Humanity is sporadically subjected to leaders with deviant behavior, ego problems, or psychiatric disorders, potentially leading to social instability. Bipolar disorder is not common in all populations, but, coincidentally, studies suggest that it affected two sovereigns that were contemporaries, King George III of England, who died 201 years ago, and Queen Maria I of Portugal, who died 205 years ago. They lived during a time when Europe was in turmoil with the French Revolution and Napoleonic Wars, which also coincided with the rise of psychiatry. Both monarchs were forced to have prince regents rule in their place, due to their emotional decline, and they shared the same medical consultant, Francis Willis. Indeed, insanity and politics are often intertwined.The mental health of some unusual monarchs, prime ministers, presidents, and political leaders in general has been questioned, and others were unmistakably mentally ill, potentially threatening their nations’ stability.As with the general population, much of the insanity in political leaders is influenced by genetics, which is most tragic when these leaders occupy hereditary political positions.Thus, when monarchs develop a mental illness, several steps are needed to remove them from power. We discuss two such late 18th-century/early 19th-century sovereigns of nations with close political relations.George III of England, the “Mad King,” died 201 years ago. Four years earlier, Queen Maria I of the United Kingdom of Portugal, Brazil, and the Algarve, the ‘Crazy Queen’, passed away. Both monarchs were 81 years old at the time of their deaths and there were many other coincidences with repercussions for three countries .In the late 18th and early 19th centuries, it was not possible to make proper psychiatric diagnoses and treat sidelined sovereigns during their own lifetimes. Both the monarchs discussed here have been assumed to have suffered from bipolar disorder (BPD). They also shared the same attending physician, Francis Willis.This article raises questions concerning the two monarchs’ mental symptoms and the impact of their physician’s immersion in the medical knowledge of the time. These issues belonged to an age of turmoil in Europe.Monarchs turn their daily exercise into a grand dramatization, in a balancing act of power through their titles, medals, and privileges. As gifts bearing the leader’s image, these monarchic rituals help foster reverence and extend the monarchs’ own personalities, hovering high over their subjects’ heads.In a monarchy, if psychological instability arises within the court, the natural substitution within the family hierarchy begins to be articulated. Even if the probable succession favors an older child, court dealings may always happen.Prolonged mental illness in a monarch can have psychological effects on his or her subjects, besides arousing interest among successors and members of the court.A leader is expected to guide the people, show the way, and determine the nation’s political scenario. Thus, unstable and psychologically compromised behavior with evident loss of control tends to result in the leader becoming discredited and losing the ability to remain in power.Political leaders are not replaced this way in democratic systems, which require constitutional provisions to ensure substitution in the case of such impediment. Although a leader may appear insane or reckless, more reliable methods to confirm or disprove his or her insanity are required, which was not the case in the late 18th and early 19th centuries, a time when diverse behavioral changes were labeled as madness.George III  inherited the English throne upon the death of his father in 1751. The American colonies gained independence during his reign, which also witnessed the French Revolution and the Napoleonic Wars, which finally ended with Napoleon’s defeat.apudPearce, state that the king suffered from porphyria, a metabolic disease that can affect the central nervous system. These findings were widely covered by the English press, but the main diagnostic hypothesis today would be bipolar disorder.England was shaken by King George’s erratic behavior. Macalpine & Hunter (1969),During George III’s illness, the Prince of Wales was regularly sent letters by his father’s physicians, reporting on his habits and behaviors. There are several reports of the king’s illness. It was noted in 1788 that “His Majesty had become more peevish than he used to be and is agitated and talking incessantly and incoherently.” Later that month, on December 20, the king’s condition worsened still further, because “H.M became so ungovernable that recourse was had to the strait waistcoat: His legs were tied, & he was secured down across his Breast, & in this melancholy situation he was, when I came to make my morning Enquiries.”When the king was stricken by “madness” in the summer of 1788, his condition worsened, and he was finally removed from power after a major mental crisis. To control variations in the king’s behavior, physician Francis Willis was summoned to treat his disorder. As his doctors were unable to explain the king’s illness, false stories about his condition spread.George III was excluded from contact with the people, due to an alleged plot by his son and allies, pressured by a populace with a supposedly insane ruler who was unfit to rule.The English people appeared to be right, because the first criterion for determining an individual’s insanity is to demonstrate that he is unfit for his job. Stories of his mental instability included compliments to a tree as if it were the King of Prussia, causing his physicians to tie him to the bed until he regained calm. Following some improvement, when he was behaving more cogently, he was again deemed fit to rule over his court.The king’s condition worsened over the course of 1788, giving rise to moves to replace him with a prince regent. In November of the same year, he was seriously demented, talking nonstop for hours.If observed today, this behavioral variation would be considered a sign of bipolarity, an element that would make exercise of political power unacceptable in the eyes of the people.Political unrest during the reign of George III was not due only to his psychological instability. Legal aspects of the monarchic regime were also present in the government.In early 1789, the Regency Bill authorizing the Prince of Wales to act as regent was submitted to and approved by the House of Commons. However, George III recovered before the bill was passed by the higher legal and political body, the House of Lords. (House of Commons and House of Lords).The entire search for succession unfolded in a turbulent way in Parliament, with regard to the terms of the regency during the king’s disability. Both of the prevailing political factions agreed that George III’s eldest son and heir apparent would act as regent. One faction was fighting for approval of this legal and political measure by vote in ParliamentMeanwhile, the British were worried by the turmoil of the French Revolution, which had overthrown the French monarchy in 1789. George III increased taxes, summoned armies, and suspended the right to habeas corpus and other legal safeguards, thereby exacerbating the political instability.In 1801, and again in 1804, George III had relapses that further fueled the legal and political turmoil with this psychological component, from 1810 until his death in 1820.Contemporary accounts credit Dr. Francis Willis (1718-1807) for facilitating the king’s recovery from his main episode of acute mania in 1788-89, enhancing Willis’ reputation and expanding his clinical practice.Since Dr. Francis Willis was credited for King George III’s recovery from this serious episode of acute mania in 1788-89, he was summoned to Lisbon to advise on Queen Maria I’s mental health problems. He recommended a moral management policy, psychotherapy, and adequate nutrition rather than medication, and the initial reports were encouraging. However, unlike his treatment of George III, Willis’ role in Maria’s case was merely advisory, and the queen’s prognosis may have been worse than that of George III.Willis was awarded his medical degree at the University of Oxford in 1759. He was successful in treating the mentally ill and even ran a private rural asylum in Lincolnshire, where his patients were encouraged to perform manual labor. The clinic’s bucolic rural setting probably contributed to the patients’ recovery. In November 1788, he was summoned to attend King George, whose behavior was becoming increasing erratic. With Willis’ methods, the king’s mental health improved slowly but remarkably .3,12Maria I  was heir to the throne of Portugal. As a woman, for legal reasons, she could only accede to the throne if she married a Portuguese citizen, so she married her uncle, Infant Pedro of Portugal, in 1760.In May 1786, the queen’s husband died, and her condition deteriorated further after the death of her eldest son (1788) and her confessor. The alarming news of the French Revolution may have further contributed to the queen’s mental instability. Her mental disorder left the queen unable to deal with state affairs starting in 1792, when her son, who would later become King João VI, officially served as Prince Regent, from 1799 onwards.The antithesis of Maria I of Portugal was the Marquis of Pombal, a kind of prime minister of Portugal at the time, who tried to have her dismissed when she ascended to the throne. Signs of her dementia appeared two years after the death of her spouse. In 1792, a medical board declared her unfit to rule, transferring the powers of government to her son Dom João (later João VI). In 1799 he received the title of First Regent and later became king in 1816 following his mother’s death.The impact of a “crazy” ruler, plus the opposition led by Pombal (with whose ideas and actions the queen disagreed) was extremely relevant. She was classified as “crazy” but was probably depressed due to several deaths in the family and that of her friend and confessor Friar Inácio.The queen was highly popular, and her demise and removal from power must have had a significant impact on her subjects, with whom she had interacted a great deal.Maria I’s mood swings may explain why, having subjected the Marquis de Pombal to an inquiry to investigate his alleged illicit enrichment and excesses committed in his Ministry, she nevertheless forgave him without further consequences. In August 1781, Pombal was indicted and merited exemplary punishment, but the queen did not order further proceedings due to her serious illness and decrepit state. Queen Maria I issued a decree pardoning the former minister while ordering him to be kept 20 leagues from the court, but maintaining his salary as secretary of state and awarding him the Commendation of St James (São Tiago).Would such dualities be signs of bipolarity, a mental disorder unknown in the early 19th century? How might these mood swings have impacted Maria I’s decisions as Portuguese sovereign?From 1792 on, Dom João ruled Portugal as Prince Regent and his mother’s psychological instability no longer interfered in government affairs. In 1807, in response to the French Revolution, which had started in 1789 and was already threatening to affect Portugal, Dom João decided to flee Portugal with his entire court, landing in Brazil in January 1808. Dom João legally transferred the administration of the Kingdom of Portugal to Brazil, which became the kingdom’s official seat.Maria I and two of her three sisters (Mariana and Dorothea) had similar symptoms of the same mental disorder. Mariana died at the age of 77 in Brazil, and Dorothea at the age of 32. The Queen’s son, Dom João/João VI, also suffered from episodes of melancholy.Queen Maria I  became Bipolar disorder was not known as such in the 18th and early 19th centuries, but both monarchs apparently suffered from this mental disorder, classified as “madness” due to the limitations of prevailing medical knowledge. Regardless of the type of disorder, a monarch’s health or illness is an important psychological factor and thus a predictor of their own stability and that of their kingdom. Psychological, legal, and political factors are intrinsically intertwined in this scenario.Bipolar disorder affected two sovereigns, contemporaries, who underwent the generic treatment imposed on mental patients at the time by the same attending physician, but with serious limitations to its effectiveness.Queen Maria I of Portugal had worse prognosis than King George III of England and responded less to specific recommendations from the same physician. Worthy of note is the high degree of consanguinity of the Portuguese royal lineage, which resulted in marked family incidence of mental illness.In conclusion, with regard to concerns of State, monarchies have an appropriate hierarchy to respond and adjust when the sitting monarch displays mental incompetency, as occurred with George III and Maria I.


There is also growing recognition of the reversal of relative age advantage, a phenomenon that sees significantly higher numbers of earlier born players leaving talent systems before the elite level. However, there has been little investigation of the mechanisms that underpin relative age, or advantage reversal. This paper aimed to investigate (a) the lived experience of relative age in talent development (TD) systems, (b) compare the experience of early and late born players, and (c) explore mechanisms influencing individual experiences. (2) Methods: interviews were conducted with a cohort of near elite and elite rugby union players. Data were subsequently analysed using reflexive thematic analysis and findings considered in light of eventual career status. (3) Results: challenge was an ever-present feature of all players journeys, especially at the point of transition to senior rugby. Psycho-behavioural factors seemed to be a primary mediator of the response to challenge. (4) Conclusions: a rethink of approach to the relative age effect is warranted, whilst further investigations of mechanisms are necessary. Relative age appears to be a population-level effect, driven by challenge dynamics. Effective and efficient talent identification and talent development (TD) processes are a significant part of the strategic management of TD systems. Increasing curiosity and investigation of such elements is a significant challenge for many national governing bodies (NGBs). TD systems are under increasing scrutiny, with data challenging established paradigms in relation to many TD dynamics . Of signOne such factor suggested as underpinning these selection biases is the relative age effect (RAE) ,8. The iExplanations for these effects have tended to focus on advanced physical maturation offering relatively older individuals up to 12 months advantage over their relatively younger peers ,10. LessThe orientation for the majority of RAE literature in sport has led to a focus on the potential negative effects age groupings have on the identification of individuals and their experiences . These sMore recently, the literature has challenged these assumptions and has begun to report a potential positive that emerges from the attritional and/or challenging experiences of the relatively young. This has separately been identified as the ‘underdog hypothesis’  and ‘advThis would suggest that the current literature base is limited by some key assumptions and by a lack of mechanistic focus. Those who are born earlier in the selection year are more likely to be selected for a TD system. It also appears that, at the population level, their relatively younger peers are more likely to continue through the TD system to elite performance. Yet, to this point, much of the extant literature has focused on ‘solving’ a variety of early advantage effects by focusing on levelling the playing field, for example: bio-banding ; age ordMotivation is a significant factor in sports participation, progression and drop out ,32,33. OAccordingly, there appears to be increasing evidence pointing to the interaction of challenge and psycho-behavioural skills ,38,39. TReflecting these complexities, and beyond establishing RAEs and consequently advantage reversals in different contexts, there is a need to understand the mechanisms at play . This isGrounded in the real-world factors covered in our introduction, alongside our desire to deepen knowledge in RAE for practical purposes, a pragmatic philosophy was adopted for the present study . The priBased on the aims established in our introduction, including the need to move understanding of RAE beyond statistical phenomena, an interpretivist epistemology and qualitative strategy were selected for the present study . More spTo explore experiences of the RAE, eight male players who had entered the academy system in English Premiership rugby union and reached the transition point to the professional game  were purposefully sampled via the contacts of the first author. At the time, he was an Academy Director at a professional club. To avoid the risks of collecting data overly influenced by situational factors, participants were also selected on the basis that they had gone through the academy system across various periods of time . As such, data were collected from participants who had transitioned out of the academy programme at different times over the course of eight seasons. For sufficient comparison of experience (as per our third aim) individuals were also identified on the basis that their birthday was at either end of the sport’s selection year .N = 8) and actively involved as professional players either at an English Premiership (if retained) or Championship team (if released after reaching the end of the academy phase). Details relating to each specific participant’s birth quartile, initial, mid and overall career status (the latter using criteria from two) are provided in At the time of interview, all players were aged between 21–32 years of age  and the fourth quartile (N = 4), players were further grouped according to initial career status  from each birth quartile.Following data collection, all interviews were transcribed verbatim and analyzed using QSR NVivo software. Coherent with our desire to understand lived RAE experiences, plus the meanings attributed to this by participants, a reflexive thematic analysis (TA) was chosen as the specific analytic strategy . SimilarBased on the established TA process , analysiAs well as the approaches detailed in Regarding data analysis, trustworthiness was enhanced by the first author’s use of a reflexive journal to document methodological and analytical considerations, the rationale behind decisions, and the interaction of the research team’s assumptions and biases . In addiAddressing the first aim of the study and considering the different experiences of challenge through the pathway for each participant, Across the sample it appeared that, regardless of birthdate in the selection year, there did not appear to be a pattern in the volume or intensity of the challenges faced on the journey to the professional game. Importantly however, this did not appear to be the case for players that were subsequently released. It appears that players born in Q1 and subsequently released experienced a challenge-free journey prior to academy entry at 16 years of age. Players born in Q4, and subsequently released, plotted their experiences in a similar manner. This contrasted significantly with the experiences of retained athletes with first and fourth quartile birthdates, who plotted a consistent series of bumpy challenging experiences prior to and through the academy system.As athletes progressing through the talent system, all identified a variety of challenges such as selection dynamics, peer to peer competition and increased stress from managing competing demands. Many of these challenges were associated with maturation dynamics. For example, consider the experience of these retained players:I was tiny between 14 and 16. When I turned up at the academy at 16, I was 70 kg and still very small…I was always very small all the way until I was 16 or 17, that was when I actually really grew… I would never be able to physically dominate anyone at all. The only hope I had was to use my feet and pace which I think really, really helped and it’s probably why I ended up at 9 I think (Player 1: Q1—Retained).It was only the fact that at 18 or 19 I found a bit of pace that kind of gave me that X factor to try to compensate a little bit for not being the strongest or the most physical. Physicality is one thing that has always been brought out with me in any review (Player 2: Q1—Retained).I wasn’t physically muscular I don’t think I was strong I think compared to the others but I was quite tall and slim but I wasn’t massive, I don’t think I stood out from the crowd in any manner I was just a bit taller or you know probably in the top third of height—things like that at that age (Player 7: Q4—Retained).For all eight participants, awareness of maturational status was a significant feature of their journey. These perceptions were emotionally laden and appeared to influence a wide range of behaviours. Despite self-identified, later-maturing players being present across quartiles, those who were retained did not express a perception of disadvantage, irrespective of birth quartile. Indeed, whilst reflecting on the consequences of later maturation, players appeared to perceive this as an enabling factor and something to work with over the long term. This contrasted with many released athletes who experienced early advantages through maturation:I was bigger so I could run through people and get around people. It was easier to play because I was a little bit bigger. Skillset-wise I seemed to be a little bit behind (Player 8: Q4—Released).It seemed seamless to me [transition into senior environment] to be honest I think it was because I was brought in to play in the second team games and then you come to some of the first team training sessions as well and then eventually, they brought you in full time… it was a good transition, it was easy (Player 4: Q1—Released).I was bigger and taller than a lot of them, that’s the main bit. I had always been taller than everyone my own age (Player 5: Q4—Released).As players progressed through the academy, significant differences emerged in their ability to deal with challenges. Across the retained group, players appeared to have the ability to utilise and reflect on past experiences of being disadvantaged. This perspective-taking appeared to influence perceptions of competence and control:I knew I was better than players I was playing with at school level, but then you come somewhere like (club)… you know you are far from where you think you are. I kept my head down and worked hard, but I never felt like I didn’t deserve to be in the academy. I sort of felt that I deserved a chance to be in it and give it a shot, but when you get here you sort of realise there are 18-year olds who are way more physical… but that is good. At 16 you strive because you think I have got to catch him up, you know, it gives you goals (Player 1: Q1—Retained).There was like older guys there as well… so we had 18/19-year-olds who were a lot more physically developed and experienced and better players than us so we were exposed to that and trained with that day in day out, at times like it was difficult… I had to deal with some right XXXX and eventually you start to find your way (Player 6: Q4—Retained).I was still very small, I was still told probably too small to be a rugby player… it was never a thought of mine to be a professional rugby player but I was always going to be a small skinny player as far as I was concerned (Player 7: Q4—Retained).In contrast, the released group struggled to cope with the increased range and intensity of challenges they faced. The response to these challenges was often perceived outside the player’s locus of control, with problems attributed to external factors. This contrasted with the retained group who saw challenges as obstacles to overcome by deploying a range of psycho-behavioural resources. As a consequence, released players appeared less equipped to cope with and learn from challenging periods:It was frustrating that I could not do things that I used to do at 14/15 (years old), running and scoring plenty of tries, but my game changed a lot and I turned into a very different player due to that and it was frustrating (Player 8: Q4—Released).It was quite scary because I had not played much in senior rugby, I just did not really know… so it was just quite scary not knowing where I was going to be and not knowing what I was going to do… I just lost direction (Player 3: Q1—Released).Obviously, it was a lot more physically demanding and nothing you were sort of used to before. It was really tough… Just a lot more intense, a lot more volume with the actual rugby skill development and the strength and conditioning development. I’d never had it before, wasn’t really expecting it either (Player 4: Q1—Released).The first couple of months it really p*ssed me off. You feel like you are standing still and you are desperate to play at that age, and then I remember just speaking to [brother] and my old man, and he just said ‘work hard and make sure that when you do get a go, you are ready to go’… it was then a case of looking at it from a different angle and saying I need to keep working at my passing and my kicking, the gym, the speed (Player 1: Q1—Retained).As players continued their journey, these features seemed to become even more prominent, with overcoming a range of challenges seemingly a key differentiator.Finally, in addition to exploring the individual players’ responses to various challenges, we also sought to understand the mechanisms that seemed to influence their overall experience.There appeared to be significant differences between the nature of the commitment to the sport between those who were retained and those released. Retained athletes seemed to engage and play with a focus on progression and enjoyment of the developmental process, rather than winning or domination of the game at earlier stages. In contrast, the released group seemed to heavily invest, from an early stage, with a focus on playing and winning matches, rather than engagement in other sports or training:I moved there because it was the best team, the team I was with wasn’t that great and the mini set up was like fading out rather than like getting stronger and at the time (community club) had a strong mini section, so I joined that (Player 5: Q4—Released).Released players also tended to focus solely on the outcome of selection in the short term, either for international rugby, or inclusion in an academy programme. This contrasted with retained players who seemed to focus on improving themselves rather than on an end goal of selection:I was very rugby-focused not thinking too much about school. The next level for me was to get into the [club] academy and play for England at under 16s level, that was my driving goal (Player 8: Q4—Released).The only thing I fixed on was decision making, two on ones, three on ones and obviously the backs were doing something different, all those skills I think that really benefited me and I remember thinking just focus on getting this stuff done... you’ll be better (Player 1: Q1—Retained).Many of the retained group reflected on the use of experiences as a platform for reflection. Significantly, this seemed to be promoted by various supportive influences. This guiding of reflection seemed to be a key factor by which players were able to maintain perceptions of control during challenging experiences. In essence, this support seemed to be more facilitative, when compared to direct and ‘driving’ input of those who did not progress:Mum and Dad used to make me clean my boots and that, I had one pair of boots and they had to last me for a season, so I was always told to polish them and look after them and make sure they did not split (Player 1: Q1—Retained).I think by the time it came around to me playing they were supportive but not until I was about 16… I pretty much had to make sure that I got myself sorted for everything (Player 6: Q4—Retained).Some subtle differences were observed between the retained and released groups in terms of the nature of the support from parents as they began to progress towards the transition to the senior game. In contrast to the retained players, the released group experienced far higher levels of support than those who were retained, indeed, something that did not appear to change, even as athletes progressed.My Mum and Dad were so supportive that I didn’t need anything. They sort of volunteered and bought me wherever I needed to go—it was literally all for me (Player 8: Q4—Released).In addition, there appeared significant differences in the response of players to challenge and also how they learned from their experiences. Amongst the retained group, there appeared to be a greater perception of control during periods of challenge. As a result, players seemed to have the confidence to deploy previously developed skills and capitalize on the emotional experience of challenge. When this was not the case, especially amongst the released group, it appeared to be a barrier to long term progression. For player 8 reflecting on his early transition to the senior team and the changing perceptions of his earlier size advantage, led to the regret that he was unable to deploy the necessary skills to navigate the challenge:You have got guys who were probably 20 kg heavier than me…I think a lot of it may have come down to confidence and I didn’t integrate well going into a first team environment… holding back a little bit more than I should have (Player 8: Q4—Released).The differential response appeared to be a result of a lack of previous experience, reflection on, or development of the skills to cope with or learn from challenge. In contrast, amongst the retained group, players seemed to actively seek out challenging experiences. For example, player 1 deliberately chose to play in an age group beyond his chronological age as a means of increasing his challenge: “I was too young for that age group so at Sunday rugby I always played a year above” (Player 1: Q1—Retained).We can also consider player 1′s perceptions of challenge as he progressed into the senior squad:There was the likes of XXX and, a lot of the senior players who either were playing or had just retired and were coaching, really kind of nurtured me along the way… it was pretty tough period and I just kept focusing on getter better… yeah tough (Player 1: Q1—Retained).The specific aims of this study were firstly to generate a deeper understanding of the lived experience of the RAE, secondly to compare the lived experiences of early and late birth players, and finally to understand the mechanisms that influenced individual experience. We responded to criticisms of the existing body of research in RAE which has focused at the population level with limited use of qualitative methodologies to understand underpinning mechanisms.Whilst our exploratory approach set out to understand the impact of challenge in relation to RAE, what emerged was the impact of challenge irrespective of RAE. That is, later born players did not necessarily experience higher levels of challenge, nor did increased challenge necessarily lead to greater psychological growth ,45. As sConsequently, whilst relative age did not appear to be a mechanism in itself, there appeared to be three core factors that influenced player’s perceptions of control, confidence and overall perspective . ParticiBy exploring the relative advantages and disadvantages of players at stages of their TD journey, against their later career success, we show that birth quartile number means very little without a deeper understanding of individual biopsychosocial context. What did appear critical for players to make the most of high challenge and subsequent emotional disturbance was the use of an appropriate range of psycho-behavioural skills ,67. RelaOf course, no research is without limitations. In this particular case, a common criticism of a pragmatic approach is that it risks provincialism, that is knowledge that is simply located in a particular context . Indeed,The evidence presented here raises the intriguing question of the extent to which various push and pull factors can be deliberately implemented in the experience of the athlete and at what point might they be appropriate. We would suggest that a sustained consideration  of push and pull factors should be a key feature of TD and, perhaps, participation environments . This isFor many TD systems, it has been assumed that an appropriate target for selection has been a balance across quartiles, ensuring an appropriate number of Q4s are given opportunities . We, norThis study has considered the lived experience of relative age amongst a cohort of elite and near-elite rugby union players, analysed in light of eventual career status. Data presented clearly challenge beliefs held by the field of both researchers and practitioners. We suggest the need for a rethink of assumptions in the field, including the idea that RAE should be tackled with blanket policies. It is likely that RAE is a statistical outcome of challenge dynamics at the population level. We would therefore suggest a broader consideration of the dynamics of challenge, with a focus on the various push and pull factors that an athlete may be exposed to.


Con). Under acute hyperglycemia, control hearts showed an infarct size of 63 ± 5%. Applying RIPC plasma under short hyperglycemic conditions led to a significant infarct size reduction of 41 ± 4% (p < 0.05 vs. HGs Con). However, the cardioprotective effect of RIPC plasma under normoglycemia was significantly stronger compared with acute hyperglycemic conditions . Prolonged hyperglycemia (HGl RIPC) completely abolished the cardioprotective effect of RIPC plasma .The adverse impact of common diseases like diabetes mellitus and acute hyperglycemia on morbidity and mortality from myocardial infarction (MI) has been well documented over the past years of research. In the clinical setting, the relationship between blood glucose and mortality appears linear, with amplifying risk associated with increasing blood glucose levels. Further, this seems to be independent of a diagnosis of diabetes. In the experimental setting, various comorbidities seem to impact ischemic and pharmacological conditioning strategies, protecting the heart against ischemia and reperfusion injury. In this translational experimental approach from bedside to bench, we set out to determine whether acute and/or prolonged hyperglycemia have an influence on the protective effect of transferred human RIPC-plasma and, therefore, might obstruct translation into the clinical setting. Control and RIPC plasma of young healthy men were transferred to isolated hearts of young male Wistar rats in vitro. Plasma was administered before global ischemia under either short hyperglycemic  conditions, prolonged hyperglycemia , or under normoglycemia . Infarct sizes were determined by TTC staining. Control hearts showed an infarct size of 55 ± 7%. Preconditioning with transferred RIPC plasma under normoglycemia significantly reduced infarct size to 25 ± 4% ( The adverse impact of common diseases like diabetes mellitus and acute hyperglycemia on morbidity and mortality from myocardial infarction (MI) has been well defined over the past years of research.Hyperglycemia is commonly documented during the perioperative period in patients undergoing cardiac surgery . InteresUntil now, causal therapy in the form of immediate restoration of coronary blood circulation, either as a percutaneous coronary intervention or as a coronary bypass surgery, remains the gold standard for patients suffering from MI . ParadoxBased on these findings, in this study, we focused on investigating a possible effect of isolated acute and prolonged hyperglycemia on RIPC. For this translational approach from bedside to bench, we employed RIPC plasma collected from young, healthy, male volunteers. Plasma was transferred to an isolated rat heart under either temporary acute hyperglycemic conditions or prolonged hyperglycemia, without distortion by other confounders. We set out to determine whether acute and/or prolonged hyperglycemia has an influence on the protective effect of transferred human RIPC plasma and, therefore, might obstruct translation into the clinical setting.No differences were detected between and within all groups of this study regarding body weight, wet heart weight, and level or time of maximal ischemic contracture .p < 0.05 vs. Con). Under short hyperglycemia, control hearts (HGs Con) showed an infarct size of 63 ± 5%. Applying RIPC plasma under short hyperglycemic conditions (HGs RIPC) leads to a significant infarct-size-reducing effect . Under long hyperglycemic conditions, infarct size measured 59 ± 5% in control hearts (HGl Con). Preconditioning with RIPC plasma under prolonged hyperglycemia (HGl RIPC) did not induce infarct size reduction compared with the control . Notably, the protective effect of RIPC plasma under short hyperglycemia (HGs RIPC) is considerably attenuated compared with RIPC, but still significantly reduces infarct size . In contrast, long hyperglycemia completely abolishes the positive impact of preconditioning with RIPC plasma, compared with normoglycemia and short hyperglycemia .All infarct sizes are demonstrated in Hemodynamic data from all groups are pictured in In the present study, we focused on the influence of disturbed glucose hemostasis on cardioprotection induced by transferred human RIPC plasma.Our results demonstrate that prolonged hyperglycemia fully abolishes the beneficial effect of transferred RIPC plasma on infarct size after I/R injury. Interestingly, a short transient episode of hyperglycemia before ischemia—during preconditioning with transferred RIPC plasma—does not completely abrogate cardioprotection. RIPC plasma transfer in fact still induces infarct size reduction; however, it is less pronounced compared with under normoglycemic conditions.Owing to its noninvasive nature and high practicability, RIPC maneuver seems to be an optimal therapeutic strategy inducing inter-organ protection against I/R injury. Multiple pieces of experimental evidence ,16,17 exThese discrepancies between experimental evidence and clinical ineffectiveness are attributed to confounding variables such as choice of anesthetic regime, concomitant medication, patient’s characteristic, or comorbidities like diabetes and hyperglycemia .In our study, we performed an inter-species transfer of human RIPC plasma on an isolated rat heart under both normal and disturbed glucose hemostasis. The results demonstrate a powerful cardioprotective effect of transferred human RIPC plasma significantly reducing infarct size from 55 ± 7% of the left ventricle to 25 ± 4% under normoglycemic conditions. Previously, Heinen et al.  investigThe viability of transferring human blood samples after RIPC to an isolated heart, initiating cardioprotection, supports the concept of the release of humoral factors as an important signaling step of the inter-organ communication . AlthougOur result, showing that transferred RIPC plasma from young male volunteers has a strong infarct-limiting effect, is in line with previous findings, indicating that humoral factors can be transferred to a naïve heart to initiate cardioprotection.Different clinical studies show evidence that the concomitant occurrence of hyperglycemia in patients suffering myocardial infarction increases the risk of mortality and morbidity, irrespective of whether the patient is diagnosed with diabetes ,24. InteATP) channels. Similar KATP channels are located in the mitochondrial membrane and have been proven to play a key role in different cardioprotective strategies. Their activation ultimately results in suppression of mPTP opening, inducing myocardial protection [ATP channels, showing that a nonselective blockade of mKATP channels completely eliminated the cardioprotective effect of RIPC in a donor heart. Especially during reperfusion, the activation of mKATP channels plays a crucial role in cascades inducing cardioprotection. Thus, it might be considerable that, during prolonged hyperglycemia, the effect of excessively, ongoing elevated ATP levels on mKATP-channels—especially in the reperfusion—is more pronounced compared with the subgroup of short hyperglycemia. Ergo, the activation of mKATP channels might be only partly affected under short episode of hyperglycemia, still initiating cardioprotective signaling cascades.The detailed mechanism of hyperglycemia blocking cardioprotection is yet not fully revealed, but has been one major focus of cardioprotective research, acquiring increasing knowledge. In this context, Craig et al.  describeotection ,30. In totection  discusseBesides the changes in ATP level, hyperglycemia induces an excessive mitochondrial overproduction of ROS, causing matrix swelling, release of pro-apoptotic factors, opening of mPTP, and finally cell death ,33,34.Lastly, acute hyperglycemia seems to block different parts of myocardial signaling cascades involved in the cardioprotective properties of RIPC, such as Akt phosphorylation, endothelial NO synthase (eNOS), or protein kinase G (PKG) ,36.Interestingly, the results from our study report that transferred RIPC plasma under short, transient hyperglycemia still induces a cardioprotective effect, even though it is less profound compared with the infarct size reduction under normoglycemia. In contrast, prolonged hyperglycemia completely abolished myocardial protection by RIPC plasma.This distinct difference in results indicates that the duration and/or timing of hyperglycemia might be an important factor in the context of blocked cardioprotection.ATP channels, is involved in cardioprotection, excessive amounts of ROS lead to opening of the mPTP, which ultimately induces cell damage [As the results demonstrate, peracute hyperglycemia before ischemia only partly interferes with RIPC-induced preconditioning, while prolonged hyperglycemic conditions during reperfusion seem to be critical. In line with our data are the findings of Kehl et al. ,37, showl damage ,39,40. HIn line with our findings, Wider et al.  report tClinical studies indicate that myocardium of patients suffering from diabetes mellitus may be susceptible to episodes of ischemia/reperfusion, per se causing larger infarct sizes . FurtherHowever, not only the condition of the myocardium as a target itself seems to be relevant for conditioning strategies with RIPC plasma, but also patients’ comorbidities influencing the release of mediating humoral factors. Jensen et al.  describeWhile most of the confounders are difficult to alter  or cannot be changed at all (age or gender), hyperglycemia is fairly easy to modify, especially in the perioperative setting. Therefore, the results from our current study are of critical importance and emphasize the significant role of preserving or establishing normoglycemia with regard to myocardial conditioning. Nevertheless, further research is needed investigating the various patient characteristics. The translational concept, focusing not only on bench to bedside, but also bedside to bench, might be one promising approach in this context.ATP channels in the context of blocked cardioprotection under hyperglycemia.There are limitations of our study that need to be mentioned. The induction of short and prolonged hyperglycemia only simulates a temporary state of physiological conditions rather than the complex pathophysiology of a chronic diabetes mellitus disease. As a first step, this current study was designed to focus on one main comorbidity, deliberately, the fact that patients with hyperglycemia or even diabetes mellitus often suffer from multiple cardiovascular risk factors. A model representing the chronic stages of the disease should be a follow-up-investigation. In this study, we address the question of whether RIPC plasma mediates cardioprotection in the presence of hyperglycemia, employing a translational approach with an inter-species plasma transfer using human RIPC plasma. We acknowledge that more extensive research on the exact underlying mechanisms is required for generating specific clinical interventions that are potent for protecting the heart against ischemia-reperfusion injury. Considering the above-mentioned research, future studies should focus on mitochondrial ATP levels and mKInvestigations were approved by the local ethics committee (#2018-160_1) and the local Animal Care and Use Committee of the University of Duesseldorf (project number O27/12). All experiments included in this study were conducted in accordance with the Guide for the Care and Use of Laboratory Animals published by the U.S. National Institute of Health . The results were reported according to the ARRIVE guidelines.2) male adult volunteers undergoing a protocol of RIPC-maneuver. Demographic data and criteria of inclusion/exclusion of the probands are shown in After written informed consent, plasma was collected from 10 healthy, young (age 18–30 years), normal body weight  under constant pressure (80 mmHg) at a temperature of 37 °C. The Krebs–Henseleit buffer was supplemented with a mixture of 95% O2 and 5% CO2. A fluid-filled balloon was inserted into the left ventricle, measuring standardized hemodynamic parameters, setting the baseline left ventricular end-diastolic pressure to 4–6 mmHg. For all experiments, heart rate, left ventricular end-systolic pressure (LVESP), and left ventricular end-diastolic pressure (LVEDP) were continuously measured and digitized by an analogue to digital converter  at a sampling rate of 500 Hz. Data were recorded using Labchart 8.0 for Windows . Left ventricular developed pressure (LVDP) was calculated as LVESP–LVEDP.All in vitro experiments were performed in the isolated male rat heart. The surgical preparation was performed as described in detail previously . Male WiCoronary flow (CF) and glucose level in the coronary effluent were measured at given time points see . AdditioAfter successfully completing the experiment at the end of reperfusion, each heart was removed from the Langendorff system and cut into eight transverse slices (2 mm each slice) to examine the infarct size. A 0.75% triphenyltetrazoliumchloride (TTC) solution was applied to investigate the infarcted area compared with viable tissue. A blinded, experienced investigator analyzed infarct sizes using planimetry (SigmaScan Pro5 software), determined as the percentage of infarct area per total area of the left ventricle .n = 4–5 per group), as shown in Hearts were randomized into six experimental groups  or RIPC (RIPC) plasma from volunteers. Preconditioning with human RIPC plasma was achieved by administrating undiluted plasma via a syringe pump  at an infusion rate of 1% of the coronary flow. Plasma was not dissolved but applied purely.To induce hyperglycemia, hearts were perfused with a total concentration of 22 mmol/L glucose . Glucose treatment was started 2 min prior to perfusion with Con or RIPC plasma to ensure hyperglycemic conditions at the start of preconditioning. The protocol for induction of hyperglycemia was taken from our previous investigations . HyperglCon: Hearts were perfused with control plasma for 10 min as preconditioning under normoglycemia.RIPC: Hearts were perfused with RIPC plasma for 10 min as preconditioning under normoglycemia.HGs Con: Hearts were perfused with control plasma for 10 min as preconditioning under short hyperglycemia.HGs RIPC: Hearts were perfused with RIPC plasma for 10 min as preconditioning under short hyperglycemia.HGl Con: Hearts were perfused with control plasma for 10 min as preconditioning under long hyperglycemia.HGl RIPC: Hearts were perfused with RIPC plasma for 10 min as preconditioning under long hyperglycemia.n = 4 for detecting a 25% mean difference and a standard deviation of 15% in infarct size ). We performed a two-way analysis of variance (ANOVA) and a Tukey post hoc test  for comparison of hemodynamic data and glucose levels between groups as well as between different time points within groups. Data are presented as mean ± standard deviation (SD). Infarct sizes were analyzed by a one-way ANOVA and a Tukey´s post hoc test. p < 0.05 was considered statistically significant for changes within and between groups.Sample size calculation  revealed a group size of With this bed to benchside approach, we demonstrate that cardioprotection can be induced by transfer of human RIPC plasma to the isolated rat heart. The simultaneous occurrence of hyperglycemia interferes with the cardioprotective effect of RIPC. Interestingly, this blockage depends on the duration of hyperglycemia. While prolonged hyperglycemia completely blocks infarct size reduction by RIPC plasma, myocardial protection by transfer of RIPC plasma under short transient hyperglycemia—although less pronounced—is still effective.


This belief is unfounded because it is based on a questionable use of Bayes Theorem and on incorrect causal interpretation of conditional probabilities. In Bell-local realistic model, hidden variables describe only photonic beams created by a source, thus they cannot depend on randomly chosen experimental settings. However, if hidden variables describing measuring instruments are correctly incorporated into a contextual probabilistic model a violation of inequalities and an apparent violation of no-signaling reported in Bell tests can be explained without evoking quantum non-locality. Therefore, for us, a violation of Bell-CHSH inequalities proves only that hidden variables have to depend on settings confirming contextual character of quantum observables and an active role played by measuring instruments. Bell thought that he had to choose between non-locality and the violation of experimenters’ freedom of choice. From two bad choices he chose non-locality. Today he would probably choose the violation of MI understood as contextuality.A violation of Bell-CHSH inequalities does not justify speculations about quantum non-locality, conspiracy and retro-causation. Such speculations are rooted in a belief that setting dependence of hidden variables in a probabilistic model (called a violation of  Quantum mechanics (QM) provides probabilistic predictions and the main question debated since nearly 100 years is: are these probabilities irreducible or do they emerge from some more detailed description of physical reality and experiments used to probe it. Einstein strongly believed that QM should emerge from a more detailed description of individual physical systems .Bell was a realist who believed that physical objects possess definite properties ,4. In 19measurement independence (MI), free choice or no conspiracy has been believed, for many years, to be a direct consequence of experimenters’ freedom of choice (FC). For majority of scientists FC is a prerequisite of science and its violation would be unacceptable.In LRHVM, it is correctly assumed that hidden variables, describing only photonic beams created by a source, do not depend on randomly chosen experimental settings: However, a choice of statistical independence) does not restrict FC. A misunderstanding is based on incorrect causal interpretation of conditional probabilities [λ can causally influence, how statistical dependence does not imply a causal dependence and correlation does not mean causation.In this article we review and generalize arguments given in ,10,11,12bilities ,10,11,12statistical dependence is incorporated into this model and easy to understand. As Bohr insisted one may not separate the behavior of atomic objects and the interaction with measuring instruments.CHV contains setting dependent  variables describing measuring instruments thus noncontextual probabilistic coupling. In fact, CHSH are noncontextuality inequalities for a 4-cyclic Bell scenario [noncontextuality and its violation contextuality.In QM experiments performed in incompatible experimental contexts are described by specific dedicated probabilistic models. In LRHVM, MI allows implementing random variables, describing random experiments performed using incompatible experimental settings, on a unique probability space, on which they are jointly distributed. Such implementation defines a scenario . TherefoStatistical dependence does not restrict FC, thus talking about a violation of free choice as a resource [statistical independence could be violated due to superdeterminism understood as specific causal influences from the common past of photonic beams, experimenters and instruments they are using in distant laboratories. Next, hidden variables and experimenters’ choices could be influenced in a way, to make experimental outcomes comply with QM. This explains why MI is called free choice or no conspiracy and Bell clearly preferred non-locality to the violation of free choice.resource ,12 in Beλ distant outcomes are strictly predetermined and correlated. In SHVM for a fixed λ they are created in two random independent experiments. In LRHVM, ‘entangled photon pairs’ are described as pairs of socks. In SHVM, they are described as pairs of dice and in each setting λ. A detailed discussion of these two models and experimental protocols, implied by them, may be found in [There are two probabilistic hidden variable models: LRHVM and a stochastic hidden variable model (SHVM) ,6. Contrfound in .local realism, classicality or counterfactual definiteness. Local realism implies MI and the existence of a probabilistic coupling. CHSH are significantly violated in various Bell Tests. Therefore, experimental outcomes are not predetermined by the properties of photonic signals and as Peres correctly concluded: unperformed experiments have no results [In LRHVM, outcomes (clicks on detectors coded ±1) are locally predetermined by variables describing correlated photonic signals, produced by a source. Local predetermination of outcomes of all experiments, by some ontic properties of signals, is called usually:  results .λ can be anything even the quantum wave function of Universe is misleading and meaningless. Hidden random variables describe details of an experimental protocol consistent with a given probabilistic model [Various metaphysical assumptions may motivate a choice of a probabilistic model. However, once a model is chosen, its meaning and its implications can only be rigorously discussed in a probabilistic framework. This is why, for us, saying that ic model .q in contexts c. Properties of experimental scenarios and possible hidden variable models are studied without evoking any metaphysical assumptions. Free choice is equivalent to context-independent mapping and experimenters’ free will assumption is completely redundant [The ideal EPRB experiments and perfect correlations do not exist . Random edundant ,22,23. IAt the end of this introduction, we want to summarize in a simpler language, what is the main motivation of this paper? What is new, what the conclusions are and how they are derived in detail in subsequent sections.It is well known that CHSH may be derived for 4 jointly distributed random variables describing a random experiment in which 4 outcomes are outputted in each trial. In such experiment estimates of pair-wise expectations obey this inequality for any finite sample.It is clear, that random variables describing outcomes of EPRB and Bell Tests are not jointly distributed and Bell never claimed the opposite. One may ask: how could he derive his inequalities. He could do it, because in LRHVM, there exists a JP of 4 random variables, and he used implicitly this JP in his proof. In the literature about Bell inequalities no distinction is made between these two sets of random variables. In It allows explaining more clearly, how LRHVM defines a probabilistic coupling for EPRB experiments. This probabilistic coupling is neither consistent with quantum predictions nor with experimental data in Bell Tests.The existence of a probabilistic coupling does not mean that CHSH hold in the experiments performed using incompatible settings and described using this coupling. CHSH can be and are violated in these experiments by estimates of pair-wise expectations obtained using finite samples. The existence of a probabilistic coupling only allows deriving probability bounds on how large and how frequent violations may be observed in these experiments. This problem is discussed in statistical independence in our model does not justify speculations about the violation of free choice or conspiracy. This result was derived for the first time in [In  time in  and repr time in ,12. In p time in ,10,11,12In local realism, statistical independence and superdeterminism.We discuss LRHVM and its implications using a rigorous probabilistic framework, what avoids misunderstanding.A beam (ensemble) E of entangled pairs of particles is created by a source. One particle is sent to Alice and its twin partner to Bob in distant laboratories, who chose independently experimental settings Particles pass by corresponding beam splitters (PBS) and produce clicks on detectors, which are coded by two random variables The experimental protocol of an ideal EPRB is the following :A beam  means only, that a non-contextual probabilistic coupling (9) does not exist and that CHSH inequalities are simply scenario  which caλ being values of a random variable L distributed according to a probability distribution A marble is drawn from an urn (or a box) E. Properties of marbles in E are described by Experimenters, choose at random one among 4 available incompatible settings The marble is returned to the box and another marble is drawn from the box.Probabilistic models describe a scatter of observed outcomes without entering into details how these data were produced. However, there is an intimate relation between probabilistic models and experimental protocols ,38. If wL and its probability distribution do not depend on how the settings experimenters’ freedom of choice (FC) is never compromised.Since In Bell Tests, instead of a marble we have ‘pairs of photons’. In LRHVM they are described as pairs of socks which may have different colors and sizes. In SHVM, they are described as pairs of dice. More detailed discussion of these probabilistic models and their intimate relation with experimental protocols may be found in .In LRHVM, each experiment  of time ,40,41,42An experimental protocol consistent with LRHVM is similar to the experimental protocol of a following thought experiment . In eachS ≤ 4 [In real experiments, 4N × 4 spreadsheets do not exist and four N × 2 spreadsheets describing the data obtained using 4 incompatible settings, are not simple random samples drawn from columns of some 4N × 4 spreadsheet ,33. Theys: S ≤ 4 .In Bell Tests, some data violate no-signaling ,43,44,45contextuality loophole, because it does not incorporate correctly hidden variables describing measuring instruments, as they are perceived by incoming photonic signals.It is clear, that LRHVM and SHVM are oversimplified probabilistic models unable to describe these experimental data from Bell Tests. As Theo Nieuwenhuizen ,47,48 coIf setting dependent hidden variables, describing instruments, are added to LRHVM, the data in Bell Tests may be described by a contextual probabilistic model:superdeterminism.This model violates statistical independence and Using (11) and Bayes Theorem we obtainconspiracy and FC is not compromised. In each trial, labels The equation: ere used ,10,11,12contextuality and not conspiracy or superdeterminism. In CbD approach, contextuality has a different more restricted meaning.However, if an event  time in . TherefoIn (11), variables describing photonic signals are causally independent but stochastically dependent; variables describing measuring instruments are also causally independent but stochastically dependent In Bell Tests, two distant time series of clicks have to be converted into two discrete correlated samples using synchronized time windows. In ,11,15,33statistical dependence more precise predictions for expectations θ is a relative angle between polarization axes of polarization filters. Therefore, if λ are hidden variables describing a polarization filter how it is ‘perceived’ by an incoming beam at the moment of a measurement, it is plausible to assume, that after a rotation by an angle θ, the same filter is described by variables θ dependence of estimated expectations The model (10) allows explaining data from Bell Tests in a local and causal way. Choosing a particular  be made . We knowarl Hess .In , Lambarestatistical independence, believing that the violation of MI would mean conspiracy.They claim that talking about joint probabilities is misleading because LRHVM, which they call LHV model, may be derived using local causality, perfect correlations and MI. However, they do not realize that the conjunction of these three assumptions implies the existence of a counterfactual non-contextual probabilistic coupling (9) and a joint probability of 4 random variables (JP), which was implicitly used by Bell to derive CHSH. The authors’ finite sample proof of CHSH fails, if JP does not exist. If MI is violated if LRHVM is used to describe EPRB, then some pair-wise cyclic expectations obey Bell-CHSH inequalities, which for some settings are violated by quantum predictions. JP of n- random variables only exists, if in each trial n-results are outputted [Fine demonstrated, that CHSH are necessary and sufficient conditions for the existence of JP of 4 only pair-wise measurable random variables ,36. Noboutputted ,9,38,51.utputted .L taking values X taking values x = {1, −1}, Y taking values y = {1, −1}, L describes an experiment in which hidden variables are sampled from Λ by rolling a dice, X and Y are random variables describing flipping fair coins in order to determine experimental settings In their counterexample we have: 7 random variables: We have 4 incompatible experiments, labeled by Expectations (14) do not violate the inequality (7). Lambare and Franco incorrectly conclude: “according to Fine’s theorem A, a joint probability The random variables The random variables Using (16) we immediately obtain:λ both Alice and Bob flip two fair coins each, and output their outcomes calculated using (13). After N trials Bob sends his N × 2 spreadsheet to Alice, who displays her and his results (strictly preserving the order) in a new N × 4 spreadsheet. Only these data are described by JP of 4 random variables and now various pair-wise correlations between them can be estimated and they obey strictly (7) for all values of N. This is the main problem in real Bell Tests, because there is no unambiguous ordering between distant clicks produced by entangled photonic signals [Jointly distributed  signals ,33.“To describe random events in any particular experiment we do not need to abandon the Kolmogorov axioms of probability theory. However, the measured probabilities in the different experiments may not be determined by conditionalization from a unique probability space. The last assumption was used in all the proofs of Bell inequalities.”It is difficult to understand, why such arguments are not understood and are still a minority stance . Alreadylocal realism, classicality or counterfactual definiteness (CFD). Since different authors attach a different meaning to the notion of realism, thus CFD understood as local predetermination of outcomes is less ambiguous.In LRHVM clicks on detectors (coded ±1) are locally predetermined by variables describing correlated photonic signals, Local predetermination of outcomes of experiments, by some ontic properties of signals, is called usually: “I’m a realist… I think that in actual daily practice all scientists are realists, they believe that the world is really there, that it is not a creation of their mind. They feel that there are things there to be discovered, not a world to be invented but a world to be discovered. So I think that realism is a natural position for a scientist and in this debate about the meaning of quantum mechanics I do not know any good arguments against realism.” [Such assumption was proven incorrect, but it was not stupid. Reinhold Bertlmann remembers, what his friend John said to him: ealism.” .free choice, no conspiracy or MI, and the existence of probabilistic coupling (3–9).This paper is about assumptions underlying various probabilistic hidden variable models and their meaning. CHSH can be rigorously derived for random experiments described by 4 jointly distributed random variables. In EPRB and in Bell Tests such JP does not exist. CFD implies statistical independence, called also Bell inequalities are violated in several experiments in physics and in cognitive science ,55,56, wIn Bell Tests, some data violating inequalities violate also no-signalling ,43,44,45quantum nonlocality are based on incorrect interpretations of QM and/or incorrect mental pictures of quantum phenomena [quantum nonlocality.The speculations about henomena ,75. Andrhenomena ,67,70,71henomena ,87,88,89statistical dependence and correlation between distant outcomes are incorrectly interpreted as causation one has two options: spooky influences between distant measurements or correlated common causes (possibly coming from a Big Bang) making Nature to comply with the laws of QM.If hidden variables depend on settings, then using Bayes Theorem one concludes that settings depend statistically on hidden variables (12). If explained by superdeterminism instead of non-local influences. This is what he said in 1985 in BBC interview: “There is a way to escape the inference of superluminal speeds and spooky action at a distance. But it involves absolute determinism in the universe, the complete absence of free will. Suppose the world is super-deterministic, with not just inanimate nature running on behind-the-scenes clockwork, but with our behavior, including our belief that we are free to choose to do one experiment rather than another, absolutely predetermined, including the “decision” by the experimenter to carry out one set of measurements rather than another, the difficulty disappears. There is no need for a faster than light signal to tell particle A what measurement has been carried out on particle B, because the universe, including particle A, already “knows” what that measurement, and its outcome, will be.”In QM, it is taken for granted that experimenters can choose their setting as they wish, and Bell never doubted in it. However, after discussions with Shimony, Horn and Clauser ,91 he adsuperdeterminism was recognized as one of possible loopholes in Bell Tests. Jan-Åke Larsson in his excellent review article about possible loopholes in Bell Tests concluded [loophole of superdeterminism cannot be closed by scientific methods; the assumption that the world is not superdeterministic is needed to do science in the first place”. Nevertheless, several toy models explaining how superdeterminism allows preserving local causality were proposed [In 1964, Bell assumed CFD, thus for him it was obvious that hidden variables could not depend on chosen experimental settings. In 1985, hidden variables were assumed to describe any local causes of clicks registered in distant laboratories and oncluded : “The loproposed ,94,95.superdeterminism [Sabine Hossenfelder and Tim Parker succeeded to revive recently discussions about erminism ,97,98.“the observed violations of Bell’s inequality can be said to show that maintaining local causality requires violating statistical independence. We wish to stress that this is not merely an issue of interpretation. The statistical independence assumption is mathematically necessary for the formulation of Bell-type inequalities.” They also correctly underline that correlation does not mean causation and that “the mathematical assumption of statistical independence bears no relevance to the philosophical discussion of free will.” We also agree with their conclusion: “Contrary to what is often stated, these observations do not demonstrate that “spooky action at a distance” is real and nature, therefore, non-local. Rather, the observations show that if nature is local, then statistical independence must be violated.”In a recent letter to Nature Physics, Jonte Hance and Sabine Hossenfelder  correctlstatistical independence is due to superdeterminism, which she defines as: “Superdeterminism, then, means that the measurement settings are part of what determines the outcome of the time-evolution of the prepared state. What does it mean to violate Statistical Independence? It means that fundamentally everything in the universe is connected with everything else, if subtly so. You may be tempted to ask where these connections come from, but the whole point of superdeterminism is that this is just how nature is. It’s one of the fundamental assumptions of the theory, or rather; you could say one drops the usual assumption that such connections are absent.”However, for Sabine Hossenfelder , the viostatistical independence is violated but neither retro-causality, superderminism [extended causal networks [contextuality.In this paper we reviewed and extended the arguments given in ,10,11,12erminism  nor extenetworks ,101 are nonlocal. It is misleading because using a contextual hidden variable model they may be explained in a local and causal way [Correlations between distant experimental outcomes predicted by QM are often called usal way ,15,33. Busal way  explain We explained that the violation of Bell-CHSH inequalities have quite limited metaphysical implications. Nevertheless, the research stimulated by Bell Theorem and beautiful experiments designed and performed to test inequalities, rewarded recently by a Nobel prize, paved the road to important applications of “nonlocal “quantum correlations in quantum information and in quantum technologies.For us, the violation of BI-CHSH inequalities in Bell Tests ,109,110 nonlocality and superdeterminism understood as the violation of experimenters’ freedom of choice. From two bad choices he chose nonlocality. Today he would probably choose violation of statistical independence understood as contextuality.Bell thought that he had to choose between