Hence Alenka Zupančič’s claim that “[i]f there is an ontology that follows from psychoanalytic (Lacanian) theory, this can only be an ontology as ‘disoriented’ by what he calls the object a” – in short, an “object-disoriented ontology” [93].

Such an object-disoriented ontology – or, as Joan Copjec has dubbed it, an “object a ontology” – would, as Lacan himself knew, more accurately be characterized as a “para-ontology” insofar as the objet a, the inscription of the subject into reality, is “not of the order of being” but is, rather, being’s “inherent impasse,” the cut or crack that “curves and determines” being’s “appear[ance]” by “haunt[ing it] from within, in-form[ing] it” [94], leaving it “beside itself,” “ex-static.” To strike a Derridean note, we might say that the subject is “hauntological,” a “ghost in the machine” of being.

To strike – and end on – a more Ljubljanian note, we might say that the subject is the “short circuit” in being.

This, above all else, is why we so “dogmatically” insist upon the subject’s necessity to any future materialism whatsoever.


For the third consecutive year, there were a sufficient number of submissions for Open Philosophy to assemble a special issue on the theme of “Object-Oriented Ontology and its Critics.” My editorials for the first and second such issues, in 2019 and 2020, can be consulted by anyone interested in seeing what themes were covered there [1].

Among the six articles newly published in the present issue, two (by Tim Flohr Sørensen and Russell Sbriglia) are responses to previous articles of mine in past volumes of Open Philosophy, one gives my response to Catherine Malabou’s recent political critique of Speculative Realism, another (by Jordi Vivaldi) gives an object-oriented response to our occasional critic Rosi Braidotti, and two (by Gonzalo Vaillo and Niki Young) propose technical developments in Object-Oriented Ontology itself. I will cover the articles briefly in that order.


The prolific archaeologist Tim Flohr Sørensen makes a welcome first visit to Open Philosophy in his piece “That Raw and Ancient Cold: On Graham Harman’s Recasting of Archaeology” [2].

It is the latest installment in an exchange triggered in 2018 by his fellow archaeologists Þóra Pétursdóttir and Bjørnar Olsen in “Theory Adrift: The Matter of Archaeological Theorizing,” which found fault with what the authors regarded as the excessively textual and insufficiently material approach to the Dutch East India Company in my 2016 book Immaterialism [3].

My response, in a 2019 article in the pages of this journal entitled “The Coldness of Forgetting,” was to contest the claim of Pétursdóttir and Olsen that the specific feature of archaeology is its focus on material remains rather than texts.

It would be better, I proposed, to view archaeology as focused especially on situations of low information, with history being the proper field to process situations in which relevant information is either ample or downright excessive.

I linked this idea to Marshall McLuhan’s famous though sometimes embattled distinction between “hot” and “cold” media, with the former possessing a high density of information and the latter possessing fainter traces of data, and therefore in need of more participation by the viewer [4].

In response, Sørensen contests my claim that archaeology is a low-data field, pointing to what amounts in fact to an information overload in the profession [5].

To miss this, he holds, is to conflate archaeology as a “trope” with what it really is as an “ecology of practices,” a phrase beloved among New Materialists [6].

Sørensen’s article marks another important engagement by an archaeologist with philosophy, and will be read with interest by the audience of this journal.

Rather than respond to Sørensen in the pages of Open Philosophy, I have done so in a portion of a book chapter entitled “The Shipwreck of Theseus,” which can be found in a collection edited by Peter Campbell and Sara Rich, Contemporary Philosophy for Maritime Archaeology [7].


The second response piece in this year’s issue is “Notes Toward an Extimate Materialism” by Russell Sbriglia of Seton Hall University, an emerging figure in the Ljubljana School which by now is quite famous for its fusion of Hegelian philosophy and Lacanian psychoanalysis [8].

In 2020, Sbriglia and Slavoj Žižek were co-editors of a much anticipated volume entitled Subject Lessons, which featured numerous articles by Ljubljana School members old and young, defending the intellectual contributions of Hegel and Lacan while criticizing recent schools that depart from the priority of the subject, such as New Materialism and Object-Oriented Ontology [9].

I read this book with great interest immediately following publication, and quickly penned a response: “The Battle of Objects and Subjects,” which appeared in this journal a few months later [10].


Sbriglia’s strategy in “Notes Toward an Extimate Materialism” is twofold.

First, he responds to my complaint that the authors in Subject Lessons are too quick to conflate New Materialism with Object-Oriented Ontology.

While conceding that there are numerous differences between these two schools, Sbriglia counters that such distinctions are of less importance than the shared move in both groups toward a “flat ontology,” which he takes to be the real bone of contention between New Materialism and Object-Oriented Ontology on one side and the Ljubljana School on the other.

Second, Sbriglia rejects my claim that Ljubljana calls itself “materialist” solely in order to wrap itself in the mantle of Enlightenment prestige.

Instead, the Ljubljana species of materialism is characterized by its rejection of any totality or whole.

For those who doubt that this is what materialism has ever meant, Sbriglia points to Adrian Johnston’s historical argument published recently in Prolegomena to Any Future Materialism, Volume 2, A Weak Nature Alone [11].


This pair of articles eventually led to a fruitful online discussion between me and Sbriglia on October 29, 2021 (just one week before this writing) at the Psychoanalytic Practices Seminar of the Mahindra Humanities Center at Harvard University.

Video of the debate should be available online shortly.


My own article in this year’s issue is “Malabou’s Political Critique of Speculative Realism.” In a recent article in French, “Le vide politique du réalisme contemporain” (“The Political Void of Contemporary Realism”), the prominent philosopher Catherine Malabou critiques the Speculative Realism movement (founded in 2007 by Ray Brassier, Iain Hamilton Grant, Quentin Meillassoux, and me) for turning too much force over to reality itself and leaving too little for the human subject [12].

In a political context, Malabou holds, this suppresses the radical creative impulses she sees at work in the emerging politics of recent years.

She argues the point by focusing on two pieces by Brassier (his doctoral dissertation at the University of Warwick, and his well-known article “Concepts and Objects”) and two by me (“The Future of Continental Realism” and the book chapter “The Four Most Typical Objections to OOO”) [13].

Whereas Speculative Realism strongly emphasizes a real that exists independently of human thought, Malabou charts an opposite course, invoking Louis Althusser’s idea of a materialism that would not be determined by anything pre-existing: one in which matter would only be summoned into its existence by its relations, and be marked by an entirely unpredictable contingency freed from the bonds to autonomous matter found in the rather different model of contingency in Meillassoux [14].

In response, I point to some problems that emerge when non-human reality is left out of consideration in politics and society, citing as evidence the joint work of Shirley Strum and Bruno Latour [15].


Readers of this journal are already familiar with Jordi Vivaldi, who in 2020 published a thoroughly fresh article called “The Twofold Limit of Objects,” which applied concepts from the Spanish philosopher Eugenio Trías to interpret Timothy Morton’s concept of “rift” [16].

Now, in a detailed piece entitled “Xenological Subjectivity,” Vivaldi considers the work of Rosi Braidotti, charismatic intellectual leader of one of the major sub-schools of New Materialism, and a prolific author of influential philosophical works [17].

As Vivaldi tells us, he thinks Braidotti succeeds in accounting for the self as a “transversal multiplicity” and the world as “non-hierarchized by nature-culture distinctions” [18].

Like many other Deleuzeans, however, Braidotti invests too heavily in a neo-Spinozistic monism, and thereby “blurs the notions of finitude, agency, and change, obscuring the possibility of critical dissent while decreasing the overall theory’s consistency” [19].

Vivaldi’s proposal is that Braidotti can avoid these difficulties by opening up to the object-oriented notion of “withdrawal,” reflecting the influence on OOO of Martin Heidegger [20].


Gonzalo Vaillo’s “Superficiality and Representation” marks his debut in Open Philosophy, though he is already well-known in object-oriented circles [21].

As Vaillo aptly remarks, there are two basic positions when it comes to the relation between appearance and reality, which he calls “reality as appearance” and “reality beyond appearance” [22].

While OOO clearly belongs to the second of these families, Vaillo also notes that it distinguishes between ontologies of continuity and ontologies of discreteness: Deleuze is mentioned as a good example of the first, and Kant and OOO as models of the second.

On the basis of these distinctions, Vaillo makes several intriguing claims.

He first considers the direct realisms of Thomas Reid and James J. Gibson, the “bundle” theory of David Hume, and the refutation of the latter by Edmund Husserl’s introduction of the intentional object (Franz Brentano’s earlier intentional object is too close to the Humean bundle to match Husserl’s significant breakthrough) [23].

At least in the cases of Reid, Gibson, and Hume, it turns out that communication between different observers of the world will be difficult, given that they are excessively locked into private viewpoints without possibility of unification.

In an especially clever twist, Vaillo even interprets Husserl’s Polish rival Kasimir Twardowski as a “superficialist” despite his distinction between deep objects and superficial qualities, since his notion of depth is merely projected retroactively as the result of some specific perception [24].


Turning next to theories of reality beyond appearance, Vaillo shows more sympathy for OOO’s discrete ontology than for the continuisms of Deleuze and Henri Bergson, though he also identifies multiple problems facing both my version of OOO and Levi Bryant’s (“onticology”), including their inability to do justice to what Morton calls “hyperobjects” [25].

Vaillo expresses the additional concern that my claim that “knowledge” and “truth” have nothing to do with each other runs the risk of an epistemological idealism that grants too much weight to the position of the observer and too little to the object of knowledge [26].

Vaillo’s original solution consists, in part, in denying the view of Kant and Clement Greenberg that aesthetics is an end in itself [27].

Instead, the experience of allure generates a number of side-effects that also contribute to our knowledge of objects, rather than knowledge being walled off from aesthetics as a dangerous threat to its autonomy.

After many readings, I am not yet sure that I have exhausted the complexity of Vaillo’s theory.


The final article in this year’s OOO issue, “Object, Reduction, and Emergence” is written by Niki Young, another Open Philosophy veteran [28].

Our issue of last year features Young’s already influential “On Correlationism and the Philosophy of (Human) Access,” with its insistence on drawing a distinction between Meillassoux’s famous term “correlationism” and my own closely related “philosophy of access” [29].

In the same general timeframe, though elsewhere, he published “Only Two Peas in a Pod,” a powerful piece on the increasingly important OOO topic of “onto-taxonomy” [30].


The premise of “Object, Reduction, and Emergence” is that OOO so far has relied heavily on the concept of emergence without providing any centralized discussion of the topic: a lacuna that Young aims to fill.

This claim rings true, to the extent that most OOO discussions of emergence so far have simply adopted Manuel DeLanda’s discussion of it as their starting point [31].

Even Morton’s interesting discussion of emergence in Realist Magic treats it as a “sensual” phenomenon, rather than as the emergence of a “real” object as my own position would seem to require [32].

While there is a negative sense of emergence throughout OOO in the context of the unreachable withdrawal of objects, Young identifies a positive sense of the term in my 2010 article “Time, Space, Essence, and Eidos,” and from here he pushes further, showing along the way how the OOO conception of emergence must depart from David Chalmers’ distinction between “strong” and “weak” versions of the concept [33].

After reminding the reader that my 2005 book Guerrilla Metaphysics argued that causation is always vicarious, asymmetrical, and buffered, Young goes on to expand this trio of terms to six: adding that it must also be binary, alluring, and aesthetic [34].


The rapid influence of Young’s article can be seen in the fact that it is already cited in Vivaldi’s “Xenological Subjectivity,” discussed earlier.


It perhaps goes without saying that I have learned a great deal about Object-Oriented Ontology from each of these articles; otherwise, they could never have survived the review process for this issue.


In the UK, more than 50% of medical students and 45% of practising doctors are female [1].

In the specialty of anaesthesia, 32% of UK consultants are female.

The proportion of female consultants has risen consistently between 2007 and 2015 [2].


However, compared with males, females are under-represented as authors of articles published in high-impact journals.

In one study [3] researchers examined articles published between 2005 and 2017 in 15 major science and neuroscience journals, including Nature, Science, Proceedings of the National Academy of Sciences (PNAS), Nature Neuroscience and Neuropsychology Review.

Females accounted for approximately 25% of first authors in Nature and Science and just over 35% of first authors in Proceedings of the National Academy of Sciences.

In only one journal, Neuropsychology Review, did female first authors outnumber males (by 53-47%).

This study also highlighted an inverse relationship between the prevalence of female authors and a journal's impact factor: the higher the impact, the lower the proportion of female first authors.


It is widely recognised that there is a 'glass ceiling' within academic medicine that may contribute to these findings.

Only 29% of UK professors in medicine are female.

Anaesthesia has one 1432 © 2019 Association of Anaesthetists Anaesthesia 2019, 74, 1432-1438 doi:10.1111/anae.14797 of the lowest proportions of female professors (8%) than any other medical discipline [4].


However, with an increasing proportion of the anaesthetic consultant workforce being female, more clinically-based publications, such as case reports, may not be as affected by sex bias.

We decided to perform a retrospective analysis of the proportion of female first authors of case reports submitted to Anaesthesia Cases including rejected, as well as accepted, submissions.


We examined all submissions to Anaesthesia Cases since its inception in January 2013, to August 2018.

For both rejected and accepted case reports, we noted the sex of the first author.

If we could not immediately identify the sex of the author we used Google TM , Google images TM , Facebook TM , LinkedIn TM and ResearchGate TM in order to determine the sex of an author.

If this was not possible, we emailed the first author for further information.


We defined authors by their sex (male or female), that is, biological characteristics rather than gender (masculine or feminine), which reflects psychological, behavioural and sociological characteristics.

For clarity, the term 'sex' will be used throughout the article to differentiate between male and female authors.

We did not enquire whether an author considered themselves as having a specific preference such as gender dysphoria (incongruity between a person's sense of themselves and the sexual characteristics they were born with), a trans woman (a woman who was assigned male at birth), a trans man (a man who was assigned female at birth) or non-binary transgender (someone who does not exclusively identify as man or woman, masculine or feminine, male or female).


Data were explored using descriptive statistics.

A chi-square test was performed using SPSS version 25 (IBM â , Armonk, NY, USA) software to compare proportions of female first authors in accepted and rejected articles, and OR were manually calculated.


There were 802 submissions to Anaesthesia Cases over the 4.5-year period.

Sixteen submissions were excluded; nine were duplicates and seven were administration test submissions (Fig. 1).

Out of the remaining 786 submissions, 279 were accepted and 507 rejected, an acceptance rate of 35.5%.

Twenty (2.5%) authors' sex could not be identified and were excluded from overall analysis.


The overall proportion of female first authors was 37.1%.

The proportion of female first authors of accepted case reports was 42.1% and females were first authors of rejected case reports in 34.4%.

There was a significant association between the sex of first author and whether a submission was accepted (χ 2 (1) 4.095, 1 df and p = 0.043).

The odds of acceptance were 1.39 times higher if the first author was female rather than if the first author was male.


The number of female first authors increased over time as shown in Fig. 2.

There was an increase in the proportion of submissions by female first authors during the period studied, rising from 35% in 2013 to 40% in 2017 (Fig. 3).


Anaesthesia Cases was launched in January 2013 as an online library of case reports in anaesthesia, pain management and intensive care medicine.

These are case reports that previously would have been considered for publication in Anaesthesia.

Journals have reduced the number of case reports they publish, or even excluded them altogether.

Anaesthesia Cases was created as an online library for the continued publication of informative, educational and important case reports.

Since its launch, submission and publication in Anaesthesia Cases has been free for authors.

All submissions are assessed for suitability by two editors.

Anaesthesia Cases became so popular that it was relaunched in May 2019 as Anaesthesia Reports, a fully independent journal publishing cases in clinical practice.


To our knowledge, this is the first review of an anaesthetic publication that considers the influence of the first author's sex on the outcomes of all submissions (both accepted and rejected articles).

In our study, the overall proportion of female first authors for any submission was 37%.

This reflects the proportion of female anaesthetists currently working throughout the UK (32% consultants and 39% staff and associate specialist doctors are female) [2].

Comparing the proportion of female first authors between anaesthesia-specific journal publications, females represented a higher proportion of published first authors (42%) in Anaesthesia Cases than female first authors of original research papers in the British Journal of Anaesthesia for the year 2011 (30%) [5], or selected original articles published in the journals Anesthesiology and Anesthesia and Analgesia over a 15-year period (both 26%) [6].

Thus, in terms of sex bias, Anaesthesia Cases compares favourably with these other anaesthetic journals (Fig. 4).


© 2019 Association of Anaesthetists 1433 Laycock and Bailey | Author sex and Anaesthesia Cases Anaesthesia 2019, 74, 1432-1438 13652044, 2019, 11, Downloaded from https://associationofanaesthetists-publications.onlinelibrary.wiley.com/doi/10.1111/anae.14797 by Mcgill University, Wiley Online Library on [19/05/2024].

See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License influence acceptance rates.

Since the inception of Anaesthesia Cases (now Anaesthesia Reports), females have represented between 50% and 67% of the editorial Board.


This is in contrast to 20% female editors of the British Journal of Anaesthesia in 2013 and 16% female Editorial Board membership of Anesthesiology and Anesthesia and Analgesia in 2018.

There was no active positive discrimination strategy for editorial review at Anaesthesia Cases to favour female first authors; however, as submissions are not anonymised, editors' subconscious bias could have contributed to these results.


It could be that the proportion of female doctors within a specialty influences the likelihood of females being first authors in specialty-specific publications.

In general, irrespective of the medical specialty, females appear to be under-represented in subject-specific publications as first authors compared with the proportion of the workforce they represent in that specialty.

Table 1 highlights the proportion of the UK workforce that are female for a selection of medical specialties, alongside the proportion of female authors for specialty-specific publications, evaluated at a similar time period.


Specialties within the table fall into three possible groups.

Firstly, those with a female dominant workforce, where greater than 50% of the workforce are female (dermatology and paediatrics).

Second, specialties that have a similar female-to-male proportion of the workforce to anaesthesia (psychiatry, general practice and ophthalmology) and third, specialties where less than 25% of the workforce are female (otorhinolaryngology and orthopaedic surgery).


For most specialties represented in Table 1, there appears to be around a 10% discrepancy in the proportion of female authors compared with the UK workforce proportion.

Exceptions to this include dermatology, where despite females representing nearly two thirds of the workforce, only 50% of authors were female [7, 8].

Conversely, otorhinolaryngology has a similar proportion of female first authors in speciality-specific publications [9] compared with their proportion within the UK workforce.

Although the available data fail to account for differences in female workforce proportions in different countries, they do suggest that under-representation of females as first authors in publishing is not confined to one specialty.


In the wider medical publishing world, it is clear that females are under-represented.

Bendels et al. [ 10] examined 54 journals listed in Nature Index between 2008 This proportion is similar to that found by Filardo et al. [ 11] who looked at six high-impact medical journals over a 20- year period.

The journals examined were the British Medical Journal (BMJ), the New England Journal of Medicine (NEJM), Lancet, Annals of Internal Medicine, Archives of Internal Medicine and Journal of the American Medical Association. They found that overall female first authorship increased from 27% in 1994 to 37% in 2014 and that first authors were more likely to be female in the BMJ and less likely to be female in NEJM.


Females also appear under-represented as authors in publications from allied medical professions, such as pharmacy and nursing.

In pharmacy, Dotson [12] found that although the incidence of female first authors increased from 30% in 1989 to 52% in 2009, this was still an under-representation.

It is also noticable in nursing, where 90% of the workforce are females yet only 70% of articles in three nursing journals had females as first authors [13].


The ability to publish requires time for research to be conducted and articles to be written, submitted and revised.

Doctors who publish, especially early in their careers, are required to fit this in around clinical and out of hours on call commitments, as few have dedicated research time.

A critical time for career development occurs between the ages of 21 and 35, and this coincides with the ages at which females are most likely to start a family.

Female doctors are more likely to work less than full time (LTFT), thus reducing the time available to spend within the working week on these projects.

A survey of over 10,000 medical graduates over a 10-year period in the UK by Lachish et al. demonstrated that, for doctors working in the NHS, approximately 42% of female doctors worked LTFT compared with 7% of male doctors [14].

Although there are a number of reasons for individuals to choose to work LTFT, including caring for ill or older relatives, this survey found child rearing responsibilities significantly influenced the probability that females worked LTFT but had no effect on the likelihood that male doctors worked LTFT.

This is in keeping with other evidence in this area and suggests that starting a family could in turn reduce the available time to publish.


Females are also less likely than males to enter academic medicine or have research allocation within their job plan, again reducing the time necessary to produce publications [4].

In general, females who do enter academic medicine, compared with males, seem to have more difficulty in securing grants from funders.

A meta-analysis of 21 studies considering whether an applicant's sex influenced decisions in grant peer review found that males had statistically significant greater odds, around 7%, of receiving grants than females [15].

There are also data to suggest that grants obtained by females are of lower value [16]; however, the interpretation of this is more nuanced, as it may represent females being less ambitious in their funding requests.

Notably a recent publication found there was no sex effect on the likelihood of being awarded a National Institute of Academic Anaesthesia research grant (p = 0.484) [17], although whether this is applicable to female anaesthetists applying to other funding bodies is not known.


This may also represent a loss of females from the academic workforce at each stage of career progression.

A report in 2013 by the Academy of Medical Sciences showed that although approximately half (52%) of junior clinical fellowships were awarded to females, this decreased to 37% of intermediate fellowships and 12% of senior fellowships [18].

Females are, therefore, under-represented in senior academic posts, with the proportion of females in academic grades decreasing with seniority.

The small proportion of female leaders in academic medicine may impact on sex bias in publishing; there is evidence to suggest that females in leadership roles who are last authors on manuscripts are more likely to have female co-authors and have more female authors contributing to their research [19].

Additionally, the traditional entry into publishing was first by publishing a case report and then building experience with more extensive pieces of writing whilst developing an academic career.

Although academic careers that follow formalised training schemes, such as those delivered by the UK National Institute for Health Research, may not depend as heavily on this stepwise approach to publishing, a positive experience at an early stage will surely encourage future engagement.


Success in publishing is aided by presenting at scientific conferences, yet females are very under- represented at major medical meetings.

A common picture is that of the all-male panels of speakers, or 'manel' (now officially adopted by the Oxford English Dictionary).

This reflects the fact that females are not invited as often as they should be.

There are positive signs of a change in sex


Publications by females would undoubtedly be helped by having more female journal editors, yet they are still very under-represented on editorial boards.

In 2008, only 12% of 16 biomedical journals had females as board members [21] and in 2011 only 16% of the editors-in-chief of 60 top ranked medical journals were female [22].

This sex disparity on journal editorial boards and unconscious bias likely contributes to less female authorship.

Females are also under-used in the peer review process.

In 2014 and 2015 less than a quarter of reviewers in Nature were female [23].

However, the journal highlighted that this is in part due to authors submitting manuscripts and only recommending approximately 12% female reviewers to evaluate their articles.

This relates to authors requesting senior academics to review their submissions and, as already highlighted, females are under-represented in senior academic roles.


A limitation of our study is that, due to the structure of the database, we could only retrieve the name of the first author rather than all the authors' names.

Additionally we did not consider international differences in female proportions of the workforce and whether this affected the international authorship of the journal.

A strength of the study is that we extracted the first author name of every submission to Anaesthesia Cases over the last 5 years and could not identify the sex of the author in only 2.5% of all submissions.


In conclusion, we found that, compared with previous studies on female sex bias in publishing, there was a relatively high (42%) proportion of female first authors publishing in Anaesthesia Cases and this accurately reflects the proportion of female anaesthetists currently working.

Case reports from female first authors were more likely to be accepted than those from male first authors.

Authorship is an important reflection of career success.

It is the culmination of career development, mentorship, funding and support.

We suggest that sex inequity must be tackled at all levels, from application to medical school, through research funding, journals and Editorial Boards.


I congratulate Drs Laycock and Bailey on their recent publication [1] and observation that ‘female first authors were more likely to be accepted than male first authors’ for case reports published in Anaesthesia Cases.

Data from the Universities and College Admissions Service demonstrate that, in the UK, 59% of those accepted to medical school in 2017 were women, possibly reflecting the fact that traditionally women achieve better A-level grades than men.


However, I find the suggestion by the authors that ‘publications by women would undoubtedly be helped by having more female journal editors’ extremely worrying. I would like to think that, in an era of evidence-based medicine, a publication has been accepted for its scientific merit and not, as Laycock and Bailey seem to suggest, because an editor has unconsciously selected the publication on the basis of the author’s sex.


As a reviewer of many manuscripts I have been blinded to the name and sex of the author and my decision to accept or reject a submission has been based upon the scientific quality of the article.

As an author, I would like to think that my publications have been accepted or rejected in a fair and transparent process and that my rejections have been decided by the content of my work rather than my sex.


Although I agree with the authors that we should strive to achieve parity of the sex balance of journal editors, I think the most important issue is to ensure that publications are chosen for scientific quality irrespective of authors’ sex.


We thank Dr Efthymiou for his letter [1] regarding our recent article [2] and for increasing the dialogue on what we consider an interesting, yet controversial, topic.

We agree wholeheartedly with Dr Efthymiou, that submissions should be accepted on scientific merit alone and not be biased by an author’s sex, gender, race, ethnicity, institution or any other factors for that matter.

He argues that ‘a publication has been accepted for its scientific merit... in a fair and transparent process’ and that he, as a reviewer himself, has been blinded to the name and sex of the author.

Publication metrics are still considered by many institutions as markers of scientific success, and in the medical world, where women are underrepresented at all levels, especially in senior positions, any potential for mitigating these inequities is important and should be highlighted.


We agree with Dr Efthymiou that striving to achieve sex balance of journal editors is key, alongside increasing female representation among reviewers and raising awareness of possible bias that occurs, often unknowingly, in publishing.

Unfortunately, this type of double-blind review (where both author and reviewer identities are concealed) is practically very difficult and may cause more problems than it solves.

Although a full discussion is beyond the scope of this letter [3], it is likely that a reviewer, being an expert in their field, will be able to identify a well-known author from the nature of their work, style of writing or particular research technique, even when every effort has been made to anonymise the submission.

Conversely, if the author is not well known then there is no need to conceal their identity.

In the double-blind review process there is no requirement for the reviewer to disclose any conflicts of interest and therefore to identify possible bias and, when the authors are deduced from a manuscript’s content, the double-blind review effectively becomes a single blind review, which is what is practised in our journal.

This at least allows the reviewer to recluse themselves if they do have any conflicts and may also identify author self-plagiarism.


In a recent publication, Murray et al. considered the peer review outcomes of more than 30,000 submissions to the biosciences journal eLife [4].

They found that gatekeepers (i.e. the reviewers) favoured manuscripts from authors of the same sex and same country, and that sex inequity was greatest when teams of reviewers were all men.

Although the influences on success rates are multiple and complex, including not only the process of peer review but also differing submissions rates, it appears that the sex of a reviewer regrettably plays a part.


The epidemic curve is the number of reported cases by date of symptom onset.

For each reported case i, we denote the symptom onset date by t i .

For the SARS epidemics in Hong Kong, Vietnam, and Singapore, we derived the dates of symptom onset from epidemic curves provided by the World Health Organization (9).

For Canada, we used the epidemic curve provided by Health Canada (10).


The generation interval, denoted by τ, is the time from symptom onset in a primary case to symptom onset in a secondary case.

Sometimes this generation interval is called the serial interval (8) or generation time (11).

The generation intervals observed during the SARS outbreak in Singapore are well described by a Weibull distribution with a shape parameter α and a scale parameter β, with values corre- sponding to a mean generation interval of 8.4 days and a standard deviation of 3.8 days (8).

We denote this distribu- tion by τ ∼ w(τ|α,β).


The key epidemiologic variable that characterizes the transmission potential of a disease is the basic reproduction number, R 0 , which is defined as the expected number of secondary cases produced by a typical primary case in an entirely susceptible population (12-15).

When infection is spreading through a population, it is often more convenient to work with the effective reproduction number, R, which is defined as the actual average number of secondary cases per primary case.

The value of R is typically smaller than the value of R 0 , and it reflects the impact of control measures and depletion of susceptible persons during the epidemic.

If R exceeds 1, the number of cases will inevitably increase over time, and a large epidemic is possible.

To stop an epidemic, R needs to be persistently reduced to a level below 1.

Estima- tion of R is a simple affair if there is information about who infected whom.

Then it is possible to construct an infection network (11), wherein cases are connected if one person infected the other.

Estimation of R involves simply counting the number of secondary infections per case.


Often, estimation of the effective reproduction number is a complicated affair, because only the epidemic curve is observed and there is no information about who infected whom.

Recent analyses of closely monitored epidemics have shown that it is possible to estimate the probability that one person has infected another if the spatial locations of the infected persons are available (11, 16).

However, when only times of symptom onset are available, most investigators resort to approximating R by assuming an exponential increase in the number of cases over time (8, 17) or by fitting a specific model that summarizes assumptions about the epidemiology of the disease (7, 18, 19).

Such assumptions can be avoided by using a likelihood-based estimation proce- dure that infers "who infected whom" from the observed dates of symptom onset as provided by the epidemic curve.

However, the computational burden of a straightforward numerical evaluation of the likelihood appears to be enor- mous, since it requires consideration of all possible infection networks, and even for a small outbreak of 50 cases there are almost 7 × 10 82 possible infection networks (see Appendix 1).


Here we show that it is possible to obtain likelihood-based estimates of R while avoiding the computational problems if we use pairs of cases rather than the entire infection network.

The relative likelihood p ij that case i has been infected by case j, given their difference in time of symptom onset t i - t j , can be expressed in terms of the probability distribution for the generation interval.

This distribution for the generation interval is available for many infectious diseases, and we denote it by w(τ).

The relative likelihood that case i has been infected by case j is then the likelihood that case i has been infected by case j, normalized by the likelihood that case i has been infected by any other case k:


The effective reproduction number for case j is the sum over all cases i, weighted by the relative likelihood that case i has been infected by case j:


Note that we are not making any assumption regarding the distribution of numbers of secondary infections per case (i.e., the p ij are independent in j).

Additional detail on the derivation of these equations is provided in Appendix 1.

The estimation algorithm allows estimation of the effective reproduction numbers for infectious diseases at a finer temporal resolution under more general assumptions than was previously possible.


To test how well the estimation procedure approximates the underlying value of an effective reproduction number during a typical SARS outbreak, we estimate the effective reproduction numbers from simulated epidemic curves.

We have constructed a stochastic, individual-based model that simulates epidemic processes with exactly specified proper- ties.

The model allows for a variable effective reproduction number R t as a function of symptom onset data t, and the model parameters are estimated from observations on the SARS epidemic in Singapore (see Appendix 2).

Applying the estimation procedure to simulated epidemic curves shows that most of the estimates are close to the actual repro- duction numbers and that a few estimates based on small outbreak sizes are below the actual values that are used in the simulation model.

On average, the estimates tend to be lower than the actual values but deviate less than 5 percent from the actual reproduction numbers.

If we account for the effects of incomplete reporting and temporal change in generation interval, the estimates become only slightly less accurate, and on average they deviate less than 15 percent from the actual reproduction numbers (see Appendix 2).


For Hong Kong, Vietnam, Singapore, and Canada, we have converted the epidemic curves into the time course of effective reproduction numbers.

The results are shown in figure 1, parts e-h.

These four large outbreaks were sparked almost simultaneously by the same index patient.

All regions have faced erratic "super-spread events" wherein cases produced more than 10 secondary infections.

These "super-spread events" show up in parts e-h of figure 1 as temporary increases in effective reproduction numbers around the symptom onset date of the index case for the "super-spread event." In Hong Kong, Vietnam, and Singapore, there were "super-spread events" marking the start of the outbreak.

In Hong Kong, Singapore, and Canada, there were "super-spread events" after control measures were implemented.


During the early phase of the SARS epidemic, before the first World Health Organization global alert was issued on March 12, 2003, the average effective reproduction numbers were markedly similar across the regions: Each case produced approximately three secondary infections (table 1).

A value of R slightly higher than 3 is consistent with the observed epidemics in all four regions.


Around mid-March, control measures were implemented in all regions, and during this period the effective reproduction numbers decreased sharply.

For some regions, the effective reproduc- tion numbers continued to decrease at a slow pace, suggesting improvement of control measures while the epidemic was going on.


After the first World Health Organi- p ij w t i t j - ( ) w t i t k - ( ).

i k ≠ ∑ ⁄ = R j p ij .

i ∑ = Am J Epidemiol 2004;160:509-516 zation global alert, each case produced approximately 0.7 secondary infections (table 1).

A value of R = 0.7 is consis- tent with all four regions, except Canada.


By the beginning of July 2003, transmission of the SARS virus had been stopped in all regions where the infection was introduced in late February 2003 (1).


To explore the range of epidemic curves that can result from the same epidemic process, we performed extensive computer simulations using a model of epidemics with char- acteristics similar to those of SARS (see Appendix 2).

The outcome of 10,000 simulations shows a highly variable epidemic size and epidemic duration: The mean epidemic size is 685 cases (95 percent confidence interval (CI): 27, 2,446), and the mean epidemic duration is 98 days (95 percent CI: 32, 187).

All observed sizes and durations of SARS epidemics are within this very wide range of possible outcomes resulting from chance alone.

Additionally, we used computer simulations to explore the effect of the timing of implementation of control measures on the epidemic size and duration, in a setting that is typical for the SARS outbreaks.

The simulation results show a high sensitivity to the timing of implementation of control.

On average, a 1- week delay in implementation of control measures results in a 2.6-fold increase in mean epidemic size and a 4-week extension of the mean epidemic duration.


This study showed that there exists a direct relation between the epidemic curve and the time course of the repro- duction number R. This relation is determined by the distri- bution of the generation intervals.

The relation can be used to monitor the combined effects of transmission potential and control measures during an epidemic.

We have shown that the epidemic curves for SARS in Hong Kong, Vietnam, Singapore, and Canada, though apparently different, are all consistent with a single time course of the effective repro- duction numbers for SARS.

This apparent difference in epidemic curves arises because chance effects, such as the occurrence of a rare "super-spread event," leave a lasting trace on the epidemic curve.

In contrast, chance events mani- fest only as temporary increases in the reproduction number.

Our analysis of the epidemic curves for SARS shows that one should be cautious in taking a smaller epidemic size and a shorter epidemic duration as proof of better infection control.


We have presented the relation between observed epidemic curves and inferred reproduction numbers from an infection-network perspective.

We are certainly not the first researchers to do so: Infection networks have been used extensively in the area of sexually transmitted diseases (20), and an infection-network perspective was adopted to analyze a closely observed foot-and-mouth epidemic in Great Britain (11).

Our contribution is the deri- vation of likelihood-based estimates of effective reproduc- tion numbers, requiring only the observed time of symptom onset for the observed cases.

The use of a likelihood frame- work provides a set of powerful tools for inference, uncer- tainty analysis, and model selection (20); the use of only time of symptom onset allows us to apply this method to routinely collected epidemic-curve data.

However, estima- tion of effective reproduction numbers from epidemic curves has an intrinsic limitation that should be kept in mind: The effective reproduction number contains entan- gled information about the transmission potential (i.e., the basic reproduction number) and the effectiveness of control measures.

These two components can be disentangled only when we obtain additional information-for example, about the time of implementation of control measures.

Moreover, individual contributions to the effective repro- duction number are entangled if their date of symptom onset is smaller than the generation interval.

This limitation can be overcome if more detailed information on who infected whom is available (see Appendix 1).


For the SARS outbreak in Hong Kong, it is possible to compare our results with previously published estimates.

Our estimate of the average effective reproduction number prior to the first global alert (R = 3.6, 95 percent CI: 3.1, 4.2) is more precise than the estimate obtained by assuming an exponential increase in the number of cases (R = 3.5, 95 percent CI: 1.5, 7.7) (8) and more precise than the estimated lower bound excluding "super-spreading events" (R > 2.7) (7).

Our estimate of the average effective reproduction number after the first global alert (R = 0.7, 95 percent CI: 0.7, 0.8) is much higher than the previously estimated lower bound excluding "super-spread events" (R > 0.14) (7).

This comparison illustrates that the estimation algorithm presented here allows more precise estimation of the effec- tive reproduction numbers for infectious diseases under more general assumptions than was previously possible.


The effectiveness of control measures against SARS can be estimated if it is assumed that the sudden decrease in the effective reproduction number for SARS around the time of the first global alert was indeed caused by the implementa- tion of control measures.

The decrease in the reproduction number from 3 to 0.7 then suggests that the control measures taken around this time prevented approximately 77 percent (100 × (3 - 0.7)/3 percent ≈ 77 percent) of all potential secondary infections.

This effectiveness suffices for eventu- ally stopping infections in situations where each case causes up to 4.3 (1/(1 - 0.77) ≈ 4.3) secondary infections.

Recalling that before implementation of control measures, each SARS case produced, on average, approximately three secondary infections, this effectiveness has been barely sufficient for the eventual interruption of the chain of human-to-human transmission of the SARS virus.


As the direct threat of a worldwide SARS epidemic has waned, the question arises as to how we can use the experi- ence with SARS to improve infection control against new infectious diseases.

Our analysis of the epidemic curves for SARS, as reported for Hong Kong, Vietnam, Singapore, and Canada, shows how crucial the rapid implementation of control measures has been in limiting the impact of the epidemics, both in terms of preventing more casualties and in terms of shortening the period during which stringent infection control measures were in place.

A first lesson from the several SARS epidemics is that a timely alert against a new infectious disease is most essential.

Our anal- ysis suggests that the control measures implemented prevented approximately three quarters of all potential secondary infections; this may be insufficient to stop another new infectious disease.

A second lesson, then, is that it is crucial to estimate the transmission potential of a new emerging disease as soon as possible and to establish whether additional, more stringent control measures are required.


Health officials faced a daunting task with the emergence of severe acute respiratory syndrome (SARS) last year: forecasting the trajectory of an emerging infectious disease and implementing effective control measures, even as the etiologic agent was still being identified.

Investigators initially had little to go on beyond crude epidemiologic data such as the timing of new cases (the epidemic curve).

With such limited data, it was difficult to disentangle two fundamental epidemiologic quantities: the time from one transmission of the infection to the next, known as the serial interval or generation time, and the average number of secondary cases resulting from each infection, known as the reproductive number.


A simple example illustrates the problem.

Compare two idealized diseases, A and B. Disease A has a short generation time of 4 days but has relatively low transmissibility, such that each primary infection generates two secondary infections.

Disease B has a longer generation time of 8 days but is more transmissible, such that each primary infection generates four secondary infections.

The initial epidemic curves for these two infections will be nearly superimposable, with approximately a doubling of new cases every 4 days.


(These calculations are approximate.

In fact, the generation time for any given transmission will be a random variable, with some distribution.

This distribution will affect the precise doubling time of the epidemic and will also affect the shape of the epidemic curve in the period before the epidemic enters an exponential growth phase [1–3].) Thus, investigators cannot separate generation time from reproductive number on the basis of the epidemic curves alone.

As a result, they are limited in their ability to predict the efficacy of potential interventions.

Despite nearly identical epidemic curves, an outbreak of disease A can be stemmed by an intervention that reduces transmission threefold, while disease B will continue to spread even with such control measures in place.


In the current issue of the Journal, Wallinga and Teunis [4] present a statistical escape from this analytical Catch-22.

Their approach is this: Once epidemiologists have traced the chains of transmission in a single isolated outbreak, they can use the transmission network to infer the distribution of generation times for that disease.

This distribution, which results from the biology of host-pathogen interaction, should be relatively constant in comparison with transmission rates, which will vary from location to location and over the course of an epidemic as the pool of susceptible persons declines and as control measures are implemented.

Therefore, investigators can use this generation time distribution as a grounding point from which to infer the reproductive number, R, from epidemic curves observed in other settings where extensive contact tracing may not have been achieved.

Most importantly, Wallinga and Teunis describe an elegant method for following the instantaneous reproductive number as it evolves over time in a single epidemic.

They provide a means of transforming the time series of cases, along with a “known” distribution for the generation time, into a time series of estimated values for the instantaneous reproductive number on each day.


This method allows nearly real-time tracking of the effect of control measures and other changes in an epidemic on the level of transmission ongoing in the population.

Estimates are not precisely real-time, because accurate estimates of the instantaneous reproductive number on a given date cannot be made until some time after that date.

Specifically, one can only estimate the number of persons a given case has infected when a sufficient amount of time has passed that all patients with secondary cases generated by that case (and by other, surrounding cases) have become infected, become symptomatic, and had their infections reported.

While this lag period (slightly more than the generation time, plus the incubation period, plus the reporting delay) could be decades long for diseases with extended latency periods such as human immunodeficiency virus disease, in the case of SARS the lag period is a matter of a few weeks, and the information provided is as fresh as one could obtain, given the available data.


Wallinga and Teunis’s elegantly simple approach is related to more complex applications of back-calculation that have been used to derive incidence of infection from data on disease prevalence or incidence in human immunodeficiency virus disease [5] and to derive annual average reproductive numbers from case data in the United Kingdom epidemic of bovine spongiform encephalopathy [6].

The present work is distinguished by its real-time applicability to a rapidly transmitted disease and its requirements for only the serial interval distribution and the epidemic curve as inputs.


In their report [4], Wallinga and Teunis demonstrate the power of this analytical approach by improving our understanding of the 2003 SARS outbreaks in Hong Kong, Vietnam, Singapore, and Canada.

The authors find that despite the very different epidemic curves observed in each location, pre-intervention reproductive numbers appear to have been similar.

Furthermore, they infer that control interventions appear to have reduced transmission rates approximately fourfold in each location—enough to stop the epidemics, but only barely.


Like any model, this one has some limitations, which the authors note.

First, the method makes the simplifying assumption of independence of transmission events—that the assignment of a source to any case A is independent of the assignment of the source to each other case B. This is, at best, an approximation.

For example, if different persons vary in their degree of infectiousness (e.g., because of differences in viral shedding) or in their duration of infectiousness, the numbers of secondary infections per individual will be overdispersed (even within the same short time period).

Put another way, if we know that case i was still infectious at a time when case j became infected, we know that case i is a likely candidate for having infected other secondary cases around the same time.

Second, the method assumes that interventions do not affect the generation time of the pathogen.

In reality, when interventions involve improved monitoring followed by either isolation or effective treatment, most transmissions will occur early, before detection.

As a result, the mean generation time will be reduced, and the algorithm presented here could lead to an overestimate of the instantaneous transmission rate for the period subsequent to intervention.


So will Wallinga and Teunis’s approach work despite these limitations? Computer simulations offer some limited evidence that it will, but further study is warranted to assess its performance under various departures from its assumptions.

If the method proves robust, it will be a very useful tool for policy-makers in the midst of an outbreak.

Rapid assessment of the reproductive number of an emerging infection in the absence of interventions is a crucial first step in understanding and controlling the disease.


Control of a disease in a population requires that the reproductive number be brought below 1 and kept there.

By assessing the initial reproductive number (before the implementation of control measures), health officials can estimate the magnitude of the control measures that will be necessary.

As the infection spreads in a particular population and as control measures are instituted, real-time tracking is needed to establish the impact of control.

The success of a control program for a disease like SARS, in which isolation of symptomatic patients and quarantine of contacts were the key control measures, can be measured in part by “process” indicators, such as the time from the onset of symptoms in a case to the isolation of that case to prevent transmission, or the fraction of incident cases that were identified by contact tracing prior to symptom onset.

However, real-time measurements of disease transmission, using methods like the one developed by Wallinga and Teunis, will provide “bottom-line” evidence of whether an epidemic is being brought under control.

During the 2003 SARS outbreak, health officials used a conservative definition—no new cases in a time span exceeding twice the longest known incubation period for the infection—to declare an epidemic fully controlled in a particular jurisdiction, but health officials responsible for daily control efforts need a more immediate and quantitative measure of the effects of control measures as they work toward the goal of eliminating the local epidemic.

Wallinga and Teunis’ method of tracking the instantaneous reproductive number provides just such a measure.


More broadly, new tools are needed to facilitate data entry, management, visualization, analysis, and forecasting in the early days of an outbreak.

For example, epidemiologists attempting to track a natural outbreak of a disease like SARS or pandemic influenza or the deliberate release of a biologic agent would benefit from the ability to manipulate a rapidly changing database with ease, to map spatial and temporal patterns in disease incidence according to the home, school, hospital, or workplace of cases, and to perform key analyses in ways that have been thought through and validated in advance.

As data become available during the course of an epidemic, public health officials should have at their disposal tools to allow the integration of these data into real-time predictions of the relative costs and benefits of potential control strategies.

Many such tools were developed in real time during the 2001 epizootic outbreak of foot-and-mouth disease in the United Kingdom [7], and since then, refined methods for “predictive” vaccination strategies have been proposed [8].

It would be encouraging to see similar effort being put toward planning for human disease outbreaks.


Spurred by the perceived threat of biological terrorism, current epidemiologic efforts to prepare for outbreaks have taken two major forms.

The first is the development of “syndromic surveillance” systems designed to detect the first anomalous cases and alert health officials that an outbreak is under way [9].

While they are well suited to this purpose, such systems are not designed to provide much additional information once the outbreak has been identified.

Other efforts have concentrated on modeling particular attack scenarios with different pathogens, particularly smallpox [10, 11] and anthrax [12, 13].

These models provide valuable a priori guidance about the range of possible responses to given scenarios, but they require, of necessity, untestable assumptions about the size and nature of the outbreak; moreover, to some degree, each of these models gives results whose application is limited to the pathogen under consideration or pathogens that closely resemble it.

As with syndromic surveillance, the usefulness of such models is greatest prior to or at the moment of an attack, but unless the models are designed to incorporate up-to-the-minute data on the state of the outbreak, they will provide limited real-time assistance once an outbreak is under way.


Given the indisputable creativity of Nature and the potential creativity of biologically sophisticated evildoers, we cannot expect to have an appropriate a priori model for every outbreak.

Therefore, development of tools for understanding and responding to a novel outbreak as it unfolds is a pressing task, and one that differs from those that have received the most epidemiologic attention thus far.

Transmission models, as well as the spatial-temporal analysis tools used in syndromic surveillance, may be readily adapted to meet the need for analysis of and response to an outbreak in progress, but the adaptation requires additional work.

The technique described by Wallinga and Teunis would be a valuable component of a suite of tools that should be made available to public health officials before the next important outbreak occurs.


We thank Drs.

Lipsitch and Bergstrom [1] for their thoughtful commentary on our article [2], which appears in this issue of the Journal. They discuss the method we developed in the context of real-time analysis of case notifications.

We would like to add a few more thoughts along these lines.


The contribution of the method toward real-time analysis of incoming notifications is, as Lipsitch and Bergstrom aptly summarized, to provide “a means of transforming the time series of cases… into a time series of estimated values for the instantaneous reproductive number on each day” [1].

The transformation is from calendar time to generation time and from number to relative increase in number.

The key variable involved in this transformation is the generation interval, which is the time interval between a primary case and a secondary case.

Literature on this key variable has been scant and has been blurred by the use of confusing terminology.

We cannot think of a better introduction to the concept of generation intervals than was provided by Professor Paul Fine in a recent article in this journal [3].

Fine illustrates the relatedness of the generation interval, epidemic curves, transmission chains, and reproduction numbers.

Our contribution is simply to specify these relations further.


In our article [2], we emphasized that under certain technical conditions, only a few simple computational steps are needed to transform the time series of severe acute respiratory syndrome cases into a time series of estimated reproduction numbers.

Here we would like to add that such a transformation could be carried out for any infectious disease that is transmitted from person to person.

Lipsitch and Bergstrom [1] correctly note that a short generation interval facilitates real-time interpretation of incoming case reports; for infections with a long generation interval (such as human immunodeficiency virus, herpesvirus, or mycobacterial infection), the transformation might be less useful.


At the moment, we are studying the possibility of extending the method to account for reporting delay, unobserved cases, and heterogeneous transmission.

However, the finding that transformation is in any case feasible, and in many cases computationally trivial, opens up perspectives for estimating reproduction numbers from time series of case notifications.


The reason for emphasizing the relevance of real-time estimation of reproduction numbers of emerging infectious diseases is that after syndromic surveillance systems have signaled the emergence of a new disease, we know little more about the novel infectious agent than that each case has been infected by another case and that successive generations of cases are separated by a typical generation interval.

This is not enough information with which to build a mathematical transmission model, but it is sufficient for real-time estimation of reproduction numbers, and hence for real-time estimation of the additional control effort required.


Lipsitch and Bergstrom assert that, when the next important outbreak arrives, such almost parameter-free estimation tools for reproduction numbers can be a valuable addition to syndromic surveillance systems and mathematical transmission models.

We could not agree more.


In recent years, a tremendous effort has been made to identify approaches for combatting metabolic disturbances and mito- chondrial dysfunction, such as those seen in ageing [1] and type 2 diabetes mellitus [2, 3] by specifically targeting the sirtuin (SIRT) enzyme family [4].

SIRTs are NAD + -dependent deacetylating enzymes that regulate cellular metabolism [5].

To date, seven mammalian SIRT enzymes (SIRT1-7) have been identified, each having its own characteristic tissue and subcellular compartment expression, enzyme activity and tar- gets.

We kindly refer readers to Houtkooper et al [6] for a comprehensive review on SIRTs.


Several SIRT-targeting strategies have been deployed, dem- onstrating the metabolic benefits of SIRT activation.

In mice, a SIRT1 gain-of-function mutation evoked a metabolic profile that protected against insulin-resistant diabetes by increasing hepatic insulin sensitivity, hepatic glucose tolerance and overall metabol- ic efficiency [7, 8].

Moreover, a proposed SIRT1 activator, SRT1720, increased mitochondrial respiration and improved in- sulin sensitivity [9], mimicking the signalling profile observed with caloric restriction [10] in high-fat-diet (HFD)-challenged mice.

Resveratrol, an AMP-activated protein kinase (AMPK)- activating polyphenol that activates SIRT1, improved skeletal muscle mitochondrial function in healthy obese men, in individ- uals with type 2 diabetes and in first-degree relatives of those Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-019-4831-3) contains a slideset of the figures for download, which is available to authorised users.

The concept of influencing NAD + bioavailability to activate the SIRTs was recently proposed for combatting metabolic distur- bances and mitochondrial dysfunction in humans [13, 14].

This is supported by reports that decreased NAD + bioavailability con- tributes to metabolic disturbances in ageing mice [15, 16] and humans [17, 18], and also in a rodent model of type 2 diabetes mellitus [16].

SIRTs are important consumers of NAD + and de- pend on this rate-limiting substrate to act as metabolic sensors, responding to the level of available NAD + .


Considering the limited scope of this review, we will not digress into detail of the NAD + metabolism and refer the read- er to more comprehensive reviews on this topic [5, 19-21].

Briefly, however, as NADH is the predominant electron donor to the electron transport chain, NADH/NAD + redox potential is an important indicator of the bioenergetic status of the cell and is tightly regulated [21].

The cytosolic and mitochondrial NADH/NAD + and NADPH/NADP + redox states are strongly connected.

These states depend on the formation of NAD + from NADH through cellular processes, such as the glycolytic enzyme activity, the citric acid cycle and the electron transport chain [20], thereby exemplifying the essentiality of NAD + and its redox potential within cellular metabolism.


The NAD + pool is maintained through a continuous process of biosynthe- sis and breakdown, stemming from the salvage and the Preiss- Handler pathways or from de novo biosynthesis at one end, and enzymatic consumption at the other [20] (Fig. 1).


Exercise and caloric restriction share a common denomina- tor in that they affect AMPK activity, which can modulate NAD + bioavailability (Fig. 2).

To support this, AMPK acti- vation in C2C12 myotubes increases cellular NAD + levels and, in turn, activates SIRT1 and the subsequent PGC-1α- dependent upregulation of mitochondrial and lipid metabo- lism [28].

An increased demand for energy by the cell, such as during exercise, activates AMPK.

With this in mind, it was shown that exercise induces the expression of nicotin- amide phosphoribosyltransferase (NAMPT), the rate- limiting enzyme that converts nicotinamide into NAD + [29], thereby increasing NAD + bioavailability [30, 31].

The induc- tion of NAMPT expression through AMPK has been sug- gested to be a mechanistic adaptation to the metabolic stress derived from both exercise and caloric restriction [32-34].


Moreover, exercise in rats has been demonstrated to induce


Various research groups have pursued sustained SIRT activa- tion through an increase in endogenous NAD + bioavailability.

Preclinical research in ageing or HFD-challenged mice has shown that boosting NAD + levels by supplementation with NAD + precursors, such as nicotinamide mononucleotide (NMN) or nicotinamide riboside, attenuates age-related de- cline of muscle strength [1, 36], increases lifespan and healthspan [36].

In addition, oxidative metabolism and activa- tion of SIRT1 and SIRT3 are enhanced in HFD-fed mice sup- plemented with NAD + precursors [26].

In aged mice, NAD + precursor supplementation also restored arterial SIRT1 activ- ity, which was associated with improved vascular function and decreased aortic stiffness [37].

These findings demonstrate the feasibility of altering NAD + bioavailability and subsequent SIRT activation.


More specifically, in HFD-fed mice, exogenous adminis- tration of the NAD + precursor NMN was demonstrated to be a viable method of increasing endogenous NAD + bioavailabil- ity and inducing SIRT1 activity, thereby attenuating the effects of the HFD and improving glucose tolerance and hepatic in- sulin sensitivity [16].

Long-term administration of NMN was also found to mitigate the age-associated decline in energy metabolism, insulin sensitivity and lipid metabolism [36].

Similarly, supplementation of HFD-challenged mice with nic- otinamide riboside (another NAD + precursor), also improved hepatic insulin sensitivity [26].

Additionally, an improved glu- cose tolerance and lipid profile were observed in mouse models of age-induced type 2 diabetes upon NMN supple- mentation [16].


The NAD + precursors nicotinic acid and nicotinamide have also been used to supplement HFD-challenged mice, increas- ing hepatic NAD + levels and improving glucose tolerance.

In one study, nicotinamide proved to be a more potent booster of NAD + than nicotinic acid as it was also found to specifically alter the expression of SIRT1, SIRT2 and SIRT6 [38].

Lastly, Acipimox, a synthetic nicotinic acid analogue, has been shown to elevate NAD + in C2C12 myotubes [39].


Together, these preclinical data suggest that dietary supple- mentation of NAD + precursors can increase NAD + levels and beneficially affect metabolic health.


Preclinical research has explored compounds that can inhibit the NADases CD38 [40] and poly(ADP-ribose) polymerase-1 (PARP-1), reducing the enzymatic competition for their shared substrate, for example by reducing their NAD + -bind- ing capacity, and thus enhancing SIRT1 activity (Fig. 2).

Following this line of thought, a decrease in PARP-1 activity coincides with a rise in SIRT activity and NAD + levels in worms [41] and mice [27], with PARP-1 −/− mice displaying a leaner phenotype with higher energy expenditure compared with PARP-1 +/+ mice.

In line with this, in skeletal muscle, PARP-1 inhibitor-induced increases in SIRT1 activity were accompanied by improved mitochondrial function, enhanced energy expenditure and endurance performance [42].

In endo- thelial progenitor cells, PARP-1 inhibition also preserved cel- lular NAD + content [43].

Similarly, Cd38 knockout mice have elevated NAD + levels and are protected against HFD-induced


Regular exercise and caloric restriction are well known to im- prove metabolic health in humans [47].

Alongside improving insulin sensitivity, metabolic flexibility and mitochondrial func- tion, exercise also upregulates the expression of NAMPT in hu- man skeletal muscle [48] (Fig. 2).

Endurance-trained athletes have a twofold higher expression of NAMPT in skeletal muscle compared with baseline levels in sedentary obese, non-obese and type 2 diabetic individuals.

After completing a 3 week training intervention, the non-obese group displayed increased NAMPT expression over baseline.

NAMPT levels correlated positively with PGC-1α expression, mitochondrial content, maximal mito- chondrial ATP synthesis in skeletal muscle and overall maximal aerobic capacity [48].

Concordantly, increased skeletal muscle SIRT3 content and PGC-1α expression were reported in men who were sedentary obese at baseline after a 12 week aerobic exercise intervention [49].

In a 6 week one-leg endurance exer- cise intervention, NAMPT protein levels only increased in the trained leg as compared with the untrained leg [34], further supporting the paradigm of activating the NAD + /SIRT axis through exercise and NAMPT induction.


Continuing, during a caloric restriction-induced weight- loss intervention, NAMPT and subsequent SIRT1 expression were found to be increased in adipose tissue of healthy obese participants [50] when compared with healthy lean partici- pants.

The participants were studied prior to, and after 5 months and 12 months, of the intervention, with the inter- vention resulting in a loss of 17.1% of body weight in the obese group.

At baseline, gene expression of SIRT1, SIRT3, SIRT7 and NAMPT were significantly lower and PARP-1 ac- tivity significantly higher in the obese participants when com- pared with the lean group, indicating a state of low NAD + bioavailability in obese individuals.

With weight loss, SIRT1 expression increased, whereas PARP-1 activity declined in the subcutaneous adipose tissue of the obese group [50].


Evidence that a state of obesity or overnutrition indeed lowers NAD + levels also comes from studies of longer-term overfeeding using an HFD for 8 weeks in young, healthy men.

This result- ed in reduced NAD + levels and SIRT activity in skeletal mus- cle when compared with baseline [51].

This was further sup- ported by PGC-1α hyperacetylation in the same skeletal mus- cle biopsies.

Concurring with these findings, a study in young adult monozygotic twins (n = 26 obesity-discordant pairs and n = 14 obesity-concordant pairs) reported that obesity was as- sociated with lower NAD + /SIRT axis activation in subcutane- ous adipose tissue [14].

Together, these findings suggest that a state of energy abundance is prone to reduce the activity of the NAD + /SIRT axis and that inducing a state of energy demand may aid to restore NAD + levels.


From a human dietary perspective, Trp, nicotinic acid, nico- tinamide, and nicotinamide riboside are the predominant NAD + precursors currently used in intervention trials, with nicotinamide riboside being the latest addition to the array of dietary NAD + precursors (Fig. 1).

The efficacy and safety of treatment with each of these NAD + precursors are discussed in more detail below.


Nicotinamide Phase 0 and phase 1 trials have demonstrated tolerance and safety of nicotinamide in daily pharmacological doses up to 3.5 g [52-56] and single doses of up to 6 g [57-59].

However, at doses above this, nicotinamide can be- come hepatotoxic [60].


Nicotinic acid and Acipimox Nicotinic acid is the most effec- tive pharmacological drug available for elevating HDL- cholesterol and lowering total cholesterol, LDL-cholesterol and triacylglycerol levels, thereby reducing the overall cardio- vascular risk profile of the user [61].

However, nicotinic acid can elevate plasma glucose levels by inducing insulin resis- tance following a rebound increase in circulating NEFAs [62].

This poses a challenge when using nicotinic acid as (add-on to statin) therapy for dyslipidaemia in individuals with impaired glucose tolerance, impaired fasted glucose or type 2 diabetes, with the reduction in overall cardiovascular disease risk on one hand and compromised glycaemic control on the other.

The worsening of hyperglycaemia with nicotinic acid use would possibly require additional therapeutic fine tuning to be implemented on an individual level to maintain glycaemic control.

Alternatively, a reduction in the dose of nicotinic acid could improve glycaemic control, however, this may require acceptance of reciprocal compromise of the lipid profile or additional therapy to be initiated.


A large clinical trial evaluated the efficacy of nicotinic acid as a treatment for hypercholesterolaemia, with a daily dose of 1-3 g, for a duration of 96 weeks [63].

Overall, nicotinic acid was well tolerated.

However, flushing was reported as a major adverse event.

In contrast to nicotinamide, nicotinic acid is a vasoactive compound [64] and activates the G protein- coupled receptor, GPR109A, thereby inducing flushing [65].

In an attempt to reduce the occurrence of flushing and improve adherence, synthetic and extended- and sustained-release for- mulations of nicotinic acid were developed.

Acipimox is a synthetic nicotinic acid analogue and, thereby, an NAD + NADH NADH supplementation has also been used to boost NAD + levels in humans.


In a small study, 80 adults with chronic fatigue syndrome received daily doses of 20 mg of NADH combined with 200 mg of coenzyme Q 10 and were compared with placebo-treated individuals [68, 69].

The in- tervention improved reported fatigue [68] and increased max- imal heart rate after 8 weeks of treatment [69] but did not alter body weight or blood pressure.

Additionally, in peripheral blood mononuclear cells (PBMCs), the intervention signifi- cantly reduced NAD + levels and increased NADH levels, thus, significantly lowering the NAD + /NADH ratio over base- line.

Furthermore, ATP content and citrate synthase activity were significantly increased in PBMCs [68].

Unfortunately, it cannot be distinguished whether the observed results were solely attributed to NADH supplementation considering the co-administration of coenzyme Q 10 in this study.


In contrast to nicotinic acid, nicotin- amide riboside is not vasoactive and does not cause flushing [70], thereby overcoming one of the adverse effects of nico- tinic acid supplementation.

In a recently published placebo- controlled, double-blind, randomised, phase 1 crossover trial, a daily dose of 1000 mg of nicotinamide riboside for 6 weeks was demonstrated to be well tolerated and adverse events were no more frequent than in the placebo arm [71].

These findings are confirmatory of the preceding phase 1 trials [72-74].

Additionally, nicotinic acid adenine dinucleotide (NAAD) has been confirmed as a reliable and sensitive biomarker for assessing changes in NAD + levels following nicotinamide riboside supplementation [72].


Daily nicotinamide riboside supplementation of up to 2000 mg can effectively enhance blood NAD + levels, achieving higher steady-state concentrations over baseline [73].


Concordantly, a more recent study demonstrated that nicotin- amide riboside supplementation increased NAAD and NAD + levels by~60% in PBMCs.

In this study, the effect of 6 weeks of nicotinamide riboside supplementation vs placebo was tested in healthy middle-aged and older adults.

It was also found that 6 weeks of nicotinamide riboside supplementation tended to im- prove systolic blood pressure and pulse-wave velocity, both of which are markers of cardiovascular health [71].

However, no effect of nicotinamide riboside supplementation was found on physical performance outcomes, such as the 4 metre or 6 minute walk test, handgrip strength or maximum torque.

Moreover, met- abolic variables, such as V O 2max during a treadmill exhaustion test, respiratory exchange ratio, and insulin sensitivity assessed by an IVGTT, did not differ between the groups.

From these findings, it was concluded that long-term nicotinamide riboside supplementation is a viable strategy for enhancing NAD + in humans and potentially has cardiovascular benefits that require further exploration in larger trials.


Most recently, an RCT of daily treatment with 2000 mg of nicotinamide riboside for 12 weeks was reported, evaluating safety, insulin sensitivity and other metabolic variables in 40 healthy, obese, middle-aged men [75].

Overall, nicotinamide riboside was well tolerated and only four adverse events were reported: pruritus, excessive sweating, bloating and transient changes in stools.

Nicotinamide riboside supplementation in- creased NAD + metabolism, as was seen by an increase in uri- nary metabolites.

Using the hyperinsulinaemic-euglycaemic clamp technique, insulin sensitivity was found to be un- changed before and after supplementation and when compared with the placebo condition.

In addition, resting energy expen- diture and respiratory exchange ratio were not affected by nic- otinamide riboside supplementation.

Also, intrahepatic lipid content and body composition remained unchanged in the treatment group vs baseline and compared with the placebo group.

Finally, a significant but modest increase in serum tri- acylglycerol levels was detected after nicotinamide riboside supplementation when compared with baseline values.

The authors concluded that this study was underpowered and future studies should be larger and focus on other variables of meta- bolic health, such as intrahepatic lipid content, which showed significant changes in rodents [76, 77] treated with nicotin- amide riboside and approached significance in this study.


Tryptophan Another dietary NAD + precursor, Trp, is an es- sential amino acid and is metabolised into NAD + through de novo biosynthesis in the liver and kidneys [20].

This route is critical for maintaining the NAD + pool, even though the con- version ratio of Trp to NAD + is low in humans, averaging 60:1 [78].

Nonetheless, Trp is deemed capable of meeting the met- abolic demands of NAD + metabolism in nicotinic acid- and nicotinamide-deficient diets, and is well tolerated at high doses, between 30 and 50 mg/kg bodyweight, apart from drowsiness/sleepiness [79].

Recently, higher circulating Trp levels were identified as a predictive marker for the development of type 2 diabetes in a large prospective Chinese cohort [80].

However, to date, no dietary supplementation studies are available that directly as- sess whether boosting NAD + through Trp might be metabol- ically beneficial in humans.


The drawback of pharmacological strategies involving CD38 and PARP-1 inhibition is the original intended therapeutic use in malignancies [81, 82].

As such, no clinical trials with PARP-1 or CD38 inhibitors that focus on improving metabol- ic variables have been conducted in humans.

This, however, does not imply that this strategy must be abandoned altogeth- er, as a viable work-around to exploit the theoretical metabolic benefit of inhibition of NAD + consumers may present itself in due time, allowing us to assess their efficacy in clinical trials.


The current evidence base from preclinical research on NAD + is setting the stage for trials in humans by identifying the points at which intervening in the NAD + metabolism process seems to be clinically and physiologically relevant (see Summary text box).

Even though many results have not been replicated in humans at this point in time, phase 0 and phase 1 trials have proven the feasibility and safety of NAD + boosting in humans.

As most evidence that increased NAD + levels may be beneficial to human metabolism comes from indirect ob- servations, such as exercise and weight loss interventions, the assessment of efficacy in well-powered phase 2 and phase 3 trials is urgently awaited in order to draw clear conclusions.

Additionally, studies in metabolically disturbed individuals must be considered as these are more in line with the preclin- ical models used.

To date, generally healthy populations have been included in studies in this area, in which the range of improvement may be too small to detect significant changes.

The combination of strategies to increase NAD + , such as ex- ercise, caloric restriction, or CD38 and PARP-1 inhibitors, with NAD + precursor supplementation may also be consid- ered, to evaluate added efficacy of such approaches, as seen in mice [15] (see Recommendations text box).


Currently, a number of clinical trials (Table 1) are underway in which NAD + precursor supplementation is being used to improve (often disturbed) metabolic health variables.

The coming years will prove whether the promising results ob- served in preclinical studies can indeed find human translation.


To the Editor: Schrauwen and colleagues have recently reviewed the emerging field of NAD+ metabolism in Diabetologia [1].

Their manuscript includes a description of a clinical trial of dietary nicotinamide riboside supplementation effects on whole body insulin sensitivity in obese men, conducted by us, together with our colleagues at Aarhus and Copenhagen Universities, Denmark [2].

As posted on clinicaltrials.gov (NCT02303483), this placebo-controlled, randomised clinical trial used M value determined by the hyperinsulinaemic–euglycaemic clamp (HEC) technique, the gold-standard approach for directly quantifying insulin sensitivity, as the primary endpoint.


We report a negative outcome of the trial, and while this may be disappointing in terms of the possible future use of nicotinamide riboside supplementation for the prevention of type 2 diabetes, we believe it is important to publish such outcomes and to cite these correctly.

We were therefore disconcerted to find the following description of our manuscript in the review by Schrauwen and colleagues: ‘The authors concluded that this study was underpowered and future studies should be larger and focus on other variables of metabolic health’.

We find this to be a severe misrepresentation of a central conclusion of our work.


As outlined in our manuscript, power calculations were conducted prior to enrolment into our study to determine an appropriate sample size for detecting clinically meaningful differences in the primary endpoint and to try to evade type I and type II errors resulting from insufficient sample size.

We powered the study to detect a difference in the HEC-derived M value of 1.5 mg kg−1 min−1, which has previously been achieved with insulin-sensitising drugs or exercise [3, 4].

We used a conservative estimate of the SD of 1.6 mg kg−1 min−1 in the power calculation, based on in-house experience from previous clamp examinations [2].


The primary endpoint, the M value, was not affected by nicotinamide riboside supplementation (p for interaction = 0.68).

However, the actual SD for the difference between the baseline and the end-of-study M value within the placebo group was only 0.48 mg kg−1 min−1.

Therefore, in retrospect, the assumed SD was probably too conservative.

With an SD of 0.5 and n of 40, we would be able to detect a significant difference in the M value of 0.45 mg kg−1 min−1 with a power of 0.80.

Hence, we do not suspect that the lack of effects of nicotinamide riboside can be attributed to the study being underpowered (i.e. a type II error).


In addition to the M value, our study included several predefined secondary endpoints, and the combined outcomes of these were also negative.

In line with standard study design, the trial was powered to detect significant differences in the primary endpoint and, therefore, where the risk of a type II error was discussed in our paper, this was in terms of the secondary endpoints [2].


When citing a clinical trial, it is important to respect the distinction between endpoints.

When quoting the authors as concluding that the study was underpowered, unless otherwise stated, it will be assumed that this conclusion refers to the primary outcome of the study.

Dietary supplements, such as nicotinamide riboside, are already commercially available and are being promoted as facilitating healthy ageing in humans by an industry that is not subject to the same strict regulatory demands as the traditional pharmaceutical industry.

This stresses the need for scientific testing of safety and efficacy of dietary supplements in rigorously designed human clinical trials, and the outcomes of such trials should be reported correctly in subsequent review papers, irrespective of whether the outcome is positive or negative.


To the Editor: Jessen and colleagues [1] have commented on our recent review of NAD+ metabolism in Diabetologia [2].

In their letter, they comment on the discussion and citation of a clinical trial that they performed, in which dietary nicotinamide riboside was supplemented in obese men to assess the effects on whole body insulin sensitivity [3].


We concede to the argument made by Jessen and colleagues that it is important to make a clear distinction between endpoints when citing clinical trials, as this may otherwise lead to unwanted assumptions regarding the endpoint(s) that are discussed.

In our review, we did not have the intention to suggest that the study by Dollerup et al [3] was underpowered for its primary endpoint, insulin sensitivity, but unfortunately omitted to add ‘for these secondary endpoints’, for which we do apologise.


Nevertheless, the overall message and conclusion of our review does not change and we agree with Jessen and colleagues that more human studies are needed to test the efficacy of dietary supplements in rigorously designed human clinical trials.


Forty HCC patients with portal hypertension who were treated with TIPSS between 1995 and 2012 were included in the analysis.

Medical records and imaging studies were analysed.

The indication for TIPSS implantation, pro- cedure-related complications, treatment success and overall survival were assessed.


TIPSS implantation was performed in 23 patients (57.5%) due to treatment refractory ascites, in 14 patients (35.0%) due to recurrent variceal bleeding and in three patients (7.5%) due to ascites and variceal bleeding.

Primary tech- nical success was assessed in all patients.

After TIPSS implantation, no variceal bleeding reoccurred and ascites was controlled in 74.1%.

No severe procedure- related complications and no deterioration of liver function were observed.

Post-TIPSS hepatic encephalopathy occurred in 40.0% of all patients.

30-day, 90-day-, 1-year- and 5-year survival rates were 97.5%, 75.0%, 42.5% and 7.5%, respectively.

Median overall survival after TIPSS implantation was 180 days.


Transjugular intrahepatic portosystemic shunt implantation is an effective and safe treatment for portal hypertension in patients with HCC.


Portal hypertension in patients with liver cirrhosis can lead to the development of ascites and/or oesophageal varices that can cause life-threatening upper gastrointes- tinal bleeding.

The development of these complications is associated with increased mortality and morbidity.

1, 2 Furthermore, liver cirrhosis is a major risk factor for the development of hepatocellular carcinoma (HCC).

3 As HCC typically represents a late-stage complication of liver cirrhosis, therefore, most of these patients are also affected by symptomatic portal hypertension (SPH).

Importantly, portal hypertension in HCC patients may not only be due to liver cirrhosis but also due to portal vein thrombosis (PVT) that can occur during HCC pro- gression as a result of increased clotting or portal vein invasion.


Previous studies reported an incidence of portal hypertension of approximately 30% in patients with HCC, but as in these studies portal hypertension has been evaluated using clinical parameters instead of portal vein pressure measurement, a higher frequency of portal hypertension in these patients is estimated.

4, 5 Impor- tantly, portal hypertension directly affects treatment of HCC.

6 Indeed, according to the current guidelines of the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) liver cirrhosis with portal hypertension is considered as a relative contraindication for hepatic resection because of the high risk of post-operative liver failure.

7, 8 Furthermore, complications of portal hyper- tension in patients with HCC contribute to the poor prognosis.

9-11 Despite the high incidence and poor prog- nosis of portal hypertension in HCC patients, however, there are no established guidelines for the treatment of SPH in patients with HCC.


During the last 25 years the TIPSS has been estab- lished as an effective and minimally invasive procedure for the treatment of portal hypertension and its compli- cations.

12, 13 Refractory ascites, recurrent and also acute variceal bleeding, hepatic hydrothorax, hepatorenal syndrome and Budd-Chiari syndrome are the most com- mon and accepted indications for TIPSS implanta- tion.

14-24 Next to absolute contraindications for TIPSS insertion such as right heart failure, severe hepatic fail- ure, systemic infection and uncontrolled hepatic enceph- alopathy, hepatic malignancy is considered a relative contraindication.

12, 25 Of note, few studies with small sample size investigated the implantation of TIPSS in patients with hepatic malignancy including primary liver cancers as well as hepatic metastases from extrahepatic malignancies.

These studies showed a good efficacy of TIPSS implantation and no association with severe pro- cedure-related complications.

26-28 However, these studies are characterised by rather small patient cohorts and by hepatic tumours of different entities.

In addition, data to the OS are limited.

To address this important clinical issue, we analysed the OS, safety and efficacy of TIPSS implantation in HCC patients presenting with SPH due to advanced liver cirrhosis with or without PVT.


From November 1995 to December 2012, 40 patients with HCC and SPH received TIPSS implantation at our institution.

Patients with intra - or extrahepatic cholan- giocarcinoma or metastases from extrahepatic malignan- cies were excluded from this analysis.

Decision for TIPSS implantation in HCC patients was discussed individually for each patient regarding technical feasibility and hepatic expansion of HCC.

Due to these inclusion criteria, approximately 15% of HCC patients with severe SPH (three of 20 patients per year) received TIPSS implantation.


In 23 patients, TIPSS was performed after diagnosis of HCC has been established.

The median time from HCC diagnosis to TIPSS implantation was 6.0 (1-38) months in these patients.

Seventeen patients were admitted to our Liver Centre for evaluation of TIPSS implantation and HCC was suspected in the pre-interventional setting with color doppler ultrasound (CDUS).

We confirmed HCC diagnosis as cited below.

Although diagnosis of HCC was established, we performed TIPSS implantation as planned.


The diagnosis of HCC was based on histology or unequivocal radiological features in at least two con- trast-enhanced imaging techniques (CT, magnetic reso- nance imaging (MRI), ultrasound) according to the current EASL guidelines which have been applied retro- spectively.

7 Centrally located tumour masses were local- ised in segment VIII, V and IV according to Couinaud.

29 Diagnosis of liver cirrhosis was defined on ultrasound, CT or MRI, clinical findings and laboratory tests.

Clinically significant portal hypertension was defined as (i) presence of oesophageal varices or gastric varices, TIPSS implantation in patients with HCC 13652036, 2015, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/apt.12994 by Mcgill University, Wiley Online Library on [18/05/2024].

See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License (ii) thrombocytopenia with platelet count <100 9 10 9 /L associated with splenomegaly and (iii) presence of asci- tes.

The presence of oesophageal varices was assessed by endoscopy.

30 SPH was defined as presence of ascites or one or more episode of variceal bleeding.


According to Moore et al., treatment refractory ascites was defined as (i) nonresponse to sodium-restricted diet and diuretic treatment, (ii) intolerance of diuretic ther- apy and (iii) rapid recurrence of ascites after therapeutic paracentesis.

31 Response to TIPSS treatment was defined as follows: absence of clinically detectable ascites with or without diuretic therapy or ascites needing no further paracente- sis and/or no further variceal bleeding episodes after TIPSS implantation.

Development of large amount of ascites as well as variceal bleeding after TIPSS implanta- tion was defined as nonresponse.


All patients underwent follow-up examination.

During follow-up none of our HCC patients was transplanted.

Patients receiving TIPSS had routine physical examina- tion and laboratory testing before TIPSS and 1 and 3 months after TIPSS implantation and thereafter fol- low-up was performed in 3-month intervals.

The median follow-up time after TIPSS implantation was 211 days (3-2919 days).

On each admission, CDUS was per- formed to evaluate shunt function.

Shunt insufficiency was defined as (i) maximum flow velocity less than 60 cm/s or above 180 cm/s within the shunt or less than 30 cm/s in the portal vein, 13 (ii) recurrent or increasing ascites and (iii) recurrent variceal haemorrhage.

Shunt dysfunction resulted in TIPSS revision and during this intervention shunt dysfunction was confirmed by portog- raphy and an elevated portosystemic pressure gradient by more than 12 mmHg.


Diagnosis of hepatic encephalopathy (HE) was estab- lished in clinical examination and West-Haven criteria were applied to assess severity of HE.

32 HCC-specific treatment was determined according the Barcelona Clinic Liver Cancer (BCLC) classification.

7, 33 Treatment response was assessed using contrast-enhanced CT or MRI and the modified RECIST (mRECIST) criteria were applied.

34 Model of end-stage liver disease (MELD) score and Child-Pugh stage were determined according the medi- cal records.

Intrahepatic tumour expansion was classified according to the Milan criteria.


Before TIPSS implantation, CDUS was performed in all patients to evaluate if TIPSS procedure was technically possible and to assess portal and hepatic vein patency and vascular abnormalities.


The technique of TIPSS implantation has been described previously.

15, 36-38 In brief, a transjugular approach was used to advance a puncture needle into a hepatic vein.

Puncture of a por- tal vein was done using ultrasound guidance.

After suc- cessful puncture portography was performed, following dilatation of the parenchymal tract with introduction of the stent graft.


Before and after TIPSS implantation, portal vein pressure and central venous pressure were measured to calculate the pre- and post-shunt portosys- temic gradient (PSG).

Technical success was assessed by final portography.


In 16/40 patients (40%) covered stents (Viatorr; W. L. Gore & Associates, Inc., Flagstaff, AZ, USA) were used while in 24/40 patients (60%) bare metal stents (BMS; Palmaz stents; Cordis, Miami, FL, USA, Wallstent; Boston Scientific, Malborough, MA, USA, Luminexx; Bard Medical Division, Covington, GA, USA) were implanted.


The decision whether BMS or covered stents were implanted was an individual deci- sion of the TIPSS- performing operator and was not defined in the study protocol.