In this study, we analyze the DSA images of a subject-specific left posterior AVM case and customize a generic electric analog model for cerebral circulation accordingly. The generic model consists of electronic components representing 49 major cerebral arteries and veins, and yields their blood pressure and flow rate profiles. The model was adapted by incorporating the supplying and draining patterns of the AVM to simulate some typical AVM features such as the blood “steal” syndrome, where the flow rate in the left posterior artery increases by almost three times (∼300 ml/min vs 100 ml/min) compared with the healthy case. Meanwhile, the flow rate to the right posterior artery is reduced to ∼30 ml/min from 100 ml/min despite the presence of an autoregulation mechanism in the model. In addition, the blood pressure in the draining veins is increased from 9 to 22 mmHg, and the blood pressure in the feeding arteries is reduced from 85 to 30 mmHg due to the fistula effects of the AVM. In summary, a first DSA-based AVM model has been developed. More subject-specific AVM cases are required to apply the presented  These asyndrome . Still, syndrome . For exasyndrome .A number of AVM models have been developed over the past two decades, in particular by Young and his co-workers . Among tin silico simulations, which are all lumped parameter models where the mass of vessels within an AVM are lumped into one or several electronic components to simulate the blood pressure gradient and flow through it , and Rn is the resistance under a normal pressure range (80–120 mmHg).where The autoregulation mechanism of Eq. (1) was tested using an artificial pressure waveform, which contained five phases with 10 cardiac cycles for each phase . A normaThe Endovascular Intervention Unit of the Neurosurgery Department of the West China Hospital (WCH) treats approximately 70 AVM patients annually. Of these patients, about 50% receive surgeries following endovascular treatments. We randomly selected an AVM case for flow simulations.An 18-year-old female patient was referred to the WCH with symptoms of eyesight loss of her right eye and headache. CT scans revealed left cortex deformation and a suspected AVM growth at the left occipital lobe. The AVM was confirmed by a DSA procedure  . The lefAn endovascular embolism procedure was performed for the patient . Intra-pThe supplying and draining vessels revealed from DSA images were critical for the diagnosis and treatment of the AVM. The small vessels and the AVM nidus can be lumped into several electronic elements. In our implementation, the AVM was modeled by two parallel resistors with equal resistance to simulate the AVM plexiform. Another parallel branch consisting of a resistor with much lower resistance was used to mimic the fistula . This arSince the feeding arteries arise from the left PCA and PICA, the left PCA is rerouted onto the nidus network, bypassing the posterior capillary bed, and adjoining to the AVM nidus .In the current implementation, the AVM does not have an intranidal adaptation mechanism, following what is suggested in literature . In otheThe baseline model shown in With the introduction of a left AVM in the model, the flow rates at the left PCA, PICA, and the right PCA are shown in Compared to the left PCA (diameter ∼2 mm), the diameter of the left PICA (diameter ∼1 mm) is smaller, and its contribution to the AVM flow is not as significant as the PCA. However, the flow rate (∼35 ml/min) in the left PICA is much higher than the normal value of 10 ml/min , leadingA question raised is whether the circulation “steal” effects are located in the vicinity of the AVM  or they We also compared the blood pressures proximal and distal to the AVM, i.e., in the feeding artery, the left PCA, and the draining vein SSS. The results are shown in Advanced imaging technologies nowadays have revealed more AVM cases, including many that are asymptomatic . Clinicain silico models can provide useful insights in certain aspects of AVM, such as the extranidal adaption to hypotension (It has been shown that otension  and the otension . The latotension .However, it is still controversial whether regional regulation functions may be deprived due to the presence of an AVM, or just their lower limits are displaced . An updaOur model provides certain support to the hyperemia theory. We have shown in the transnidal pressure simulation  that theThe novelty of the work is that it is the first AVM model that incorporates subject-specific information from DSA image. Since the morphological arrangement of the AVM in the cerebral circulation model is subject-specific, a different AVM patient requires having an AVM model customized and re-adapted in the generic 0D model to account for the specificity.in vivo data. This is another important limitation of the current study.There are some limitations pertaining to the current model. Firstly, the implementation of the autoregulation mechanism is rather simple. The model assumes that the CBF responds to blood pressure variations only, yet CBF autoregulation is a complex process that involves neurogenic, metabolic, and myogenic mechanisms . Secondlin vivo measurements such as CBF velocities measured using transcranial ultrasound (It is also worth noting that while our model results were compared to DSA data, the calibration was rather phenomenological than quantitative. In trasound  or phasein silico platform for further AVM investigations. An immediate future work would be to numerically investigate the embolization of AVMs and those AVM cases located at different regions of the brain, e.g., in the anterior circulation region. Indeed, AVM occurs at the anterior circulation in 70–80% of the time (Nevertheless, the presented model provides an the time . Anotherin silico model be used as the basis for further AVM investigations.In this study, we used the information from DSA images of an AVM patient to alter an electrical analog model for cerebral circulation. Our simulations reproduced multiple flow phenomena that can be observed from the DSA images. We suggest the current All datasets generated for this study are included in the article/Supplementary Material.The studies involving human participants were reviewed and approved by The Ethics Committee of the West China Hospital, Sichuan University. The patients/participants provided their written informed consent to participate in this study.CZ performed the endovascular procedure of the AVM case and provided clinical insight. NC made the numerical simulation. HH drafted the manuscript. All authors reviewed and agreed the current form of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The RAE was not found in the female senior category  or male senior category (2013) (p>0.05). All playing positions were impacted by the RAE (p<0.001), and especially strong effect sizes were noted for male pivots (Vc = 0.66/0.68/0.60) and female center backs (Vc = 0.71/0.65/0.71). In our analysis of the handball continental federations, the RAE was found in all regions, except Oceania (p>0.05). The RAE also affected athlete performance: the oldest athletes played more minutes and achieved better performances. The RAE was associated with the final placement of the teams in each championship category, except in the male youth category. The findings clearly demonstrated that the RAE has a significant impact on the selection of male and female athletes to international competitions and the performance of both men and women in international handball. The potential implications of these findings for policy and practice are discussed.This study examines the relative age effect (RAE) and its impact on the performance of elite male  and female  handball players in the U-19 , U-21 , and senior  categories of the 2013/2014, 2015/2016 and 2017/2018 World Handball Championships organised by the International Handball Federation (IHF). The distribution of the players´ birth dates  by categories, handball playing positions, and membership of continental federations, were analysed for each of the three two-year periods in which the World Handball Championships took place. Differences between the observed and expected birth dates were tested using a chi-square goodness of fit test, and subsequent calculations were tested using odds ratios. The Spearman’s correlation coefficient was applied to test the correlation between the relative age of the athletes and (their) performance parameters. The results revealed a prevalence of the RAE on both male and female in the U-19 and U-21 categories ( Successful talent identification and development (TID) systems are regarded by policy makers as vital to achieving success in adult elite sports, and are based usually on the selection of athletes for special activities, teams and/or competitions . The intIn 2009, Cobley et al. , basketbStudies focusing on the impacts of the RAE on the selection of athletes to TID systems in handball have also reported mixed findings. Schorer et al. , for exaWrang et al.  confirmeth Men’s Youth World Championship held in 2017. Findings showed the prevalence of the RAE in the population sample but found no relationship between the age of the players and the success of each team–measured as a team´s championship ranking. Surprisingly, it was concluded that the selection bias shown at the youth international team level, did not influence the long-term sporting achievements of the athletes.Only one study has compared the impact of the RAE in different countries. In a study of athletes selected to international youth competitions in handball, Fonseca et al.  includedTo the best of our knowledge, no studies have investigated the prevalence of the RAE at the international senior, U-21 and U-19 levels, or male/female team categories in handball. Other studies of the RAE in handball have been limited to specific geographical areas, specific countries or handball federations, or have focused on particular categories, male/female categories, years/seasons, or championship levels. Moreover, the extent to which the RAE affects future performance, after an athlete´s initial selection, remains unclear. The aim of this study, therefore, is to analyse the impacts of the RAE across different countries on the selection of athletes to international youth competitions, and the influence of the RAE on athlete and team performance in the U-19, U-21, and senior categories during the 2013/14, 2015/16 and 2017/18 World Handball Championships. The importance of this research lies in the need to interrogate the systematic attempts to facilitate talent development in sports, and helps to question whether the current procedures used in talent development systems are evidence-based. A lack of in-depth analysis of the RAE prevents a full understanding of its potential impacts and unintended consequences. It may also lead to the identification of other, more effective and appropriate practices .The sample of the study consisted of 6,631 handball players  who had played for teams registered in the World Handball Championships, which are organised annually by the International Handball Federation (IHF). The IHF groups athletes according to their chronological age in categories of 2 years , and uses January 1 as the start date for each two-year period. In the years 2013, 2015 and 2017, the World Handball Championships were for men and senior women; in 2014, 2016 and 2018, the Championships were for youth and junior women athletes. Players were allocated to one of three categories in the championships: youth or under 19 years old (U-19), junior or under 21 years old (U-21), and senior. Our study used the same allocation categories. However, in the youth and junior categories, players who were born outside the biannual cycle of international competition were excluded from the study because the sample could otherwise potentially have included duplicated subjects in the competition categories we analysed. Thus, 9.36% of all the male players (226) were excluded from the sample, and 9.35% of all the female players (229) were excluded. The athletes who were included were then further categorised according to their handball field positions, and by the continental federation to which their national team belonged. The sample of players was divided further by the year in which the World Championships took place  to prevent any players from being included again in subsequent analyses. This step was taken because some players participated in two different championship categories in the same year. The description and distribution of the handball players’ positions and continental federations, by competition and by category, are shown in https://www.ihf.info/competitions). Senior players’ birth dates were categorised into four quartiles because their selection year corresponded with the regular calendar year. However, the birth dates of the youth and junior players were divided into eight quarters, each corresponding with the eight quarters in the biannual time range. Players born in even numbered birth years were therefore included in one of the following groups: Quartile 1 (Q1)–players born between January 1 and March 31; Quartile 2 (Q2)–players born between April 1 and June 30; Quartile 3 (Q3)–players born between July 1 and September 30; Quartile 4 (Q4)–players born between October 1 and December 31. Players born in odd-numbered birth years were categorised as follows: Quartile 5 (Q5)–players born between January 1 and March 31; Quartile 6 (Q6)–players born between April 1 and June 30; Quartile 7 (Q7)–players born between July 1 and September 30; Quartile 8 (Q8)–players born between October 1 and December 31.All data were acquired from an IHF database and downloaded from the ´Competitions´ Section of the IHF website –players born between January 1 and June 30; Semester 2 (S2)–players born between July 1 and December 31. For players born in odd-numbered birth years, the categories were as follows: Semester 3 (S3)–players born between January 1 and June 30; Semester 4 (S4)–players born between July 1 and December 31.The following six continental federation categories were also included: the African Handball Confederation; the North America and the Caribbean Handball Confederation; the South and Central America Handball Confederation; the Asian Handball Federation; the European Handball Federation; and the Oceania Continent Handball Federation. The following age categories were analysed: U-19; U-21, and Senior. The following five playing positions were analysed: goalkeeper; wing; lateral back; center-back; and pivot. percentage of effectiveness in shot (PESh), the percentage of effectiveness in saves (PESa), assists, technical faults-turnovers (TF-TO), steals (ST), blocked shots (BS), penalties (PEN), minutes played (MIN), and the championships ranking. The performance categories steal and blocked shot were not provided by the IHF for the youth and junior competitions. In the disputed Youth and Junior Women’s Championships of 2018, the category time played was not used. The number of handball penalties was quantified as the sum of the number of yellow cards plus the number of exclusions or red/blue cards. The classification of team performance was determined by the placement of each national team. In order to adjust for the individual performance of each player, all statistical data were normalised in relation to the number of minutes that each player played. Thus, the possible effect of time on each player was eliminated.Statistics about player performance were taken from the website of the IHF to correlate the following parameters with the potential impacts of RAE in handball: the Statistical Package for Social Sciences , and Windows Office Excel 2010. The differences between the observed and expected birth date distributions were tested using the chi-square goodness of fit test. In most countries, the distribution of births remains constant across the year, and therefore no significant variation was assumed. For the purposes of statistical analysis, the expected frequency of births in a quartile is 25%, assuming a homogeneous sample distribution [Data analysis was conducted using the ribution .Vc > 0.80, a very strong association [We calculated odds ratios and 95% confidence intervals (CI) for the quartile and half-year distributions so that we could examine subgroup differences with respect to the potential non-uniformity of the birth date distribution. The odds ratios compared the birth date distribution of a particular quartile  or semester  with a reference group consisting of the relatively youngest players (Q8 or S4). A higher odds ratio would indicate an increased likelihood of players who were born in that particular quartile compared to the reference quartile. In order to determine the strength of association, a Cramer’s V statistical test was applied, in which 0.10 to 0.20 indicated a weak association; 0.20 to 0.40, a moderate association; 0.40 to 0.60, a relatively strong association; 0.60 to 0.80, a strong association; and ociation . The levp < 0.001). The largest effect sizes observed were in the U-19 category for women in the 2014 and 2018 World Championships (Vc = 0.48), and in the U-19 category for men in the 2017 World Championship (Vc = 0.52). No significant differences were evident in the female senior players in the 2013, 2015 and 2017 World Championships, and the male senior players in the 2013 World Championship (p > 0.05). Similar findings were evident in the birth date distribution by semester . The largest effect size was found in the U-19 category for men in the 2017 World Championship (Vc = 0.49).semester : signifip < 0.001). The largest effect size we found was for women playing as center backs at the women’s World Championships of 2013/2014 (Vc = 0.71), 2015–2016 (Vc = 0.65) and 2017/2018 (Vc = 0.71). For men, the largest effect size was among those playing in the position of pivot . Similar results were observed in the birth date distribution by semesters (p < 0.001) , and for men in the pivot position .< 0.001) . The larTables p<0.05) in the U-19 and U-21 categories. No significant findings were found in the senior category (p>0.05), except among athletes in the African Handball Federation (p<0.01) in the 2015/16 and 2017/18 World Championships, and for the European Handball Federation (p<0.05) in the 2017/18 World Championships.In addition, we performed a chi-square analysis to investigate the relationship between the relative age of the players in the continental federations . Signifip<0.05) for both genders, except in the female senior category (p>0.05) (p<0.01). This means that relatively older athletes played more minutes than younger athletes in their corresponding competition categories. Relative age was correlated significantly (p<0.01) to the number of assists in the youth and junior female categories, and penalties in youth and junior male and youth female categories. Relative age correlated positively (p<0.05) to the percentage of shot effectiveness in the male senior category, technical faults-turnovers in the male and female youth and male junior categories, and the number of steals in the male senior category.Positive correlations were observed between the relative age of the players and the number of minutes played ((p>0.05) . The finp<0.05) with the percentage of effectiveness in saves per minute in the male senior category and female youth category, assists per minute in the female junior category, and penalties per minute in the male junior category. Significant positive correlations (p<0.01) were found in the percentage of effectiveness in shots in the male youth category, and the percentage of effectiveness in saves per minute in the male senior category.p>0.05)  . This inThe key purpose of this study was to examine the RAE in the context of the highest levels of international handball competition. Our research focussed specifically on whether age affects the availability of opportunities in the sporting careers of male and female athletes. As expected, we observed a skewed distribution of birth dates in the youth and junior categories and noted that relatively older players were overrepresented. At the senior level, no uneven birth date distribution was observed among female players in any of the Championships. Non-uniform birth date distributions were observed for male players in the Championships of 2015 and 2017. The observed tendency of a decrease in the RAE at the senior level mirrors similar findings from other studies of team sports  and indiThe persistence of the RAE in handball is far from surprising due to the high correlation that has been observed between the level of athlete performance and the physical and physiological demands that are made ,37. AnthIn the analysis of the relationship between the date of birth and the gender of athletes, the RAE was found to impact on the categories and competitions we analysed, except among female athletes in the senior World Championships. Our findings stand in contrast to other studies that reported no RAE impacts on athletes taking part in women´s sport, including in handball and other sports –42. HoweStudies that have investigated athlete selection to international or national youth and junior teams within TID systems in handball have reported similar RAE impacts in women’s handball ,43,44. TOur results confirm findings from previous research that has shown that the influence of the RAE decreases as the level of competition increases ,46. ThisIn the analysis of the relationship between the dates of birth of the athletes and playing positions, the RAE appears to be one of the factors that determine athlete selection for particular field positions ,55. Our In the analysis of the relationship between the athletes´ dates of birth and the differences in their continental federations, we observed that the RAE impacted athletes across all geographical settings, except Australia (the only participating country in the Oceania Confederation). One possible explanation for this is that the handball cut-off date used by countries such as Australia is August 1, instead of the more common, and internationally recognised date of January 1.In our analysis of the relationship between the athletes´ dates of birth and the performance parameters, we observed that relatively older players, except those in the female senior category, played more minutes compared to relatively younger players. Consequently, older participating players obtained better scores on some performance parameters, such as technical faults-turnovers, assists and penalties in the youth and junior categories. In the male senior category, older athletes achieved higher effectiveness percentages in shots and steals. This finding is contrary to the results reported by Bjørndal et al.  who obseBy gender, differences were observed regarding the individual player performance. Relatively older female handball players (in the U-19 and U-21 categories) produced more assists, both in absolute numbers and relative to the amount of playing time. This may possibly also be due to anthropometric parameters, such as hand length. Older players, as we have suggested, are more likely to have larger hand sizes. This would give them a more stable ball grip and, therefore, better pass action techniques ,65. HoweThe total number of technical faults and turnovers was found to be higher for relatively older male players (in the U-19 and U-21 categories). While this could be seen as a sign of a decline in the individual performance of athletes, this difference disappears when this parameter is weighted by the number of minutes played. Potential explanations for this finding may be that relative older players play more minutes and are therefore likely to make more mistakes. However, because they are more experienced than their younger counterparts, they might also be assumed to make fewer mistakes per minute played. A similar age variation was found with regard to penalties.Interestingly, the analysis of the relationship between date of birth and team performance showed that the RAE was associated with the final placement in the Championships, except for players in the male youth category. This finding is contrary to the results reported in other studies. Werneck et al. , for exaOur findings suggest that high-performance handball competitions are biased in favour of relatively older players, and that the selection-based models currently in use may conflate the future potential of athletes with their current performance. Relatively older players typically belong to teams that achieve the best final placements in competitions and benefit from high quality training conditions . This is more likely to enable players to achieve higher performance levels ,63. HancThis study has also shown how the RAE relates to individual and team performance. It suggests that there are strong arguments to be made against selection-based models that appear to conflate future potential with current performance. The introduction of international championships for youth may only increase the risk of athletes being given unequal opportunities. This should be a great concern to policy makers and practitioners alike, as the effects of unequal opportunities is detrimental to the values of most sport organisations and may also be counterproductive to talent development, in particular.It is important that equal opportunities are available to all players. Our study findings indicate that the time may be right to question the value and appropriateness of the TID systems currently being used in national and international handball, including the introduction of international championships for youth athletes. Particular attention needs to be given to athletes who are less likely to enjoy the benefits of early maturational development.The physiological, kinanthropometric, conditional and psychological profile of players should be understood as a form, or framework, for guiding the talent development of athletes, but not as a selection tool . Thus, oOur study had some limitations. Firstly, we did not know the distribution of birth dates among the wider populations of the countries analysed . SecondlThis is the first large-scale study of international handball to demonstrate that the RAE has a significant effect on male and female athlete selection to international handball competitions in the U-19, U-21, and (only in men) the senior categories. In addition, it is one of the first studies to demonstrate that the RAE in international handball remains constant over time. The study has shown further how the RAE relates to other variables, such as athletes´ playing positions, continental federation membership, and individual and team performance. The study contributes to the growing body of evidence showing that the impacts of the RAE are persistent and affect athletes across the world.when selection mechanisms and the RAE begin to influence opportunities for the participation, development and performance of children and youth in different sport contexts. More interpretive research may also help researchers to move beyond descriptive overviews of the impacts of the RAE in sports and help to develop and reveal more appropriate strategies for talent identification and development [Future research should continue to focus on reviews of national talent development and identification systems in handball, including the selection processes associated with international youth team activities. This will enable a deeper exploration of how organisational differences and sociocultural factors influence the initial selections of players and, subsequently, their retention. Future research designs should allow for comparisons between countries and contexts. An examination of elopment .S1 Data(XLSX)Click here for additional data file.S2 Data(XLSX)Click here for additional data file.S3 Data(XLSX)Click here for additional data file.S1 Fig(TIFF)Click here for additional data file.


It is frequent in obese patients, subjects with type-2 diabetes and metabolic syndrome, both in adulthood and in childhood. This narrative review aims to offer insights into the pathophysiological mechanisms linking Mg2+ deficiency with obesity and the risk of developing metabolic syndrome and type 2 diabetes. Literature highlights critical issues about the treatment of Mg2+ deficiency, such as the lack of a clear definition of Mg2+ nutritional status, the use of different Mg2+ salts and dosage and the different duration of the Mg2+ supplementation. Despite the lack of agreement, an appropriate dietary pattern, including the right intake of Mg2+, improves metabolic syndrome by reducing blood pressure, hyperglycemia, and hypertriglyceridemia. This occurs through the modulation of gene expression and proteomic profile as well as through a positive influence on the composition of the intestinal microbiota and the metabolism of vitamins B1 and D.Magnesium (Mg Almost all the body Mg2+ is found in the bones (about 60%) and soft tissues (about 40%), while <1% is in the blood. It is a cofactor of hundreds of enzymatic reactions, acting both on the enzymes as a structural or catalytic component and on the substrates. An example of Mg2+ bioactive activity is given by the reactions involving the complex Mg-ATP, which is an essential cofactor of kinases. For this reason, Mg2+ is a rate-limiting factor for many enzymes involved in carbohydrate and energy metabolism. Furthermore, Mg2+ is essential in the intermediary metabolism for the synthesis of the macromolecules [2+-dependent functions are muscle contraction and relaxation, normal neurological function, and release of neurotransmitters [Magnesium Mg+ is the 2+ homeostasis is fine-tuned by the coordinated activity of membrane channels and transporters. Some of them are ubiquitously expressed, such as transient receptor potential melastatin (TRPM) 7, Mg2+ transporter 1 (MagT1) and solute carrier family 41 member 1 (SLC41A1). Others are tissue-specific, such as TRPM6, expressed in the kidney and the colon, cyclin and CBS domain divalent metal cation transport mediator cyclin M2 (CNNM2), expressed in the kidney, and CNNM4, expressed in the colon [At the cellular level, Mghe colon . 2+ deficit is frequent in obese subjects [2+ depletion can promote chronic inflammation both directly [Obesity, metabolic syndrome, and type 2 diabetes mellitus are three interrelated conditions that share a series of pathophysiological mechanisms attributable to “low-grade” systemic inflammation . Mg2+ desubjects  and is asubjects . Besidesdirectly ,7,8 and directly .2+ deficiency with obesity and the risk of developing metabolic syndrome and type 2 diabetes  of Mg females ,23,24. Toor soil . Hypomag disease , inflamm disease ,27,28 or disease . Additiobalances . Hypomagbalances . Moreoveficiency .2+ status may also have genetic origins and derive from mutations of genes such as TRPM6, CLDN16-19 (claudin 16 and 19), KCNA1 (potassium voltage-gated channel subfamily A member 1), CNNM2 [2+ deficit may be observed after intensive sport activities with an increase in sweating, in healthy postmenopausal women [2+ status is generally impaired in older people [A low-Mg), CNNM2 . These m), CNNM2 . Finallyal women  or durinal women . Moreover people . 2+ deficiency induces a chronic low-grade inflammation sustained by the release of inflammatory cytokines and production of free radicals, which exacerbate a pre-existing inflammatory status [2+ depletion is considered a risk factor for pathological conditions characterized by chronic inflammation, such as hypertension and cardiovascular disorders but also metabolic syndrome and diabetes [Considering the focus of this work, it is important to underline that a moderate or subclinical Mgy status . For thidiabetes ,37,38.2+ deficient [2+ deficit is more prevalent in subjects with body mass index (BMI) in the obese range than in the normal American population [2+ intake is impaired in 35% of French individuals with BMI > 35 kg/m2 [2+ intake is inversely associated with the incidence of obesity and with the levels of C reactive protein [2+ supplementation prevents the accumulation of adipose tissue [2+ intake and markers of adiposity, such as BMI and waist circumference [Obesity and its comorbidities, including metabolic syndrome and type 2 diabetes, are a relevant medical problem worldwide. Obesity is the result of unhealthy diets, high in calories, but poor in essential nutrients. As a consequence, obese subjects are often Mgeficient . Indeed,pulation ,41. Anal35 kg/m2 . The 30- protein . Besidese tissue  and humamference ,46,47.2+-dependent and Mg2+ is necessary also for the activation of vitamin B1 into thiamine diphosphate (TDP) that is another critical coenzyme of oxidative metabolism. Importantly, TDP-dependent enzymes require Mg2+ to reach optimal activation [2+ and/or TDP may alter the oxidative metabolism of glucose. In the liver, a decrease of the activity of the Mg2+- and TDP-dependent enzyme pyruvate dehydrogenase may divert glucose metabolism into the oxidative phase of the pentose phosphate pathway, thus generating an excess of NADPH [In obese subjects, most of the energy of the diet derives from refined grains and simple sugars and, consequently, their hepatic glucose catabolism is very active. Several key enzymes of glucose oxidation pathways are Mgtivation . Therefoof NADPH . NADPH pof NADPH ,50,51. 2+ is essential also for vitamin D synthesis and activation [2+ status may be fundamental for optimizing vitamin D status [2+ deficiency and/or Vitamin D deficiency predispose non-diabetic obese subjects to an increased risk of cardiometabolic diseases. Meanwhile, maintaining a normal Mg2+ status improves the beneficial effect of Vitamin D on cardiometabolic risk indicators [2+ in obese but not in non-obese subjects after vitamin D intramuscular injection, probably caused by increased Mg2+ renal retention induced by vitamin D and emphasized by baseline Mg2+ deficiency of the obese subjects [Moreover, obese subjects are often deficient also in vitamin D ,52 both tivation . A randoD status . BecauseD status . Moreovedicators . Interessubjects .2+ intake and MetS risk independently from other risk factors such as age, gender, BMI, race, educational attainment, marital status, smoking, alcohol intake, exercise, energy intake, percentage of calories from saturated fat, use of an antihypertensive or lipid medication [2+ intake is inversely associated with the prevalence of MetS [2+ intake and the prevalence of MetS [2+ intake lowers systemic inflammation and the risk of the MetS [2+ in drinking municipalities water and the prevalence of hypertension and MetS [Obesity and metabolic syndrome (MetS) are both characterized by excessive accumulation of body fat. However, while obesity only implies the accumulation of excess body fat, metabolic syndrome is a disorder of accumulation and use of energy, promoted by low-grade systemic inflammation, and resulting in central adiposity, hypertension, dyslipidemia, or insulin resistance. Many studies have found a positive correlation between low dietary Mgdication ,62,63,64 of MetS . In morethe MetS . An inteand MetS .2+ intake reduces cardiometabolic risk and is associated with a reduced hazard of cardiovascular disease, diabetes, and all-cause mortality [2+ are associated with a lower risk of cardiovascular disease, mainly coronary artery disease [MetS exponentially increases the risk of developing type 2 diabetes, cardiovascular disease and, in general, morbidity and mortality. Proper Mgortality ,68,69,70 disease .2+ dietary intake leads to serum and intracellular Mg2+ deficiency. This is particularly evident in obese people with MetS, in elderly subjects and non-white people with insulin resistance [Low chronic Mgsistance ,73,74.2+ is a natural calcium (Ca2+) antagonist, and its metabolic effect needs to be discussed according to Ca2+ concentration. A recent meta-analysis suggests that high Ca2+ dietary intake reduces the risk of MetS [2+/Mg2+ intracellular ratio, induced by a diet high in Ca2+ and low in Mg2+, may lead to hypertension, insulin resistance, and MetS [2+ and Ca2+ have reduced risk of MetS [2+ and Ca2+ work together to regulate the metabolic response of overweight and obese subjects, and an unbalanced Ca2+/Mg2+ ratio maximizes the effect of their single deficiency. The optimal Ca2+/Mg2+ ratio leads to the best-decreased risk of MetS [Mg of MetS . Other eand MetS . Accordi of MetS . Mg2+ an of MetS ,78. 2+ homeostasis and Mg2+ intake is inversely associated with the risk of T2D in a dose-response manner [2+ depletion in patients with T2D is mainly caused by a low intake and an increased urinary loss of Mg2+, probably resulting from impaired renal function [2+ homeostasis, at the same time Mg2+ is also a significant determinant of post-receptor insulin signaling. The influence of Mg2+ on glucose metabolism, insulin sensitivity, and insulin action could explain the negative association between Mg2+ intake and T2D incidence [2+ and, consequently, insulinemia is inversely correlated with magnesemia. Circulating glucose is easily taken from cells β through the glucose transporter 2 (GLUT2), and then converted in glucose-6-phosphate (G6P) by glucokinase (GK). The oxidation of G6P in glycolysis determines an increase in the ATP/ADP ratio leading to the closure of ATP-sensitive K+ channels (KATP channels) and, consequently, to the depolarization of the membrane, followed by the opening of voltage-dependent Ca2+ channels [2+ triggers the fusion of insulin-containing granules with the membrane and the subsequent release of their content. The molecular mechanisms by which Mg2+ contributes to insulin resistance are mostly unrevealed. However, it is accepted that Mg2+ deficiency has a significant impact on insulin secretion and may contribute to dysfunction of pancreatic beta cells in T2D [2+ in the glucose-dependent signaling inducing insulin release. The activities of GK and many glycolytic enzymes depend on Mg-ATP complex, thus, a low intracellular Mg2+ concentration results in decreased ATP level in the cells. In addition, the closure of KATP channels depends on ATP binding to the Kir6.2 subunit, while the opening of these channels depends on Mg-ATP binding to the SUR1 subunit. The reduction in the intracellular levels of both ATP and Mg-ATP deranges the fine regulation of KATP channels. This leads to an increase in the basal secretion of insulin and induces hyperinsulinemia, thus contributing to a chronic exposure of cells to insulin and to the development of insulin resistance fostered also by the concomitant low grade inflammation [2+, thus perpetuating a vicious cycle [2+ transport, thus increasing intracellular Mg2+ content. It is noteworthy that low intracellular Mg2+ impairs cell responsiveness to insulin, because low intracellular Mg2+ alters the tyrosine-kinase activity of the insulin receptor (INSR), leading to the development of post-receptor insulin resistance and decreased cellular glucose utilization [2+ and Mg-ATP complex are key regulators of the PI3K/Akt kinase pathway downstream to the INSR. This pathway starts with INSR auto-phosphorylation, which triggers the downstream kinase cascade. Insulin receptor substrate (IRS) mainly activates phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K), which generates the second messenger phosphatidylinositol-3,4,5-triphosphate (PIP3). PIP3 activates 3-phosphoinositide dependent protein kinase-1 (PDK1), which activates Akt. Akt regulates the metabolic actions of insulin, including glucose uptake by GLUT4 mobilization in skeletal muscle and adipose tissue, glycogen and protein synthesis and lipogenesis. For this reason, the lower is the basal intracellular Mg2+ concentration, the higher is the amount of insulin required to metabolize the same glucose load, indicating decreased insulin sensitivity [2+ concentration. Type 2 diabetes (T2D) is often associated with altered Mge manner ,80. Epide manner ,82. Mg2+function . In partncidence ,85,86,87channels . The incs in T2D . This deammation . Moreoveus cycle . In addilization ,91. In psitivity ,91. All 2+ deficiency can also contribute to T2D through the modulation of Na+/K+-ATPase that is crucial for maintaining the membrane potential and low cytoplasmic sodium concentration. Mg2+ ions drive the conformational change of the sodium pump whose dysfunction has been correlated to T2D [Mgd to T2D ,93. Mored to T2D . 2+ levels further supports this assumption and suggests a substantial interdependence between Mg2+ deficiency and the development of insulin resistance and T2D. Mg2+ deficiency may not be a secondary consequence of T2D, but it may contribute to insulin resistance and altered glucose tolerance, thereby leading to T2D [The observation that several pharmacological treatments for diabetes, such as metformin, appear to increase Mgg to T2D .2+ deficiency in obese children may be secondary to decreased dietary Mg2+ intake. Obese children show lower serum Mg2+ levels than the normal-weight control group. In obese children and adolescents, Mg2+ blood concentration is inversely correlated with the degree of obesity and is related to an unfavorable serum lipid profile and higher systemic blood pressure than healthy controls [2+ deficiency and insulin resistance has been described also in childhood [2+ supplementation or increased intake of Mg2+-rich foods to correct its deficiency may represent an essential and inexpensive tool in preventing T2D in obese children.Few studies have discussed the relationship between hypomagnesemia and metabolic disorders in childhood and adolescence. Mgcontrols ,96. The hildhood . Mg2+ suThe gut microbiota is a complex microbial ecosystem, symbiotic with humans, that plays a crucial role in a series of pathophysiological processes. In healthy subjects the gut microbiota is rich in microbial species and, through its genes and metabolites , it acts as an immunologic and metabolic organ ,99. By c2+ deficiency and gut microbiota in humans, while some data are available in animal models. A 6-week Mg2+-deficient diet in rodents altered the gut microbiota and was associated with anxiety-like behavior [2+ deficiency may mediate an imbalance of the microbiota–gut–brain axis, which contributes to the development of depressive-like behavior [2+ deficiency also through the involvement of the gut microbiome [2+ deficiency is a nutritional disorder connected to a low-grade, latent chronic inflammatory state. Interestingly, in Mg2+-deficient mice, changes in intestinal bifidobacteria levels are associated with an inflammatory response, thus creating an effective link between Mg2+ status, gut microbiota and inflammation [Little is known about Mgbehavior . In partbehavior . It shoubehavior . Moreovebehavior  and PPI crobiome . As prevammation . 2+ supplementation might help in remodeling the microbiota. Indeed, Mg2+ supplementation in obese subjects with and without T2D affects microbial composition and functional potential [2+ and other trace elements, significantly enhances the gut microbial diversity in adult male rats [It is now widely accepted that an altered gut microbiota composition participates in systemic low-grade inflammation ,109,110.otential . Moreoveale rats .2+ dietary intake could positively affect the composition of the intestinal microbiota and, consequently, the host metabolism, thus helping in preventing metabolic alterations associated with the development of MetS and TD2. However, the path for clarifying the impact of Mg2+ in this emerging field of research is still long. To conclude, an adequate Mg2+, including whole grains, nuts and seeds, legumes, and dark-green vegetables, were associated with a lower incidence of obesity, T2D and MetS [2+. However, because of agronomic and environmental factors as well as food processing, Mg2+ content in fruits and vegetables dropped in the last 50 years [2+ for three months improves glycemic control in T2D subjects as demonstrated by the significant reduction of glycated hemoglobin, insulin levels, C-peptide, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) [2+ deficiency. Indeed, the supplementation with 360 mg of Mg2+ for the same period does not improve insulin sensitivity in normomagnesemic T2D patients [2+ for 12 weeks improved the wound healing of diabetic foot ulcers, decreasing the lesion size, and ameliorating glucose metabolism [The intakes of food rich in Mgand MetS . Therefo50 years  and it mHOMA-IR) . This efpatients . The admtabolism . Mg2+ cotabolism . It is ntabolism .2+ supplementation seems to improve blood pressure control and vascular resistance in patients with essential hypertension [2+ for one month decreases systolic and diastolic pressures, systemic vascular resistance, and left cardiac work [2+ supplementation with 600 mg for 12 weeks is associated with moderate but consistent ambulatory blood pressure reduction in patients with mild hypertension [2+ is a Ca2+ antagonist, increases the synthesis of vasodilators such as prostacyclin and nitric oxide, and inhibits vascular calcifications through the modulation of TRPM7 [2+ channel TRPM6 could explain the antihypertensive effects of Mg2+ supplementation. The increase of TRPM6 mRNA expression is obtained with the administration of 360 mg of Mg2+ for four months [2+ supplementation on blood pressure is also reported in patients already undergoing drug treatment for hypertension. In thiazide-treated women, the administration of 600 mg of Mg2+ improves endothelial function and subclinical atherosclerosis [2+ for six months decreases carotid intimate-media thickness, which is a marker of cardiovascular disease. This effect is not associated with an improvement of endothelial function measured by brachial artery flow-mediated dilatation and might be explained by the modulation of calcification through the regulation of calcium and phosphorus concentration in blood [2+ daily for 24 weeks [Mgrtension . The admiac work . The orartension . This reof TRPM7 ,124. An clerosis . In hemoin blood . In disa24 weeks ,127.2+ status lowers blood pressure, corrects lipid profile and ameliorates the control of glycemia, it is not surprising that Mg2+ supplementation has positive effects in MetS. The supplementation of 380 mg of Mg2+ for 16 weeks improves MetS by reducing blood pressure, hyperglycemia, and hypertriglyceridemia [2+ on the lipid profile is still debated and appears to be mediated by the improvement of insulin resistance and appears to be present only if Mg2+ supplementation corrects a previous deficiency [2+ in healthy normomagnesemic young men with a family history of MetS does not show beneficial effects on blood pressure, vascular function, and glycolipid profile [2+ administration is only registered if the supplementation corrects a condition of hypomagnesemia.Since correcting Mgeridemia , becauseeridemia . The effficiency . The adm profile . For Met2+ supplementation in the treatment of MetS, T2D, and hypertension. Considering the literature just discussed [2+ varies from 250 mg to 600 mg, with a median of 380 mg  300–500 mg). The time of Mg2+ supplementation ranges between 7 days and six months, with a median of about three months (95% CI 4–24 weeks). Besides, there is no consensus on the type of Mg2+ salt to use. The bioavailability of different Mg2+ salts has been investigated in depth [2+ supplementation. In part, the differences in the bioavailability of Mg2+ salt is due to their different solubility [2+ salts were slightly more bioavailable than inorganic Mg2+ salts, inorganic Mg2+ salts have been administered to patients with interesting clinical outcomes. The choice of the type of Mg2+ salt based on its bioavailability conditions its dosage and the possible side effects, especially as intestinal symptoms of osmotic dysentery [Some critical issues emerge from the analysis of the literature and complicate the interpretation of the data . First, iscussed ,123,124,in depth ,133,134.lubility . Althougysentery  (Figure 2+ deficiency. In metabolic diseases, a low Mg2+ status mainly due to unhealthy diets contributes to generate a pro-inflammatory environment that exacerbates metabolic derangement. Mg2+ supplementation seems to foment the correction of this vicious loop, but at the moment it is hard to interpret whether Mg2+ beneficial effects occur through a direct effect on metabolic pathways or an indirect action on inflammation, or both.Obesity, type 2 diabetes, and metabolic syndrome are intertwined conditions characterized by chronic low-grade inflammation partly attributable to Mg2+ salt and which dosage guarantee better outcomes. In addition, the investigation of microbiota in hypomagnesemic subjects might provide interesting hints and suggest targeted dietary approaches aimed at harmonizing the gut microbial ecosystem. In addition, biomarkers that grant the possibility of evaluating Mg2+ homeostasis should be identified. At the cellular and molecular level, it is important to focus on the role of intracellular Mg2+ in modulating cell function, from the regulation of metabolism to the release of inflammatory mediators.Several important points need to be clarified. At the clinical level, more studies are necessary to define which Mg2+ might represent an inexpensive but valuable tool to contain the occurrence and the progression of these conditions.Considering the worldwide prevalence of obesity, type 2 diabetes and metabolic syndrome, the correction of bad dietary habits and, eventually, the supplementation of Mg


The Chiropractic Academy for Research Leadership (CARL) was formed in 2016 in response to a need for a global network of early career researchers and leaders in the chiropractic profession. Thirteen fellows were accepted competitively and have since worked together at residentials and virtually on many research and leadership projects. In 2020, the CARL program ended for this first cohort, and it is now timely to take stock and reflect on the achievements and benefits of the program. In this paper we present the structure of CARL, the scientific and leadership outputs as well as the personal value of CARL for the participating fellows. As a result of the success of the first CARL cohort, organizations from Europe, North America, and Australia have supported a second cohort of 14 CARL fellows, who were competitively accepted into the program in early 2020.The online version contains supplementary material available at 10.1186/s12998-021-00363-8. The Chiropractic Academy for Research Leadership (CARL) was conceived in late 2015 by three senior academics  to identify and mentor talented, promising early career chiropractic researchers in a global network [In late 2015 an international call for applications was launched. Through a competitive process that involved assessments of written applications  and personal interviews, 13 CARL fellows were accepted into the program. Three years later in June 2020, CARL ended for this first cohort and a second cohort of Fellows, CARL II, was accepted using the same procedure.The overall aim of this paper is to report on the process and outcomes of the first cohort of CARL fellows, those participating in the program between 2016 and 2020. Specifically, we aim to describe the content and activities of the three-year program, its scientific and leadership outputs, the contextual and informal impact of the program for the fellows and mentors, and finally the implications for the chiropractic profession.Here we provide an overview of the structure and outputs from the first cohort in the Chiropractic Academy for Research Leadership (CARL) program. A detailed list of outputs can be found in Additional file The CARL program is structured around annual week-long residentials rotating each year between Denmark, Canada, Australia (mentor’s universities) and in connection with relevant international conferences or meetings. The inaugural CARL residential was held in April of 2017 at the campus of the University of Southern Denmark, Odense, Denmark (Hartvigsen); the second was held in April of 2018 at the campus of the University of Alberta, Edmonton, Canada (Kawchuk); the third was held in March of 2019 in Berlin, Germany, prior to the 2018 World Federation of Chiropractic bi-annual conference; and the fourth residential was to be held in 2020 on the campus of the University of Technology Sydney, Sydney, Australia (Adams) but was postponed due to the COVID-19 pandemic. In between residentials, there were regularly scheduled videoconferences for all fellows and mentors as well as numerous teleconferences of sub-groups based on specific research and leadership activities.Problem Solved” session where each fellow presents a challenge or problem to the group, and the group then reflects and discusses potential solutions. Challenges can be work-related or from personal life. Another recurrent session has been collective brainstorming sessions about research and leadership projects where fellows and mentors present and discuss ideas and possibilities often based on existing datasets or upcoming collaborative opportunities. The residentials have also contained substantial periods for working together in groups to develop and advance projects design, data analyses, and manuscript writing. Finally, one session every day has included physical activity ranging from indoor football, Zumba (a recurring favorite) and organized walks through unique areas of the hosting city.The residentials were structured into blocks of guest speakers, group discussions, worktime and common physical activities. Guest speakers have included a range of successful early career and senior academics from different fields who have presented and discussed diverse topics with the fellows such as career planning, work-life balance in academia, women in research, emerging technologies, and research about management and leadership. Some guest speakers have also been from industry including the CEO of a Canadian provincial bank. Group discussions have spanned similar issues but focused at a personal level and in confidence. One recurrent session throughout all the residentials has been the “A CARL publication was defined as a paper published as a result of a collaborative CARL project with at least two fellows and a mentor as co-authors. CARL projects collectively produced 38 international peer-reviewed papers published in 20 different journals with an average impact factor (IF) of 2.582 . A CARL conference presentation was similarly defined, with CARL fellows having a total of 81 conference abstracts accepted . Of the 24 conferences where CARL fellows presented, 10 were national and 14 were international meetings . Six CARL fellows were awarded PhD degrees while participating on the program. Collectively, the fellows received 17 research awards, and 14 new professional academic appointments or promotions were obtained amongst the fellows since their participation on the program (Table it has made me a better person and a better researcher.” CARL fellows discussed gaining confidence as early career researchers (ECRs) and overall personal growth: “CARL has given the individual fellows leadership and mentorship skills to develop into mature academics.”. CARL fellows acknowledged the professional development and opportunities that CARL had opened up for them, advancing their career: “The program has been a catalyst and allowed me to make major leaps in my development in multiple areas, leaps that otherwise wouldn’t have been possible or taken much longer to achieve.”. Overall, CARL was seen to be valuable for the chiropractic profession: “CARL has created young leaders for the profession, aspirational role models for the next generation of chiropractic researchers.”.At the end of this three-year program, all fellows were given an opportunity to reflect on the value of the CARL program in writing. Feedback was analyzed and collated by one of the fellows with expertise in qualitative methodology (Holmes). Several themes emerged such as CARL fellows feeling that the program has had a substantial impact on their life: “The program provided support and direction at a vulnerable career stage.”. Many fellows highlighted the difficulties they faced as ECRs prior to CARL, including feeling isolated and frustrated in academia, having a lack of confidence, and doubting one’s self and abilities as a researcher. However, CARL provided a platform for advice, support, celebrating successes, comfort during failures, decision making, and solving challenges: “CARL is the glue that keeps my professional life together”. The support received from the mentors, exceeded fellows’ initial expectations: “CARL has given me the opportunity to learn from research mentors I could only dream of working with”. The fellows reflected that mentors provided research collaborations, individual support, and advice from their own personal academic careers.CARL fellows also appreciated the supportive nature of CARL: “life-long network of peer mentors”, described as one of the most valued benefits of the program. As well as providing advice and support, such network also allowed fellows to engage in new methodologies, broaden their understanding of the chiropractic profession, and to develop new, international research project collaborations. Of equal importance, the fellows also valued the friendship that had emerged from the program: “CARL gave me true friends, who support me not only professionally, but also in my personal life”.In addition, the CARL fellows valued the personal relationships that had developed between them while participating on the program – providing a “Upon the completion of the first CARL cohort, we have presented its structure, output and results. The selection of an international group of ambitious and talented ECRs that are mentored together in an innovative, supportive environment, has resulted in significant research and leadership output as well as a coherent and tightly knit network of successful investigators who are realizing their potential as established academics.It cannot be over emphasized that the choice of an academic career places ECRs at risk of vulnerability through isolation and reclusion. Workdays for most involve substantial teaching loads, academic administration, reporting, and corresponding with limited time and flexibility to read, write, collect and synthesize data, attend meetings and conferences, and connect with fellow academics from diverse backgrounds. Consequently, academics, and especially those in the early stages of their careers face substantial challenges with respect to job progression, performance pressure, high expectations and imbalances between work and life outside of work. Added to these challenges are additional issues for those CARL Fellows who are women, minorities and/or who lack chiropractic peers at their home academic institutions. All of these factors combine to create tremendous pressure on ECRs who must be highly successful to compete for a decreasing number of available academic positions in competition with other highly qualified candidates  all whilWhile the CARL program cannot solve all issues faced by chiropractic ECRs (no one initiative can aim to do so), it does nevertheless facilitate opportunities for participants to share challenges balancing research and teaching obligations and to establish their own global network of support, which is typically unavailable in just one institution. Such a network helps fellows increase their research productivity and strengthen their chances of advancing to a mid-career, senior and leadership position/role.Although building a network of peers may be possible within a group of motivated ECRs, mentorship is a vital component of the success of CARL fellows as there are relatively few senior academics in the profession and likely fewer in close proximity to ECRs. An effective mentorship relationship includes both career support and psychosocial support , with boIn addition to growing the research capacity of the chiropractic profession, CARL can also be a catalyst that nudges chiropractic towards a mainstream evidence-based model of healthcare that is integrative and collaborative across medical and allied-health settings. Brosnan describes these types of academic outputs as social capital, which can impact the construction of professional identity and guide the future direction of the profession . Indeed,Research is the currency needed for the chiropractic profession to claim the cultural authority it seeks to achieve . AccordiNot only has the first 3 years of the CARL program been successful in terms of tangible output and metrics, the program has been able to raise support for its next cohort, CARL II. Importantly, sufficient financial resources are a prerequisite for CARL as ECRs would not have the individual funding to be part of this network otherwise. In addition to retaining the original partners and sponsors of the first CARL cohort of fellows, other sponsors have now also joined in supporting the program and securing the next 4 years of CARL residentials and initiatives. These resources also indirectly help the CARL I cohort to stay involved with the program and create opportunities for them to directly increase research capacity and thereby expanding the CARL footprint. Although the challenges of COVID-19 have delayed plans to have a transition meeting between the two cohorts, the possibility remains of not only involving CARL I fellows in the mentorship of CARL II fellows, but also the possibility of employing CARL I fellows as an additional resource to mentor other ECRs in their local jurisdictions.While resources for CARL II are in place for the next 4 years, the recent challenges of COVID-19 have meant in-person annual residentials let alone attend international meetings have not been possible throughout 2020. Presently, adaptation to the COVID-19 challenge has resulted in more regular virtual meetings as well as scheduled virtual drop-in sessions for CARL fellows to remain in more frequent contact. Intermediate residential strategies are also planned which will allow fellows in the same geographic region to connect in person  prior to being allowed to travel further afield to international meetings.The first cohort of the CARL program have met at yearly residentials and more regularly via videoconference. CARL has significantly contributed to the global research capacity in chiropractic through publication of original scientific papers, conference presentations, and leadership activities. Many CARL fellows have completed PhD theses, achieved employment in or promotion to new academic positions, and have attracted significant competitive research funding. Importantly, the CARL fellows have become a tightly knit, supportive group of successful and highly capable early career researchers who have the potential to further grow and shape the global research agenda for chiropractic over future decades.Additional file 1. Detailed list of journals where CARL publications have been published and/or submitted as of July 1, 2020.


Unmanned aerial vehicles (UAVs) have become a very popular way of acquiring video within contexts such as remote data acquisition or surveillance. Unfortunately, their viewpoint is often unstable, which tends to impact the automatic processing of their video flux negatively. To counteract the effects of an inconsistent viewpoint, two video processing strategies are classically adopted, namely registration and stabilization, which tend to be affected by distinct issues, namely jitter and drifting. Following our prior work, we suggest that the motion estimators used in both situations can be modeled to take into account their inherent errors. By acknowledging that drifting and jittery errors are of a different nature, we propose a combination that is able to limit their influence and build a hybrid solution for jitter-free video registration. In this work, however, our modeling was restricted to 2D-rigid transforms, which are rather limited in the case of airborne videos. In the present paper, we extend and refine the theoretical ground of our previous work. This addition allows us to show how to practically adapt our previous work to perspective transforms, which our study shows to be much more accurate for this problem. A lightweight implementation enables us to automatically register stationary UAV videos in real time. Our evaluation includes traffic surveillance recordings of up to 2 h and shows the potential of the proposed approach when paired with background subtraction tasks. However, their viewpoint is not constant over the course of a video. Using off-the-shelf background subtraction (BGS), comparing object trajectories on such flux is, at best, tedious  have gained popularity within the past few years as a means of acquiring data in a number of tasks ,2. In paIn , we propIn our work, video registration must be understood as the action of keeping the background content of the video stable over the course of a video. Our application purpose includes traffic surveillance from stationary UAVs, where many objects may enter and leave the field of view. Therefore, we cannot expect the existence of a dense mapping between every pixel from one video frame to one another, including foreground pixels, as in the case of the registration hypothesized in .Our problem is to estimate an image transformation that optimally compensates for camera motion. When a significant part of the image  is available throughout the video sequence, we can estimate this transformation between any current frame and a reference image. This is the video registration approach. A stabilization approach does not usually make such an assumption. In this scenario, the camera may change angle and even content over the course of a sequence, and the goal is to remove shakiness, as is often the case with hand-held devices. Under such circumstances, the image content, including the background, is not necessarily consistent over time. The typical approach can be understood, very roughly, as primarily estimating a trajectory, which is defined as a combination of short-term inter-frame motions. This trajectory is then filtered to generate a smooth trajectory. Finally, the image is re-projected to follow the desired, stable trajectory ,9.Other techniques are designed to determine the camera position and orientation, such as Structure from Motion (SfM)  or SimulIn the case of a stationary UAV, we may assume that a background is constantly visible over the course of a sequence. Therefore, this results in a situation in which both registration and stabilization techniques apply and should ideally provide similar results.The straightforward application of registration techniques has been reported to generate a high-frequency noise, referred to as jitter, in previous studies ,13,14. FStandard stabilization techniques ,9 have bMost of the previously cited works about camera motion compensation state that this problem is made increasingly difficult by lighting and content changes. These phenomena are almost impossible to avoid with longer video sequences, especially in scenarios such as traffic or crowd monitoring which feature numerous mobile objects. In our case, the use of tethered drones, which allows virtually unlimited flight time, has emphasized the need to address those issues. Based on our observations, stabilization techniques have shown limitations when registering video sequences longer than several minutes. Despite progress in designing efficient and robust motion estimators, such as in , computaIn , we propIn both cases, stabilizing or registering a video is the action of compensating for undesired camera motion while preserving the image content variability over time.This compensation is performed using an image alignment; that is, a warping operation applied to an image so that it matches the view of another image.Let es (TPS) , homograes (TPS)  are bijeLet We can also define the inverse transform Suppose that we want to register two images i and Let us align every image in the video sequence to a reference frame denoted as  a video  may be eOne issue is that performing frame-to-frame alignment in this fashion does not take into account temporal coherence. Most camera movements are compensated, but an additional high-frequency noise, referred to as jitter by the authors ,13,14, tJitter in video is avoided by the use of stabilization techniques.i, Stabilizing a video is typically a problem of smoothing the observed camera movements over the course of a video. Although not always explicitly described this way in the literature, we can model it by constructing a short-term trajectory; by a short-term trajectory, we mean a series of transforms that is representative of recent motion relative to the background in the video. We define a trajectory as a series of warping transforms:We define A stabilization solution aims at removing the high-frequency motion, considered as noise, from the trajectory. It requires the definition of a filter that is able to smooth trajectories.This kind of filter is a function In an online context, the filter can only use trajectory elements from the previous and the current frames, meaning that i, we first cancel the observed trajectory To stabilize the video at frame Tws˜n,i) :(3)ws(i)While not designed to register to a constant background over the course of a video, this approach is effectively designed to remove high-frequency motion relative to the background.Note that when In this section, we adapt the method presented in  to the mThe general idea is to assert the existence of a unique transform A range of registration methods, either holistic  or sparsFollowing Equations  and 4),,4), we hFollowing Equations  and 4),,4), we hAssuming that camera movements are such that a constant background is consistently available over the course of the video, we have, by construction,For instance,When The attractiveness of this model lies in the fact that the nature of the terms The more dissimilar Designing a robust registration or stabilization technique in the presence of a constant background is therefore equivalent to estimating quations  and 6)..Ewr˜ are a much more accurate model than 2D-rigid transforms. They are also represented by 3 × 3 matrices, and they are defined up to a scale factor. However, multiplying such matrices does not guarantee that we can stay within the group of homographies. Interpolation (needed for filtering) should also not be performed directly on 3 × 3 matrices.One can represent homographies by associating two sets of ordered quartets of 2D points. We used this to compose and interpolate between homographies. Every element of isserman , degradeWe now need to define how to compose and interpolate between homographies. Composition is performed as follows: let Interpolation is performed by applying a unique coefficient to the displacement of all four corners. Interpolating between homographies implies that every intermediate position between two homographies stays within To lower the risks of falling into a degraded case, we need to prevent the series of transforms from diverging infinitely. For this reason, we need the term δ in  to be noNote that representing homographies as a set of corner displacements is only used to allow operations such as inverting, composing and interpolating between elements of To evaluate our method, we used 10 RGB, 1080p (Full HD) video sequences, of which the shortest eight had already been used in . Most seWe used the OpenCV version 4.3 library  and C++ In both 2D-rigid and perspective cases, images were set to one-channel grayscale and resized to 576 × 24. Motion estimators  corners  and used corners  as a tras converted into a logarithmic scale, meaning that the KF worked linearly with this parameter.For 2D-rigid transforms, all tracked points were used to compute For perspective transforms, we used all tracked points (at most 200 following the LKPOF method) and the robust estimators implemented in OpenCV to generate homography matrices. Consecutive transforms were implemented by using the non-parametric least median algorithm, while the registration transforms were implemented by using RANSAC, with the error and threshold parameters set as default following the OpenCV implementation. The reason why we used different estimators between both motion estimations is that the KLT approach performed on consecutive images at 30 fps produces few outliers, allowing the least median robust estimator to be efficient while computationally less expensive. Meanwhile, the estimator used to compute In both cases, our implementation used CPU-only operation and ran at a minimum of 60 fps, on a 2.5 Ghz Intel Core i7 MacBook Pro. This enabled real-time operation and left room for further processing analysis.None of our experiments seemed to indicate a particular sensitivity towards a given set of parameters.Raw: the original, unprocessed video.StabKalRig : the video stabilized by the algorithm described in Equation : the video registered by the algorithm described as i, in the 2D-rigid (or the 2D homographies) domain.RegKalRigid : the video registered by the algorithm described as CombiRig (or CombiPer): the proposed combination method, as described in To show the benefits of the proposed combination, we have compared it with different arrangements of its elementary components, in both 2D-rigid transforms and homography configurations. The following settings were evaluated:It is necessary to quantify two different properties: the registration (the ability of a solution to remain registered to the same viewpoint), and the stability (the ability of a solution to avoid background motion). Lacking the ground-truth for camera movements and the image content, we used the same protocol as in  as a basfd) measure, which consisted of measuring the median displacement of a set of feature points tracked from the reference frame to the current frame. In practice, we tracked 200 Shi–Tomasi corners through LKPOF, following the KLT approach. To reject the worst outliers, the measure was performed using only the 100 best points according to their matching score.Registration properties were evaluated with the frame displacement (mpvd), which consisted of measuring the evolution of pixels’ grayscale intensity between consecutive images. In practice, we warped frames according to the evaluated setting; then, we calculated the absolute difference between consecutive frames, pixel by pixel, thus forming a new image. The mpvd measure consisted of computing the average pixel value on this differential image, only within the area where both warped consecutive images were overlapped. This measure was computed on 8-bit images converted to floating points, and thus ranged from 0 to 255. Our assumption was as follows: when the video is stable, only mobile objects should cause pixel values to change significantly from one frame to the next one; when the video is unstable, the intensity values of a significant part of the pixels from the background may change in addition to foreground objects, causing this measure to increase.Stabilization properties were evaluated through a measure called the mean pixel values difference (fd (or mpvd) measure.In general, better registration (or stability) was found with the lowest fgr, fused both stability and registration properties. When the video was correctly registered—i.e., the background was stable—only pixels related to foreground motion were classified as foreground. When the background drifted or was shaky, pixels from the background may also have been wrongly classified as foreground. Thus, we believe that, in general, the lower fgr is, the better. This measure shows the relevance of different registration or stabilization approaches in an applied context. For this measure, and because of its computational efficiency, we used ViBe [fgr was only used complementary to mpvd to measure stability properties.In addition to the evaluation protocol available in , we propsed ViBe  without fd measure for all tested videos. As anticipated, stabilization approaches  performed poorly. All of the tested 2D-rigid registration techniques  displayed comparable results on relatively short sequences with little camera motion, such as “C0”, “C1” and “M2”.First, we must assess how the tested methods remained registered to an initial viewpoint. The results in fd measurement was globally lower on registration methods in the perspective domain, such as RegLPosPer, RegKalPer and foremost the proposed combination of CombiPer. For our dataset, 2D-rigid transforms were not expressive enough to compensate for camera motions. In both cases, a filtered registration  suffered from the inertia and sometimes even strong divergence , that occurred when the optical flow algorithm was badly initialized, and it could not track enough points to provide a good registration. It is also important to note that the use of a gimbal, as in L2, did not provide viewpoint registration. With the fd indicator, results for the L2 raw video were remarkably similar to those obtained with software stabilization. On all tested videos, when the proposed method could not provide the best performance, it was well within a subpixel range from the best solution. The same can be stated when only using rigid transforms, as in [fd indicator on the longer sequences of the database. On those figures, we can observe the significantly improved stability of the proposed method over time. As shown by a linear regression on the various curves displayed, the proposed combination in the perspective domain was remarkably stable, although following a slightly increasing slope. The trend is however much more stable than other tested approaches, which the results suggest to be more affected by noise. However, the s, as in , even wimpvd indicator. Results emphasize the effect of jitter, with registration solutions (both in rigid and perspective cases) performing even more poorly than the original video on longer sequences, including MFull and L2. Filtered registration techniques , even when diverging, provided better stability performances. Meanwhile, stabilization techniques displayed significantly better performance, with a slight overall advantage towards homographies. Results for L2 show that even a video acquired from camera mounted on a gimbal in a stationary flight can be positively affected by software stabilization. The proposed combination, especially when using perspectives, was the most consistent solution of all, suggesting that it is jitter-free and driftless.fgr using a baseline background subtraction algorithm, ViBe [The last proposed evaluation showed the impact of our approach in an applied context. hm, ViBe . ViBe pafgr to its 15 min subsets M1, M2, M3 and M4, while the other competing registration methods tended to output a higher ratio for the full sequence than for its subsets, suggesting that jitter tends to increase over time  was used to smooth what can be understood as the difference between a short-term trajectory and a long-term registration. After the short-term trajectory was updated with a new frame, the KF allowed us to predict where to initialize the next registration estimation. Since a motion estimation step is essentially a minimization problem, a better initialization means a more efficient and accurate estimation. Another advantage of our method is its ability to handle the temporary disappearance of the background provided in the reference frame . When the registration estimation is unable to converge, we can set it as the identity of the proposed combination. Under this circumstance, our approach is still capable of staying registered to the initial viewpoint by relying on the short-term trajectory inversion. One drawback of the proposed hybrid combination is that we always assume that the short-term trajectory estimation produces a low-magnitude, slowly evolving error term. If the short-term trajectory happened to generate a high-magnitude, high-frequency noise, our method would be likely to fail, since it would be unable to differentiate the error terms caused by registration and stabilization, respectively. One way to avoid this is to work with high fps video acquisition. The more similar consecutive images are, the less likely erroneous short-term trajectory estimations will be. For real-time application, this may imply that the end-user has to find a trade-off between frame-rate and resolution.Although our evaluation shows that we can properly handle video sequences of up to two hours, significantly longer sequences remain a challenge that still needs to be addressed. In our approach, we can compensate noise in the registration step by filtering out its corresponding motion estimation. This step relies on the assumption that this estimation is, although very noisy, averagely accurate. This assumption may not hold when drastic appearance changes occur; for instance, when we try to register a night view from a scene that was initialized in daylight. More sophisticated motion estimation techniques can be integrated in the general scheme of our approach and may prove helpful to tackle this kind of challenging situation. Another approach might be, in this case, to design a reference frame-updating procedure. In future works, we will focus on this challenging situation.


Along with the recent growth of Internet of Things (IoT) security camera market, there have been a number of personal information leakage incidents from security attacks targeting such cameras. Therefore, a permutation-based video encryption algorithm was proposed to secure video streams in low-performance processors such as IoT security cameras. However, existing permutation-based video encryption algorithms are vulnerable to known-plaintext attacks since they use the same permutation list for every frame. Moreover, situation deduction based on the color composition is possible. In this paper, we propose a new permutation-based video encryption algorithm that updates the permutation list for every frame using a crypto secure pseudo-random number generator without significantly increasing memory usage. By doing so, the algorithm becomes robust to known-plaintext attacks, which has been a common problem with existing permutation-based video encryption algorithms. In addition, color channel separation can prevent attackers from deducing situations through color composition. Pre-compression encryption is applied to make the algorithm robust to data loss because of packet loss. We implement the proposed algorithm and conduct an experiment to show its performance in terms of probability of data loss because of packet loss, encryption speed, and memory usage. Internet of Things (IoT) security camera is a type of IoT sensor device that captures video from a place in need of surveillance and streams it to outside users in real time . Since aIoT security cameras use a low-power processor because they should always be activated . The lowTo solve the massive processing overhead problem of video stream encryption using a block cipher algorithm, Liu and Koenig  proposedIn this paper, we propose an improved permutation-based video encryption algorithm that has low processing overhead and high security. To avoid a known-plaintext attack, which is a common problem with permutation-based video encryption algorithms, the proposed algorithm updates the permutation list for each frame using crypto secure pseudo-random number generator (CSPRNG). In addition, the proposed algorithm improves security through separate color channels.Block cipher-based video encryption algorithms that work on lightweight protocols  and constrained application protocol (CoAP) ) have beTo address the processing overhead problem, a hardware-based AES encryption mechanism has been proposed in . Here, aA permutation-based video encryption algorithm encrypts video by permutating a specific part in the frame with another specific part. Video frame data includes a significant amount of pixel information. Thus, recovering the original location of all pixels is almost impossible. For full high definition (FHD) resolution, which is mostly adopted for multimedia contents, a frame includes The encryption speed of permutation-based video encryption is much faster than the block cipher-based encryption. Generally, the size of video data is significantly larger than text data. Block cipher-based encryption brings high overhead since it performs an operation at the same part of data repeatedly. Thus, adopting block cipher-based video encryption on real-time video streaming is practically impossible. Permutation-based video encryption algorithms do not perform permutation at the same part of data repeatedly. Thus, it can encrypt video with lower overhead than block cipher-based video encryption.The position of the encryption algorithm classifies the permutation-based video encryption algorithms see . A videoLiu and Koenig , SultanaThe algorithm proposed by Liu and Koenig is a post-compression encryption algorithm that separates a compressed video frame into blocks of a specific size, and then permutates them to encrypt videos . Since tThe algorithm proposed by Sultana and Shubhangi  is a preIn this paper, while maintaining the efficiency of existing permutation-based algorithms, we propose a robust permutation-based video encryption algorithm for known-plaintext attacks, which is a common vulnerability of such algorithms. CSPRNG is used to update the permutation lists for each video frame. Instead of generating a permutation list for each frame, the random values generated by CSPRNG are added to the permutation list used in the previous frame. Accordingly, we can solve the problem of key exchanging and permutation list generating overhead, a weakness in Liu and Koenig’s algorithm . In addiThe proposed algorithm was based on the permutation-based video encryption mechanism; it included a permutation list management module to resolve the vulnerabilities of the previously proposed permutation-based video encryption algorithms, and a video processing module to improve security. The permutation list management module stores and updates the permutation list for each frame using CSPRNG. The image processing module performs the permutation on the video frame, including color channel permutation and pixel permutation, using the permutation list. The communication module performs the seed exchange and the cryptographic video frame exchange.The jumble lightweight video encryption algorithm (JLVEA) encryption module includes a seed management module, a permutation list management module, an image processing module, and a communication module see . The seeThe seed management module includes a hardware random number generator (HRNG), seed storage, and RSA encryption/decryption module see . The seeThe permutation list management module includes CSPRNG and permutation list storage see . CSPRNG CSPRNG updates the permutation list (see Algorithm 1). The minimum and maximum updated values are determined by the row and column length of the video frame. If the updated elements of the permutation list are negative, the maximum value is added. If they exceed the maximum value, the maximum value is subtracted. This brings the new values within the matrix size range of the video frame. CSPRNG is set to follow a continuous uniform distribution. This ensures that the elements of the permutation list are not concentrated in a specific range. The permutation list following the continuous uniform distribution can encrypt all frames to a similar level since the distribution characteristic is maintained after the permutation list is updated. By having the CSPRNG update the permutation list, updating the permutation list for every frame without using additional memory becomes possible.Algorithm 1: Permutation List Update.w, height h, and permutation list PInput: Frame width Output: Updated permutation list Pp in P do01: for p % 2 == 0, then02:    if index of r = random03:     04:    else, thenr = random05:     06:    end ifp = p + r07:    p % 2 == 0, then08:    if index of p > w then09:     if p = p – w10:      p < 0, then11:     else if p = p + w12:      13:     end if14:    else, thenp > h, then15:     if p – h16:      p < 0, then17:     elseif p + h18:      19:     end if20:    end if21: end forThe image processing module loads and performs matrix permutation on the video frame using the permutation list. Before matrix permutation, the color channels are separated, and matrix permutation for each channel is performed. The permutated channels are then merged to produce the final cryptographic video frame. Owing to the separated color channels and a different matrix permutation on each channel, an attacker cannot verify the color composition of the original video frames. The communication module exchanges the seed and encrypted video stream with other devices.The encryption and streaming process can be divided into five phases: connection establishment, video stream encryption, transmission, video stream decryption, and permutation list update see . The serThe proposed algorithm is designed to be robust to known plain-text attacks by applying different permutation lists to all frames. If the encryption module creates a new permutation list for each frame, the permutation list updating process may result in storage and processing overheads. The proposed algorithm is designed to increase storage space and speed efficiency, and to be robust against known-plaintext attacks by updating the permutation list using CSPRNG instead of pre-generating the corresponding permutation list for each frame.For the JLVEA encryption module’s performance evaluation, we first implemented it and then performed a security analysis, encryption speed analysis, and memory efficiency analysis. The proposed algorithm along with Liu and Koenig’s  and SultIn order to analyze the security of the proposed algorithm, the video frame encrypted with the algorithm of ,15 and tThe original frame has its own color composition according to the information contained within the frame. In the case of encrypted frames, the original color composition was completely removed by color channel separation and recombination. If the encrypted frame has a color composition similar to the original frame, the attackers may deduce some information in the original video frame, such as whether someone resides at their home or not. This experimental result shows the difficulty of information deduction based on color composition on the proposed algorithm. See The permutation list also has a critical impact on security. The proposed algorithm can generate 47,483,761,585,029,120,000 different permutation lists. It takes 55 days to generate all permutation lists with a 10 TFlops computing machine. Moreover, since the frames encrypted by the proposed algorithm did not include internal file structures such as header markers or EOFs, it was not possible to automate the verification that they have been normally decrypted. It means all 47,483,761,585,029,120,000 frames reassembled through a brute-force attack must be verified directly by humans. Therefore, it was practically impossible to decrypt frames encrypted with the proposed algorithm through a permutation list brute-force attack. The attacker could deduce the permutation list if the attacker would succeed to extort an encrypted frame and the corresponding original frame. However, even if the extortion happens in the proposed algorithm, the attacker cannot decrypt the next frame because it does not use the same permutation list used for the previous frame. Liu and Koenig’s algorithm  can geneThe seed should be strongly protected to ensure the security described above. Seed exchange was conducted only once for the whole encryption process. Thus, we adopted a public key infrastructure-based key exchanging mechanism to exchange the seed without considering the encryption overhead. We could use security proven algorithms such as RSA  or ECDSAWe compared the encryption time of the proposed algorithm, Liu and Koenig’s algorithm , and SulWe compared the memory usage of Liu and Koenig’s algorithm , the proWe simulated a packet loss scenario to check how many frames became unrecognizable in post-compression encryption algorithms and pre-compression encryption algorithms see . Liu andIn the proposed algorithm, a part of the video frame was misplaced or lost because of packet loss. However, the contents of the video frame can be fully recognized. These experimental results show that post-compression encryption algorithm for real-time video streaming was vulnerable to packet loss. On the other hand, the proposed algorithm could recognize the content of video frame except the lost parts even when some packets are lost.In this paper, we proposed a lightweight permutation-based video encryption algorithm to encrypt and transmit a video steam in real time on low-performance devices, such as IoT security cameras. Based on the permutation-based video encryption mechanism, we proposed an improved algorithm for a higher encryption performance than block cipher, while also being robust against problems such as known-plaintext attacks, header inference, and packet loss vulnerability from previously proposed permutation-based video encryption algorithms. Using CSPRNG, we solved the known-plaintext attack vulnerability by creating a new permutation list for each frame, and achieved a high security level through color channel separation, making it more difficult to deduce the contents of the video frame. Moreover, a permutation-based encryption was applied before compression so that the content of the original video frame could be recognized except for the lost part, even with packet loss during real-time video streaming. In the future, we would like to conduct further studies with the aim of minimizing the increased encryption time to the level of post-compression encryption algorithms.