eight genera for this diagnostic model [Based on the observed differences in the composition of the gut microbiota in malignancies, certain characteristics could be used as a noninvasive diagnostic tool. However, the most important factor in studying gut microbiota as a potential diagnostic tool is its highly dynamic variability and the consequent difficulty in defining a healthy control group. Indeed, daily stool samples from the same patient may show variations in bacterial composition, even if the composition remains stable in terms of percentages. Intestinal transit, genetic factors, lifestyle, eating habits, environmental factors, drug intake, and even bile composition contribute the most to intra- and interpersonal variations . Despiteic model .Burkholderia-Caballeronia-Paraburkholderia, Faecalibacterium, and Ruminococcus-1) was also suggested as a potential noninvasive biomarker to distinguish CCA patients from healthy controls. The authors investigated the differences in gut microbiota between CCA patients, patients with cholelithiasis, and healthy controls. CCA patients and healthy controls had a more species-rich and homogeneous microbiota than the cholelithiasis group, while there were differences in alpha-diversity between healthy controls and CCA patients. The authors finally identified the 20 most influential genera in patients with CCA and healthy controls and proposed this new diagnostic model that uses the presence and association of these three genera (B-F-R) in stool samples as diagnostic features for CCA [In the multicenter study by Zhang et al. , the pat for CCA .Bacteroides, Geobacillus, Meiothermus, and Anoxybacillus were significantly more abundant in the bile ducts of eCCA patients compared with controls. This suggests that eCCA is associated with bile duct dysbiosis, which allows these patients to be distinguished from controls with cholelithiasis.Saab et al.  characteLactobacillus, Actinomyces, Peptostreptococcaceae, Alloscardovia, and Bifidobacteriaceae compared to patients with HCC or cirrhosis and healthy individuals. The authors found no significant differences in bile composition in the three populations studied, but they noted that the plasma/stool ratio (PSR) of tauroursodeoxycholic acid (TUDCA-PSR) and glycoursodeoxycholic acid (GUDCA-PSR) can be used to distinguish patients with CCA from other groups. In addition, TUDCA-PSR appears to have a strong positive correlation with the presence of Lactobacillus and Alloscardovia in the stool samples. Interestingly, in this study, it was observed that patients with CCA and vascular invasion (VI) had higher beta-diversity than patients with CCA without VI. However, the potential diagnostic significance of these associations needs further investigation [Finally, another study by Jia and colleagues  charactetigation . In partEmerging data from the characterization of the gut microbiota in CCA patients, which, if confirmed, could play a role in the diagnosis of this cancer, are encouraging and reinforce the idea that the microbiota could also be a therapeutic target. At present, several new molecules are under investigation for the prophylaxis of CCA in the areas of target therapy ,88 and iSince the alteration of the biliary immune system due to the influence of the gut microbiota plays an important role in the development of CCA, as shown by the available data in the literature, we can speculate that manipulation of the microbiota could soon have interesting therapeutic implications for this cancer.The role of the microbiota in the microenvironment of CCA is an area of active research that is still not fully understood, although it may be associated with specific etiopathological mechanisms related to the carcinogenesis of CCA. However, there is evidence that the microbiota may play a role in the development and progression of CCA.One perspective is that the microbiota may contribute to the development of CCA through its effects on the immune system and inflammation. Specifically, dysbiosis, or an imbalance in the microbiota, has been linked to a dysregulation of the intestinal barrier that may lead to an increased load of inflammation and immune dysfunction, which in turn may increase cancer risk. Moreover, the dysregulation of the intestinal barrier and the consequent bacterial contamination of the otherwise sterile bile ducts have been found to produce toxins or other substances that may promote the development of cancer. Both the biliary invasion by specific bacterial species and the PSR alteration of determined bile acids imply a chronic inflammation of the biliary tree, with a magnified pro-tumorigenic risk.These aspects could be clinically important and may lead to considering the exciting implications of implementing both diagnostic and therapeutic strategies targeting the microbiota-immune system axis, especially in the subset of CCA.From a diagnostic perspective, ongoing studies are searching for new biomarkers for early detection of CCA. In this scenario, future diagnostic perspectives should focus on the identification of a gut-microbiota-based signature of CCA, which must be reliable, reproducible, and the least influenced by environmental factors such as diet, lifestyle, and pharmacotherapy.From a therapeutic perspective, targeting the microbiota could be a potential approach for the prevention or treatment of CCA. This could include the use of probiotics or other microbial therapies to alter the composition of the microbiota and potentially reduce the risk of CCA or slow its progression. Consequently, as far as prophylactic perspectives are concerned, microbiological and molecular research should focus on the development of technologies capable of effectively modifying the composition of the gut microbiota, whether this is fecal microbiota transplantation or the oral administration of antibiotics or probiotics, to specifically target the most commonly altered species in case of CCA, to restore the intestinal barrier, and thus to limit the consequent chronic biliary inflammation.Ultimately, the intestinal microbiota could play a significant role in terms of response variation to standard pharmacological therapies for CCA. Future efforts should therefore also focus on the manipulation of the intestinal microbiota in order to optimize the response to these therapies. However, further research is needed to fully understand the role of the microbiota in CCA and to identify the most effective strategies to influence the microbiota to achieve therapeutic benefit.


To improve the safety and efficacy of this minimally invasive endoscopic access, this study summarizes and highlights the lessons we have learned, acting as a template for newly established cardiac surgeons in minimally invasive techniques.Since its inception more than a quarter of a century ago, minimally invasive cardiac surgery has attracted the increasing interest of cardiac surgeons worldwide. The need to surgically treat patients with smaller and better-tolerated incisions coupled with high-quality clinical outcomes, particularly in structural heart disease, has become imperative to keep pace with the evolution of transcatheter valve implantation. We have learned numerous lessons from our longstanding experience in this field of surgical care, especially in terms of endoscopic access  The term “minimally invasive cardiac surgery (MICS)” covers a vast field of procedures, including valve surgeries, coronary artery bypass graft surgery (CABG), and intracardiac tumor resections, and has shown success in terms of safety and efficacy compared to conventional sternotomy (CS) . MICS tevia mini-thoracotomy to reach different cardiac structures has gained popularity among surgeons who perform minimally invasive cardiac surgery. The steep learning curve and technical difficulties of the different procedural steps such as CPB cannulation, myocardial protection, and deairing maneuvers discourage many surgeons from including these minimally invasive procedures in their routine surgical practice . The choice of the surgical technique is the net result of the application of an internal policy recommendation, which is exactly tailored to meet the requirements of an individual patient. An increased EuroSCORE and the age of the patient alone are not contraindications for endoscopic MICS. Elderly patients benefit even from the slightest advantages of endoscopic MICS by decreasing surgical trauma and perioperative pain, blood transfusions, hospital and intensive care unit (ICU) length of stay, ventilation time, wound infections, cost of hospitalization, and rehabilitation when compared to the CS. Moreover, for the young patient group, these techniques improve the cosmetic, quality of life, and patient satisfaction with an earlier return to normal activities , 4, 6. ESeveral structural pathologies of the heart including extensive endocarditis or severe calcification of the mitral valve (MV) annulus or severe calcification of the abdominal and/or iliac aorta are major limitations of this technique . Therefo®, LSI Solutions, Rochester, NY, USA)  .a) The use of a 3D camera is preferred:- to enable the surgery to be undertaken in an endoscopic manner using only a soft tissue retractor without rib resection and without using a rib retractor to reduce post-operative pain,- to securely place the Chitwood clamp  on the aorta under full camera visualization to avoid any possible injury to the pulmonary artery or the left atrial appendage, and- to enable the surgeon to see all parts of the operating field and to properly resect the leaflets, to radically decalcify the valve annulus, and to precisely place the annulus sutures, especially in cases of left-sided deviated heart or the bicuspid valve with limited exposure of the aortic valve (AV).b) Likewise, the use of long surgical instruments enables access to all structures of the aorta and the heart.c) The fixation of the valve prosthesis in the annulus can also be more easily, rapidly, and securely performed by using automated knot technology.All these instruments simplify and facilitate the procedure, thereby reducing the operating time without compromising the safety and the efficacity of the technique .As regards the learning curve, we believe that beginner surgeons must have at least experience with performing conventional surgery involving a minimum of 100 cases in each procedure . Simultaneously, they must undergo or should have undergone dry training with an endoscope, which is mandatory to achieve an imagination in endoscopic surgery. The first cases must be carefully selected for endoscopic MICS by considering the body mass index (BMI) under 30, favorable anatomical conditions of the heart and the chest, and a non-complex underlying pathology.The assistance of an experienced surgeon in endoscopic MICS is a fundamental requirement at this learning stage. Another aspect that contributes to facilitating the surgical procedure is clear and effective communication between the surgeon, the anesthetist, the perfusionist, and the scrub nurse. Considerable experience in performing MICS is required for all the above mentioned members .From our experience, we can easily speculate that new surgeons feel technically safe from 50 cases onward and the operative time decreases by increasing the number of operated cases.Arterial and venous femoral cannulation for the CPB is the standard procedure used to perform an endoscopic MICS through mini-thoracotomy. Preoperative CTA of the aorta is crucial to determining whether the MICS procedure is suitable for the patient . Severe TM system demonstrates this tool to be an effective, fast, and safe device, which also has a positive effect on the operating time compared to the surgical access for CPB in endoscopic MICS  to the level of the superior vena cava (SVC) and the arterial cannula  to the level of the right external iliac artery. While in the conventional open surgical approach, the common femoral artery is directly sutured under direct vision after decannulation, the percutaneous innovative collagen-based MANTA™ Vascular Closure Device (VCD)  is used in MICS. It serves as an elegant, safe, and reproducible closure device to manage this small bore access by immediate sealing . Otherwipic MICS , 10.As regards clamping of the aorta, we routinely use the Chitwood clamp. Alternatively, endoaortic balloon (EAB) occlusion with the endoaortic balloon clamp , which is introduced from the femoral artery into the ascending aorta right above the sinotubular junction, can be used . Crystalvia right anterior mini-thoracotomy (RAMT) is a safe and feasible technique without compromising on the surgical quality, the post-operative outcomes, or the patient safety when performed by a team very well-experienced in performing MICS  procedure remains the best surgical access in MICS for AVR, which can be performed by a wide range of surgeons . Howevering MICS , 4. Compterature . Severe echnique .via the second ICS. The pericardium is opened 5 cm above the phrenic nerve between the innominate vein cranial and the inferior vena cava (IVC) caudal. The use of two stay sutures on the right side of the pericardium superiorly and inferiorly to the right superior pulmonary vein helps to reduce the work distance. Multiple 4–0 Prolene stay sutures in the aortic wall and the aortic valve commissures help in the exposure of the valve. In some cases, the AV annulus sits below the third ICS, requiring surgeons to face the challenge of working through a tunnel. Therefore, long-shaft instruments belong to the standard surgical setup for MICS. For a newly established surgeon in MICS, patient selection is an important step, and they should carefully consider the pre-operative anatomical CTA findings of the concerned patient . The chest wall access is a keyhole through the third ICS using a soft tissue retractor  for optimal exposure without resection or dislocation of the rip and for preserving the right internal thoracic artery and vein intact. The 3D camera port access and Chitwood clamp are usually placed medially and laterally, respectively, The use of the 3D camera in AV surgery allows the surgeon to resect the leaflets properly, radically decalcify the valve annulus, and place the annulus sutures precisely, especially in the right coronary sinus. In cases of bicuspid AV, the role of the 3D camera is very important for localizing the left and right coronary sinus for a geometric ideal placement of the AV prosthesis beginning from the knots at the right coronary sinus . Considering their excellent long-term durability, simple, and efficacious MV repair is preferred over MV replacement in the treatment of degenerative MR in terms of superior early and late survival, improved reverse ventricular remodeling and ejection fraction (EF) recovery, and a better quality of life , 16. MICThe complexity of MV reconstruction makes the MICS procedure more challenging for surgeons who require a longstanding experience in this technique. Thus, we believe that surgeons must first become thoroughly proficient in performing the MICS for MV replacement and standard open MV repair before practicing these techniques in an almost closed chest.TM  are required. In this regard, concomitant trans-mitral septal myectomy and MV surgery via RAMT were enrolled in our experience in endoscopic MICS performing 14 cases safely with excellent surgical outcomes  is mostly performed as a concomitant procedure to MV surgery with increased incidence due to various reasons, which include an increase in the implantation of intracardiac devices and the prevalence of atrial fibrillation . Venous Our experience with endoscopic MICS suggests that this concept can be safely, effectively, and reproducibly performed by a wide range of surgeons. This study is intended to serve as a template for newly established cardiac surgeons in minimally invasive techniques in the hope of accelerating the learning curve while improving patient outcomes.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.AE-S and FB contributed to conception and design of the study. SS wrote the first draft of the manuscript. AE-S wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.