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With the emergence of high-profile climate activists and a wider appreciation of the need for sustainable buy discount levitra healthcare, training within radiology can no longer be excused from its responsibility to consider the environment in its actions. In this paper, we aim to evaluate the environmental impact of the travel undertaken by trainees within the Peninsula training programme, with the aim of developing practices and providing suggestions (evidence-based where possible) on how to improve the impact on the environment of trainee travel. We envisage that many of the lessons and suggestions may be transferrable to other training schemes in the UK and further afield. During the early months of 2020, buy discount levitra in addition to the environmental crisis, erectile dysfunction treatment escalated to a levitra resulting in the alteration of working practices across the UK (and the rest of the world).

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IntroductionLa Peste (Camus 1947) has served as a basis for several buy levitra tablets critical works, including some in the field of medical humanities (Bozzaro 2018. Deudon 1988. Tuffuor and buy levitra tablets Payne 2017). Frequently interpreted as an allegory of Nazism (with the plague as a symbol of the German occupation of France) (Finel-Honigman 1978.

Haroutunian 1964), it has also received philosophical readings beyond the sociopolitical context in which it was written (Lengers 1994). Other scholars, on the other hand, have buy levitra tablets centred their analyses on its literary aspects (Steel 2016).The erectile dysfunction treatment levitra has increased general interest about historical and fictional epidemics. La Peste, as one of the most famous literary works about this topic, has been revisited by many readers during recent months, leading to an unexpected growth in sales in certain countries (Wilsher 2020. Zaretsky 2020).

Apart from that, commentaries about the novel, especially among health sciences buy levitra tablets scholars, have emerged with a renewed interest (Banerjee et al. 2020. Bate 2020. Vandekerckhove 2020 buy levitra tablets.

Wigand, Becker, and Steger 2020). This sudden curiosity is easy to understand if we consider both La Peste’s literary value, and people’s desire to discover real or fictional situations similar to theirs. Indeed, Oran inhabitants’ experiences are not quite far from our own, even if geographical, chronological and, specially, scientific factors (two different diseases occurring at two different stages buy levitra tablets in the history of medical development) prevent us from establishing too close resemblances between both situations.Furthermore, it will not be strange if erectile dysfunction treatment serves as a frame for fictional works in the near future. Other narrative plays were based on historical epidemics, such as Daniel Defoe’s A Journal of the Plague Year or Giovanni Boccaccio’s Decameron (Wigand, Becker, and Steger 2020.

Withington 2020). The biggest levitra in the last century, the so-called ‘Spanish Influenza’, has been described as not very fruitful in this sense, even if it produced famous novels such as buy levitra tablets Katherine A Porter’s Pale Horse, Pale Rider or John O’Hara’s The Doctor Son (Honigsbaum 2018. Hovanec 2011). The overlapping with another disaster like World War I has been argued as one of the reasons explaining this scarce production of fictional works (Honigsbaum 2018).

By contrast, we may think that erectile dysfunction treatment is having a global impact hardly overshadowed by other buy levitra tablets events, and that it will leave a significant mark on the collective memory.Drawing on the reading of La Peste, we point out in this essay different aspects of living under an epidemic that can be identified both in Camus’s work and in our current situation. We propose a trip throughout the novel, from its early beginning in Part I, when the Oranians are not aware of the threat to come, to its end in Part V, when they are relieved of the epidemic after several months of ravaging disasters.We think this journey along La Peste may be interesting both to health professionals and to the lay person, since all of them will be able to see themselves reflected in the characters from the novel. We do not skip critique of some aspects related to the authorities’ management of erectile dysfunction treatment, as Camus does concerning Oran’s rulers. However, what we want to foreground is La Peste’s intrinsic value, its suitability to be read now and after erectile dysfunction treatment has passed, when Camus’s novel endures as a solid art work and erectile dysfunction treatment remains only buy levitra tablets as a defeated plight.MethodsWe confronted our own experiences about erectile dysfunction treatment with a conventional reading of La Peste.

A first reading of the novel was used to establish associations between those aspects which more saliently reminded us of erectile dysfunction treatment. In a second reading, we searched for some examples to illustrate those aspects and tried to detect new associations. Subsequent readings of certain parts were done to integrate the buy levitra tablets information collected. Neither specific methods of literary analysis, nor systematic searches in the novel were applied.

Selected paragraphs and ideas from Part I to Part V were prepared in a draft copy, and this manuscript was written afterwards.Part ISome phrases in the novel could be transposed word by word to our situation. This one pertaining to its start, for instance, may make us remember the first months of 2020:By now, it will be easy to accept that nothing could lead the people of our town to expect the events that took place in the spring of that buy levitra tablets year and which, as we later understood, were like the forerunners of the series of grave happenings that this history intends to describe. (Camus 2002, Part I)By referring from the beginning to ‘the people of our town’, Camus is already suggesting an idea which is repeated all along the novel, and which may be well understood by us as erectile dysfunction treatment’s witnesses. Epidemics affect the community as a whole, they are present in everybody’s mind and their joys and sorrows are not individual, but collective.

For example (and we are anticipating Part II), the narrator says:But, once the gates were closed, they all noticed that they were in the same buy levitra tablets boat, including the narrator himself, and that they had to adjust to the fact. (Camus 2002, Part II)Later, he will insist in this opposition between the concepts of ‘individual’, which used to prevail before the epidemic, and ‘collective’:One might say that the first effect of this sudden and brutal attack of the disease was to force the citizens of our town to act as though they had no individual feelings. (Camus 2002, Part II)There were no longer any individual destinies, but a collective history that was the plague, and feelings shared by all. (Camus 2002, Part III)This distinction is not trivial, since the story will display a strong confrontation between those who get involved and buy levitra tablets help their neighbours and those who remain behaving selfishly.

Related to this, Claudia Bozzaro has pointed out that the main topic in La Peste is solidarity and auistic love (Bozzaro 2018). We may add that the disease is so attached to people’s lives that the epidemic becomes the new everyday life:In the morning, they would return to the pestilence, that is to say, to routine. (Camus 2002, Part III)Being collective buy levitra tablets issues does not mean that epidemics always enhance auism and solidarity. As said by Wigand et al, they frequently produce ambivalent reactions, and one of them is the opposition between auism and maximised profit (Wigand, Becker, and Steger 2020).

Therefore, the dichotomy between individualism and collectivism, a central point in the characterisation of national cultures (Hofstede 2015), could play a role in epidemics. In fact, concerning erectile dysfunction treatment, some authors have described a greater impact of the levitra in those countries with higher levels of individualism buy levitra tablets (Maaravi et al. 2021. Ozkan et al.

2021). However, this finding should be complemented with other national cultures’ aspects before concluding that collectivism itself exerts a protective role against epidemics. Concerning this, it has been shown how ‘power distance’ frequently intersects with collectivism, being only a few countries in which the last one coexists with a small distance to power, namely with a capacity to disobey the power authority (Gupta, Shoja, and Mikalef 2021). Moreover, those countries classically classified as ‘collectivist’ (China, Japan, South Korea, India, Vietnam, etc.) are also characterised by high levels of power distance, and their citizens have been quite often forced to adhere to erectile dysfunction treatment restrictions and punished if not (Gupta, Shoja, and Mikalef 2021).

Thus, it is important to consider that individualism is not always opposed to ‘look after each other’ (Ozkan et al. 2021, 9). For instance, the European region, seen as a whole as highly ‘individualistic’, holds some of the most advanced welfare protection systems worldwide. It is worth considering too that collectivism may hide sometimes a hard institutional authority or a lack in civil freedoms.Coming back to La Peste, we may think that Camus’s Oranians are not particularly ‘collectivist’.

Their initial description highlights that they are mainly interested in their own businesses and affairs:Our fellow-citizens work a good deal, but always in order to make money. They are especially interested in trade and first of all, as they say, they are engaged in doing business. (Camus 2002, Part I)And later, we see some of them trying selfishly to leave the city by illegal methods. By contrast, we observe in the novel some examples of more ‘collectivistic’ attitudes, such as the discipline of those quarantined at the football pitch, and, over all, the main characters’ behaviour, which is generally driven by auism and common goals.Turning to another topic, the plague in Oran and erectile dysfunction treatment are similar regarding their animal origin.

This is not rare since many infectious diseases pass to humans through contact with animal vectors, being rodents, especially rats (through rat fleas), the most common carriers of plague bacteria (CDC. N.d.a, ECDC. N.d, Pollitzer 1954). Concerning erectile dysfunction, even if further research about its origin is needed, the most recent investigations conducted in China by the WHO establish a zoonotic transmission as the most probable pathway (Joint WHO-China Study Team 2021).

In Camus’s novel, the animal’s link to the epidemic seemed very clear since the beginning:Things got to the point where Infodoc (the agency for information and documentation, ‘ all you need to know on any subject’) announced in its free radio news programme that 6,231 rats had been collected and burned in a single day, the 25th. This figure, which gave a clear meaning to the daily spectacle that everyone in town had in front of their eyes, disconcerted them even more. (Camus 2002, Part I)This accuracy in figures is familiar to us. People nowadays have become very used to the statistical aspects of the levitra, due to the continuous updates in epidemiological parameters launched by the media and the authorities.

Camus was aware about the relevance of figures in epidemics, which always entail:…required registration and statistical tasks. (Camus 2002, Part II)Because of this, the novel is scattered with numbers, most of them concerning the daily death toll, but others mentioning the number of rats picked up, as we have seen, or combining the number of deaths with the time passed since the start of the epidemic:“ Will there be an autumn of plague?. Professor B answers. €˜ No’ ”, “ One hundred and twenty-four dead.

The total for the ninety-fourth day of the plague.” (Camus 2002, Part II)We permit ourselves to introduce here a list of recurring topics in La Peste, since the salience of statistical information is one of them. These topics, some of which will be treated later, appear several times in the novel, in various contexts and stages in the evolution of the epidemic. We synthesise them in Table 1, coupled with a erectile dysfunction treatment parallel example extracted from online press. This ease to find a current example for each topic suggests that they are not exclusive of plague or of Camus’s mindset, but shared by most epidemics.View this table:Table 1 Recurring topics in La Peste.

Each topic is accompanied by two examples from the novel and one concerning erectile dysfunction treatment, extracted from online press.Talking about journalism and the media (one of the topics above), we might say that erectile dysfunction treatment’s coverage is frequently too optimistic when managing good news and too alarming when approaching the bad. Media’s ‘exaggerated’ approach to health issues is not new. It was already a concern for medical journals’ editors a century ago (Reiling 2013) and it continues to be it for these professionals in recent times (Barbour et al. 2008).

It is well known that media tries to attract spectators’ attention by making the news more appealing. However, they deal with the risk of expanding unreliable information, which may be pernicious for the public opinion. Related to the intention of ‘garnishing’ the news, Aslam et al. (2020) have described that 82% of more than 100 000 pieces of information about erectile dysfunction treatment appearing in media from different countries carried an emotional, either negative (52%) or positive (30%) component, with only 18% of them considered as ‘neutral’ (Aslam et al.

2020). Some evidence about this tendency to make news more emotional was described in former epidemics. For instance, a study conducted in Singapore in 2009 during the H1N1 crisis showed how press releases by the Ministry of Health were substantially transformed when passed to the media, by increasing their emotional appeal and by changing their dominant frame or their tone (Lee and Basnyat 2013). In La Peste, this superficial way of managing information by the media is also observed:The newspapers followed the order that they had been given, to be optimistic at any cost.

(Camus 2002, Part IV)At the first stages of the epidemic in Oran, journalists proclaim the end of the dead rats’ invasion as something to be celebrated. Dr Rieux, the character through which Camus symbolises caution (and comparable nowadays to trustful scientists, well-informed journalists or sensible authorities), exposes then his own angle, quite far from suggesting optimism:The vendors of the evening papers were shouting that the invasion of rats had ended. But Rieux found his patient lying half out of bed, one hand on his belly and the other around his neck, convulsively vomiting reddish bile into a rubbish bin. (Camus 2002, Part I)Camus, who worked as a journalist for many years, insists afterwards on this cursory interest that some media devote to the epidemic, more eager to grab the noise than the relevant issues beneath it:The press, which had had so much to say about the business of the rats, fell silent.

This is because rats die in the street and people in their bedrooms. And newspapers are only concerned with the street. (Camus 2002, Part I)By then, Oranians continue rejecting the epidemic as an actual threat, completely immersed in that phase that dominates the beginning of all epidemics and is characterised by ‘denial and disbelief’ (Wigand, Becker, and Steger 2020, 443):A pestilence does not have human dimensions, so people tell themselves that it is unreal, that it is a bad dream which will end. […] The people of our town were no more guilty than anyone else, they merely forgot to be modest and thought that everything was still possible for them, which implied that pestilence was impossible.

They continued with business, with making arrangements for travel and holding opinions. Why should they have thought about the plague, which negates the future, negates journeys and debate?. They considered themselves free and no one will ever be free as long as there is plague, pestilence and famine. (Camus 2002, Part I)Probably to avoid citizens' disapproval, among other reasons, the Oranian Prefecture (health authority in Camus' novel) does not want to go too far when judging the relevance of the epidemic.

While not directly exposed, we can guess in this fragment the tone of the Prefect’s message, his intention to convey confidence despite his own doubts:These cases were not specific enough to be really disturbing and there was no doubt that the population would remain calm. None the less, for reasons of caution which everyone could understand, the Prefect was taking some preventive measures. If they were interpreted and applied in the proper way, these measures were such that they would put a definite stop to any threat of epidemic. As a result, the Prefect did not for a moment doubt that the citizens under his charge would co-operate in the most zealous manner with what he was doing.

(Camus 2002, Part I)The relevant role acquired by health authorities during epidemics is another topic listed in our table. Language use, on the other hand, is an issue linkable both with the media topic and with this one. As in La Peste, during erectile dysfunction treatment we have seen some public figures using words not always truthfully, carrying out a careful selection of words that serves to the goal of conveying certain interests in each moment. Dr Rieux refers in Part I to this language manipulation by the authorities:The measures that had been taken were insufficient, that was quite clear.

As for the ‘ specially equipped wards’, he knew what they were. Two outbuildings hastily cleared of other patients, their windows sealed up and the whole surrounded by a cordon sanitaire. (Camus 2002, Part I)He illustrates the need of frankness, the preference for clarity in language, which is often the clarity in thinking:No. I phoned Richard to say we needed comprehensive measures, not fine words, and that either we must set up a real barrier to the epidemic, or nothing at all.

(Camus 2002, Part I)At the end of this part, his fears about the inadequacy of not taking strict measures are confirmed. Oranian hospitals become overwhelmed, as they are now in many places worldwide due to erectile dysfunction treatment.Part IILeft behind the phases of ‘denial and disbelief’ and of ‘fear and panic’, it appears among the Oranians the ‘acceptance paired with resignation’ (Wigand, Becker, and Steger 2020, 443):Then we knew that our separation was going to last, and that we ought to try to come to terms with time. […] In particular, all of the people in our town very soon gave up, even in public, whatever habit they may have acquired of estimating the length of their separation. (Camus 2002, Part II)In erectile dysfunction treatment as well, even if border closure has not been so immovable as in Oran, many people have seen themselves separated from their loved ones and some of them have not yet had the possibility of reunion.

This is why, in the actual levitra, the idea of temporal horizons has emerged like it appeared in Camus’s epidemic. In Spain, the general lockdown in March and April 2020 made people establish the summer as their temporal horizon, a time in which they could resume their former habits and see their relatives again. This became partially true, and people were allowed in summer to travel inside the country and to some other countries nearby. However, there existed some reluctance to visit ill or aged relatives, due to the fear of infecting them, and some families living in distant countries were not able to get together.

Moreover, autumn brought an increase in the number of cases (‘the second wave’) and countries returned to limit their internal and external movements.Bringing all this together, many people nowadays have opted to discard temporal horizons. As Oranians, they have noted that the epidemic follows its own rhythm and it is useless to fight against it. Nonetheless, it is in human nature not to resign, so abandoning temporal horizons does not mean to give up longing for the recovery of normal life. This vision, neither maintaining vain hopes nor resigning, is in line with Camus’s philosophy, an author who wrote that ‘hope, contrary to what it is usually thought, is the same to resignation.’ (Camus 1939, 83.

Cited by Haroutunian 1964, 312 (translation is ours)), and that ‘there is not love to human life but with despair about human life.’ (Camus 1958, 112–5. Cited by Haroutunian 1964, 312–3 (translation is ours)).People nowadays deal with resignation relying on daily life pleasures (being not allowed to make further plans or trips) and in company from the nearest ones (as they cannot gather with relatives living far away). Second, they observe the beginning of vaccination campaigns as a first step of the final stage, and summer 2021, reflecting what happened with summer 2020, has been fixed as a temporal horizon. This preference for summers has an unavoidable metaphorical nuance, and their linking to joy, long trips and life in the streets may be the reason for which we choose them to be opposed to the lockdown and restrictions of the levitra.We alluded previously to the manipulation of language, and figures, as relevant as they are, they are not free from manipulation either.

Tarrou, a close friend to Dr Rieux, points out in this part of the novel how this occurred:Once more, Tarrou was the person who gave the most accurate picture of our life as it was then. Naturally he was following the course of the plague in general, accurately observing that a turning point in the epidemic was marked by the radio no longer announcing some hundreds of deaths per week, but 92, 107 and 120 deaths a day. €˜The newspapers and the authorities are engaged in a battle of wits with the plague. They think that they are scoring points against it, because 130 is a lower figure than 910.’ (Camus 2002, Part II)Tarrou collaborates with the health teams formed to tackle the plague.

Regarding these volunteers and workers, Camus refuses to consider them as heroes, as many essential workers during erectile dysfunction treatment have rejected to be named as that. The writer thinks their actions are the natural behaviour of good people, not heroism but ‘a logical consequence’:The whole question was to prevent the largest possible number of people from dying and suffering a definitive separation. There was only one way to do this, which was to fight the plague. There was nothing admirable about this truth, it simply followed as a logical consequence.

(Camus 2002, Part II)We consider suitable to talk here about two issues which represent, nowadays, a great part of erectile dysfunction treatment fears and hopes, respectively. New genetic variants and treatments. Medical achievements are another recurrent issue included in table 1, and we write about them here because it is in Part II where Camus writes for the first time about treatments, and where it insists on an idea aforementioned in Part I. That the plague bacillus affecting Oran is different from previous variants:…the microbe differed very slightly from the bacillus of plague as traditionally defined.

(Camus 2002, Part II)Related to erectile dysfunction treatment new variants, they represent a challenge because of two main reasons. Their higher transmissibility and/or severity and their higher propensity to skip the effect of natural or treatment-induced immunity. Public health professionals are determining which is the actual threat of all the new variants discovered, such as those first characterised in the UK (Public Health England 2020), South Africa (Tegally et al. 2021) or Brazil (Fujino et al.

2021). In La Peste, Dr Rieux is always suspecting that the current bacteria they are dealing with is different from the one in previous epidemics of plague. Since several genetic variations for the bacillus Yersinia pestis have been characterised (Cui et al. 2012), it could be possible that the epidemic in Oran originated from a new one.

However, we should not forget that we are analysing a literary work, and that scientific accuracy is not a necessary goal in it. In fact, Rieux’s reluctances have to do more with clinical aspects than with microbiological ones. He doubts since the beginning, relying exclusively on the symptoms observed, and continues doing it after the laboratory analysis:I was able to have an analysis made in which the laboratory thinks it can detect the plague bacillus. However, to be precise, we must say that certain specific modifications of the microbe do not coincide with the classic description of plague.

(Camus 2002, Part II)Camus is consistent with this idea and many times he mentions the bacillus to highlight its oddity. Insisting on the literary condition of the work, and among other possible explanations, he is maybe declaring that that in the novel is not a common (biological, natural) bacteria, but the Nazism bacteria.Turning to treatments, they constitute the principal resource that the global community has to defeat the erectile dysfunction treatment levitra. Vaccination campaigns have started all over the world, and three types of erectile dysfunction treatments are being applied in the European Union, after their respective statements of efficacy and security (Baden et al. 2021.

Polack et al. 2020. Voysey et al. 2021), while a fourth treatment has just recently been approved (EMA 2021a).

Although some concerns regarding the safety of two of these treatments have been raised recently (EMA 2021b. EMA 2021c), vaccination plans are going ahead, being adapted according to the state of knowledge at each moment. Some of these treatments are mRNA-based (Baden et al. 2021.

Polack et al. 2020), while others use a viral vector (Bos et al. 2020. Voysey et al.

2021). They are mainly two-shot treatments, with one exception (Bos et al. 2020), and complete immunity is thought to be acquired 2 weeks after the last shot (CDC. N.d.b, Voysey et al.

2021). Other countries such as China or Russia, on the other hand, were extremely early in starting their vaccination campaigns, and are distributing among their citizens different treatments than the aforementioned (Logunov et al. 2021. Zhang et al.

2021).Even if at least three types of plague treatments had been created by the time the novel takes place (Sun 2016), treatments do not play an important role in La Peste, in which therapeutic measures (the serum) are more important than prophylactic ones. Few times in the novel the narrator refers to prophylactic inoculations:There was still no possibility of vaccinating with preventive serum except in families already affected by the disease. (Camus 2002, Part II)Deudon has pointed out that Camus mixes up therapeutic serum and treatment (Deudon 1988), and in fact there exists a certain amount of confusion. All along the novel, the narrator focuses on the prophylactic goals of the serum, which is applied to people already infected (Othon’s son, Tarrou, Grand…).

However, both in the example above (which can be understood as vaccinating household contacts or already affected individuals) and in others, the differences between treating and vaccinating are not clear:After the morning admissions which he was in charge of himself, the patients were vaccinated and the swellings lanced. (Camus 2002, Part II)In any case, this is another situation in which Camus stands aside from scientific matters, which are to him less relevant in his novel than philosophical or literary ones. The distance existing between the relevance of treatments in erectile dysfunction treatment and the superficial manner with which Camus treats the topic in La Peste exemplifies this.Part IIIIn part III, the plague’s ravages become tougher. The narrator turns his focus to burials and their disturbance, a frequent topic in epidemics’ narrative (table 1).

Camus knew how acutely increasing demands and hygienic requirements affect funeral habits during epidemics:Everything really happened with the greatest speed and the minimum of risk. (Camus 2002, Part III)Like many other processes during epidemics, the burial process becomes a protocol. When protocolised, everything seems to work well and rapidly. But this perfect mechanism is the Prefecture’s goal, not Rieux’s.

He reveals in this moment an aspect in his character barely shown before. Irony.The whole thing was well organized and the Prefect expressed his satisfaction. He even told Rieux that, when all was said and done, this was preferable to hearses driven by black slaves which one read about in the chronicles of earlier plagues. €˜ Yes,’ Rieux said.

€˜ The burial is the same, but we keep a card index. No one can deny that we have made progress.’ (Camus 2002, Part III)Even if this characteristic may seem new in Dr Rieux, we must bear in mind that he is the story narrator, and the narration is ironic from time to time. For instance, speaking precisely about the burials:The relatives were invited to sign a register –which just showed the difference that there may be between men and, for example, dogs. You can keep check of human beings-.

(Camus 2002, Part III)In Camus’s philosophy, the absurd is a core issue. According to Lengers, Rieux is ironic because he is a kind of Sisyphus who has understood the absurdity of plague (Lengers 1994). The response to the absurd is to rebel (Camus 2013), and Rieux does it by helping his fellow humans without questioning anything. He does not pursue any other goal than doing his duty, thus humour (as a response to dire situations) stands out from him when he observes others celebrating irrelevant achievements, such as the Prefect with his burial protocol.

In the field of medical ethics, Lengers has highlighted the importance of Camus’s perspective when considering ‘the immediacy of life rather than abstract values’ (Lengers 1994, 250). Rieux himself is quite sure that his solid commitment is not ‘abstract’, and, even if he falls into abstraction, the importance relies on protecting human lives and not in the name given to that task:Was it truly an abstraction, spending his days in the hospital where the plague was working overtime, bringing the number of victims up to five hundred on average per week?. Yes, there was an element of abstraction and unreality in misfortune. But when an abstraction starts to kill you, you have to get to work on it.

(Camus 2002, Part II)Farewells during erectile dysfunction treatment may have not been particularly pleasant for some families. Neither those dying at nursing homes nor in hospitals could be accompanied by their families as previously, due to corpses management protocols, restrictions of external visitors and hygienic measures in general. However, as weeks passed by, certain efforts were made to ease this issue, allowing people to visit their dying beloved sticking to strict preventive measures. On the other hand, the number of people attending funeral masses and cemeteries was also limited, which affected the conventional development of ceremonies as well.

Hospitals had to deal with daily tolls of deaths never seen before, and the overcrowding of mortuaries made us see rows of coffins placed in unusual spaces, such as ice rinks (transformation of facilities is another topic in table 1).We turn now to two other points which erectile dysfunction treatment has not evaded. s among essential workers and epidemics’ economic consequences. The author links burials with s among essential workers because gravediggers constitute one of the most affected professions, and connects this fact with the economic recession because unemployment is behind the large availability of workers to replace the dead gravediggers:Many of the male nurses and the gravediggers, who were at first official, then casual, died of the plague. […] The most surprising thing was that there was never a shortage of men to do the job, for as long as the epidemic lasted.

[…] When the plague really took hold of the town, its very immoderation had one quite convenient outcome, because it disrupted the whole of economic life and so created quite a large number of unemployed. […] Poverty always triumphed over fear, to the extent that work was always paid according to the risk involved. (Camus 2002, Part III)The effects of the plague over the economic system are one of our recurrent topics (table 1). The plague in Oran, as it forces to close the city, impacts all trading exchanges.

In addition, it forbids travellers from arriving to the city, with the economic influence that that entails:This plague was the ruination of tourism. (Camus 2002, Part II)Oranians, who, as we saw, were very worried about making money, are especially affected by an event which jeopardises it. In erectile dysfunction treatment, for one reason or for another, most of the countries are suffering economic consequences, since the impact on normal life from the epidemic (another recurrent topic) means also an impact on the normal development of trading activities.Part IVIn Part IV we witness the first signals of a stabilisation of the epidemic:It seemed that the plague had settled comfortably into its peak and was carrying out its daily murders with the precision and regularity of a good civil servant. In theory, in the opinion of experts, this was a good sign.

The graph of the progress of the plague, starting with its constant rise, followed by this long plateau, seemed quite reassuring. (Camus 2002, Part IV)At this time, we consider interesting to expand the topic about the transformation of facilities. We mentioned the case of ice rinks during erectile dysfunction treatment, and we bring up now the use of a football pitch as a quarantine camp in Camus’s novel, a scene which has reminded some scholars of the metaphor of Nazism and concentration camps (Finel-Honigman 1978). In Spain, among other measures, a fairground was enabled as a field hospital during the first wave, and it is plausible that many devices created with other purposes were used in tasks attached to healthcare provision during those weeks, as occurred in Oran’s pitch with the loudspeakers:Then the loudspeakers, which in better times had served to introduce the teams or to declare the results of games, announced in a tinny voice that the internees should go back to their tents so that the evening meal could be distributed.

(Camus 2002, Part IV)Related to this episode, we can also highlight the opposition between science and humanism that Camus does. The author alerts us about the dangers of a dehumanised science, of choosing procedures perfectly efficient regardless of their lack in human dignity:The men held out their hands, two ladles were plunged into two of the pots and emerged to unload their contents onto two tin plates. The car drove on and the process was repeated at the next tent.‘ It’s scientific,’ Tarrou told the administrator.‘ Yes,’ he replied with satisfaction, as they shook hands. €˜ It’s scientific.’ (Camus 2002, Part IV)Several cases with favourable outcomes mark Part IV final moments and prepare the reader for the end of the epidemic.

To describe these signs of recovering, the narrator turns back to two elements with a main role in the novel. Rats and figures. In this moment, the first ones reappear and the second ones seem to be declining:He had seen two live rats come into his house through the street door. Neighbours had informed him that the creatures were also reappearing in their houses.

Behind the walls of other houses there was a hustle and bustle that had not been heard for months. Rieux waited for the general statistics to be published, as they were at the start of each week. They showed a decline in the disease. (Camus 2002, Part IV)Part VGiven that we continue facing erectile dysfunction treatment, and that forecasts about its end are not easy, we cannot compare ourselves with the Oranians once they have reached the end of the epidemic, what occurs in this part.

However, we can analyse our current situation, characterised by a widespread, though cautious, confidence motivated by the beginning of vaccination campaigns, referring it to the events narrated in Part V.Even more than the Oranians, since we feel further than them from the end of the problem, we are cautious about not to anticipate celebrations. From time to time, however, we lend ourselves to dream relying on what the narrator calls ‘a great, unadmitted hope’. erectile dysfunction treatment took us by surprise and everyone wants to ‘reorganise’ their life, as Oranians do, but patience is an indispensable component to succeed, as fictional and historical epidemics show us.Although this sudden decline in the disease was unexpected, the towns-people were in no hurry to celebrate. The preceding months, though they had increased the desire for liberation, had also taught them prudence and accustomed them to count less and less on a rapid end to the epidemic.

However, this new development was the subject of every conversation and, in the depths of people’s hearts, there was a great, unadmitted hope. […] One of the signs that a return to a time of good health was secretly expected (though no one admitted the fact) was that from this moment on people readily spoke, with apparent indifference, about how life would be reorganized after the plague. (Camus 2002, Part V)We put our hope on vaccination. Social distancing and other hygienic measures have proved to be effective, but treatments would bring us a more durable solution without compromising so hardly many economic activities and social habits.

As we said, a more important role of scientific aspects is observed in erectile dysfunction treatment if compared with La Peste (an expected fact if considered that Camus’s story is an artistic work, that he skips sometimes the most complex scientific issues of the plague and that health sciences have evolved substantially during last decades). Oranians, in fact, achieve the end of the epidemic not through clearly identified scientific responses but with certain randomness:All one could do was to observe that the sickness seemed to be going as it had arrived. The strategy being used against it had not changed. It had been ineffective yesterday, and now it was apparently successful.

One merely had the feeling that the disease had exhausted itself, or perhaps that it was retiring after achieving all its objectives. In a sense, its role was completed. (Camus 2002, Part V)They receive the announcement made by the Prefecture of reopening the town’s gates in 2 weeks time with enthusiasm. Dealing with concrete dates gives them certainty, helps them fix the temporal horizons we wrote about.

This is also the case when they are told that preventive measures would be lifted in 1 month. Camus shows us then how the main characters are touched as well by this positive atmosphere:That evening Tarrou and Rieux, Rambert and the rest, walked in the midst of the crowd, and they too felt they were treading on air. Long after leaving the boulevards Tarrou and Rieux could still hear the sounds of happiness following them… (Camus 2002, Part V)Then, Tarrou points out a sign of recovery coming from the animal world. In a direct zoological chain, infected fleas have vanished from rats, which have been able again to multiply across the city, making the cats abandon their hiding places and to go hunting after them again.

At the final step of this chain, Tarrou sees the human being. He remembers the old man who used to spit to the cats beneath his window:At a time when the noise grew louder and more joyful, Tarrou stopped. A shape was running lightly across the dark street. It was a cat, the first that had been seen since the spring.

It stopped for a moment in the middle of the road, hesitated, licked its paw, quickly passed it across its right ear, then carried on its silent way and vanished into the night. Tarrou smiled. The little old man, too, would be happy. (Camus 2002, Part V)Unpleasant things as a town with rats running across its streets, or a man spending his time spitting on a group of cats, constitute normality as much as the reopening of gates or the reboot of commerce.

However, when Camus speaks directly about normality, he highlights more appealing habits. He proposes common leisure activities (restaurants, theatres) as symbols of human life, since he opposes them to Cottard’s life, which has become that of a ‘wild animal’:At least in appearance he [ Cottard ] retired from the world and from one day to the next started to live like a wild animal. He no longer appeared in restaurants, at the theatre or in his favourite cafés. (Camus 2002, Part V)We do not disclose why Cottard’s reaction to the end of the epidemic is different from most of the Oranians’.

In any case, the narrator insists later on the assimilation between common pleasures and normality:‘ Perhaps,’ Cottard said, ‘ Perhaps so. But what do you call a return to normal life?. €™ ‘ New films in the cinema,’ said Tarrou with a smile. (Camus 2002, Part V)Cinema, as well as theatre, live music and many other cultural events have been cancelled or obliged to modify their activities due to erectile dysfunction treatment.

Several bars and restaurants have closed, and spending time in those who remain open has become an activity which many people tend to avoid, fearing contagion. Thus, normality in our understanding is linked as well to these simple and pleasant habits, and the complete achievement of them will probably signify for us the desired defeat of the levitra.In La Peste, love is also seen as a simple good to be fully recovered after the plague. While Rieux goes through the ‘reborn’ Oran, it is lovers’ gatherings what he highlights. Unlike them, everyone who, during the epidemic, sought for goals different from love (such as faith or money, for instance) remain lost when the epidemic has ended:For all the people who, on the contrary, had looked beyond man to something that they could not even imagine, there had been no reply.

(Camus 2002, Part V)And this is because lovers, as the narrator says:If they had found that they wanted, it was because they had asked for the only thing that depended on them. (Camus 2002, Part V)We have spoken before about language manipulation, hypocrisy and public figures’ roles during epidemics. Camus, during Dr Rieux’s last visit to the old asthmatic man, makes this frank and humble character criticise, with a point of irony, the authorities’ attitude concerning tributes to the dead:‘ Tell me, doctor, is it true that they’re going to put up a monument to the victims of the plague?. €™â€˜ So the papers say.

A pillar or a plaque.’‘ I knew it!. And there’ll be speeches.’The old man gave a strangled laugh.‘ I can hear them already. €œ Our dead…” Then they’ll go and have dinner.’ (Camus 2002, Part V)The old man illustrates wisely the authorities’ propensity for making speeches. He knows that most of them usually prefer grandiloquence rather than common words, and seizes perfectly their tone when he imitates them (‘Our dead…’).

We have also got used, during erectile dysfunction treatment, to these types of messages. We have also heard about ‘our old people’, ‘our youth’, ‘our essential workers’ and even ‘our dead’. Behind this tone, however, there could be an intention to hide errors, or to falsely convey carefulness. Honest rulers do not usually need nice words.

They just want them to be accurate.We have seen as well some tributes to the victims during erectile dysfunction treatment, some of which we can doubt whether they serve to victims’ relief or to authorities’ promotion. We want rulers to be less aware of their own image and to stress truthfulness as a goal, even if this is a hard requirement not only for them, but for every single person. Language is essential in this issue, we think, since it is prone to be twisted and to become untrue. The old asthmatic man illustrates it with his ‘There’ll be speeches’ and his ‘Our dead…’, but this is not the only time in the novel in which Camus brings out the topic.

For instance, he does so when he equates silence (nothing can be thought as further from wordiness) with truth:It is at the moment of misfortune that one becomes accustomed to truth, that is to say to silence. (Camus 2002, Part II)or when he makes a solid statement against false words:…I understood that all the misfortunes of mankind came from not stating things in clear terms. (Camus 2002, Part IV)The old asthmatic, in fact, while praising the deceased Tarrou, remarks that he used to admire him because ‘he didn’t talk just for the sake of it.’ (Camus 2002, Part V).Related to this topic, what the old asthmatic says about political authorities may be transposed in our case to other public figures, such as scholars and researchers, media leaders, businessmen and women, health professionals… and, if we extend the scope, to every single citizen. Because hypocrisy, language manipulation and the fact of putting individual interests ahead of collective welfare fit badly with collective issues such as epidemics.

Hopefully, also examples to the contrary have been observed during erectile dysfunction treatment.The story ends with the fireworks in Oran and the depiction of Dr Rieux’s last feelings. While he is satisfied because of his medical performance and his activity as a witness of the plague, he is concerned about future disasters to come. When erectile dysfunction treatment will have passed, it will be time for us as well to review our life during these months. For now, we are just looking forward to achieving our particular ‘part V’.AbstractThis study addresses the existing gap in literature that ethnographically examines the experiences of Spanish-speaking patients with limited English proficiency in clinical spaces.

All of the participants in this study presented to the emergency department (ED) for evaluation of non-urgent health conditions. Patient shadowing was employed to explore the challenges that this population face in unique clinical settings like the ED. This relatively new methodology facilitates obtaining nuanced understandings of clinical contexts under study in ways that quantitative approaches and survey research do not. Drawing from the field of medical anthropology and approach of narrative medicine, the collected data are presented through the use of clinical ethnographic vignettes and thick description.

The conceptual framework of health-related deservingness guided the analysis undertaken in this study. Structural stigma was used as a complementary framework in analysing the emergent themes in the data collected. The results and analysis from this study were used to develop an argument for the consideration of language as a distinct social determinant of health.emergency medicinemedical anthropologymedical humanitiesData availability statementData sharing not applicable as no datasets were generated and/or analysed for this study..

IntroductionLa Peste (Camus 1947) has served as a basis for several http://mangomgmt.co.uk/shops/shop-creative-metro/ critical works, including some in the field of medical buy discount levitra humanities (Bozzaro 2018. Deudon 1988. Tuffuor and Payne buy discount levitra 2017). Frequently interpreted as an allegory of Nazism (with the plague as a symbol of the German occupation of France) (Finel-Honigman 1978. Haroutunian 1964), it has also received philosophical readings beyond the sociopolitical context in which it was written (Lengers 1994).

Other scholars, on the other hand, have centred their analyses on its buy discount levitra literary aspects (Steel 2016).The erectile dysfunction treatment levitra has increased general interest about historical and fictional epidemics. La Peste, as one of the most famous literary works about this topic, has been revisited by many readers during recent months, leading to an unexpected growth in sales in certain countries (Wilsher 2020. Zaretsky 2020). Apart from that, commentaries about the novel, especially buy discount levitra among health sciences scholars, have emerged with a renewed interest (Banerjee et al. 2020.

Bate 2020. Vandekerckhove 2020 buy discount levitra. Wigand, Becker, and Steger 2020). This sudden curiosity is easy to understand if we consider both La Peste’s literary value, and people’s desire to discover real or fictional situations similar to theirs. Indeed, Oran buy discount levitra inhabitants’ experiences are not quite far from our own, even if geographical, chronological and, specially, scientific factors (two different diseases occurring at two different stages in the history of medical development) prevent us from establishing too close resemblances between both situations.Furthermore, it will not be strange if erectile dysfunction treatment serves as a frame for fictional works in the near future.

Other narrative plays were based on historical epidemics, such as Daniel Defoe’s A Journal of the Plague Year or Giovanni Boccaccio’s Decameron (Wigand, Becker, and Steger 2020. Withington 2020). The biggest levitra in the last century, the so-called ‘Spanish Influenza’, has been described as not very fruitful in this sense, even if it produced famous novels such as Katherine buy discount levitra A Porter’s Pale Horse, Pale Rider or John O’Hara’s The Doctor Son (Honigsbaum 2018. Hovanec 2011). The overlapping with another disaster like World War I has been argued as one of the reasons explaining this scarce production of fictional works (Honigsbaum 2018).

By contrast, we may think that erectile dysfunction treatment is having a global impact hardly overshadowed by other events, and that it will leave a significant mark on the collective memory.Drawing on the reading of La Peste, we point out in this essay different aspects of living under buy discount levitra an epidemic that can be identified both in Camus’s work and in our current situation. We propose a trip throughout the novel, from its early beginning in Part I, when the Oranians are not aware of the threat to come, to its end in Part V, when they are relieved of the epidemic after several months of ravaging disasters.We think this journey along La Peste may be interesting both to health professionals and to the lay person, since all of them will be able to see themselves reflected in the characters from the novel. We do not skip critique of some aspects related to the authorities’ management of erectile dysfunction treatment, as Camus does concerning Oran’s rulers. However, what we want to foreground is La Peste’s intrinsic value, its suitability to be read now and after erectile dysfunction treatment has passed, when Camus’s novel endures as a solid art work and erectile dysfunction treatment remains only as a defeated plight.MethodsWe confronted our own experiences about erectile dysfunction treatment with buy discount levitra a conventional reading of La Peste. A first reading of the novel was used to establish associations between those aspects which more saliently reminded us of erectile dysfunction treatment.

In a second reading, we searched for some examples to illustrate those aspects and tried to detect new associations. Subsequent readings of buy discount levitra certain parts were done to integrate the information collected. Neither specific methods of literary analysis, nor systematic searches in the novel were applied. Selected paragraphs and ideas from Part I to Part V were prepared in a draft copy, and this manuscript was written afterwards.Part ISome phrases in the novel could be transposed word by word to our situation. This one pertaining to its start, for instance, may make us remember the first months of 2020:By now, it will be easy to accept that nothing could lead the people buy discount levitra of our town to expect the events that took place in the spring of that year and which, as we later understood, were like the forerunners of the series of grave happenings that this history intends to describe.

(Camus 2002, Part I)By referring from the beginning to ‘the people of our town’, Camus is already suggesting an idea which is repeated all along the novel, and which may be well understood by us as erectile dysfunction treatment’s witnesses. Epidemics affect the community as a whole, they are present in everybody’s mind and their joys and sorrows are not individual, but collective. For example (and we are anticipating Part II), the narrator says:But, once the gates were closed, they all noticed that they were in the same boat, including the narrator himself, and that they had buy discount levitra to adjust to the fact. (Camus 2002, Part II)Later, he will insist in this opposition between the concepts of ‘individual’, which used to prevail before the epidemic, and ‘collective’:One might say that the first effect of this sudden and brutal attack of the disease was to force the citizens of our town to act as though they had no individual feelings. (Camus 2002, Part II)There were no longer any individual destinies, but a collective history that was the plague, and feelings shared by all.

(Camus 2002, Part III)This distinction is not trivial, since the story will display a buy discount levitra strong confrontation between those who get involved and help their neighbours and those who remain behaving selfishly. Related to this, Claudia Bozzaro has pointed out that the main topic in La Peste is solidarity and auistic love (Bozzaro 2018). We may add that the disease is so attached to people’s lives that the epidemic becomes the new everyday life:In the morning, they would return to the pestilence, that is to say, to routine. (Camus 2002, Part III)Being collective buy discount levitra issues does not mean that epidemics always enhance auism and solidarity. As said by Wigand et al, they frequently produce ambivalent reactions, and one of them is the opposition between auism and maximised profit (Wigand, Becker, and Steger 2020).

Therefore, the dichotomy between individualism and collectivism, a central point in the characterisation of national cultures (Hofstede 2015), could play a role in epidemics. In fact, buy discount levitra concerning erectile dysfunction treatment, some authors have described a greater impact of the levitra in those countries with higher levels of individualism (Maaravi et al. 2021. Ozkan et al. 2021).

However, this finding should be complemented with other national cultures’ aspects before concluding that collectivism itself exerts a protective role against epidemics. Concerning this, it has been shown how ‘power distance’ frequently intersects with collectivism, being only a few countries in which the last one coexists with a small distance to power, namely with a capacity to disobey the power authority (Gupta, Shoja, and Mikalef 2021). Moreover, those countries classically classified as ‘collectivist’ (China, Japan, South Korea, India, Vietnam, etc.) are also characterised by high levels of power distance, and their citizens have been quite often forced to adhere to erectile dysfunction treatment restrictions and punished if not (Gupta, Shoja, and Mikalef 2021). Thus, it is important to consider that individualism is not always opposed to ‘look after each other’ (Ozkan et al. 2021, 9).

For instance, the European region, seen as a whole as highly ‘individualistic’, holds some of the most advanced welfare protection systems worldwide. It is worth considering too that collectivism may hide sometimes a hard institutional authority or a lack in civil freedoms.Coming back to La Peste, we may think that Camus’s Oranians are not particularly ‘collectivist’. Their initial description highlights that they are mainly interested in their own businesses and affairs:Our fellow-citizens work a good deal, but always in order to make money. They are especially interested in trade and first of all, as they say, they are engaged in doing business. (Camus 2002, Part I)And later, we see some of them trying selfishly to leave the city by illegal methods.

By contrast, we observe in the novel some examples of more ‘collectivistic’ attitudes, such as the discipline of those quarantined at the football pitch, and, over all, the main characters’ behaviour, which is generally driven by auism and common goals.Turning to another topic, the plague in Oran and erectile dysfunction treatment are similar regarding their animal origin. This is not rare since many infectious diseases pass to humans through contact with animal vectors, being rodents, especially rats (through rat fleas), the most common carriers of plague bacteria (CDC. N.d.a, ECDC. N.d, Pollitzer 1954). Concerning erectile dysfunction, even if further research about its origin is needed, the most recent investigations conducted in China by the WHO establish a zoonotic transmission as the most probable pathway (Joint WHO-China Study Team 2021).

In Camus’s novel, the animal’s link to the epidemic seemed very clear since the beginning:Things got to the point where Infodoc (the agency for information and documentation, ‘ all you need to know on any subject’) announced in its free radio news programme that 6,231 rats had been collected and burned in a single day, the 25th. This figure, which gave a clear meaning to the daily spectacle that everyone in town had in front of their eyes, disconcerted them even more. (Camus 2002, Part I)This accuracy in figures is familiar to us. People nowadays have become very used to the statistical aspects of the levitra, due to the continuous updates in epidemiological parameters launched by the media and the authorities. Camus was aware about the relevance of figures in epidemics, which always entail:…required registration and statistical tasks.

(Camus 2002, Part II)Because of this, the novel is scattered with numbers, most of them concerning the daily death toll, but others mentioning the number of rats picked up, as we have seen, or combining the number of deaths with the time passed since the start of the epidemic:“ Will there be an autumn of plague?. Professor B answers. €˜ No’ ”, “ One hundred and twenty-four dead. The total for the ninety-fourth day of the plague.” (Camus 2002, Part II)We permit ourselves to introduce here a list of recurring topics in La Peste, since the salience of statistical information is one of them. These topics, some of which will be treated later, appear several times in the novel, in various contexts and stages in the evolution of the epidemic.

We synthesise them in Table 1, coupled with a erectile dysfunction treatment parallel example extracted from online press. This ease to find a current example for each topic suggests that they are not exclusive of plague or of Camus’s mindset, but shared by most epidemics.View this table:Table 1 Recurring topics in La Peste. Each topic is accompanied by two examples from the novel and one concerning erectile dysfunction treatment, extracted from online press.Talking about journalism and the media (one of the topics above), we might say that erectile dysfunction treatment’s coverage is frequently too optimistic when managing good news and too alarming when approaching the bad. Media’s ‘exaggerated’ approach to health issues is not new. It was already a concern for medical journals’ editors a century ago (Reiling 2013) and it continues to be it for these professionals in recent times (Barbour et al.

2008). It is well known that media tries to attract spectators’ attention by making the news more appealing. However, they deal with the risk of expanding unreliable information, which may be pernicious for the public opinion. Related to the intention of ‘garnishing’ the news, Aslam et al. (2020) have described that 82% of more than 100 000 pieces of information about erectile dysfunction treatment appearing in media from different countries carried an emotional, either negative (52%) or positive (30%) component, with only 18% of them considered as ‘neutral’ (Aslam et al.

2020). Some evidence about this tendency to make news more emotional was described in former epidemics. For instance, a study conducted in Singapore in 2009 during the H1N1 crisis showed how press releases by the Ministry of Health were substantially transformed when passed to the media, by increasing their emotional appeal and by changing their dominant frame or their tone (Lee and Basnyat 2013). In La Peste, this superficial way of managing information by the media is also observed:The newspapers followed the order that they had been given, to be optimistic at any cost. (Camus 2002, Part IV)At the first stages of the epidemic in Oran, journalists proclaim the end of the dead rats’ invasion as something to be celebrated.

Dr Rieux, the character through which Camus symbolises caution (and comparable nowadays to trustful scientists, well-informed journalists or sensible authorities), exposes then his own angle, quite far from suggesting optimism:The vendors of the evening papers were shouting that the invasion of rats had ended. But Rieux found his patient lying half out of bed, one hand on his belly and the other around his neck, convulsively vomiting reddish bile into a rubbish bin. (Camus 2002, Part I)Camus, who worked as a journalist for many years, insists afterwards on this cursory interest that some media devote to the epidemic, more eager to grab the noise than the relevant issues beneath it:The press, which had had so much to say about the business of the rats, fell silent. This is because rats die in the street and people in their bedrooms. And newspapers are only concerned with the street.

(Camus 2002, Part I)By then, Oranians continue rejecting the epidemic as an actual threat, completely immersed in that phase that dominates the beginning of all epidemics and is characterised by ‘denial and disbelief’ (Wigand, Becker, and Steger 2020, 443):A pestilence does not have human dimensions, so people tell themselves that it is unreal, that it is a bad dream which will end. […] The people of our town were no more guilty than anyone else, they merely forgot to be modest and thought that everything was still possible for them, which implied that pestilence was impossible. They continued with business, with making arrangements for travel and holding opinions. Why should they have thought about the plague, which negates the future, negates journeys and debate?. They considered themselves free and no one will ever be free as long as there is plague, pestilence and famine.

(Camus 2002, Part I)Probably to avoid citizens' disapproval, among other reasons, the Oranian Prefecture (health authority in Camus' novel) does not want to go too far when judging the relevance of the epidemic. While not directly exposed, we can guess in this fragment the tone of the Prefect’s message, his intention to convey confidence despite his own doubts:These cases were not specific enough to be really disturbing and there was no doubt that the population would remain calm. None the less, for reasons of caution which everyone could understand, the Prefect was taking some preventive measures. If they were interpreted and applied in the proper way, these measures were such that they would put a definite stop to any threat of epidemic. As a result, the Prefect did not for a moment doubt that the citizens under his charge would co-operate in the most zealous manner with what he was doing.

(Camus 2002, Part I)The relevant role acquired by health authorities during epidemics is another topic listed in our table. Language use, on the other hand, is an issue linkable both with the media topic and with this one. As in La Peste, during erectile dysfunction treatment we have seen some public figures using words not always truthfully, carrying out a careful selection of words that serves to the goal of conveying certain interests in each moment. Dr Rieux refers in Part I to this language manipulation by the authorities:The measures that had been taken were insufficient, that was quite clear. As for the ‘ specially equipped wards’, he knew what they were.

Two outbuildings hastily cleared of other patients, their windows sealed up and the whole surrounded by a cordon sanitaire. (Camus 2002, Part I)He illustrates the need of frankness, the preference for clarity in language, which is often the clarity in thinking:No. I phoned Richard to say we needed comprehensive measures, not fine words, and that either we must set up a real barrier to the epidemic, or nothing at all. (Camus 2002, Part I)At the end of this part, his fears about the inadequacy of not taking strict measures are confirmed. Oranian hospitals become overwhelmed, as they are now in many places worldwide due to erectile dysfunction treatment.Part IILeft behind the phases of ‘denial and disbelief’ and of ‘fear and panic’, it appears among the Oranians the ‘acceptance paired with resignation’ (Wigand, Becker, and Steger 2020, 443):Then we knew that our separation was going to last, and that we ought to try to come to terms with time.

[…] In particular, all of the people in our town very soon gave up, even in public, whatever habit they may have acquired of estimating the length of their separation. (Camus 2002, Part II)In erectile dysfunction treatment as well, even if border closure has not been so immovable as in Oran, many people have seen themselves separated from their loved ones and some of them have not yet had the possibility of reunion. This is why, in the actual levitra, the idea of temporal horizons has emerged like it appeared in Camus’s epidemic. In Spain, the general lockdown in March and April 2020 made people establish the summer as their temporal horizon, a time in which they could resume their former habits and see their relatives again. This became partially true, and people were allowed in summer to travel inside the country and to some other countries nearby.

However, there existed some reluctance to visit ill or aged relatives, due to the fear of infecting them, and some families living in distant countries were not able to get together. Moreover, autumn brought an increase in the number of cases (‘the second wave’) and countries returned to limit their internal and external movements.Bringing all this together, many people nowadays have opted to discard temporal horizons. As Oranians, they have noted that the epidemic follows its own rhythm and it is useless to fight against it. Nonetheless, it is in human nature not to resign, so abandoning temporal horizons does not mean to give up longing for the recovery of normal life. This vision, neither maintaining vain hopes nor resigning, is in line with Camus’s philosophy, an author who wrote that ‘hope, contrary to what it is usually thought, is the same to resignation.’ (Camus 1939, 83.

Cited by Haroutunian 1964, 312 (translation is ours)), and that ‘there is not love to human life but with despair about human life.’ (Camus 1958, 112–5. Cited by Haroutunian 1964, 312–3 (translation is ours)).People nowadays deal with resignation relying on daily life pleasures (being not allowed to make further plans or trips) and in company from the nearest ones (as they cannot gather with relatives living far away). Second, they observe the beginning of vaccination campaigns as a first step of the final stage, and summer 2021, reflecting what happened with summer 2020, has been fixed as a temporal horizon. This preference for summers has an unavoidable metaphorical nuance, and their linking to joy, long trips and life in the streets may be the reason for which we choose them to be opposed to the lockdown and restrictions of the levitra.We alluded previously to the manipulation of language, and figures, as relevant as they are, they are not free from manipulation either. Tarrou, a close friend to Dr Rieux, points out in this part of the novel how this occurred:Once more, Tarrou was the person who gave the most accurate picture of our life as it was then.

Naturally he was following the course of the plague in general, accurately observing that a turning point in the epidemic was marked by the radio no longer announcing some hundreds of deaths per week, but 92, 107 and 120 deaths a day. €˜The newspapers and the authorities are engaged in a battle of wits with the plague. They think that they are scoring points against it, because 130 is a lower figure than 910.’ (Camus 2002, Part II)Tarrou collaborates with the health teams formed to tackle the plague. Regarding these volunteers and workers, Camus refuses to consider them as heroes, as many essential workers during erectile dysfunction treatment have rejected to be named as that. The writer thinks their actions are the natural behaviour of good people, not heroism but ‘a logical consequence’:The whole question was to prevent the largest possible number of people from dying and suffering a definitive separation.

There was only one way to do this, which was to fight the plague. There was nothing admirable about this truth, it simply followed as a logical consequence. (Camus 2002, Part II)We consider suitable to talk here about two issues which represent, nowadays, a great part of erectile dysfunction treatment fears and hopes, respectively. New genetic variants and treatments. Medical achievements are another recurrent issue included in table 1, and we write about them here because it is in Part II where Camus writes for the first time about treatments, and where it insists on an idea aforementioned in Part I.

That the plague bacillus affecting Oran is different from previous variants:…the microbe differed very slightly from the bacillus of plague as traditionally defined. (Camus 2002, Part II)Related to erectile dysfunction treatment new variants, they represent a challenge because of two main reasons. Their higher transmissibility and/or severity and their higher propensity to skip the effect of natural or treatment-induced immunity. Public health professionals are determining which is the actual threat of all the new variants discovered, such as those first characterised in the UK (Public Health England 2020), South Africa (Tegally et al. 2021) or Brazil (Fujino et al.

2021). In La Peste, Dr Rieux is always suspecting that the current bacteria they are dealing with is different from the one in previous epidemics of plague. Since several genetic variations for the bacillus Yersinia pestis have been characterised (Cui et al. 2012), it could be possible that the epidemic in Oran originated from a new one. However, we should not forget that we are analysing a literary work, and that scientific accuracy is not a necessary goal in it.

In fact, Rieux’s reluctances have to do more with clinical aspects than with microbiological ones. He doubts since the beginning, relying exclusively on the symptoms observed, and continues doing it after the laboratory analysis:I was able to have an analysis made in which the laboratory thinks it can detect the plague bacillus. However, to be precise, we must say that certain specific modifications of the microbe do not coincide with the classic description of plague. (Camus 2002, Part II)Camus is consistent with this idea and many times he mentions the bacillus to highlight its oddity. Insisting on the literary condition of the work, and among other possible explanations, he is maybe declaring that that in the novel is not a common (biological, natural) bacteria, but the Nazism bacteria.Turning to treatments, they constitute the principal resource that the global community has to defeat the erectile dysfunction treatment levitra.

Vaccination campaigns have started all over the world, and three types of erectile dysfunction treatments are being applied in the European Union, after their respective statements of efficacy and security (Baden et al. 2021. Polack et al. 2020. Voysey et al.

2021), while a fourth treatment has just recently been approved (EMA 2021a). Although some concerns regarding the safety of two of these treatments have been raised recently (EMA 2021b. EMA 2021c), vaccination plans are going ahead, being adapted according to the state of knowledge at each moment. Some of these treatments are mRNA-based (Baden et al. 2021.

Polack et al. 2020), while others use a viral vector (Bos et al. 2020. Voysey et al. 2021).

They are mainly two-shot treatments, with one exception (Bos et al. 2020), and complete immunity is thought to be acquired 2 weeks after the last shot (CDC. N.d.b, Voysey et al. 2021). Other countries such as China or Russia, on the other hand, were extremely early in starting their vaccination campaigns, and are distributing among their citizens different treatments than the aforementioned (Logunov et al.

2021. Zhang et al. 2021).Even if at least three types of plague treatments had been created by the time the novel takes place (Sun 2016), treatments do not play an important role in La Peste, in which therapeutic measures (the serum) are more important than prophylactic ones. Few times in the novel the narrator refers to prophylactic inoculations:There was still no possibility of vaccinating with preventive serum except in families already affected by the disease. (Camus 2002, Part II)Deudon has pointed out that Camus mixes up therapeutic serum and treatment (Deudon 1988), and in fact there exists a certain amount of confusion.

All along the novel, the narrator focuses on the prophylactic goals of the serum, which is applied to people already infected (Othon’s son, Tarrou, Grand…). However, both in the example above (which can be understood as vaccinating household contacts or already affected individuals) and in others, the differences between treating and vaccinating are not clear:After the morning admissions which he was in charge of himself, the patients were vaccinated and the swellings lanced. (Camus 2002, Part II)In any case, this is another situation in which Camus stands aside from scientific matters, which are to him less relevant in his novel than philosophical or literary ones. The distance existing between the relevance of treatments in erectile dysfunction treatment and the superficial manner with which Camus treats the topic in La Peste exemplifies this.Part IIIIn part III, the plague’s ravages become tougher. The narrator turns his focus to burials and their disturbance, a frequent topic in epidemics’ narrative (table 1).

Camus knew how acutely increasing demands and hygienic requirements affect funeral habits during epidemics:Everything really happened with the greatest speed and the minimum of risk. (Camus 2002, Part III)Like many other processes during epidemics, the burial process becomes a protocol. When protocolised, everything seems to work well and rapidly. But this perfect mechanism is the Prefecture’s goal, not Rieux’s. He reveals in this moment an aspect in his character barely shown before.

Irony.The whole thing was well organized and the Prefect expressed his satisfaction. He even told Rieux that, when all was said and done, this was preferable to hearses driven by black slaves which one read about in the chronicles of earlier plagues. €˜ Yes,’ Rieux said. €˜ The burial is the same, but we keep a card index. No one can deny that we have made progress.’ (Camus 2002, Part III)Even if this characteristic may seem new in Dr Rieux, we must bear in mind that he is the story narrator, and the narration is ironic from time to time.

For instance, speaking precisely about the burials:The relatives were invited to sign a register –which just showed the difference that there may be between men and, for example, dogs. You can keep check of human beings-. (Camus 2002, Part III)In Camus’s philosophy, the absurd is a core issue. According to Lengers, Rieux is ironic because he is a kind of Sisyphus who has understood the absurdity of plague (Lengers 1994). The response to the absurd is to rebel (Camus 2013), and Rieux does it by helping his fellow humans without questioning anything.

He does not pursue any other goal than doing his duty, thus humour (as a response to dire situations) stands out from him when he observes others celebrating irrelevant achievements, such as the Prefect with his burial protocol. In the field of medical ethics, Lengers has highlighted the importance of Camus’s perspective when considering ‘the immediacy of life rather than abstract values’ (Lengers 1994, 250). Rieux himself is quite sure that his solid commitment is not ‘abstract’, and, even if he falls into abstraction, the importance relies on protecting human lives and not in the name given to that task:Was it truly an abstraction, spending his days in the hospital where the plague was working overtime, bringing the number of victims up to five hundred on average per week?. Yes, there was an element of abstraction and unreality in misfortune. But when an abstraction starts to kill you, you have to get to work on it.

(Camus 2002, Part II)Farewells during erectile dysfunction treatment may have not been particularly pleasant for some families. Neither those dying at nursing homes nor in hospitals could be accompanied by their families as previously, due to corpses management protocols, restrictions of external visitors and hygienic measures in general. However, as weeks passed by, certain efforts were made to ease this issue, allowing people to visit their dying beloved sticking to strict preventive measures. On the other hand, the number of people attending funeral masses and cemeteries was also limited, which affected the conventional development of ceremonies as well. Hospitals had to deal with daily tolls of deaths never seen before, and the overcrowding of mortuaries made us see rows of coffins placed in unusual spaces, such as ice rinks (transformation of facilities is another topic in table 1).We turn now to two other points which erectile dysfunction treatment has not evaded.

s among essential workers and epidemics’ economic consequences. The author links burials with s among essential workers because gravediggers constitute one of the most affected professions, and connects this fact with the economic recession because unemployment is behind the large availability of workers to replace the dead gravediggers:Many of the male nurses and the gravediggers, who were at first official, then casual, died of the plague. […] The most surprising thing was that there was never a shortage of men to do the job, for as long as the epidemic lasted. […] When the plague really took hold of the town, its very immoderation had one quite convenient outcome, because it disrupted the whole of economic life and so created quite a large number of unemployed. […] Poverty always triumphed over fear, to the extent that work was always paid according to the risk involved.

(Camus 2002, Part III)The effects of the plague over the economic system are one of our recurrent topics (table 1). The plague in Oran, as it forces to close the city, impacts all trading exchanges. In addition, it forbids travellers from arriving to the city, with the economic influence that that entails:This plague was the ruination of tourism. (Camus 2002, Part II)Oranians, who, as we saw, were very worried about making money, are especially affected by an event which jeopardises it. In erectile dysfunction treatment, for one reason or for another, most of the countries are suffering economic consequences, since the impact on normal life from the epidemic (another recurrent topic) means also an impact on the normal development of trading activities.Part IVIn Part IV we witness the first signals of a stabilisation of the epidemic:It seemed that the plague had settled comfortably into its peak and was carrying out its daily murders with the precision and regularity of a good civil servant.

In theory, in the opinion of experts, this was a good sign. The graph of the progress of the plague, starting with its constant rise, followed by this long plateau, seemed quite reassuring. (Camus 2002, Part IV)At this time, we consider interesting to expand the topic about the transformation of facilities. We mentioned the case of ice rinks during erectile dysfunction treatment, and we bring up now the use of a football pitch as a quarantine camp in Camus’s novel, a scene which has reminded some scholars of the metaphor of Nazism and concentration camps (Finel-Honigman 1978). In Spain, among other measures, a fairground was enabled as a field hospital during the first wave, and it is plausible that many devices created with other purposes were used in tasks attached to healthcare provision during those weeks, as occurred in Oran’s pitch with the loudspeakers:Then the loudspeakers, which in better times had served to introduce the teams or to declare the results of games, announced in a tinny voice that the internees should go back to their tents so that the evening meal could be distributed.

(Camus 2002, Part IV)Related to this episode, we can also highlight the opposition between science and humanism that Camus does. The author alerts us about the dangers of a dehumanised science, of choosing procedures perfectly efficient regardless of their lack in human dignity:The men held out their hands, two ladles were plunged into two of the pots and emerged to unload their contents onto two tin plates. The car drove on and the process was repeated at the next tent.‘ It’s scientific,’ Tarrou told the administrator.‘ Yes,’ he replied with satisfaction, as they shook hands. €˜ It’s scientific.’ (Camus 2002, Part IV)Several cases with favourable outcomes mark Part IV final moments and prepare the reader for the end of the epidemic. To describe these signs of recovering, the narrator turns back to two elements with a main role in the novel.

Rats and figures. In this moment, the first ones reappear and the second ones seem to be declining:He had seen two live rats come into his house through the street door. Neighbours had informed him that the creatures were also reappearing in their houses. Behind the walls of other houses there was a hustle and bustle that had not been heard for months. Rieux waited for the general statistics to be published, as they were at the start of each week.

They showed a decline in the disease. (Camus 2002, Part IV)Part VGiven that we continue facing erectile dysfunction treatment, and that forecasts about its end are not easy, we cannot compare ourselves with the Oranians once they have reached the end of the epidemic, what occurs in this part. However, we can analyse our current situation, characterised by a widespread, though cautious, confidence motivated by the beginning of vaccination campaigns, referring it to the events narrated in Part V.Even more than the Oranians, since we feel further than them from the end of the problem, we are cautious about not to anticipate celebrations. From time to time, however, we lend ourselves to dream relying on what the narrator calls ‘a great, unadmitted hope’. erectile dysfunction treatment took us by surprise and everyone wants to ‘reorganise’ their life, as Oranians do, but patience is an indispensable component to succeed, as fictional and historical epidemics show us.Although this sudden decline in the disease was unexpected, the towns-people were in no hurry to celebrate.

The preceding months, though they had increased the desire for liberation, had also taught them prudence and accustomed them to count less and less on a rapid end to the epidemic. However, this new development was the subject of every conversation and, in the depths of people’s hearts, there was a great, unadmitted hope. […] One of the signs that a return to a time of good health was secretly expected (though no one admitted the fact) was that from this moment on people readily spoke, with apparent indifference, about how life would be reorganized after the plague. (Camus 2002, Part V)We put our hope on vaccination. Social distancing and other hygienic measures have proved to be effective, but treatments would bring us a more durable solution without compromising so hardly many economic activities and social habits.

As we said, a more important role of scientific aspects is observed in erectile dysfunction treatment if compared with La Peste (an expected fact if considered that Camus’s story is an artistic work, that he skips sometimes the most complex scientific issues of the plague and that health sciences have evolved substantially during last decades). Oranians, in fact, achieve the end of the epidemic not through clearly identified scientific responses but with certain randomness:All one could do was to observe that the sickness seemed to be going as it had arrived. The strategy being used against it had not changed. It had been ineffective yesterday, and now it was apparently successful. One merely had the feeling that the disease had exhausted itself, or perhaps that it was retiring after achieving all its objectives.

In a sense, its role was completed. (Camus 2002, Part V)They receive the announcement made by the Prefecture of reopening the town’s gates in 2 weeks time with enthusiasm. Dealing with concrete dates gives them certainty, helps them fix the temporal horizons we wrote about. This is also the case when they are told that preventive measures would be lifted in 1 month. Camus shows us then how the main characters are touched as well by this positive atmosphere:That evening Tarrou and Rieux, Rambert and the rest, walked in the midst of the crowd, and they too felt they were treading on air.

Long after leaving the boulevards Tarrou and Rieux could still hear the sounds of happiness following them… (Camus 2002, Part V)Then, Tarrou points out a sign of recovery coming from the animal world. In a direct zoological chain, infected fleas have vanished from rats, which have been able again to multiply across the city, making the cats abandon their hiding places and to go hunting after them again. At the final step of this chain, Tarrou sees the human being. He remembers the old man who used to spit to the cats beneath his window:At a time when the noise grew louder and more joyful, Tarrou stopped. A shape was running lightly across the dark street.

It was a cat, the first that had been seen since the spring. It stopped for a moment in the middle of the road, hesitated, licked its paw, quickly passed it across its right ear, then carried on its silent way and vanished into the night. Tarrou smiled. The little old man, too, would be happy. (Camus 2002, Part V)Unpleasant things as a town with rats running across its streets, or a man spending his time spitting on a group of cats, constitute normality as much as the reopening of gates or the reboot of commerce.

However, when Camus speaks directly about normality, he highlights more appealing habits. He proposes common leisure activities (restaurants, theatres) as symbols of human life, since he opposes them to Cottard’s life, which has become that of a ‘wild animal’:At least in appearance he [ Cottard ] retired from the world and from one day to the next started to live like a wild animal. He no longer appeared in restaurants, at the theatre or in his favourite cafés. (Camus 2002, Part V)We do not disclose why Cottard’s reaction to the end of the epidemic is different from most of the Oranians’. In any case, the narrator insists later on the assimilation between common pleasures and normality:‘ Perhaps,’ Cottard said, ‘ Perhaps so.

But what do you call a return to normal life?. €™ ‘ New films in the cinema,’ said Tarrou with a smile. (Camus 2002, Part V)Cinema, as well as theatre, live music and many other cultural events have been cancelled or obliged to modify their activities due to erectile dysfunction treatment. Several bars and restaurants have closed, and spending time in those who remain open has become an activity which many people tend to avoid, fearing contagion. Thus, normality in our understanding is linked as well to these simple and pleasant habits, and the complete achievement of them will probably signify for us the desired defeat of the levitra.In La Peste, love is also seen as a simple good to be fully recovered after the plague.

While Rieux goes through the ‘reborn’ Oran, it is lovers’ gatherings what he highlights. Unlike them, everyone who, during the epidemic, sought for goals different from love (such as faith or money, for instance) remain lost when the epidemic has ended:For all the people who, on the contrary, had looked beyond man to something that they could not even imagine, there had been no reply. (Camus 2002, Part V)And this is because lovers, as the narrator says:If they had found that they wanted, it was because they had asked for the only thing that depended on them. (Camus 2002, Part V)We have spoken before about language manipulation, hypocrisy and public figures’ roles during epidemics. Camus, during Dr Rieux’s last visit to the old asthmatic man, makes this frank and humble character criticise, with a point of irony, the authorities’ attitude concerning tributes to the dead:‘ Tell me, doctor, is it true that they’re going to put up a monument to the victims of the plague?.

€™â€˜ So the papers say. A pillar or a plaque.’‘ I knew it!. And there’ll be speeches.’The old man gave a strangled laugh.‘ I can hear them already. €œ Our dead…” Then they’ll go and have dinner.’ (Camus 2002, Part V)The old man illustrates wisely the authorities’ propensity for making speeches. He knows that most of them usually prefer grandiloquence rather than common words, and seizes perfectly their tone when he imitates them (‘Our dead…’).

We have also got used, during erectile dysfunction treatment, to these types of messages. We have also heard about ‘our old people’, ‘our youth’, ‘our essential workers’ and even ‘our dead’. Behind this tone, however, there could be an intention to hide errors, or to falsely convey carefulness. Honest rulers do not usually need nice words. They just want them to be accurate.We have seen as well some tributes to the victims during erectile dysfunction treatment, some of which we can doubt whether they serve to victims’ relief or to authorities’ promotion.

We want rulers to be less aware of their own image and to stress truthfulness as a goal, even if this is a hard requirement not only for them, but for every single person. Language is essential in this issue, we think, since it is prone to be twisted and to become untrue. The old asthmatic man illustrates it with his ‘There’ll be speeches’ and his ‘Our dead…’, but this is not the only time in the novel in which Camus brings out the topic. For instance, he does so when he equates silence (nothing can be thought as further from wordiness) with truth:It is at the moment of misfortune that one becomes accustomed to truth, that is to say to silence. (Camus 2002, Part II)or when he makes a solid statement against false words:…I understood that all the misfortunes of mankind came from not stating things in clear terms.

(Camus 2002, Part IV)The old asthmatic, in fact, while praising the deceased Tarrou, remarks that he used to admire him because ‘he didn’t talk just for the sake of it.’ (Camus 2002, Part V).Related to this topic, what the old asthmatic says about political authorities may be transposed in our case to other public figures, such as scholars and researchers, media leaders, businessmen and women, health professionals… and, if we extend the scope, to every single citizen. Because hypocrisy, language manipulation and the fact of putting individual interests ahead of collective welfare fit badly with collective issues such as epidemics. Hopefully, also examples to the contrary have been observed during erectile dysfunction treatment.The story ends with the fireworks in Oran and the depiction of Dr Rieux’s last feelings. While he is satisfied because of his medical performance and his activity as a witness of the plague, he is concerned about future disasters to come. When erectile dysfunction treatment will have passed, it will be time for us as well to review our life during these months.

For now, we are just looking forward to achieving our particular ‘part V’.AbstractThis study addresses the existing gap in literature that ethnographically examines the experiences of Spanish-speaking patients with limited English proficiency in clinical spaces. All of the participants in this study presented to the emergency department (ED) for evaluation of non-urgent health conditions. Patient shadowing was employed to explore the challenges that this population face in unique clinical settings like the ED. This relatively new methodology facilitates obtaining nuanced understandings of clinical contexts under study in ways that quantitative approaches and survey research do not. Drawing from the field of medical anthropology and approach of narrative medicine, the collected data are presented through the use of clinical ethnographic vignettes and thick description.

The conceptual framework of health-related deservingness guided the analysis undertaken in this study. Structural stigma was used as a complementary framework in analysing the emergent themes in the data collected. The results and analysis from this study were used to develop an argument for the consideration of language as a distinct social determinant of health.emergency medicinemedical anthropologymedical humanitiesData availability statementData sharing not applicable as no datasets were generated and/or analysed for this study..

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By means levitra side effects long term of concurrent publication in American Journal of Kidney Diseases (AJKD) and Journal of the American Society of Nephrology (JASN), we present the interim report of a joint task force established by the National Kidney Foundation and the American Society of Nephrology to reconsider inclusion of race in the estimation of GFR http://www.em-oberschaeffolsheim.ac-strasbourg.fr/?page_id=1837. This report comes at a time in the United States when the enormous and disproportionate burden of illness and death from erectile dysfunction disease 2019 within minority communities, as well as police violence against Black Americans, has laid bare the racial inequities in health and wellbeing in our society. Kidney disease and its complications play a prominent role in this excess burden of illness, motivating the creation of this joint task force.For nephrologists, eGFR is a levitra side effects long term critical workhorse, a starting point for much of what we do.

Diagnosis, prognostication, treatment options, and the use of medications all hinge on eGFR. We all know, of course, there is much more to kidney function levitra side effects long term than fiation, but when we ask about a patient’s kidney function, it is shorthand for wanting to know the eGFR. So, getting it right—having reliable and consistent estimates—is critical to the effective practice of nephrology and all of medicine.

Further, understanding the epidemiology of kidney disease, tracking disparities and inequities, and selecting participants for inclusion in clinical trials all depend on estimating GFR accurately and consistently.The task force’s interim report1 documents levitra side effects long term a process being undertaken with extraordinary care and thoroughness. The task force has laid out a planned course of action with three phases, this being the culmination of phase 1. It has levitra side effects long term articulated a core set of principles to be used in the subsequent stages, compiled a summary of much of the relevant evidence base, and established stakeholder input, particularly that of patients.

Mindful of the potential unintended consequences of precipitous changes in methods to estimate GFR, the task force has deferred its recommendations until its inclusive and deliberative processes are completed. The editorial teams of the two journals levitra side effects long term decided to take the unusual step of jointly publishing this report, reflecting our assessment of the importance of the task force’s work.The starting point for considering the inclusion of race in eGFR estimation must be what is best for our patients—people with kidney disease or at risk of kidney disease. The disproportionate burden of kidney disease among Black people in the United States2 and their inequitable access to care, including transplantation, must be addressed3.

The burden on Black Americans has been known for decades. It is not simply or even levitra side effects long term principally a reflection of biologic differences. Rather, deep inequities in the social determinants of health and structural racism in the delivery of health care are eroding the wellbeing of our minority communities, compounding the overall societal effects of racism on the lives of Black Americans.4,5As editors we recognize that journals have participated in the dissemination and perpetuation of science that casts race as a biologic construct.

Much is being written about how race is a flawed concept, a societal construct that oversimplifies and at times distorts.6,7 The editorial teams of both JASN and AJKD are committed to re-examining our own roles and levitra side effects long term the language we use to talk about these problems—an essential step, we believe, if we are going to participate effectively in the eradication of unacceptable health disparities. As journal editors, we recognize published research that has emphasized race as a biologic construct has contributed to a failure to address core problems.Journals play an important and privileged role in the dissemination of science, and we feel a deep responsibility not only to inform our readers of these problems but also to participate in a more informed discussion of racism. This is a levitra side effects long term start, we suggest, in the pursuit of effective interventions that will lessen race-based disparities in health.

It includes being more cognizant of how reporting of science can perpetuate racism. In this spirit, we are grateful for the opportunity to promote and disseminate the work of the task force.The task force is levitra side effects long term examining the full potential effect of removing race from eGFR expressions, both the desirable benefits and the unintended consequences. Their deliberations are focusing on how best to optimize GFR estimation for all racial and ethnic groups, while limiting any potential unintended consequences.

Although the steps undertaken by the task force may produce recommendations more slowly than some would like, we applaud its deliberative approach and have confidence it will promote improvement in the health status of the patients we serve.We eagerly await the recommendations of the task force but call upon the levitra side effects long term kidney medicine community to show as much resolve to mitigate the influence of the broad array of factors leading to racial disparities as is now being brought to the effort to reassess the use of race in the calculation of eGFR. This important work on GFR estimation should serve as a starting point to robustly address and reverse the unacceptable excessive burden of kidney disease in people within racial minority communities, a sentiment resonant with the task force’s aspiration “that the community of healthcare professionals, scientists, medical educators, students, health professionals in training, and patients to join in the larger, comprehensive effort needed to address the entire spectrum of kidney health to eliminate health disparities.”DisclosuresH.I. Feldman reports consultancy levitra side effects long term agreements from DLA Piper, LLP, InMed, Inc., Kyowa Hakko Kirin Co.

Ltd. (ongoing). Receiving honoraria from Rogosin levitra side effects long term Institute (invited speaker).

Being the Steering Committee Chair of NIH-NIDDK’s Chronic Renal Insufficiency Cohort Study. Being a member of levitra side effects long term the National Kidney Foundation (NKF) Scientific Advisory Board. And receiving funding from the NKF to support his role as AJKD Editor-in-Chief.

J.P. Briggs serves as a scientific advisor to the Executive Director of Patient Centered Outcomes Research Institute and reports having other interests/relationships including PCORI—Interim Executive Director from November 2019 through April 2020, and JASN Editor-in-Chief.FundingNone.FootnotesThis article is being published concurrently in the Journal of the American Society of Nephrology and American Journal of Kidney Diseases. The articles are identical except for stylistic changes in keeping with each journal’s style.

Either of these versions may be used in citing this article.Published online ahead of print. Publication date available at www.jasn.org.See related article, “Reassessing the Inclusion of Race in Diagnosing Kidney Diseases. An Interim Report from the NKF-ASN Task Force,” on pages 1305–1317.Copyright © 2021 by the American Society of Nephrology and the National Kidney Foundation, Inc.

By means buy discount levitra of concurrent publication in American Journal of Kidney Diseases (AJKD) and Journal of the American Society of Nephrology (JASN), we present the interim report of a joint task force established by the National Kidney Foundation and the American Society of Nephrology to reconsider inclusion of race in brand levitra online pharmacy the estimation of GFR. This report comes at a time in the United States when the enormous and disproportionate burden of illness and death from erectile dysfunction disease 2019 within minority communities, as well as police violence against Black Americans, has laid bare the racial inequities in health and wellbeing in our society. Kidney disease and its complications play a prominent role in this excess burden of illness, buy discount levitra motivating the creation of this joint task force.For nephrologists, eGFR is a critical workhorse, a starting point for much of what we do.

Diagnosis, prognostication, treatment options, and the use of medications all hinge on eGFR. We all know, of course, there is much more to kidney function than fiation, but when we ask about a patient’s kidney function, it is shorthand buy discount levitra for wanting to know the eGFR. So, getting it right—having reliable and consistent estimates—is critical to the effective practice of nephrology and all of medicine.

Further, understanding the epidemiology of kidney disease, tracking disparities and inequities, and selecting participants for inclusion in clinical trials all depend on estimating GFR accurately and consistently.The task force’s interim report1 documents a process buy discount levitra being undertaken with extraordinary care and thoroughness. The task force has laid out a planned course of action with three phases, this being the culmination of phase 1. It has articulated a core set of principles to be used in the subsequent stages, compiled a summary of much of the relevant evidence base, and established stakeholder input, particularly that buy discount levitra of patients.

Mindful of the potential unintended consequences of precipitous changes in methods to estimate GFR, the task force has deferred its recommendations until its inclusive and deliberative processes are completed. The editorial teams of the two journals decided to take the unusual step of jointly publishing buy discount levitra this report, reflecting our assessment of the importance of the task force’s work.The starting point for considering the inclusion of race in eGFR estimation must be what is best for our patients—people with kidney disease or at risk of kidney disease. The disproportionate burden of kidney disease among Black people in the United States2 and their inequitable access to care, including transplantation, must be addressed3.

The burden on Black Americans has been known for decades. It is not simply or even buy discount levitra principally a reflection of biologic differences. Rather, deep inequities in the social determinants of health and structural racism in the delivery of health care are eroding the wellbeing of our minority communities, compounding the overall societal effects of racism on the lives of Black Americans.4,5As editors we recognize that journals have participated in the dissemination and perpetuation of science that casts race as a biologic construct.

Much is being buy discount levitra written about how race is a flawed concept, a societal construct that oversimplifies and at times distorts.6,7 The editorial teams of both JASN and AJKD are committed to re-examining our own roles and the language we use to talk about these problems—an essential step, we believe, if we are going to participate effectively in the eradication of unacceptable health disparities. As journal editors, we recognize published research that has emphasized race as a biologic construct has contributed to a failure to address core problems.Journals play an important and privileged role in the dissemination of science, and we feel a deep responsibility not only to inform our readers of these problems but also to participate in a more informed discussion of racism. This is a start, we suggest, in the buy discount levitra pursuit of effective interventions that will lessen race-based disparities in health.

It includes being more cognizant of how reporting of science can perpetuate racism. In this spirit, we are grateful for the opportunity to promote and disseminate the work of the task force.The task force is examining the full potential effect buy discount levitra of removing race from eGFR expressions, both the desirable benefits and the unintended consequences. Their deliberations are focusing on how best to optimize GFR estimation for all racial and ethnic groups, while limiting any potential unintended consequences.

Although the steps undertaken by the task force may produce recommendations more slowly than some would like, we applaud its deliberative approach and have confidence it will promote improvement in the health status of the patients we serve.We eagerly await the recommendations of the task force but call upon the kidney medicine community to show as much resolve to buy discount levitra mitigate the influence of the broad array of factors leading to racial disparities as is now being brought to the effort to reassess the use of race in the calculation of eGFR. This important work on GFR estimation should serve as a starting point to robustly address and reverse the unacceptable excessive burden of kidney disease in people within racial minority communities, a sentiment resonant with the task force’s aspiration “that the community of healthcare professionals, scientists, medical educators, students, health professionals in training, and patients to join in the larger, comprehensive effort needed to address the entire spectrum of kidney health to eliminate health disparities.”DisclosuresH.I. Feldman reports consultancy buy discount levitra agreements from DLA Piper, LLP, InMed, Inc., Kyowa Hakko Kirin Co.

Ltd. (ongoing). Receiving honoraria from Rogosin Institute buy discount levitra (invited speaker).

Being the Steering Committee Chair of NIH-NIDDK’s Chronic Renal Insufficiency Cohort Study. Being a member of the National Kidney buy discount levitra Foundation (NKF) Scientific Advisory Board. And receiving funding from the NKF to support his role as AJKD Editor-in-Chief.

J.P. Briggs serves as a scientific advisor to the Executive Director of Patient Centered Outcomes Research Institute and reports having other interests/relationships including PCORI—Interim Executive Director from November 2019 through April 2020, and JASN Editor-in-Chief.FundingNone.FootnotesThis article is being published concurrently in the Journal of the American Society of Nephrology and American Journal of Kidney Diseases. The articles are identical except for stylistic changes in keeping with each journal’s style.

Either of these versions may be used in citing this article.Published online ahead of print. Publication date available at www.jasn.org.See related article, “Reassessing the Inclusion of Race in Diagnosing Kidney Diseases. An Interim Report from the NKF-ASN Task Force,” on pages 1305–1317.Copyright © 2021 by the American Society of Nephrology and the National Kidney Foundation, Inc.

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AbstractIntroduction. We report a very rare case of familial breast cancer and diffuse gastric cancer, with germline pathogenic variants in both BRCA1 and CDH1 genes. To the best of our knowledge, this is the first report of such an association.Family description.

The proband is a woman diagnosed with breast cancer at the age of 52 years. She requested genetic counselling in 2012, at the age of 91 years, because of a history of breast cancer in her daughter, her sister, her niece and her paternal grandmother and was therefore concerned about her relatives. Her sister and maternal aunt also had gastric cancer.

She was tested for several genes associated with hereditary breast cancer.Results. A large deletion of BRCA1 from exons 1 to 7 and two CDH1 pathogenic cis variants were identified.Conclusion. This complex situation is challenging for genetic counselling and management of at-risk individuals.cancer.

Breastcancer. Gastricclinical geneticsgenetic screening/counsellingmolecular geneticsIntroductionGLI-Kruppel family member 3 (GLI3) encodes for a zinc finger transcription factor which plays a key role in the sonic hedgehog (SHH) signalling pathway essential in both limb and craniofacial development.1 2 In hand development, SHH is expressed in the zone of polarising activity (ZPA) on the posterior side of the handplate. The ZPA expresses SHH, creating a gradient of SHH from the posterior to the anterior side of the handplate.

In the presence of SHH, full length GLI3-protein is produced (GLI3A), whereas absence of SHH causes cleavage of GLI3 into its repressor form (GLI3R).3 4 Abnormal expression of this SHH/GLI3R gradient can cause both preaxial and postaxial polydactyly.2Concordantly, pathogenic DNA variants in the GLI3 gene are known to cause multiple syndromes with craniofacial and limb involvement, such as. Acrocallosal syndrome5 (OMIM. 200990), Greig cephalopolysyndactyly syndrome6 (OMIM.

175700) and Pallister-Hall syndrome7 (OMIM. 146510). Also, in non-syndromic polydactyly, such as preaxial polydactyly-type 4 (PPD4, OMIM.

174700),8 pathogenic variants in GLI3 have been described. Out of these diseases, Pallister-Hall syndrome is the most distinct entity, defined by the presence of central polydactyly and hypothalamic hamartoma.9 The other GLI3 syndromes are defined by the presence of preaxial and/or postaxial polydactyly of the hand and feet with or without syndactyly (Greig syndrome, PPD4). Also, various mild craniofacial features such as hypertelorism and macrocephaly can occur.

Pallister-Hall syndrome is caused by truncating variants in the middle third of the GLI3 gene.10–12 The truncation of GLI3 causes an overexpression of GLI3R, which is believed to be the key difference between Pallister-Hall and the GLI3-mediated polydactyly syndromes.9 11 Although multiple attempts have been made, the clinical and genetic distinction between the GLI3-mediated polydactyly syndromes is less evident. This has for example led to the introduction of subGreig and the formulation of an Oro-facial-digital overlap syndrome.10 Other authors, suggested that we should not regard these diseases as separate entities, but as a spectrum of GLI3-mediated polydactyly syndromes.13Although phenotype/genotype correlation of the different syndromes has been cumbersome, clinical and animal studies do provide evidence that distinct regions within the gene, could be related to the individual anomalies contributing to these syndromes. First, case studies show isolated preaxial polydactyly is caused by both truncating and non-truncating variants throughout the GLI3 gene, whereas in isolated postaxial polydactyly cases truncating variants at the C-terminal side of the gene are observed.12 14 These results suggest two different groups of variants for preaxial and postaxial polydactyly.

Second, recent animal studies suggest that posterior malformations in GLI3-mediated polydactyly syndromes are likely related to a dosage effect of GLI3R rather than due to the influence of an altered GLI3A expression.15Past attempts for phenotype/genotype correlation in GLI3-mediated polydactyly syndromes have directly related the diagnosed syndrome to the observed genotype.10–12 16 Focusing on individual hand phenotypes, such as preaxial and postaxial polydactyly and syndactyly might be more reliable because it prevents misclassification due to inconsistent use of syndrome definition. Subsequently, latent class analysis (LCA) provides the possibility to relate a group of observed variables to a set of latent, or unmeasured, parameters and thereby identifying different subgroups in the obtained dataset.17 As a result, LCA allows us to group different phenotypes within the GLI3-mediated polydactyly syndromes and relate the most important predictors of the grouped phenotypes to the observed GLI3 variants.The aim of our study was to further investigate the correlation of the individual phenotypes to the genotypes observed in GLI3-mediated polydactyly syndromes, using LCA. Cases were obtained by both literature review and the inclusion of local clinical cases.

Subsequently, we identified two subclasses of limb anomalies that relate to the underlying GLI3 variant. We provide evidence for two different phenotypic and genotypic groups with predominantly preaxial and postaxial hand and feet anomalies, and we specify those cases with a higher risk for corpus callosum anomalies.MethodsLiterature reviewThe Human Gene Mutation Database (HGMD Professional 2019) was reviewed to identify known pathogenic variants in GLI3 and corresponding phenotypes.18 All references were obtained and cases were included when they were diagnosed with either Greig or subGreig syndrome or PPD4.10–12 Pallister-Hall syndrome and acrocallosal syndrome were excluded because both are regarded distinct syndromes and rather defined by the presence of the non-hand anomalies, than the presence of preaxial or postaxial polydactyly.13 19 Isolated preaxial or postaxial polydactyly were excluded for two reasons. The phenotype/genotype correlations are better understood and both anomalies can occur sporadically which could introduce falsely assumed pathogenic GLI3 variants in the analysis.

Additionally, cases were excluded when case-specific phenotypic or genotypic information was not reported or if these two could not be related to each other. Families with a combined phenotypic description, not reducible to individual family members, were included as one case in the analysis.Clinical casesThe Sophia Children’s Hospital Database was reviewed for cases with a GLI3 variant. Within this population, the same inclusion criteria for the phenotype were valid.

Relatives of the index patients were also contacted for participation in this study, when they showed comparable hand, foot, or craniofacial malformations or when a GLI3 variant was identified. Phenotypes of the hand, foot and craniofacial anomalies of the patients treated in the Sophia Children's Hospital were collected using patient documentation. Family members were identified and if possible, clinically verified.

Alternatively, family members were contacted to verify their phenotypes. If no verification was possible, cases were excluded.PhenotypesThe phenotypes of both literature cases and local cases were extracted in a similar fashion. The most frequently reported limb and craniofacial phenotypes were dichotomised.

The dichotomised hand and foot phenotypes were preaxial polydactyly, postaxial polydactyly and syndactyly. Broad halluces or thumbs were commonly reported by authors and were dichotomised as a presentation of preaxial polydactyly. The extracted dichotomised craniofacial phenotypes were hypertelorism, macrocephaly and corpus callosum agenesis.

All other phenotypes were registered, but not dichotomised.Pathogenic GLI3 variantsAll GLI3 variants were extracted and checked using Alamut Visual V.2.14. If indicated, variants were renamed according to standard Human Genome Variation Society nomenclature.20 Variants were grouped in either missense, frameshift, nonsense or splice site variants. In the group of frameshift variants, a subgroup with possible splice site effect were identified for subgroup analysis when indicated.

Similarly, nonsense variants prone for nonsense mediated decay (NMD) and nonsense variants with experimentally confirmed NMD were identified.21 Deletions of multiple exons, CNVs and translocations were excluded for analysis. A full list of included mutations is available in the online supplementary materials.Supplemental materialThe location of the variant was compared with five known structural domains of the GLI3 gene. (1) repressor domain, (2) zinc finger domain, (3) cleavage site, (4) activator domain, which we defined as a concatenation of the separately identified transactivation zones, the CBP binding domain and the mediator binding domain (MBD) and (5) the MID1 interaction region domain.1 6 22–24 The boundaries of each of the domains were based on available literature (figure 1, exact locations available in the online supplementary materials).

The boundaries used by different authors did vary, therefore a consensus was made.In this figure the posterior probability of an anterior phenotype is plotted against the location of the variant, stratified for the type of mutation that was observed. For better overview, only variants with a location effect were displayed. The full figure, including all variant types, can be found in the online supplementary figure 1.

Each mutation is depicted as a dot, the size of the dot represents the number of observations for that variant. If multiple observations were made, the mean posterior odds and IQR are plotted. For the nonsense variants, variants that were predicted to produce nonsense mediated decay, are depicted using a triangle.

Again, the size indicates the number of observations." data-icon-position data-hide-link-title="0">Figure 1 In this figure the posterior probability of an anterior phenotype is plotted against the location of the variant, stratified for the type of mutation that was observed. For better overview, only variants with a location effect were displayed. The full figure, including all variant types, can be found in the online supplementary figure 1.

Each mutation is depicted as a dot, the size of the dot represents the number of observations for that variant. If multiple observations were made, the mean posterior odds and IQR are plotted. For the nonsense variants, variants that were predicted to produce nonsense mediated decay, are depicted using a triangle.

Again, the size indicates the number of observations.Supplemental materialLatent class analysisTo cluster phenotypes and relate those to the genotypes of the patients, an explorative analysis was done using LCA in R (R V.3.6.1 for Mac. Polytomous variable LCA, poLCA V.1.4.1.). We used our LCA to detect the number of phenotypic subgroups in the dataset and subsequently predict a class membership for each case in the dataset based on the posterior probabilities.In order to make a reliable prediction, only phenotypes that were sufficiently reported and/or ruled out were feasible for LCA, limiting the analysis to preaxial polydactyly, postaxial polydactyly and syndactyly of the hands and feet.

Only full cases were included. To determine the optimal number of classes, we fitted a series of models ranging from a one-class to a six-class model. The optimal number of classes was based on the conditional Akaike information criterion (cAIC), the non adjusted and the sample-size adjusted Bayesian information criterion (BIC and aBIC) and the obtained entropy.25 The explorative LCA produces both posterior probabilities per case for both classes and predicted class membership.

Using the predicted class membership, the phenotypic features per class were determined in a univariate analysis (χ2, SPSS V.25). Using the posterior probabilities on latent class (LC) membership, a scatter plot was created using the location of the variant on the x-axis and the probability of class membership on the y-axis for each of the types of variants (Tibco Spotfire V.7.14). Using these scatter plots, variants that give similar phenotypes were clustered.Genotype/phenotype correlationBecause an LC has no clinical value, the correlation between genotypes and phenotypes was investigated using the predictor phenotypes and the clustered phenotypes.

First, those phenotypes that contribute most to LC membership were identified. Second those phenotypes were directly related to the different types of variants (missense, nonsense, frameshift, splice site) and their clustered locations. Quantification of the relation was performed using a univariate analysis using a χ2 test.

Because of our selection criteria, meaning patients at least have two phenotypes, a multivariate using a logistic regression analysis was used to detect the most significant predictors in the overall phenotype (SPSS V.25). Finally, we explored the relation of the clustered genotypes to the presence of corpus callosum agenesis, a rare malformation in GLI3-mediated polydactyly syndromes which cannot be readily diagnosed without additional imaging.ResultsWe included 251 patients from the literature and 46 local patients,10–12 16 21 26–43 in total 297 patients from 155 different families with 127 different GLI3 variants, 32 of which were large deletions, CNVs or translocations. In six local cases, the exact variant could not be retrieved by status research.The distribution of the most frequently observed phenotypes and variants are presented in table 1.

Other recurring phenotypes included developmental delay (n=22), broad nasal root (n=23), frontal bossing or prominent forehead (n=16) and craniosynostosis (n=13), camptodactyly (n=8) and a broad first interdigital webspace of the foot (n=6).View this table:Table 1 Baseline phenotypes and genotypes of selected populationThe LCA model was fitted using the six defined hand/foot phenotypes. Model fit indices for the LCA are displayed in table 2. Based on the BIC, a two-class model has the best fit for our data.

The four-class model does show a gain in entropy, however with a higher BIC and loss of df. Therefore, based on the majority of performance statistics and the interpretability of the model, a two-class model was chosen. Table 3 displays the distribution of phenotypes and genotypes over the two classes.View this table:Table 2 Model fit indices for the one-class through six-class model evaluated in our LCAView this table:Table 3 Distribution of phenotypes and genotypes in the two latent classes (LC)Table 1 depicts the baseline phenotypes and genotypes in the obtained population.

Note incomplete data especially in the cranium phenotypes. In total 259 valid genotypes were present. In total, 289 cases had complete data for all hand and foot phenotypes (preaxial polydactyly, postaxial polydactyly and syndactyly) and thus were available for LCA.

Combined, for phenotype/genotype correlation 258 cases were available with complete genotypes and complete hand and foot phenotypes.Table 2 depicts the model fit indices for all models that have been fitted to our data.Table 3 depicts the distribution of phenotypes and genotypes over the two assigned LCs. Hand and foot phenotypes were used as input for the LCA, thus are all complete cases. Malformation of the cranium and genotypes do have missing cases.

Note that for the LCA, full case description was required, resulting in eight cases due to incomplete phenotypes. Out of these eight, one also had a genotype that thus needed to be excluded. Missingness of genotypic data was higher in LC2, mostly due to CNVs (table 1).In 54/60 cases, a missense variant produced a posterior phenotype.

Likewise, splice site variants show the same phenotype in 23/24 cases (table 3). For both frameshift and nonsense variants, this relation is not significant (52 anterior vs 54 posterior and 26 anterior vs 42 posterior, respectively). Therefore, only for nonsense and frameshift variants the location of the variant was plotted against the probability for LC2 membership in figure 1.

A full scatterplot of all variants is available in online supplementary figure 1.Figure 1 reveals a pattern for these nonsense and frameshift variants that reveals that variants at the C-terminal of the gene predict anterior phenotypes. When relating the domains of the GLI3 protein to the observed phenotype, we observe that the majority of patients with a nonsense or frameshift variant in the repressor domain, the zinc finger domain or the cleavage site had a high probability of an LC2/anterior phenotype. This group contains all variants that are either experimentally determined to be subject to NMD (triangle marker in figure 1) or predicted to be subject to NMD (diamond marker in figure 1).

Frameshift and nonsense variants in the activator domain result in high probability for an LC1/posterior phenotype. These variants will be further referred to as truncating variants in the activator domain.The univariate relation of the individual phenotypes to these two groups of variants are estimated and presented in table 4. In our multivariate analysis, postaxial polydactyly of the foot and hand are the strongest predictors (Beta.

2.548, p<0001 and Beta. 1.47, p=0.013, respectively) for patients to have a truncating variant in the activator domain. Moreover, the effect sizes of preaxial polydactyly of the hand and feet (Beta.

ˆ’0.797, p=0123 and −1.772, p=0.001) reveals that especially postaxial polydactyly of the foot is the dominant predictor for the genetic substrate of the observed anomalies.View this table:Table 4 Univariate and multivariate analysis of the phenotype/genotype correlationTable 4 shows exploration of the individual phenotypes on the genotype, both univariate and multivariate. The multivariate analysis corrects for the presence of multiple phenotypes in the underlying population.Although the craniofacial anomalies could not be included in the LCA, the relation between the observed anomalies and the identified genetic substrates can be studied. The prevalence of hypertelorism was equally distributed over the two groups of variants (47/135 vs 21/47 respectively, p<0.229).

However for corpus callosum agenesis and macrocephaly, there was a higher prevalence in patients with a truncating variant in the activator domain (3/75 vs 11/41, p<0.001. OR. 8.8, p<0.001) and 42/123 vs 24/48, p<0.05).

Noteworthy is the fact that 11/14 cases with corpus callosum agenesis in the dataset had a truncating variant in the activator domain.DiscussionIn this report, we present new insights into the correlation between the phenotype and the genotype in patients with GLI3-mediated polydactyly syndromes. We illustrate that there are two LCs of patients, best predicted by postaxial polydactyly of the hand and foot for LC1, and the preaxial polydactyly of the hand and foot and syndactyly of the foot for LC2. Patients with postaxial phenotypes have a higher risk of having a truncating variant in the activator domain of the GLI3 gene which is also related to a higher risk of corpus callosum agenesis.

These results suggest a functional difference between truncating variants on the N-terminal and the C-terminal side of the GLI3 cleavage site.Previous attempts of phenotype to genotype correlation have not yet provided the clinical confirmation of these assumed mechanisms in the pathophysiology of GLI3-mediated polydactyly syndromes. Johnston et al have successfully determined the Pallister-Hall region in which truncating variants produce a Pallister-Hall phenotype rather than Greig syndrome.11 However, in their latest population study, subtypes of both syndromes were included to explain the full spectrum of observed malformations. In 2015, Demurger et al reported the higher incidence of corpus callosum agenesis in the Greig syndrome population with truncating mutations in the activator domain.12 Al-Qattan in his review summarises the concept of a spectrum of anomalies dependent on haplo-insufficiency (through different mechanisms) and repressor overexpression.13 However, he bases this theory mainly on reviewed experimental data.

Our report is the first to provide an extensive clinical review of cases that substantiate the phenotypic difference between the two groups that could fit the suggested mechanisms. We agree with Al-Qattan et al that a variation of anomalies can be observed given any pathogenic variant in the GLI3 gene, but overall two dominant phenotypes are present. A population with predominantly preaxial anomalies and one with postaxial anomalies.

The presence of preaxial or postaxial polydactyly and syndactyly is not mutually exclusive for one of these two subclasses. Meaning that preaxial polydactyly can co-occur with postaxial polydactyly. However, truncating mutations in the activator domain produce a postaxial phenotype, as can be derived from the risk in table 4.

The higher risk of corpus callosum agenesis in this population shows that differentiating between a preaxial phenotype and a postaxial phenotype, instead of between the different GLI3-mediated polydactyly syndromes, might be more relevant regarding diagnostics for corpus callosum agenesis.We chose to use LCA as an exploratory tool only in our population for two reasons. First of all, LCA can be useful to identify subgroups, but there is no ‘true’ model or number of subgroups you can detect. The best fitting model can only be estimated based on the available measures and approximates the true subgroups that might be present.

Second, LC membership assignment is a statistical procedure based on the posterior probability, with concordant errors of the estimation, rather than a clinical value that can be measured or evaluated. Therefore, we decided to use our LCA only in an exploratory tool, and perform our statistics using the actual phenotypes that predict LC membership and the associated genotypes. Overall, this method worked well to differentiate the two subgroups present in our dataset.

However, outliers were observed. A qualitative analysis of these outliers is available in the online supplementary data.The genetic substrate for the two phenotypic clusters can be discussed based on multiple experiments. Overall, we hypothesise two genetic clusters.

One that is due to haploinsufficiency and one that is due to abnormal truncation of the activator. The hypothesised cluster of variants that produce haploinsufficiency is mainly based on the experimental data that confirms NMD in two variants and the NMD prediction of other nonsense variants in Alamut. For the frameshift variants, it is also likely that the cleavage of the zinc finger domain results in functional haploinsufficiency either because of a lack of signalling domains or similarly due to NMD.

Missense variants could cause haploinsufficiency through the suggested mechanism by Krauss et al who have illustrated that missense variants in the MID1 domain hamper the functional interaction with the MID1-α4-PP2A complex, leading to a subcellular location of GLI3.24 The observed missense variants in our study exceed the region to which Krauss et al have limited the MID-1 interaction domain. An alternative theory is suggested by Zhou et al who have shown that missense variants in the MBD can cause deficiency in the signalling of GLI3A, functionally implicating a relative overexpression of GLI3R.22 However, GLI3R overexpression would likely produce a posterior phenotype, as determined by Hill et al in their fixed homo and hemizygous GLI3R models.15 Therefore, our hypothesis is that all included missense variants have a similar pathogenesis which is more likely in concordance with the mechanism introduced by Krauss et al. To our knowledge, no splice site variants have been functionally described in literature.

However, it is noted that the 15 and last exon encompasses the entire activator domain, thus any splice site mutation is by definition located on the 5′ side of the activator. Based on the phenotype, we would suggest that these variants fail to produce a functional protein. We hypothesise that the truncating variants of the activator domain lead to overexpression of GLI3R in SHH rich areas.

In normal development, the presence of SHH prevents the processing of full length GLI34 into GLI3R, thus producing the full length activator. In patients with a truncating variant of the activator domain of GLI3, thus these variants likely have the largest effect in SHH rich areas, such as the ZPA located at the posterior side of the hand/footplate. Moreover, the lack of posterior anomalies in the GLI3∆699/- mouse model (hemizygous fixed repressor model) compared with the GLI3∆699/∆699 mouse model (homozygous fixed repressor model), suggesting a dosage effect of GLI3R to be responsible for posterior hand anomalies.15 These findings are supported by Lewandowski et al, who show that the majority of the target genes in GLI signalling are regulated by GLI3R rather than GLI3A.44 Together, these findings suggest a role for the location and type of variant in GLI3-mediated syndromes.Interestingly, the difference between Pallister-Hall syndrome and GLI3-mediated polydactyly syndromes has also been attributed to the GLI3R overexpression.

However, the difference in phenotype observed in the cases with a truncating variant in the activator domain and Pallister-Hall syndrome suggest different functional consequences. When studying figure 1, it is noted that the included truncating variants on the 3′ side of the cleavage site seldomly affect the CBP binding region, which could provide an explanation for the observed differences. This binding region is included in the Pallister-Hall region as defined by Johnston et al and is necessary for the downstream signalling with GLI1.10 11 23 45 Interestingly, recent reports show that pathogenic variants in GLI1 can produce phenotypes concordant with Ellis von Krefeld syndrome, which includes overlapping features with Pallister-Hall syndrome.46 The four truncating variants observed in this study that do affect the CBP but did not result in a Pallister-Hall phenotype are conflicting with this theory.

Krauss et al postulate an alternative hypothesis, they state that the MID1-α4-PP2A complex, which is essential for GLI3A signalling, could also be the reason for overlapping features of Opitz syndrome, caused by variants in MID1, and Pallister-Hall syndrome. Further analysis is required to fully appreciate the functional differences between truncating mutations that cause Pallister-Hall syndrome and those that result in GLI3-mediated polydactyly syndromes.For the clinical evaluation of patients with GLI3-mediated polydactyly syndromes, intracranial anomalies are likely the most important to predict based on the variant. Unfortunately, the presence of corpus callosum agenesis was not routinely investigated or reported thus this feature could not be used as an indicator phenotype for LC membership.

Interestingly when using only hand and foot phenotypes, we did notice a higher prevalence of corpus callosum agenesis in patients with posterior phenotypes. The suggested relation between truncating mutations in the activator domain causing these posterior phenotypes and corpus callosum agenesis was statistically confirmed (OR. 8.8, p<0.001).

Functionally this relation could be caused by the GLI3-MED12 interaction at the MBD. Pathogenic DNA variants in MED12 can cause Opitz-Kaveggia syndrome, a syndrome in which presentation includes corpus callosum agenesis, broad halluces and thumbs.47In conclusion, there are two distinct phenotypes within the GLI3-mediated polydactyly population. Patients with more posteriorly and more anteriorly oriented hand anomalies.

Furthermore, this difference is related to the observed variant in GLI3. We hypothesise that variants that cause haploinsufficiency produce anterior anomalies of the hand, whereas variants with abnormal truncation of the activator domain have more posterior anomalies. Furthermore, patients that have a variant that produces abnormal truncation of the activator domain, have a greater risk for corpus callosum agenesis.

Thus, we advocate to differentiate preaxial or postaxial oriented GLI3 phenotypes to explain the pathophysiology as well as to get a risk assessment for corpus callosum agenesis.Data availability statementData are available upon reasonable request.Ethics statementsPatient consent for publicationNot required.Ethics approvalThe research protocol was approved by the local ethics board of the Erasmus MC University Medical Center (MEC 2015-679)..

AbstractIntroduction. We report a very rare case of familial breast cancer and diffuse gastric cancer, with germline pathogenic variants in both BRCA1 and CDH1 genes. To the best of our knowledge, this is the first report of such an association.Family description. The proband is a woman diagnosed with breast cancer at the age of 52 years. She requested genetic counselling in 2012, at the age of 91 years, because of a history of breast cancer in her daughter, her sister, her niece and her paternal grandmother and was therefore concerned about her relatives.

Her sister and maternal aunt also had gastric cancer. She was tested for several genes associated with hereditary breast cancer.Results. A large deletion of BRCA1 from exons 1 to 7 and two CDH1 pathogenic cis variants were identified.Conclusion. This complex situation is challenging for genetic counselling and management of at-risk individuals.cancer. Breastcancer.

Gastricclinical geneticsgenetic screening/counsellingmolecular geneticsIntroductionGLI-Kruppel family member 3 (GLI3) encodes for a zinc finger transcription factor which plays a key role in the sonic hedgehog (SHH) signalling pathway essential in both limb and craniofacial development.1 2 In hand development, SHH is expressed in the zone of polarising activity (ZPA) on the posterior side of the handplate. The ZPA expresses SHH, creating a gradient of SHH from the posterior to the anterior side of the handplate. In the presence of SHH, full length GLI3-protein is produced (GLI3A), whereas absence of SHH causes cleavage of GLI3 into its repressor form (GLI3R).3 4 Abnormal expression of this SHH/GLI3R gradient can cause both preaxial and postaxial polydactyly.2Concordantly, pathogenic DNA variants in the GLI3 gene are known to cause multiple syndromes with craniofacial and limb involvement, such as. Acrocallosal syndrome5 (OMIM. 200990), Greig cephalopolysyndactyly syndrome6 (OMIM.

175700) and Pallister-Hall syndrome7 (OMIM. 146510). Also, in non-syndromic polydactyly, such as preaxial polydactyly-type 4 (PPD4, OMIM. 174700),8 pathogenic variants in GLI3 have been described. Out of these diseases, Pallister-Hall syndrome is the most distinct entity, defined by the presence of central polydactyly and hypothalamic hamartoma.9 The other GLI3 syndromes are defined by the presence of preaxial and/or postaxial polydactyly of the hand and feet with or without syndactyly (Greig syndrome, PPD4).

Also, various mild craniofacial features such as hypertelorism and macrocephaly can occur. Pallister-Hall syndrome is caused by truncating variants in the middle third of the GLI3 gene.10–12 The truncation of GLI3 causes an overexpression of GLI3R, which is believed to be the key difference between Pallister-Hall and the GLI3-mediated polydactyly syndromes.9 11 Although multiple attempts have been made, the clinical and genetic distinction between the GLI3-mediated polydactyly syndromes is less evident. This has for example led to the introduction of subGreig and the formulation of an Oro-facial-digital overlap syndrome.10 Other authors, suggested that we should not regard these diseases as separate entities, but as a spectrum of GLI3-mediated polydactyly syndromes.13Although phenotype/genotype correlation of the different syndromes has been cumbersome, clinical and animal studies do provide evidence that distinct regions within the gene, could be related to the individual anomalies contributing to these syndromes. First, case studies show isolated preaxial polydactyly is caused by both truncating and non-truncating variants throughout the GLI3 gene, whereas in isolated postaxial polydactyly cases truncating variants at the C-terminal side of the gene are observed.12 14 These results suggest two different groups of variants for preaxial and postaxial polydactyly. Second, recent animal studies suggest that posterior malformations in GLI3-mediated polydactyly syndromes are likely related to a dosage effect of GLI3R rather than due to the influence of an altered GLI3A expression.15Past attempts for phenotype/genotype correlation in GLI3-mediated polydactyly syndromes have directly related the diagnosed syndrome to the observed genotype.10–12 16 Focusing on individual hand phenotypes, such as preaxial and postaxial polydactyly and syndactyly might be more reliable because it prevents misclassification due to inconsistent use of syndrome definition.

Subsequently, latent class analysis (LCA) provides the possibility to relate a group of observed variables to a set of latent, or unmeasured, parameters and thereby identifying different subgroups in the obtained dataset.17 As a result, LCA allows us to group different phenotypes within the GLI3-mediated polydactyly syndromes and relate the most important predictors of the grouped phenotypes to the observed GLI3 variants.The aim of our study was to further investigate the correlation of the individual phenotypes to the genotypes observed in GLI3-mediated polydactyly syndromes, using LCA. Cases were obtained by both literature review and the inclusion of local clinical cases. Subsequently, we identified two subclasses of limb anomalies that relate to the underlying GLI3 variant. We provide evidence for two different phenotypic and genotypic groups with predominantly preaxial and postaxial hand and feet anomalies, and we specify those cases with a higher risk for corpus callosum anomalies.MethodsLiterature reviewThe Human Gene Mutation Database (HGMD Professional 2019) was reviewed to identify known pathogenic variants in GLI3 and corresponding phenotypes.18 All references were obtained and cases were included when they were diagnosed with either Greig or subGreig syndrome or PPD4.10–12 Pallister-Hall syndrome and acrocallosal syndrome were excluded because both are regarded distinct syndromes and rather defined by the presence of the non-hand anomalies, than the presence of preaxial or postaxial polydactyly.13 19 Isolated preaxial or postaxial polydactyly were excluded for two reasons. The phenotype/genotype correlations are better understood and both anomalies can occur sporadically which could introduce falsely assumed pathogenic GLI3 variants in the analysis.

Additionally, cases were excluded when case-specific phenotypic or genotypic information was not reported or if these two could not be related to each other. Families with a combined phenotypic description, not reducible to individual family members, were included as one case in the analysis.Clinical casesThe Sophia Children’s Hospital Database was reviewed for cases with a GLI3 variant. Within this population, the same inclusion criteria for the phenotype were valid. Relatives of the index patients were also contacted for participation in this study, when they showed comparable hand, foot, or craniofacial malformations or when a GLI3 variant was identified. Phenotypes of the hand, foot and craniofacial anomalies of the patients treated in the Sophia Children's Hospital were collected using patient documentation.

Family members were identified and if possible, clinically verified. Alternatively, family members were contacted to verify their phenotypes. If no verification was possible, cases were excluded.PhenotypesThe phenotypes of both literature cases and local cases were extracted in a similar fashion. The most frequently reported limb and craniofacial phenotypes were dichotomised. The dichotomised hand and foot phenotypes were preaxial polydactyly, postaxial polydactyly and syndactyly.

Broad halluces or thumbs were commonly reported by authors and were dichotomised as a presentation of preaxial polydactyly. The extracted dichotomised craniofacial phenotypes were hypertelorism, macrocephaly and corpus callosum agenesis. All other phenotypes were registered, but not dichotomised.Pathogenic GLI3 variantsAll GLI3 variants were extracted and checked using Alamut Visual V.2.14. If indicated, variants were renamed according to standard Human Genome Variation Society nomenclature.20 Variants were grouped in either missense, frameshift, nonsense or splice site variants. In the group of frameshift variants, a subgroup with possible splice site effect were identified for subgroup analysis when indicated.

Similarly, nonsense variants prone for nonsense mediated decay (NMD) and nonsense variants with experimentally confirmed NMD were identified.21 Deletions of multiple exons, CNVs and translocations were excluded for analysis. A full list of included mutations is available in the online supplementary materials.Supplemental materialThe location of the variant was compared with five known structural domains of the GLI3 gene. (1) repressor domain, (2) zinc finger domain, (3) cleavage site, (4) activator domain, which we defined as a concatenation of the separately identified transactivation zones, the CBP binding domain and the mediator binding domain (MBD) and (5) the MID1 interaction region domain.1 6 22–24 The boundaries of each of the domains were based on available literature (figure 1, exact locations available in the online supplementary materials). The boundaries used by different authors did vary, therefore a consensus was made.In this figure the posterior probability of an anterior phenotype is plotted against the location of the variant, stratified for the type of mutation that was observed. For better overview, only variants with a location effect were displayed.

The full figure, including all variant types, can be found in the online supplementary figure 1. Each mutation is depicted as a dot, the size of the dot represents the number of observations for that variant. If multiple observations were made, the mean posterior odds and IQR are plotted. For the nonsense variants, variants that were predicted to produce nonsense mediated decay, are depicted using a triangle. Again, the size indicates the number of observations." data-icon-position data-hide-link-title="0">Figure 1 In this figure the posterior probability of an anterior phenotype is plotted against the location of the variant, stratified for the type of mutation that was observed.

For better overview, only variants with a location effect were displayed. The full figure, including all variant types, can be found in the online supplementary figure 1. Each mutation is depicted as a dot, the size of the dot represents the number of observations for that variant. If multiple observations were made, the mean posterior odds and IQR are plotted. For the nonsense variants, variants that were predicted to produce nonsense mediated decay, are depicted using a triangle.

Again, the size indicates the number of observations.Supplemental materialLatent class analysisTo cluster phenotypes and relate those to the genotypes of the patients, an explorative analysis was done using LCA in R (R V.3.6.1 for Mac. Polytomous variable LCA, poLCA V.1.4.1.). We used our LCA to detect the number of phenotypic subgroups in the dataset and subsequently predict a class membership for each case in the dataset based on the posterior probabilities.In order to make a reliable prediction, only phenotypes that were sufficiently reported and/or ruled out were feasible for LCA, limiting the analysis to preaxial polydactyly, postaxial polydactyly and syndactyly of the hands and feet. Only full cases were included. To determine the optimal number of classes, we fitted a series of models ranging from a one-class to a six-class model.

The optimal number of classes was based on the conditional Akaike information criterion (cAIC), the non adjusted and the sample-size adjusted Bayesian information criterion (BIC and aBIC) and the obtained entropy.25 The explorative LCA produces both posterior probabilities per case for both classes and predicted class membership. Using the predicted class membership, the phenotypic features per class were determined in a univariate analysis (χ2, SPSS V.25). Using the posterior probabilities on latent class (LC) membership, a scatter plot was created using the location of the variant on the x-axis and the probability of class membership on the y-axis for each of the types of variants (Tibco Spotfire V.7.14). Using these scatter plots, variants that give similar phenotypes were clustered.Genotype/phenotype correlationBecause an LC has no clinical value, the correlation between genotypes and phenotypes was investigated using the predictor phenotypes and the clustered phenotypes. First, those phenotypes that contribute most to LC membership were identified.

Second those phenotypes were directly related to the different types of variants (missense, nonsense, frameshift, splice site) and their clustered locations. Quantification of the relation was performed using a univariate analysis using a χ2 test. Because of our selection criteria, meaning patients at least have two phenotypes, a multivariate using a logistic regression analysis was used to detect the most significant predictors in the overall phenotype (SPSS V.25). Finally, we explored the relation of the clustered genotypes to the presence of corpus callosum agenesis, a rare malformation in GLI3-mediated polydactyly syndromes which cannot be readily diagnosed without additional imaging.ResultsWe included 251 patients from the literature and 46 local patients,10–12 16 21 26–43 in total 297 patients from 155 different families with 127 different GLI3 variants, 32 of which were large deletions, CNVs or translocations. In six local cases, the exact variant could not be retrieved by status research.The distribution of the most frequently observed phenotypes and variants are presented in table 1.

Other recurring phenotypes included developmental delay (n=22), broad nasal root (n=23), frontal bossing or prominent forehead (n=16) and craniosynostosis (n=13), camptodactyly (n=8) and a broad first interdigital webspace of the foot (n=6).View this table:Table 1 Baseline phenotypes and genotypes of selected populationThe LCA model was fitted using the six defined hand/foot phenotypes. Model fit indices for the LCA are displayed in table 2. Based on the BIC, a two-class model has the best fit for our data. The four-class model does show a gain in entropy, however with a higher BIC and loss of df. Therefore, based on the majority of performance statistics and the interpretability of the model, a two-class model was chosen.

Table 3 displays the distribution of phenotypes and genotypes over the two classes.View this table:Table 2 Model fit indices for the one-class through six-class model evaluated in our LCAView this table:Table 3 Distribution of phenotypes and genotypes in the two latent classes (LC)Table 1 depicts the baseline phenotypes and genotypes in the obtained population. Note incomplete data especially in the cranium phenotypes. In total 259 valid genotypes were present. In total, 289 cases had complete data for all hand and foot phenotypes (preaxial polydactyly, postaxial polydactyly and syndactyly) and thus were available for LCA. Combined, for phenotype/genotype correlation 258 cases were available with complete genotypes and complete hand and foot phenotypes.Table 2 depicts the model fit indices for all models that have been fitted to our data.Table 3 depicts the distribution of phenotypes and genotypes over the two assigned LCs.

Hand and foot phenotypes were used as input for the LCA, thus are all complete cases. Malformation of the cranium and genotypes do have missing cases. Note that for the LCA, full case description was required, resulting in eight cases due to incomplete phenotypes. Out of these eight, one also had a genotype that thus needed to be excluded. Missingness of genotypic data was higher in LC2, mostly due to CNVs (table 1).In 54/60 cases, a missense variant produced a posterior phenotype.

Likewise, splice site variants show the same phenotype in 23/24 cases (table 3). For both frameshift and nonsense variants, this relation is not significant (52 anterior vs 54 posterior and 26 anterior vs 42 posterior, respectively). Therefore, only for nonsense and frameshift variants the location of the variant was plotted against the probability for LC2 membership in figure 1. A full scatterplot of all variants is available in online supplementary figure 1.Figure 1 reveals a pattern for these nonsense and frameshift variants that reveals that variants at the C-terminal of the gene predict anterior phenotypes. When relating the domains of the GLI3 protein to the observed phenotype, we observe that the majority of patients with a nonsense or frameshift variant in the repressor domain, the zinc finger domain or the cleavage site had a high probability of an LC2/anterior phenotype.

This group contains all variants that are either experimentally determined to be subject to NMD (triangle marker in figure 1) or predicted to be subject to NMD (diamond marker in figure 1). Frameshift and nonsense variants in the activator domain result in high probability for an LC1/posterior phenotype. These variants will be further referred to as truncating variants in the activator domain.The univariate relation of the individual phenotypes to these two groups of variants are estimated and presented in table 4. In our multivariate analysis, postaxial polydactyly of the foot and hand are the strongest predictors (Beta. 2.548, p<0001 and Beta.

1.47, p=0.013, respectively) for patients to have a truncating variant in the activator domain. Moreover, the effect sizes of preaxial polydactyly of the hand and feet (Beta. ˆ’0.797, p=0123 and −1.772, p=0.001) reveals that especially postaxial polydactyly of the foot is the dominant predictor for the genetic substrate of the observed anomalies.View this table:Table 4 Univariate and multivariate analysis of the phenotype/genotype correlationTable 4 shows exploration of the individual phenotypes on the genotype, both univariate and multivariate. The multivariate analysis corrects for the presence of multiple phenotypes in the underlying population.Although the craniofacial anomalies could not be included in the LCA, the relation between the observed anomalies and the identified genetic substrates can be studied. The prevalence of hypertelorism was equally distributed over the two groups of variants (47/135 vs 21/47 respectively, p<0.229).

However for corpus callosum agenesis and macrocephaly, there was a higher prevalence in patients with a truncating variant in the activator domain (3/75 vs 11/41, p<0.001. OR. 8.8, p<0.001) and 42/123 vs 24/48, p<0.05). Noteworthy is the fact that 11/14 cases with corpus callosum agenesis in the dataset had a truncating variant in the activator domain.DiscussionIn this report, we present new insights into the correlation between the phenotype and the genotype in patients with GLI3-mediated polydactyly syndromes. We illustrate that there are two LCs of patients, best predicted by postaxial polydactyly of the hand and foot for LC1, and the preaxial polydactyly of the hand and foot and syndactyly of the foot for LC2.

Patients with postaxial phenotypes have a higher risk of having a truncating variant in the activator domain of the GLI3 gene which is also related to a higher risk of corpus callosum agenesis. These results suggest a functional difference between truncating variants on the N-terminal and the C-terminal side of the GLI3 cleavage site.Previous attempts of phenotype to genotype correlation have not yet provided the clinical confirmation of these assumed mechanisms in the pathophysiology of GLI3-mediated polydactyly syndromes. Johnston et al have successfully determined the Pallister-Hall region in which truncating variants produce a Pallister-Hall phenotype rather than Greig syndrome.11 However, in their latest population study, subtypes of both syndromes were included to explain the full spectrum of observed malformations. In 2015, Demurger et al reported the higher incidence of corpus callosum agenesis in the Greig syndrome population with truncating mutations in the activator domain.12 Al-Qattan in his review summarises the concept of a spectrum of anomalies dependent on haplo-insufficiency (through different mechanisms) and repressor overexpression.13 However, he bases this theory mainly on reviewed experimental data. Our report is the first to provide an extensive clinical review of cases that substantiate the phenotypic difference between the two groups that could fit the suggested mechanisms.

We agree with Al-Qattan et al that a variation of anomalies can be observed given any pathogenic variant in the GLI3 gene, but overall two dominant phenotypes are present. A population with predominantly preaxial anomalies and one with postaxial anomalies. The presence of preaxial or postaxial polydactyly and syndactyly is not mutually exclusive for one of these two subclasses. Meaning that preaxial polydactyly can co-occur with postaxial polydactyly. However, truncating mutations in the activator domain produce a postaxial phenotype, as can be derived from the risk in table 4.

The higher risk of corpus callosum agenesis in this population shows that differentiating between a preaxial phenotype and a postaxial phenotype, instead of between the different GLI3-mediated polydactyly syndromes, might be more relevant regarding diagnostics for corpus callosum agenesis.We chose to use LCA as an exploratory tool only in our population for two reasons. First of all, LCA can be useful to identify subgroups, but there is no ‘true’ model or number of subgroups you can detect. The best fitting model can only be estimated based on the available measures and approximates the true subgroups that might be present. Second, LC membership assignment is a statistical procedure based on the posterior probability, with concordant errors of the estimation, rather than a clinical value that can be measured or evaluated. Therefore, we decided to use our LCA only in an exploratory tool, and perform our statistics using the actual phenotypes that predict LC membership and the associated genotypes.

Overall, this method worked well to differentiate the two subgroups present in our dataset. However, outliers were observed. A qualitative analysis of these outliers is available in the online supplementary data.The genetic substrate for the two phenotypic clusters can be discussed based on multiple experiments. Overall, we hypothesise two genetic clusters. One that is due to haploinsufficiency and one that is due to abnormal truncation of the activator.

The hypothesised cluster of variants that produce haploinsufficiency is mainly based on the experimental data that confirms NMD in two variants and the NMD prediction of other nonsense variants in Alamut. For the frameshift variants, it is also likely that the cleavage of the zinc finger domain results in functional haploinsufficiency either because of a lack of signalling domains or similarly due to NMD. Missense variants could cause haploinsufficiency through the suggested mechanism by Krauss et al who have illustrated that missense variants in the MID1 domain hamper the functional interaction with the MID1-α4-PP2A complex, leading to a subcellular location of GLI3.24 The observed missense variants in our study exceed the region to which Krauss et al have limited the MID-1 interaction domain. An alternative theory is suggested by Zhou et al who have shown that missense variants in the MBD can cause deficiency in the signalling of GLI3A, functionally implicating a relative overexpression of GLI3R.22 However, GLI3R overexpression would likely produce a posterior phenotype, as determined by Hill et al in their fixed homo and hemizygous GLI3R models.15 Therefore, our hypothesis is that all included missense variants have a similar pathogenesis which is more likely in concordance with the mechanism introduced by Krauss et al. To our knowledge, no splice site variants have been functionally described in literature.

However, it is noted that the 15 and last exon encompasses the entire activator domain, thus any splice site mutation is by definition located on the 5′ side of the activator. Based on the phenotype, we would suggest that these variants fail to produce a functional protein. We hypothesise that the truncating variants of the activator domain lead to overexpression of GLI3R in SHH rich areas. In normal development, the presence of SHH prevents the processing of full length GLI34 into GLI3R, thus producing the full length activator. In patients with a truncating variant of the activator domain of GLI3, thus these variants likely have the largest effect in SHH rich areas, such as the ZPA located at the posterior side of the hand/footplate.

Moreover, the lack of posterior anomalies in the GLI3∆699/- mouse model (hemizygous fixed repressor model) compared with the GLI3∆699/∆699 mouse model (homozygous fixed repressor model), suggesting a dosage effect of GLI3R to be responsible for posterior hand anomalies.15 These findings are supported by Lewandowski et al, who show that the majority of the target genes in GLI signalling are regulated by GLI3R rather than GLI3A.44 Together, these findings suggest a role for the location and type of variant in GLI3-mediated syndromes.Interestingly, the difference between Pallister-Hall syndrome and GLI3-mediated polydactyly syndromes has also been attributed to the GLI3R overexpression. However, the difference in phenotype observed in the cases with a truncating variant in the activator domain and Pallister-Hall syndrome suggest different functional consequences. When studying figure 1, it is noted that the included truncating variants on the 3′ side of the cleavage site seldomly affect the CBP binding region, which could provide an explanation for the observed differences. This binding region is included in the Pallister-Hall region as defined by Johnston et al and is necessary for the downstream signalling with GLI1.10 11 23 45 Interestingly, recent reports show that pathogenic variants in GLI1 can produce phenotypes concordant with Ellis von Krefeld syndrome, which includes overlapping features with Pallister-Hall syndrome.46 The four truncating variants observed in this study that do affect the CBP but did not result in a Pallister-Hall phenotype are conflicting with this theory. Krauss et al postulate an alternative hypothesis, they state that the MID1-α4-PP2A complex, which is essential for GLI3A signalling, could also be the reason for overlapping features of Opitz syndrome, caused by variants in MID1, and Pallister-Hall syndrome.

Further analysis is required to fully appreciate the functional differences between truncating mutations that cause Pallister-Hall syndrome and those that result in GLI3-mediated polydactyly syndromes.For the clinical evaluation of patients with GLI3-mediated polydactyly syndromes, intracranial anomalies are likely the most important to predict based on the variant. Unfortunately, the presence of corpus callosum agenesis was not routinely investigated or reported thus this feature could not be used as an indicator phenotype for LC membership. Interestingly when using only hand and foot phenotypes, we did notice a higher prevalence of corpus callosum agenesis in patients with posterior phenotypes. The suggested relation between truncating mutations in the activator domain causing these posterior phenotypes and corpus callosum agenesis was statistically confirmed (OR. 8.8, p<0.001).

Functionally this relation could be caused by the GLI3-MED12 interaction at the MBD. Pathogenic DNA variants in MED12 can cause Opitz-Kaveggia syndrome, a syndrome in which presentation includes corpus callosum agenesis, broad halluces and thumbs.47In conclusion, there are two distinct phenotypes within the GLI3-mediated polydactyly population. Patients with more posteriorly and more anteriorly oriented hand anomalies. Furthermore, this difference is related to the observed variant in GLI3. We hypothesise that variants that cause haploinsufficiency produce anterior anomalies of the hand, whereas variants with abnormal truncation of the activator domain have more posterior anomalies.

Furthermore, patients that have a variant that produces abnormal truncation of the activator domain, have a greater risk for corpus callosum agenesis. Thus, we advocate to differentiate preaxial or postaxial oriented GLI3 phenotypes to explain the pathophysiology as well as to get a risk assessment for corpus callosum agenesis.Data availability statementData are available upon reasonable request.Ethics statementsPatient consent for publicationNot required.Ethics approvalThe research protocol was approved by the local ethics board of the Erasmus MC University Medical Center (MEC 2015-679)..