In our cohort sphincter disturbance is a frequent (13/46) and early symptom, and even occurs in a few (2/17) symptomatic carriers without other signs of myelopathy.

Interestingly, most females with X-linked adrenoleukodystrophy were actually relieved to find out that their symptoms were related to X-linked adrenoleukodystrophy, as often they had been told that an X-linked disease does not cause symptoms in 'carriers'.

Signs of peripheral neuropathy were mostly absent or minor clinically, and did not seem to contribute much to the overall dis- ability.

It is possible that signs and symptoms were masked by the more prominent signs of myelopathy.

Notwithstanding, on elec- trophysiological testing about 57% of the females in this cohort fulfilled the criteria for an axonal sensorimotor neuropathy.


There was no statistically significant difference in SF-36 scores between asymptomatic and symptomatic carriers (Fig. 3A).

Although any symptom may affect quality of life, it seems that the majority of symptomatic carriers have symptoms that do not impact the SF-36 enough to be visible at group level.

The z-scores are usually below zero for the symptomatic carriers on the meas- ures related to physical symptoms (Fig. 3A), but the standard de- viation is large, supporting the previous assumption.

However, symptomatic females show a trend towards reduced quality of life in domains related to physical symptoms (Fig. 3A), correspond- ing to the signs of myelopathy frequently present in our cohort.


Analysis of the AMC Linear Disability Scale revealed that mani- festing X-linked adrenoleukodystrophy carriers had similar disabil- ity as patients with Parkinson's disease 1 year after the diagnosis.

However, compared to our cohort, the Parkinson's disease cohort was significantly older (average age 67 versus 48 years), suggest- ing that the burden of disease in X-linked adrenoleukodystrophy carriers is considerable.


Somatosensory evoked potential was reported to be very sensi- tive in detecting abnormalities in X-linked adrenoleukodystrophy carriers in a presymptomatic stage (Restuccia et al., 1997).

In our cohort, however, somatosensory evoked potentials of the median nerve (arm) were normal in all asymptomatic, and abnormal in only 11% of the symptomatic females.

This is not surprising, as in none of the symptomatic females the arms were affected clin- ically.

Somatosensory evoked potentials of the posterior tibial nerve (legs) were only abnormal in 7% of the asymptomatic and 45% of the symptomatic females.

Therefore, we conclude that somatosensory evoked potential is not superior to clinical examination in detecting myelopathy in our cohort.


In agreement with an earlier report, brainstem auditory evoked potential was abnormal in 58% (Restuccia et al., 1997).

A larger proportion of the symptomatic carriers had an abnormal brainstem auditory evoked potential compared with the asymptomatic car- riers (72% versus 23%).

The findings were non-specific, mostly consisting of an increased I-V or III-V interval.

This indicates a slowing of conduction in the brainstem.

For clinical practice brain- stem auditory evoked potential has no value as a diagnostic tool.


As has been known for several decades, 15-20% of X-linked adrenoleukodystrophy carriers have normal plasma C26:0 (Moser et al., 1999).

We found that a slightly higher proportion (31%) had normal plasma C26:0.

Furthermore, even in cultured fibro- blasts the C26:0 can be normal (Moser et al., 1983), as was the case in 6/43 (14%).


Combining C26:0 levels in plasma and fibro- blasts marks 41/43 (95%) of the females in our cohort as biochemically abnormal.

This corresponds to an earlier observation that by combining very long-chain fatty acids measurements in plasma and fibroblasts 93% of carriers can be identified (Moser et al., 1983).


Peroxisomal very long-chain fatty acids beta-oxidation activity in cultured fibroblasts varied from com- pletely normal to values found in males with X-linked adrenoleu- kodystrophy.

By combining very long-chain fatty acids measurements and beta-oxidation activity, 44/45 X-linked adre- noleukodystrophy carriers (98%) could be identified.


However, this still does not reliably identify all X-linked adrenoleukodystro- phy carriers.

Therefore, in females, only ABCD1 mutation analysis identifies all carriers.


We showed that the biochemical abnormalities in fibroblasts correlated with the X-inactivation pattern, i.e. the more skewed to the mutant allele, the more abnormal the fibroblasts were bio- chemically.

Our study showed that in fibroblasts, ABCD1 allele- specific expression (ABCD1 allele-specific expression) predicts the biochemical phenotype.


X-inactivation was considered to be skewed preferentially to the mutant allele (Migeon et al., 1981).

That finding cannot be repro- duced in our data set (Fig. 5).

In fact, the median skewing was 49:51, suggesting a random ABCD1 allele-specific expression pattern.

For over two decades there has been controversy over whether X-inactivation predicts the symptomatic status of X-linked adrenoleukodystrophy carriers.

Watkiss et al. ( 1993) reported that symptomatic status and X-inactivation in fibroblasts do not correl- ate in a small sample of 12 females.

A more recent report sug- gested that skewed X-inactivation patterns in leukocytes did correlate with symptoms in X-linked adrenoleukodystrophy carriers (Maier et al., 2002).

However, the assay used in that study (HUMARA) has limitations because of the genetic distance be- tween the human androgen receptor (Xq12) and ABCD1 gene A limitation of our study is that not all X-linked adrenoleukody- strophy carriers in The Netherlands were examined.

Even though we tried to minimize selection bias by including not only females from the outpatient clinic, and $75% of the participants were recruited through the X-linked adrenoleukodystrophy patient organization (with 52 female members) and relatives, it is still possible that the participants are not a totally random sample of X-linked adrenoleukodystrophy carriers.

Based on the frequency in our cohort it can be estimated there are at least 200 X-linked adrenoleukodystrophy carriers in the Netherlands.

Our cohort therefore probably contains no more than 25-30% of all X-linked adrenoleukodystrophy carriers in The Netherlands.

It cannot be excluded that those without symptoms were less likely to participate.

Although there was no age-matched control cohort, it is unlikely that the symptoms described are attributable to normal ageing.

Myelopathy and peripheral neuropathy cannot be considered a part of healthy ageing.

Co-morbidity, like dia- betes, was rare in the cohort.


In summary, X-linked adrenoleukodystrophy carriers are highly likely to develop symptoms.

The most important predictor is age, with most carriers having some clinical manifestation beyond age 60.

Clinical manifestations are mostly related to myelopathy.

Especially striking is the high incidence of faecal incontinence.

Peripheral neuropathy is not prominent clinically, although based on nerve conduction studies 57% have a sensorimotor axonal peripheral neuropathy.


Biochemical abnormalities are common, but cannot exclude X-linked adrenoleukodystrophy with certainty in females.

The biochemical abnormalities in fibroblasts are clearly related to the X-inactivation pattern.

We were not able to show a link between X-inactivation and symptomatic status, but this may be related to the limitations stated above.


X-linked


Sir, In an interesting study recently published in Brain, Engelen et al. ( 2014) describe a cohort of 46 Dutch heterozygotes with X-linked adrenoleukodystrophy, representing 26 kindreds.

They found that signs and symptoms of neurological involvement increased with age among the females included [1].

However, the authors express concern that selection bias may have skewed their results towards preferential inclusion of symptomatic subjects.

We reported the same phenomenon of age-dependent penetrance among females in our own study (Horn et al., 2013), published in Pediatric Neurology (March, 2013), but not referred to in the present article [3].


This was the first prevalence study that looked at males and females with X-linked adrenoleukodystrophy using modern diagnostic methods, including 26 adult females belonging to 13 separate kindreds.

This study had no selection bias, as all known cases of X-linked adrenoleukodystrophy in Norway (population 5 million) were included.

All symptomatic females were older than 50 years, the asymptomatic ones were younger than 50 years.

Asymptomatic females with neurological signs of long involvement constituted a middle group age-wise.

Four tract females, reportedly healthy, were unavailable for clinical examination.

Naturally, asymptomatic females with no symptomatic family members could not be included except by screening measures, not yet established in Norway.


The findings by Engelen and coworkers lend support to our own results.

Subsequently, further support was found in our recent study (Horn et al., 2014) of small nerve fibre involvement in subjects with a disease-causing mutation in the ABCD1 gene (males and females with or without symptoms of X-linked adrenoleukodystrophy): 10 of 11 subjects showed evidence of small nerve fibre involvement [2].

This was found even among young, asymptomatic heterozygotes with no clinical signs of emerging myelopathy, and increased with age and severity of symptoms.

This indicates that the central and peripheral nervous system is affected in most or all heterozygotes with a mutation in the ABCD1 gene, hence these subjects are not simply carriers of a gene mutation.


Sir, We thank Horn et al. ( 2014) for their comments.

The paper they refer to was published after the first version of the manuscript of our paper (Engelen et al., 2014) was completed, otherwise it would have been included as a reference.


Their findings are indeed completely in line with our study.


We read with interest the recent report from Horn et al. on small nerve fibre dysfunction in X-linked adrenoleukodystrophy and will certainly look at that in our patient population in the future.


It follows that the response of services to missed appointments should be in keeping with the seriousness of the consequences, yet current evidence for telephone prompts and other interventions to encourage attendance is equivocal at best and only relates to studies in newly referred patients (Macharia et al, 1992; Reda & Makhoul, 2001).

Mitchell & Selmes (2007, this issue) state that 'Many [patients] who miss appointments because of slips and lapses later rearrange without adverse consequences'.

If this were true, there would be no indication for these authors' recommendation that further clinic appointments be sent after a non-attendance without first awaiting contact from the patient.

However, the study on which this statement is based (Sparr et al, 1993) was carried out in a military clinic for combat veterans in the USA and had several methodological limitations such that the results have to be interpreted with caution: the non-attendance rate was particularly low (9%); data were collected retrospectively from the treating clinician without corroboration from the case notes; and no definition of what was meant by an 'adverse outcome' was given.

Sparr et al reported that over 70% of patients who missed their appointment spontaneously contacted the clinic to reschedule and they concluded that there was no need for the clinic to actively re-engage non-attenders.

However, in our prospective study of non-attenders at a psychiatric out-patient clinic in London, we found that both new and follow-up patients who missed a single appointment were very


In this issue of APT Mitchell & Selmes present an article detailing why patients miss appointments and how clinicians should respond.

Many of the papers quoted relate to the psychiatric out-patient clinic.

In this commentary, as well as picking up on some of the themes that emerge from their article, I explore the attachment that psychiatrists seem to have to this particular model of patient contact.

unlikely to re-engage with the clinic (Killaspy et al, 2000), and one study from outside the UK found that only half those who missed an appointment re-engaged (Pang et al, 1996).


These 'slips and lapses' are a combination of cleri- cal error on the part of the clinic and, with regard to follow-up patients, social disorganisation secondary to the executive dysfunction and negative symptoms of the mental illness.

Clerical error accounts for a lower proportion of missed appointments in psy- chiatric clinics (5-12%: Sparr et al, 1993; Killaspy et al, 2000) than in other medical specialties (28-33%: Verbov, 1992; Potamitis et al, 1994) but this is a po- tentially preventable cause of non-attendance.

Al- though simple systems to remind patients about their appointments may appear to have face validity, they can only be effective for people who are con- tactable, such as those who actually have a work- ing telephone (Burgoyne et al, 1983).

The associated resources involved also have to be considered and there are currently no published examples of well- conducted cost-effectiveness analyses of telephone or other prompts to reduce non-attendance at mental health appointments in the UK.

Written information leaflets and orientation statements, which are help- ful in reducing anxiety about the appointment for newly referred patients, may be more effective at improving attendance rates than prompts (Kluger & Karras, 1983; Swenson & Pekarik, 1988).


Last year I was invited to write a review article for APT on the origins and future of the out-patient clinic in contemporary mental health services (Killaspy, 2006).

This article detailed the history of how the model developed some 300 years ago from a vehicle to triage new admissions to asylums and later became a replica of the approach used in other medical specialties for patient assessment and review.

Given the consistently high non- attendance rates and evidence of poor outcomes for non-attenders with severe and enduring mental health problems, I suggested that it might be time to review the usefulness of the clinic model for this client group.

I explored an alternative approach that could be integrated within our existing and highly developed community mental health services to facilitate assessment and brief interventions for newly referred patients with common mental disorders and that would provide appropriate triage for patients requiring longer-term care from secondary mental health services.


New Roles for Psychiatrists (National Working Group on New Roles for Psychiatrists, 2004) and the Mental Health Policy Implementation Guide: Community Mental Health Teams (Department of Health, 2002) have far reaching implications and contain detailed guidance on the delivery of assess- ment services for patients newly referred to mental health services and on ongoing treatment for patients with severe and enduring mental health problems.

Both documents describe a secondary mental health service that appears to have no out-patient clinics.

So why, despite the relevant policy to support a new direction, are psychiatrists still inclined to use the clinic model? Is it because we see ourselves as hospital doctors whose activity is measured in the familiar approach of the out-patient clinic? Is it that we enjoy the only part of the job where we get to form a one-to-one therapeutic alliance with our patients, providing a welcome relief from our usual role of multidisciplinary team work? Are we under- confident in our non-medical colleagues' skills in assessment and one-to-one interventions? Are there some more-challenging patients that we feel only we have the experience to contain?


None of these possible explanations has been researched, but in exploring the issue of the thera- peutic alliance, Mitchell & Selmes suggest that the patient's perception of the therapeutic alliance with the clinician and of the latter's helpfulness is important in preventing disengagement from the clinic ('Attendance at follow-up appointments is more a reflection of the patient's satisfaction with care than of the perceived need for further help').

However, the two large studies that have investigated satisfaction with psychiatric out-patient services have not found a statistically significant relationship between dissatisfaction with care and drop-out (Killaspy et al, 1998; Rossi et al, 2002), although considerable patient dissatisfaction has been expressed about being seen by the junior doctor rather than the consultant (Killaspy et al, 1998; McIvor et al, 2004).

In fact, the content of the interaction between patients with psychosis and their psychiatrists appears to be rather unsatisfactory at out-patient appointments (McCabe et al, 2002).

The report on proposed new roles for consultant psychiatrists highlighted the problems of the out- patient clinic model:


'There was almost universal dissatisfaction with out-patient clinics.

The doctor is isolated from the team and patients frequently do not attend.

Patients may present very differently in the artificial environment leading to differences with staff who see the patient at home.

Patients are brought back routinely so as not to lose touch with them rather than out of necessity' (National Working Group on New Roles for Psychiatrists, 2004: p. 12).


Since out-patient non-attendance is no longer a Healthcare Commission performance indicator, it is likely that managerial attention on the out-patient clinic will fade.

The evidence currently suggests that the out-patient model is best targeted at people who are most able and likely to keep appointments and that alternative approaches are indicated for those with more complex mental health problems, including assertive outreach for particularly 'difficult- to-engage' clients.

A more radical review of the model could allow the integration of assessment and brief interventions for newly referred patients, and multidisciplinary triage of those requiring longer- term care under the care programme approach within the full range of community mental health services.

Alternatively, we could continue to organise our services so that the most expensive member of the team sees the patients with the least complex problems and accept the resultant waste of resources when 1 in 3 do not attend.


None.


Patients miss about 20% of scheduled appointments for mental health treatment, almost twice the rate in other medical specialties.

Up to 50% of patients who miss appointments drop out of scheduled care.

Many who miss appointments because of slips and lapses later rearrange their appointments without adverse consequences.

Those that do not are at risk of further deterioration, relapse and hospital readmission.

Predictors of non-attendance are complex and linked with the predictors of missed medication.

Service barriers and administrative errors are common but are often overlooked in the absence of feedback from patients.

Of prime importance are the therapeutic alliance and degree of ‘helpfulness’ of the clinician but again these are rarely measured routinely.

Useful markers of engagement include patient-rated trust, satisfaction and degree of perceived participation in treatment decisions.

Much can be done to improve attendance in most services.

Simple measures such as offering prompt, convenient appointments, offering reminders and augmenting with telephone contact have a reasonable evidence base.

Scales to assess therapeutic alliance are now available.

Complex interventions need to be evaluated carefully in order that the overall benefits outweigh costs.

We suggest that clinicians consider accessibility, discharge policies and patient feedback when examining local rates of non-attendance.


This is the second of two articles by Mitchell & Selmes in APT on patient engagement and retention in treatment.

The first, which addressed non-adherence to medication, appears in the previous issue of the journal [1].

The financial cost of missed appointments in the National Health Service (NHS) has been estimated at £360 million per year [2], most of this accounted for by non-attendance in primary care and hospital out-patient clinics.

The purpose of this article is to review the extent and predictors of non-attendance in people with mental disorders presenting in primary and secondary care.

Although one approach may be to fundamentally question the merits of out-patient clinics [3], our approach is to examine essential predictors and solutions within current models of care.


In considering the classification of missed appointments it is important to distinguish between those who do not attend their first appointment and those who do not attend follow-up appointments.

Unfortunately, in reviewing the literature few studies uphold this distinction.

It is also useful to separate individuals who occasionally miss appointments (partial non-attendance) and those who disengage from any follow-up (often called treatment drop-outs).

To put non-attendance in context, patients may experience difficulty following medical advice at each stage of their patient journey (Fig. 1).


The extent of non-attendance in psychiatry (and perhaps its impact on the patient) may be significantly greater than in other medical specialties.

In 2002–2003, 19.1% of psychiatry out-patient appointments were missed in England, compared with an NHS-wide figure of 11.7% [4].

Of note, the Commission for Healthcare Improvement (now the Healthcare Commission) showed that non-attendance rates varied more than fivefold across 83 mental health trusts in England [5].

These national figures have been replicated in numerous small studies based in psychiatry outpatient clinics, which have reported non-attendance rates of 15.6–28% when examined as a proportion of all offered appointments [6][7][8][9].

Rates of initial non-attendance are usually higher than follow-up non-attendance, although this pattern may not hold for certain specialties [1].

The frequency of partial non-attendance is higher than the rate of full discontinuation (drop-out), echoing the findings of studies of missed medication [1].

Regarding partial non-attendance, Akerblad et al [10] in Sweden found that among 1031 patients with depression treated in primary care over a 6 month period only 54.6% of all scheduled appointments were kept.

In the largest study of full disengagement, Young et al [11] found that 31% of community psychiatric patients were lost to follow-up over the course of 1 year.

Over the course of 2 years the documented attrition rate for unscheduled drop-out may be as high as 50% [12].


In this issue of APT Mitchell & Selmes present an article detailing why patients miss appointments and how clinicians should respond.

Many of the papers quoted relate to the psychiatric out-patient clinic.

In this commentary, as well as picking up on some of the themes that emerge from their article, I explore the attachment that psychiatrists seem to have to this particular model of patient contact.


The evidence that non-attendance of patients at psychiatric out-patient clinics is a major problem that is highly wasteful of resources is unequivocal, but evidence-based guidance regarding what to do about missed appointments is much less clear.

Up to 50% of people with any form of mental health problem miss an appointment either in primary or secondary care at some point during a treatment episode, around 30% of all psychiatric out-patient appointments are missed and somewhere between a quarter and a half of people who miss an appointment completely disengage from mental health services [1][2].

However, the consequences of missing an appointment are more serious for people with severe and enduring mental health problems such as schizophrenia, schizo-affective disorder and bipolar affective disorder, who are much more likely to require a subsequent admission than those with common mental disorders [3][4][5].

Most people being seen as follow-up patients have a diagnosis of a severe and enduring mental health problem, whereas newly referred patients generally have common mental disorders [6][7][5].


Response to missed appointments


It follows that the response of services to missed appointments should be in keeping with the seriousness of the consequences, yet current evidence for telephone prompts and other interventions to encourage attendance is equivocal at best and only relates to studies in newly referred patients [8][9].

Mitchell & Selmes [2] state that ‘Many [patients] who miss appointments because of slips and lapses later rearrange without adverse consequences’.

If this were true, there would be no indication for these authors’ recommendation that further clinic appointments be sent after a non-attendance without first awaiting contact from the patient.

However, the study on which this statement is based [10] was carried out in a military clinic for combat veterans in the USA and had several methodological limitations such that the results have to be interpreted with caution: the non-attendance rate was particularly low (9%); data were collected retrospectively from the treating clinician without corroboration from the case notes; and no definition of what was meant by an ‘adverse outcome’ was given.

Sparr et al reported that over 70% of patients who missed their appointment spontaneously contacted the clinic to reschedule and they concluded that there was no need for the clinic to actively re-engage non-attenders.

However, in our prospective study of non-attenders at a psychiatric out-patient clinic in London, we found that both new and follow-up patients who missed a single appointment were very unlikely to re-engage with the clinic [5], and one study from outside the UK found that only half those who missed an appointment re-engaged [4].


These ‘slips and lapses’ are a combination of clerical error on the part of the clinic and, with regard to follow-up patients, social disorganisation secondary to the executive dysfunction and negative symptoms of the mental illness.

Clerical error accounts for a lower proportion of missed appointments in psychiatric clinics (5–12%: [10][5]) than in other medical specialties (28–33%: [11][12]) but this is a potentially preventable cause of non-attendance.

Although simple systems to remind patients about their appointments may appear to have face validity, they can only be effective for people who are contactable, such as those who actually have a working telephone [13].

The associated resources involved also have to be considered and there are currently no published examples of well-conducted cost-effectiveness analyses of telephone or other prompts to reduce non-attendance at mental health appointments in the UK.

Written information leaflets and orientation statements, which are helpful in reducing anxiety about the appointment for newly referred patients, may be more effective at improving attendance rates than prompts [14][15].


Relevance of the out-patient model in contemporary mental health services


Last year I was invited to write a review article for APT on the origins and future of the out-patient clinic in contemporary mental health services [1].

This article detailed the history of how the model developed some 300 years ago from a vehicle to triage new admissions to asylums and later became a replica of the approach used in other medical specialties for patient assessment and review.

Given the consistently high non-attendance rates and evidence of poor outcomes for non-attenders with severe and enduring mental health problems, I suggested that it might be time to review the usefulness of the clinic model for this client group.

I explored an alternative approach that could be integrated within our existing and highly developed community mental health services to facilitate assessment and brief interventions for newly referred patients with common mental disorders and that would provide appropriate triage for patients requiring longer-term care from secondary mental health services.


New Roles for Psychiatrists [16] and the Mental Health Policy Implementation Guide: Community Mental Health Teams [17] have far reaching implications and contain detailed guidance on the delivery of assessment services for patients newly referred to mental health services and on ongoing treatment for patients with severe and enduring mental health problems.

Both documents describe a secondary mental health service that appears to have no out-patient clinics.

So why, despite the relevant policy to support a new direction, are psychiatrists still inclined to use the clinic model? Is it because we see ourselves as hospital doctors whose activity is measured in the familiar approach of the out-patient clinic? Is it that we enjoy the only part of the job where we get to form a one-to-one therapeutic alliance with our patients, providing a welcome relief from our usual role of multidisciplinary team work? Are we under-confident in our non-medical colleagues’ skills in assessment and one-to-one interventions? Are there some more-challenging patients that we feel only we have the experience to contain?


None of these possible explanations has been researched, but in exploring the issue of the therapeutic alliance, Mitchell & Selmes suggest that the patient’s perception of the therapeutic alliance with the clinician and of the latter’s helpfulness is important in preventing disengagement from the clinic (‘Attendance at follow-up appointments is more a reflection of the patient’s satisfaction with care than of the perceived need for further help’).

However, the two large studies that have investigated satisfaction with psychiatric out-patient services have not found a statistically significant relationship between dissatisfaction with care and drop-out [18][19], although considerable patient dissatisfaction has been expressed about being seen by the junior doctor rather than the consultant [18][20].

In fact, the content of the interaction between patients with psychosis and their psychiatrists appears to be rather unsatisfactory at out-patient appointments [21].


The report on proposed new roles for consultant psychiatrists highlighted the problems of the out-patient clinic model:


‘There was almost universal dissatisfaction with out-patient clinics.

The doctor is isolated from the team and patients frequently do not attend.

Patients may present very differently in the artificial environment leading to differences with staff who see the patient at home.

Patients are brought back routinely so as not to lose touch with them rather than out of necessity’ [16].


Since out-patient non-attendance is no longer a Healthcare Commission performance indicator, it is likely that managerial attention on the out-patient clinic will fade.

The evidence currently suggests that the out-patient model is best targeted at people who are most able and likely to keep appointments and that alternative approaches are indicated for those with more complex mental health problems, including assertive outreach for particularly ‘difficult-to-engage’ clients.

A more radical review of the model could allow the integration of assessment and brief interventions for newly referred patients, and multidisciplinary triage of those requiring longer-term care under the care programme approach within the full range of community mental health services.

Alternatively, we could continue to organise our services so that the most expensive member of the team sees the patients with the least complex problems and accept the resultant waste of resources when 1 in 3 do not attend.


Chronic opioid use for non-cancer-related illness has been increas- ingly scrutinised in recent years.

While the total number of opioid prescriptions is decreasing in the United States, the average number of prescriptions per year remains at 51.4 per 100 citizens.

1 This im- plies that a large number of prescriptions continue to be provided for non-cancer-related conditions.

This problem is not limited to the United States, as emerging literature over the past few years from Europe reports increased rates of opioid prescriptions for non-can- cer-related pain.

2,3 Data suggest that chronic opioid use impairs clinical care with worse disease outcomes and increases all-cause mortality.


Inflammatory bowel disease (IBD) is a chronic illness with a re- lapsing and remitting course.

Disease flares are accompanied by symptoms such as abdominal pain, nausea/vomiting and diarrhoea.

These symptoms are often severe enough to prompt emergency room visits, during which patients are likely to receive opioids as our group has shown previously.

5 This phenomenon has also been docu- mented outside the US, as prior studies reported Canadian patients with chronic opioid use and IBD had more emergency department visits and decreased quality of life as compared to patients without chronic opioid use.

6,7 Furthermore, previous studies have found chronic opioid use in IBD is associated with worse surgical outcomes, longer hospital stays and increased mortality.

8,9 Many predictors of chronic opioid use are associated with poorer outcomes in IBD such as smoking, depression and therapeutic non-compliance.

5,10 We sus- pect that chronic opioid use may further interfere with productive therapy by enhancing patient behaviours that compromise effective clinical management.


In recent years, IBD therapeutic management has placed in- creasing emphasis on rapid escalation of therapy in response to disease biomarkers to improve outcomes.

11 Thus, clinicians are often hypervigilant in modifying therapeutic regimens in response to perceived disease flares.

While 'tight control' improves disease management in the vast majority of IBD patients, we suspect that it potentiates an unintended negative impact in patients who regularly receive opioids.


IBD patients receiving chronic opioids are susceptible to both IBD flares and the clinical manifestations of opioid withdrawal.

12 There is similarity between symptoms of opioid withdrawal and IBD flares including abdominal pain, nausea, diarrhoea and malaise, which falsely mimics disease re- currence and complicates disease management.


In the interest of maintaining 'tight control' of IBD, we suspect that providers abandon biologic therapies and label patients with chronic opioid use as 'primary non-responders'. 13 Currently, there are no studies investigating the impact of the recent shift in IBD management to obtain 'tight control' on patients with chronic opioid use.


We hypothesise that this group may have rapid therapeutic cycling, which quickly leaves patients without treatment options.

This study is designed to determine if chronic opioid use is associated with early discontinuation of biologic therapies independent of disease severity.


This study followed a retrospective cohort design.

The study population included individuals diagnosed with IBD who received their first biologic prescription during the years 2011-2016.

Individuals with IBD were identified utilising the ICD-9 (555.X, 556.X) or ICD-10 (K50.X, K51.X) diagnosis codes for Crohn's dis- ease and ulcerative colitis.

The study index date was identified as the earliest date associated with either inpatient administration or outpatient prescription claims of a biologic agent of interest, in- cluding adalimumab, infliximab, certolizumab, golimumab, vedoli- zumab and ustekinumab.

Inpatient administrations were identified by Healthcare Common Procedure Coding System J-codes, and outpatient prescription claims were identified by Generic Product Identifier codes.


At the index date, individuals were included if they were ≤65 years of age and fully enrolled with prescription drug bene- fits for at least 6 months prior to the index date and 2 years after the index date.

Patients >65 were excluded from analysis due to incomplete data in the Truven MarketScan Commercial Database, which does not include Medicare claims data.

Relevant covariates and outcomes of interest for each individual were extracted begin- ning 6 months prior to the index date and ending either at a gap in full enrolment or the study termination date (31 December 2016).


Individuals were then separated into cohorts based upon ob- served chronic opioid use throughout the entire study period.

Outpatient opioid prescription claims were identified utilising GPI codes beginning with '65'.

Chronic opioid use was defined as hav- ing at least a 90-day supply of outpatient opioid prescriptions in a 6-month period without any 30-day gaps in opioid coverage, a defi- nition that has been utilised in previous studies.

5,14-18 Chronic opi- oid use was observed both in the 6-month pre-index period and the post-index study period.


Insurance claims data utilised in this study were procured from the Truven MarketScan Commercial Claims and Encounters da- tabase.

The Truven MarketScan Research Databases (www.truve nheal th.com) are administrative claims-based databases represent- ing more than 255 million covered individuals and are considered representative of the privately insured population in the US.

More than 2100 peer-reviewed articles have been published utilising MarketScan data.


The primary outcome of interest was persistence to biologic ther- apy.

Persistence days were defined as the period from the index 13652036, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/apt.16269 by Stanford University, Wiley Online Library on [03/10/2025].

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 date to the first 8-week gap in supply of any biologic of interest.


An 8-week gap was chosen as it would be equivalent to missing a full dosing interval of the any of the biologics of interest.

Individuals were deemed non-persistent if they had an 8-week gap in supply prior to the end of the study window or their eligible period of en- rolment.

Secondary outcomes of interest included the number of unique biologics utilised by individuals, and the days persistence to each biologic in chronological sequence.

All persistence calculations were carried out in SAS software version 9.4 20 utilising previously validated methods.


Demographic covariates of interest were collected, including sex, age, geographic region and enrolment dates.

Diagnosis of relevant comorbid conditions and Charlson comorbidity index were evalu- ated and reported.

23 All diagnoses were identified utilising Clinical Classifications Software for ICD-9 and ICD-10 from the Healthcare Cost and Utilization Project (HCUP), as well as previous litera- ture.

24,25 Diagnoses were coded as binary variables for individuals with at least one diagnosis code during the 6-month pre-index pe- riod or the post-index study period.


Patterns of healthcare utilisation were also examined, includ- ing hospital admissions, emergency department visits, abdominal surgeries, endoscopies, the utilisation of inpatient and outpatient steroids and receipt of opioid agonist therapy.

Abdominal surger- ies and endoscopies were identified utilising Procedure Classes Software from HCUP.

26 Inpatient medication utilisation was determined by Healthcare Common Procedure Coding System J-codes, and outpatient medication claims were identified by Generic Product Identifier codes.

Variations in assessed outcomes and covariates in IBD patients with or without chronic opioid use were initially examined and assessed for statistical significance (P < 0.05) utilising Chi-square and t test methods in SAS software, version 9.4.


A survival analysis was conducted with chronic opioid use as the in- dependent variable of interest and days of biologic persistence con- sidered as the endpoint.

Patients who were persistent to biologic therapy at the end of their observation period were treated as right- censored.

Univariable survival curves were estimated for categorical variables, and the functional form of continuous variables was as- sessed.

Univariable hazard ratios were reported for categorical vari- ables and for those continuous variables that showed evidence of being linear in the log-hazard.


A Cox proportional hazards regression model was developed to assess the relationship between chronic opioid use and the risk of discontinuing therapy, while adjusting for potential confounding in- fluences.

A purposeful variable selection strategy was followed in developing the multivariate model.

27 Model discrimination and cali- bration were quantified by Harrell's c statistic and the May-Hosmer goodness-of-fit test 28 with G = 10 risk score groups respectively.

R Core Team 29 was used for the survival data analysis, with the survival package 30 for statistical modelling, and the survminer package 31 for plotting survival curves.

Significance level for null hypothesis testing was set at 5%.


The final study cohort comprised of 16 624 individuals with IBD who were initiated on biologic therapy during the study period.

In this co- hort, we identified 9013 (54.2%) individuals who received an opioid prescription, with 1768 (10.6%) meeting criteria for chronic opioid use.

Substance use disorder was diagnosed in 26.9% of the chronic opioid use cohort, and 15.2% received opioid agonist therapy.

Subjects with chronic opioid use were observed to have greater periods of continu- ous insurance coverage than others in the study population, which allowed for longer follow-up during this study period.

Individuals with chronic opioid use had a median follow-up time of 1443 days compared to 1270 days in those without a diagnosis of chronic opioid use (P < 0.0001; Table 1).

A significantly greater proportion of IBD patients with chronic opioid use had Crohn's disease as compared to those without (87% vs 84.2%, P = 0.002), whereas no significant dif- ference between the cohorts was observed in the incidence of ulcera- tive colitis and indeterminate colitis.

For this reason, disease subtype was included in the multivariable model.

However, other results were not classified by disease subtype in order to simplify reporting.


Significant differences in patient demographics were noted among those with chronic opioid use, including sex, age and geographic re- gion.

Patients with chronic opioid use were predominantly female (57.4% vs 50.8%) and older (mean age of 45 vs 37).

The majority of patients with chronic opioid use were in the age range of 45-65 years old (55.1%), while just 35.7% of IBD patients without chronic opioid use fell into this same range (P < 0.0001).

Patients with chronic opi- oid use were more likely to reside in the 'Southern' region than those without chronic opioid use (P < 0.0001), whereas patients without chronic opioid use were more likely to reside in the 'Northeast.'


IBD patients in the chronic opioid use cohort were significantly more likely to utilise more than one biologic agent during the study pe- riod (P < 0.0001; Table 2).

Subjects with chronic opioid use utilised a mean 1.5 different biologics, as compared to 1.37 biologics in the reference IBD cohort (P < 0.0001).

Individuals with chronic opioid use were significantly more likely to utilise adalimumab (P < 0.0001), golimumab (P = 0.0003), certolizumab (P < 0.0001) and ustekinumab (P = 0.029) than those in the reference IBD cohort.

Furthermore, 13652036, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/apt.16269 by Stanford University, Wiley Online Library on [03/10/2025].

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 individuals with chronic opioid use were less likely to receive inf- liximab (P = 0.0002).

There was no significant difference in vedoli- zumab use between groups.


In addition to a higher number of unique biologic agents used over the study period, we found that IBD patients with chronic opi- oid use had decreased duration of persistence to biologic therapy Table 3).

A sig- nificantly greater proportion of patients with chronic opioid use had decreased persistence to biologic therapy when compared to the IBD reference group (P < 0.0001), as evidenced by the low percentage of biologic therapy persistence observed in the chronic opioid use group (16.2%) compared to the IBD reference group (33.5%) at the end of the study period (P <0.0001) (Figure 1).

Treatment duration on the first and second biologic agents prescribed for IBD was significantly shorter in patients with chronic opioid use compared to those with- out (P < 0.0001).

However, no significant difference was observed between groups by the third, fourth or fifth lines of therapy.


Healthcare utilization, including emergency department visits, hos- pital admissions, abdominal surgeries, mean number of endosco- pies and steroid usage, was observed to be significantly higher in the chronic opioid use cohort (P < 0.0001) (Table S1).

The rates of common comorbidities and conditions, including fistula, malnutri- tion, mental disorder, cancer, chronic pain and arthritis diagnoses, were all significantly higher in the chronic opioid use cohort com- pared to the reference IBD patients.

The average Charlson comor- bidity index was significantly higher in chronic opioid use patients compared to the reference IBD patients (1.17 vs 0.69; P < 0.0001).

The chronic opioid use cohort experienced more comorbid condi- tions and disease complications, while also utilising healthcare re- sources to a greater extent than the reference cohort.


Univariable survival curves by chronic opioid use status were sig- nificantly different (P < 0.0001).

Subjects with chronic opioid use were 56% more likely to be non-persistent (hazard ratio 1.56, 95% CI [1.48-1.65]).

Among other categorical variables, only Crohn's disease failed to show a significant univariable association with risk of non- persistence (hazard ratio 0.98, 95% CI [0.93-1.03]) (Table S2).

Among After variable selection and assessment of the proportional haz- ard assumption, the main effects model included chronic opioid use, dichotomous age (<50 vs ≥50), gender, arthritis, mental disorder, ab- dominal surgery, inflammatory bowel disease type, number of inpa- tient admissions and inpatient steroid exposure (Table 4).

Subjects with chronic opioid use were 23% more likely to be non-persistent to biologic therapy, after adjusting for the other variables included in the final multivariable model (hazard ratio 1.23, 95% CI [1.16- 1.31]).

Diagnostics indicated that the final model was stable and well-calibrated (P-values in all 10 risk score groups were well above 0.05).

Concordance was c = 0.60, indicating moderate predictive accuracy.


Based upon our univariable analysis, the time to discontinuation decreases with increased comorbid conditions, emergency depart- ment visits, inpatient admissions and steroid therapies.

IBD patients with chronic opioid use in our study population were observed to have higher rates of comorbidities and healthcare utilisation as com- pared to the reference cohort.

Using these variables as surrogate markers for disease acuity, we acknowledge the possibility that chronic opioid users have more severe IBD, which contributes to higher rates of biologic failure and therefore decreased persistence to biologic therapy.

We also considered the possibility that the chronic opioid use cohort was simply sicker overall, given this group had a higher Charlson comorbidity index compared to the reference group.

However, the chronic opioid use cohort was still 23% more likely to discontinue biologic therapy early even when controlling for the most relevant surrogate factors of disease severity using a mul- tivariable predictive model.

This suggests that the difference cannot be solely attributed to greater disease severity or concomitant co- morbidities in the chronic opioid use cohort, which lends strength to the study's conclusions.


Results presented show that the risk of biologic discontinuation increased linearly as the number of emergency department visits and outpatient steroid usage increased.

IBD patients with chronic opioid use were observed to visit the emergency department more frequently and receive higher doses of steroid therapy for presumed IBD flares.

More frequent emergent healthcare utilisation in pa- tients as well as a greater reliance on rescue steroid therapy may lead to earlier determination of biologic therapy failure and subse- quently decreased persistence.


However, given that IBD patients with chronic opioid use are more likely to have early discontinuation of biologic therapy even when controlling for surrogate markers of disease severity, including measures of healthcare utilisation, we suspect that other factors associated with chronic opioid use de- crease the likelihood of persistence to biologic therapies.

Symptoms of opioid withdrawal that occur with chronic opioid use resemble IBD flares, and may lead providers to inappropriately switch bio- logic therapies under a false assumption of poor disease control.

Additionally, gaps in biologic therapy due to shorter periods of per- sistence may diminish treatment effect and increase the risk for the development of antibodies to biologics, necessitating discontinua- tion or therapeutic switch.

32 It is interesting to note that patients with chronic opioid use were significantly more likely to receive self-injectable biologic therapies than those without chronic opioid use.

This could be an additional reason for decreased persistence to therapy in this patient popula- tion, as it places increased onus on patients to obtain and self-admin- ister therapy without further provider contact.

Lack of persistence to therapy may be detected in a timelier manner in those receiving infusion therapies and allow for more rapid intervention to ensure patients remain on track with therapy.


This study relies on commercial insurance claims data, which may not be representative of the non-insured and Medicaid/Medicare populations.

The retrospective design of this study may introduce increased risk of confounding factors.

Due to the large scale of data collection, we were unable to track direct indicators of disease se- verity, including abdominal CT scan findings, endoscopy findings, faecal calprotectin, C-reactive protein, etc.

Therefore, we were un- able to directly control for disease severity and were forced to use surrogates of disease severity including abdominal surgeries, fistula and inpatient admissions.

We acknowledge that direct indicators of disease severity are a major factor in clinical decision-making with regard to therapeutic alteration.


We found that chronic opioid use is independently associated with a shorter period of persistence to biologic therapy.

The number of biologic therapeutic options for IBD remains relatively limited, and recognition of this phenomenon is of paramount importance for pre- serving therapeutic options for IBD patients.

Prior to abandoning a biologic therapy, we implore clinicians to remain hypervigilant for withdrawal symptoms, and ensure that patients with chronic opioid use demonstrate definitive biomarkers of ongoing disease activity such as elevated faecal calprotectin and/or endoscopic appearance.

Furthermore, we suggest that clinicians involved in the care of IBD pa- tients remain vigilant in identifying patients at risk for chronic opioid use and work with patients to find alternative methods for symptom and pain control.

Future study investigating the benefit of partner- ships with addiction medicine to improve outcomes in IBD is merited.


Patients with IBD frequently endure chronic pain.

Despite the drawbacks of opioids in IBD, a significant proportion of IBD patients rely on them.

In line with the global opioid epidemic, the use of opioids has increased in IBD [1].

Up to 30% of IBD outpatients and up to 70%-90% of hospitalised patients receive opioids [2].

In this journal, Rhudy et al report a retrospective study assessing the association between chronic opioid use and biologic agent persistence [3].

The authors hypothesise that IBD patients with chronic opioid use frequently experience symptoms of opioid withdrawal.

These symptoms may mimic disease recurrence, resulting in a rapid cycling of biologics.

Using the Truven MarketScan Database, 1768 out of 16,624 patients were identified as chronic opioid users.

The primary outcome ‘persistence’ was defined as the period from the index date to the first 8-week gap in supply of any biologic of interest.

The IBD patients with chronic opioid use utilised more different biologics (1.5 vs 1.37 in the reference group) and had a lower persistence on biologics (16.2% vs 33.5%).

When controlling for various confounders, patients with chronic opioid use are 1.23 more likely to be non-persistent to biologic therapy.


This does not necessarily mean that biologics are discontinued inappropriately in IBD patients with chronic opioid use.

First, reasons for discontinuation were not recorded.

Second, although the association between chronic opioid use and persistence was independent of surrogate markers of disease activity (steroids, healthcare utilisation), objective markers were missing.

Third, conclusions about causal relationships between chronic opioid use and persistence could not be drawn from the present study.

Chronic opioid users may have a more complex IBD, which is characterised by a higher turnover of different biologics.

In contrast, chronic opioid users may develop difficult to control symptoms which are interpreted as disease recurrence, leading to treatment cycling.

Despite the inherent limitations of the retrospective design, the results are strengthened by the large patient population and sound statistical methods.

More importantly, this study touches upon a relevant topic in clinical practice.

Chronic opioid use is associated with numerous side effects, increased infections, and mortality [2, 4, 5].

Even more worrisome, data supporting a benefit of opioids for pain control and quality of life are lacking [6, 7]. What to do with this information?

First, opioid use should be discussed with patients before discharge or during outpatient visits.

Second, the stepwise pain management should be critically reviewed, focusing on non-opioid pharmacological alternatives (COX-2 inhibitors, tricyclic antidepressants) and psychological and behavioural support [8].

A recent study shows that a multimodal intervention, including an IV acetaminophen protocol, a gastroenterology consult note ‘smartphrase’, an IBD pain management pathway, and automated text message alerts, substantially reduced intravenous opioid use and hospital length of stay, with similar pain scores [9].

Implementation of a multidisciplinary team and a holistic approach in order to reduce chronic opioid use and prevent further harm is of vital importance.


We thank Dr van der Have and Dr Maljaars for their commentary on our work [1], [2].

This study was inspired by observations in our IBD clinic, a large tertiary referral centre in a state plagued by the opioid epidemic.

While the limitations of using large databases such as Truven are well highlighted, we agree with the statement, 'chronic opioid users may develop difficult to control symptoms interpreted as disease recurrence, leading to treatment cycling.' This phenomenon further underscores the importance of relying on objective evidence of disease recurrence, be it elevated biomarkers (eg CRP or fecal calprotectin), weight loss, imaging, or endoscopic visualization, prior to abandoning therapy.


Drs van der Have and Maljaars provide many wonderful examples of strategies and interventions which can be pursued for identifying and treating IBD patients at risk for chronic opioid use.

We agree a multidisciplinary approach is essential for the management of IBD patients at risk for opioid dependence, and believe future studies quantifying their benefit will further incentivize widespread implementation.


The authors' declarations of personal and financial interests are unchanged from those in the original article [2].


Mitral regurgitation is a public health problem, as the most frequent valvular disease 1 leading to frequent referrals, hospitalizations, and cardiac surgery, 2 and its burden is expected to increase with ageing of the population.

1 Degenerative mitral regurgitation (DMR) with mi- tral valve prolapse is the most frequent organic mitral regurgitation and the most repairable, but it is often undertreated in routine clinical practice.

3 This prevalent under treatment in both Europe and North America has multiple causes, 4 but is favoured by sub-optimal risk as- sessment.

2 In DMR, individual risk factors have been identified 5-11 and endorsed by clinical guidelines.

12,13 However, while guidelines strongly recommend a combination of those risk factors in an inte- grated process, 12,13 there has so far been no attempt at deriving and validating a risk score satisfying such unmet need.

The lack of an inte- grated risk score usable at diagnosis contrasts with the availability of surgical risk scores, 14 which are nevertheless instrumental mainly in surgical decisions.

Current unavailability of a mortality score in DMR should not be surprising, since very large cohorts of patients with uni- form diagnosis and comprehensive clinical data are required, war- ranting multi-centre collaboration to obtain separate cohorts for the derivation and validation process (the two mandatory steps to obtain a score and to make it applicable to daily practice).

The international MIDA registries 15,16 provide the unique opportunity to analyse a comprehensive set of risk markers (prospectively and homoge- neously collected) in an integrated manner, allowing derivation and subsequent external validation of a MIDA Score specifically applicable to DMR.


Accordingly, we aimed at developing a risk score easily derivable from routinely collected clinical/echocardiographic parameters endorsed by guidelines and at validating this score externally.

We also wanted to verify the hypothesis that a user-friendly MIDA mor- tality score is independently and incrementally predictive of short- and long-term survival after diagnosis of DMR.

In summary, we aimed at providing for the first time a tool able to position a given patient within a continuous spectrum of mortality risk whether assigned to surgical treatment or to continuing medical therapy.


A fully detailed 'Methods' section is available as Supplementary material online, whereas a more concise version is reported below.


The Mitral Regurgitation International DAtabase (MIDA) registries were created by systematically merging a series of prospectively assembled electronic institutional echocardiographic databases, each originally generated to optimize echocardiographic reporting (see Appendix).

All patients provided prior informed consent for anonymous publication of their clinical data; the study was conducted in accordance with institu- tional guidelines, national legal requirements, and the revised Helsinki declaration.

The present reporting complies with the TRIPOD statement and dedicated tutorials.

17 18


All MIDA registries share analogous general eligibility criteria: (i) inclusion of consecutive patients with primary DMR by transthoracic echocardiog- raphy; (ii) availability of a comprehensive clinical/instrumental evaluation at index echocardiography; (iii) exclusion of secondary (functional) mitral regurgitation of any aetiology, ischaemic regurgitation, significant con- comitant aortic disease, mitral stenosis, active endocarditis, congenital diseases, prior valve surgery.


Patients analysed in the Derivation Cohort were those included in the MIDA-Flail Registry encompassing 1/1/1980 to 12/31/2005.

15 Patients en- rolled in the MIDA-Flail Registry fulfilled the general inclusion/exclusion criteria of the MIDA registries, but, as an additional requirement, they all received a diagnosis of DMR and flail leaflets.


The Validation Cohort consists of consecutive patients enrolled in the MIDA-BNP Registry, encompassing 1/1/2000 to 31/12/2013.

16 The MIDA-BNP Registry fulfils the general inclusion/exclusion criteria of the MIDA registries, but it additionally requires -as a specific inclusion criter- ion- a blood sample collection.

The diagnosis of flail leaflets is not manda- tory for the MIDA-BNP Registry, and both DMR and mitral valve prolapse or DMR and flail leaflets can be included.

By study design, pa- tients could be part of only one of the two cohorts.


Echocardiographic data were analysed as collected at the time of echo- cardiography 19 without subsequent modification.

The severity of DMR was based on the final diagnosis reported in the original echocardio- graphic report, which was performed by integrating all recorded echocar- diographic parameters.


Prognostic markers analysed to create the MIDA Score were selected on the basis of their known link to outcome in DMR and their guideline- based mention as a potential trigger for surgery (i.e. age > _65 years, left atrial diameter > _55 mm, ejection fraction < _60%, left ventricular end- systolic diameter > _40 mm, heart failure symptoms, atrial fibrillation, and right ventricular systolic pressure >50 mmHg).


The primary end point was long-term survival.

The secondary end point was 1-year survival.

Outcome was ascertained by investigators blinded to baseline predictors of outcome.

The follow-up was completed up to death, end of the study or at least 5 years in 3322 (91%) patients.


Since surgery is a competing risk event when analysing survival under medical management, we took advantage of competing risk analysis.

This approach makes it possible to estimate hazard rates separately for each transition, diagnosis to surgery, or diagnosis to death, stratified by centre.

A Markov proportional hazards model was used to estimate the hazard ratios (HR) for predictors at transitions from diagnosis to surgery, or diagnosis to death.

Proportional hazard assumptions were evaluated with scaled Schoenfeld residuals.


Hazard ratios of univariate competing risk models were estimated in the Derivation Cohort for the components of the Score.

Weights for these risk factors were calculated by redoing the univariate, transition-specific HR.

In order to capture the risk attached to the consequences of volume overload (rather than the nonspecific risk of death related to aging), 11 the weight for age > _ 65 years in keeping with the results of competing risk analysis was set at a value of 3 (see Supplementary material online for more explanation).

For each pa- tient the MIDA Score was calculated as the sum of these weights (Table 2).


The predictive ability of the MIDA Score for survival under med- ical management was described using a Harrell's C-statistic for the survival models.

21 The C-statistic ranges from 0.5 to 1.0, with values of 0.5 indicating no predictive ability, and a value of 1.0 indicating per- fect predictive ability.

The C-statistic was estimated by fitting a com- peting risk model to the derivation data and the validation data separately.


Since some variables may not have been detectable (e.g. systolic pulmon- ary pressure in the absence of tricuspid regurgitation), the main analysis was based on the clinical principle that absent or missing variables are counted as negative.

As an additional analysis, multiple imputation was used to generate 10 data sets and then to average the results.


Association of the MIDA Score with 1-year mortality was analysed with a logistic regression model in the Derivation Cohort and validated for the Validation Cohort.

The C-statistic (Somer's D) was used to examine the predictive power of the score in the Validation Cohort.


Baseline characteristics of 2472 patients included in the Derivation Cohort are summarized in Table 1 (left column).

Flail leaflet was idio- pathic in 2301 (93%) patients, caused by healed endocarditis in 171 (7%).

Involvement was confined to the posterior leaflet in 1956 (79%) patients and to the anterior leaflet in 346 (14%), while both leaflets were involved in 170 (7%) patients.


During follow-up (9.2 ± 5.4 years), 960 deaths occurred (390 under medical management).

Overall survival at 10 years was 68 ± 1% (56 ± 2% in patients symptomatic at diagnosis).


At univariate analysis, symptom presence, ejection fraction < _60%, left-ventricular end-systolic diameter > _40 mm, atrial fibrillation pres- ence, right ventricular systolic pressure > _50 mmHg, left atrial diam- eter > _55 mm, and age > _65 years were all associated with survival Table 2.


In the Derivation Cohort, the median MIDA Score was 4 (25th- 75th percentile: 2-6) (Table 3).

The MIDA Score adjusted for age was independently associated with an increased risk of death under med- ical follow-up (adjusted HR [95% CI] per unit 1.20 [1.15-1.25] P < 0.001).

The independent prognostic significance of the MIDA- Score was also confirmed by competing risk model and multiple im- putation (adjusted HR [95% CI] per unit 1.18 [1.13-1.23] P < 0.001).

The concordance for the model with the MIDA Score adjusted for age in the Derivation Cohort was satisfactory [c = 0.78; standard de- viation (SD) 0.02].


Mitral valve surgery was eventually performed in 1934 (78%) pa- tients (89% repair).

The median time (25th-75th percentile) from the baseline echocardiogram to the operation was 0.2 (0.1-1.9) years.

During a post-surgical follow-up of 9.2 ± 4.8 years (median [25-75th percentile], 8.7 [6.3-12.1] years), 570 patients died.

The MIDA Score regardless of age was associated with an increased risk of post- surgical death (adjusted HR [95% CI] per unit 1.15 [1.11-1.19] P < 0.0001).

Data on recurrence of regurgitation after repair were available for 1480/1713 patients; 20 years' freedom from > _3þ mitral regurgitation was 88% (95% CI, 86-90).


Baseline characteristics of the Validation Cohort (n = 1194) and MIDA Score distribution are depicted in Tables 1 and 3, respectively.

When compared to the Derivation Cohort, patients included in the Validation Cohort were more often symptomatic, although showing less severe consequences of DMR.

These findings can be explained by the limited reproducibility of symptom assessments, the higher prevalence of female patients in the Validation Cohort, and the higher use of beta-blockers rather than digoxin in this group.

22 During a follow-up of 4.8 ± 2.4 years, 191 deaths occurred (131 under medical management).

Overall survival at 10 years was 68 ± 5% (59 ± 7% in patients symptomatic at diagnosis).

Surgery was eventually per- formed in 725 patients (93% repair).


Competing risk analysis confirmed the MIDA Score to be re- gardless of age associated with long-term risk of death under medical management (adjusted HR [95% CI] per unit 1.13 [1.01-1.22]; P < 0.001) (c = 0.81; SD 0.03).

The MIDA Score re- gardless of age also predicted long term post-surgical outcome (adjusted HR [95% CI] per unit 1.35 [1.19-1.54]; P < 0.001).

Association of the MIDA Score with 1-year mortality was analysed with a logistic regression model in the Derivation Cohort and validated in the Validation Cohort and found to be satisfactory (Derivation Cohort: c = 0.7540; Validation Cohort: c = 0.7537) (Figure 1).


Since remarkably similar 5- and 10-year survival rates were recorded and an analogous prognostic ability of the MIDA Score had been con- firmed, we combined Derivation and Validation Cohorts to further increase the sample size in order to facilitate long-term follow-up and sub-group analyses.

Baseline characteristics of the Combined Cohort are reported in Tables 1 and 3, respectively.

During a follow-up of 7.8 ± 5.0 years, 1151 patients died.

Overall survival at 5 and 10 years was 84 ± 1 and 69 ± 1% years, respectively.

During a medical follow-up of 2.1 ± 3.5 years, 521 patients died.

Figure 2 reports the independent association of the MIDA Score with mortality under medical management in selected sub-groups.

Long- term survival according to the categories of MIDA Score is depicted in Figure 3A and (using multiple imputation) in Figure 4A (see Supplementary material online).


Surgery was eventually performed in 2659 patients (90% repair).

During a post-surgical follow-up of 7.8 ± 4.8 years, 630 patients died.

Perioperative mortality occurred in 40 patients (1.5%).

The mean EuroSCORE II was: 1.72% (median [25-75th percentile] 1.17 [0.75- 1.98]) in the entire population; 3.04% in patients who died during the perioperative period (vs. 1.71% in those who survived, P = 0.004); 1.99% in those who were treated exclusively medically (vs. 1.62% in those who were operated on, P < 0.001).


When the post-surgical outcome was analysed, the MIDA Score retained its independent prognostic significance from age and In conclusion, DMR management requires extensive prognostic assessment.

12,13 The MIDA Score, developed using the largest co- horts of DMR medically and surgically treated ever analysed, can for the first time position a given patient within a continuous spec- trum of short- and long-term mortality risk, overall, under medical management and after surgery, providing incremental and inde- pendent prognostic information.

Our findings-generated by analysis of data collected at multiple centres from different contin- ents-may contribute to improve DMR management, by not only facilitating guidelines application but also providing a useful tool to test new therapeutic options for patients with DMR in homoge- neous categories of risk.


In degenerative mitral regurgitation (DMR), lack of mortality scores predicting death favours misperception of individual patients’ risk and inappropriate decision-making.

The Mitral Regurgitation International Database (MIDA) registries include 3666 patients with pure, isolated, DMR consecutively diagnosed by echocardiography at tertiary centres.

The MIDA Score was derived from the MIDA-Flail-Registry by weighting all guideline-provided prognostic markers, and externally validated in the MIDA-BNP-Registry.

The MIDA Score ranged from 0 to 12 depending on accumulating risk factors.

In predicting total mortality post-diagnosis, the MIDA Score showed excellent concordance both in Derivation Cohort (c = 0.78) and Validation Cohort (c = 0.81).

In the whole MIDA population, 1-year mortality with Scores 0, 7–8, and 11–12 was 0.4, 17, and 48% under medical management and 1, 7, and 14% after surgery, respectively (P < 0.001).

Five-year survival with Scores 0, 7–8, and 11–12 was 98 ± 1, 57 ± 4, and 21 ± 10% under medical management and 99 ± 1, 82 ± 2, and 57 ± 9% after surgery (P < 0.001).

In models including all guideline-provided prognostic markers and the EuroScoreII, the MIDA Score provided incremental prognostic information (P < 0.002).

The MIDA Score may represent an innovative tool for DMR management, being able to position a given patient within a continuous spectrum of short- and long-term mortality risk, either under medical or surgical management.


Mitral regurgitation is a public health problem, as the most frequent valvular disease leading to frequent referrals, hospitalizations, and cardiac surgery, and its burden is expected to increase with ageing of the population.

Degenerative mitral regurgitation (DMR) with mitral valve prolapse is the most frequent organic mitral regurgitation and the most repairable, but it is often undertreated in routine clinical practice.

This prevalent under treatment in both Europe and North America has multiple causes, but is favoured by sub-optimal risk assessment.

In DMR, individual risk factors have been identified and endorsed by clinical guidelines.

However, while guidelines strongly recommend a combination of those risk factors in an integrated process, there has so far been no attempt at deriving and validating a risk score satisfying such unmet need.

The lack of an integrated risk score usable at diagnosis contrasts with the availability of surgical risk scores, which are nevertheless instrumental mainly in surgical decisions.

Current unavailability of a mortality score in DMR should not be surprising, since very large cohorts of patients with uniform diagnosis and comprehensive clinical data are required, warranting multi-centre collaboration to obtain separate cohorts for the derivation and validation process (the two mandatory steps to obtain a score and to make it applicable to daily practice).

The international MIDA registries provide the unique opportunity to analyse a comprehensive set of risk markers (prospectively and homogeneously collected) in an integrated manner, allowing derivation and subsequent external validation of a MIDA Score specifically applicable to DMR.

Accordingly, we aimed at developing a risk score easily derivable from routinely collected clinical/echocardiographic parameters endorsed by guidelines and at validating this score externally.

We also wanted to verify the hypothesis that a user-friendly MIDA mortality score is independently and incrementally predictive of short- and long-term survival after diagnosis of DMR.

In summary, we aimed at providing for the first time a tool able to position a given patient within a continuous spectrum of mortality risk whether assigned to surgical treatment or to continuing medical therapy.


Mitral regurgitation (MR) is the most frequent valvular disease in developed countries [1], [2].

The degenerative aetiology predominates in primary MR, therefore its management represents an important public health issue [3].

It has been observed both in Europe and in the USA that there is an underuse of surgery in patients with MR when indicated.

This occurs with the frequent finding that risk evaluation is not adequate, leading to undertreatment of the sickest patients while conversely lower risk patients are often overtreated [4]-[7].

The search for an improvement of risk stratification in patients with degenerative MR was the aim of the study published by Grigioni et al. in this issue of the journal [8].

The goal was to define a score to predict early and late mortality.

The authors should be congratulated for putting together what is the largest study ever published on degenerative MR since it included >3000 patients.

The patient population comes from two registries: the MIDA Flail registry (2472 patients) was used as a derivation cohort for the score, and the MIDA BNP registry (1194 patients) served as the validation cohort.


Among the potential limitations of the present study we should take into account the fact that the inclusion period covers more than two decades, which may lead to significant changes in practices as regards both diagnosis and management.

Although no specific information was given about co-morbidities, the patient population seems to be at relatively low risk since EuroSCORE II ranged from 1 to a maximum of 2.48, mean age was 66 years, a large proportion of patients were asymptomatic, and mean left ventricular ejection fraction was 64%.

Thus it is likely that the high-risk patients currently treated using percutaneous device are under-represented here.

We also lack precision as regards the methods used for grading the severity of MR; however, it was assessed using an integrative approach in experienced teams.

In addition, most patients had flail leaflets which usually results in severe MR.


The MIDA score was derived from the derivation cohort by weighing clinical and echocardiographic parameters which are in the guidelines: age >_65 years, left atrium diameter >_55 mm, left ventricular ejection fraction >_60%, left ventricular end-diastolic diameter >_40 mm, heart failure symptoms, atrial fibrillation, and right ventricular systolic pressure >_50 mmHg.

All criteria corresponding to recommendations for surgery in guidelines were strongly associated with outcome, and this is a further proof of the validity of guidelines and of the relevance of the proposed thresholds [9], [10].

The positive aspects of this score are that it includes both clinical and echo variables taking into account all criteria together with a weight which is proportional to their prognostic impact.

The MIDA score is simple, thus it may be expected to be user-friendly which may facilitate its use in practice.

The score showed a good discrimination and also a good calibration, with a C index of 0.78 and 0.81, respectively.


Finally it appears that the MIDA score adds incremental value in comparison with the guideline-provided prognostic markers and the EuroSCORE II for predicting 1- and 5-year mortality.

The fact that the MIDA score has a good predictive performance of 1-year mortality in medically treated patients is an important contribution in decision-making since it allows for a better assessment of the respective outcomes of operated and medically treated patients.

The predictive value of the MIDA score in operated patients further highlights the prognostic impact of the consequences of MR on the left ventricle, left atrium, and pulmonary pressures.

This is a further incentive to consider early surgery in severe MR without waiting for overt symptoms or left ventricular dysfunction.


A number of methodological limitations do, however, exist, among which one of the most important is the fact that the populations in the derivation and validation cohorts were significantly different as regards important characteristics such as gender (males: 72% in the derivation cohort vs. 65% in the validation cohort), symptoms (asymptomatic patients: 67% vs. 43%), and number of patients with flail leaflets (96% vs. 77%).

It is understandable that performing such a large study was at the price of some heterogeneity and it would be theoretically desirable to concentrate on a more homogenous population with flail leaflets only, severe MR assessed using precise quantification methods, and including only asymptomatic patients where decision-making is more difficult, while surgery is theoretically indicated when MR is severe and symptoms are present.

Finally, percutaneous treatment should be part of the treatment performed since it has a growing role in current practice when affordable [11].


Beyond the issues intrinsic to the value of this score, it is a bit of an oversimplification to think that a score can summarize all the factors in the decision, even more so when addressing a population of elderly patients with a large number of co-morbidities, which are not taken into account in the MIDA score.

A simple score could be used more often but it will not provide the solution for the management of a specific patient [12], [13].

In such cases, the only way to proceed is the judgement of a Heart Team integrating a number of clinical, anatomic, and procedural variables.

Such a process was recently put forward and is now recommended in the new ESC EACTS guidelines on the management of valvular disease [14].


The suggestion that undertreatment is largely due to the absence of such a score also somewhat oversimplifies the problem because the reasons are probably multiple.

In the MIDA registry, patients who were denied surgery were at higher operative risk, as shown by differences in risk scores.

This finding was the same in the Euro Heart Survey, in which the EuroSCORE was higher in patients referred to surgery than in those medically treated, although all of them had a theoretical indication for surgery [4], [5].

We share the opinion of the authors that this finding suggests that the operative risk is overstressed in decision-making.

High-risk patients are also likely to have a particularly poor outcome under medical therapy, but this does not seem to be fully taken into account by the practitioners in charge of the therapeutic decision.


A process needs to be followed to overcome undertreatment of MR.

The first step would be to identify gaps in knowledge.

This can be done by awareness studies performed among primary care physicians and cardiologists [15].

A similar effort was made in Europe and was presented during the last annual congress.

In parallel, another way to identify the gaps in knowledge will come from registries such as the Euro Heart Survey and its second phase which was just finalized and included >7000 patients throughout Europe, the results of which are to be expected next year.

This identification of the gaps will facilitate the development of new educational programmes specifically targeting the gaps derived from awareness studies and registries.

The efficacy of educational programmes will then be evaluated based on changes in knowledge and, more importantly, practices and outcomes to be evaluated by repeated registries.

Thus this study contributes to an improvement in our knowledge in the management of degenerative MR, but there is still a lot of work to be done.


Male lemurs have well-developed scent glands on the wrists (an- tebrachial scent glands) and shoulders (brachial scent glands).

The antebrachial gland is mainly composed of apocrine glands and secretes small quantities of a highly volatile clear fluid, whereas the brachial gland is composed of sebaceous glands that produce a brown greasy paste [5, 6].

Using these secretions, lemurs perform scent marking to advertise their social rank [7, 8] or reproductive state, as well as to demarcate territories or mediate intergroup spacing [9].

During the breeding season, male lemurs rub their wrists to mark their territory.

They rub their antebrachial and brachial scent glands on their own tails and then wave their tails to spread the glandular volatiles that threaten other males [10, 11].

With these behaviors, the male lemurs display their dominance status to potential rivals within the small multimale-multifemale groups.

Taken together, vola- tiles in glandular secretions seem to play a role in male-male communications among lemurs [12, 13].

However, male-female communications through the glandular secretions of lemurs had not yet been well examined.


Meanwhile, several studies have attempted to analyze the chemical components of lemur secretions at a molecular level.

Using gas chromatography-mass spectrometry (GC-MS) anal- ysis, long-chain acids and esters were found in the anogenital se- cretions of lemurs; the chemical profiles were distinguishable be- tween the sexes [14, 15].

The male brachial secretions have individual differences in their relative concentrations of compo- nents and, thus, are likely used for individual recognition [9, 16].

Scordato et al. [ 9] analyzed four glandular secretions (brachial, Current Biology 30, 2131-2138, June 8, 2020 ª 2020 Elsevier Inc. 2131 ll A B C D E F G H


To determine whether the degree of females' interest in male scent marks changes seasonally, the duration that females snif- fed male scent marks during the breeding season was compared with the duration of sniffing during the nonbreeding season at the Japan Monkey Centre (JMC).

We defined the breeding season af- ter the date on which estrous individuals were confirmed within the group.

In previous studies, November to February is the breeding season and March to October is the nonbreeding sea- son in the Northern Hemisphere [20, 21] and, in our cases, the breeding season began from late October to November.

Multi- male-multifemale (8 females and 4 males) groups are naturally reared in an outdoor enclosure at the center (Figure 1A), and focal male scent marks were observed.

Females sniffed male scent marks during the breeding season significantly longer than during the nonbreeding season (p = 0.038; Figures 1B and S1A).

This result indicates that female lemurs are more attracted to male scent gland secretion during the breeding season.


Next, secretions were collected, using a micropipette tip, from the antebrachial scent gland on the wrist of three male lemurs (Bon, Doitsu, and Afu) at the Research Institute of Evolutionary Biology at the Tokyo University of Agriculture (RIEB) and one male (Dan) at Yumemigasaki Zoological Park (YZP) (Figures 1C and 1D).

Se- cretions were collected twice per month from January 2013 to December 2014 and once per month from June 2018 to February 2019 (Figure 1E).

The volume of secretions tended to be larger dur- ing the breeding season (data not shown).

Each collected sample was used for GC-MS analysis and/or behavioral assay, as described in Figure 1E.

The smell of secretions collected during the breeding season was described as more fruity, floral, and sweet than those during the nonbreeding season, which were evaluated as being more bitter, leathery, animalic, and green by human senses.

Therefore, female lemurs may use this odor differ- ence as a signal to judge the timing of mating.


To examine the attractiveness of male secretions to females, the sniffing behavior of two female lemurs toward each of the male antebrachial samples (i.e., eight and six samples derived from the breeding and nonbreeding seasons, respectively, from Bon and Doitsu) was observed during the breeding season at the RIEB (Figures 1E-1G and S1B).

Before the behavioral assay, each female was isolated for approximately 1 h so she could habituate to the testing environment.

Then, the female was pre- sented with a cotton pad containing 1 mL of male secretions for 2 min; the duration of cotton pad sniffing was recorded (Figures 1F and 1G).

The total average time that the females sniffed the cotton pads that had secretions from the breeding season was significantly longer than that for the cotton pads with secretions from the nonbreeding season, or for the control cotton pads.

The sniffing frequency and the number of times the cotton pads were sniffed were variable among the samples, whereas the duration of each sniffing event was always longer for samples from the breeding season, which resulted in a longer total sniffing dura- tion.

After that, we presented cotton pads with secretions to two other females reared at the JMC, and the result was the same (Figure 1H).

These results suggest that female lemurs sniff male secretions derived from the breeding season longer than secretions from the nonbreeding season.


Next, an attempt was made to determine the chemical profiles of compounds in male antebrachial secretions that females were attracted to during the breeding season.

To identify the key com- pound(s), the profiles of volatile chemicals emitted from the male secretions obtained during the breeding and nonbreeding sea- sons were compared using GC-MS.

The GC-MS analyses demonstrated that among the many peaks that were present, 50 appeared in more than two analyzed Bon (age 9) samples; these 50 peaks were analyzed further (Table S1).


Next, the relative median peak area difference between breeding- and nonbreeding-season samples was determined.

In samples from Bon (age 9), the amounts of #21 (dodecanal), #26 (12-methyltridecanal), and #28 (tetradecanal) were higher during the breeding season than the nonbreeding season, whereas the amount of #24 (acetamide) was higher during the nonbreeding sea- son (Figures 2 and S2).

In samples from Doitsu (age 17), the amount of #26 was also higher during the breeding season, and #21 and #28 tended to be higher (Figure 2C; Table S2).

Samples from Afu (age 9) and Dan (age 23) also showed the same tendencies for #21, #26, and #28 (Figure 2C; Tables S3 and S4).

Moreover, principal- component analysis results for seven breeding-season and 10 nonbreeding-season samples from Bon showed that compounds #21, #24, #26, and #28 had a strong effect on the differences seen between the breeding and nonbreeding seasons (Figure S3).


The total ion chromatograms of Bon's samples are shown in Figure 2A.

Figure 2B shows the overlaid chromatograms of Bon's samples in which the chemical identities of #21, #24, #26, and #28 were confirmed using the retention times and mass spectra of standard samples.

The scents of #21, #26, and #28 were green, floral/fruity, and floral/green, respectively, according to the GC-MS olfactometry analysis and were Medians (bands inside boxes), quartiles (boxes), and 1.5 times the interquartile ranges (whiskers) and outliers (circles and scores beside arrows) are shown in the boxplots.

identical to those of standard samples (Figure 2B).

The scents of these compounds were also consistent with the breeding-sea- son samples evaluated by human senses.

Based on these re- sults, three C12 and C14 aldehydes are strong candidate com- pounds for female lemur attraction.


It was hypothesized that one cause of increased dodecanal, 12-methyltridecanal, and tetradecanal secretion was the higher testosterone levels reported in male lemurs during the breeding season.

To test this hypothesis, the serum testosterone level was manipulated by injecting testosterone intramuscularly into the 9-year-old male (Bon) from July to August, which corresponded to the nonbreeding season.

The testosterone level was higher during the breeding season in both the 9- and 17-year-old males (Bon and Doistu), as previously reported, although the level in the 17-year-old male was much lower than in the 9-year-old male, which was likely due to aging (Figure 3A).

The testosterone injection into the 9-year-old male during the nonbreeding season resulted in a higher serum testosterone level, and that level was similar to that in the 17-year-old male (Figure 3A).


GC-MS was used to quantify the amounts of dodecanal, A B C Report acetamide, 12-methyltridecanal, and tetradecanal in secre- tions at the indicated time after testosterone injection (Fig- ure 3A).

12-methyltridecanal and acetamide demonstrated a significant increase and decrease, respectively, in testos- terone-boosted samples (Figure 3B).

Tetradecanal had a nonsignificant tendency to increase.

No change for dodecanal was observed (Figure 3B).

These results are consistent with the observation that the amounts of 12-methyltridecanal in the 17-year-old male lemur were lower than those in the 9-year-old male (Figure 2C), which is likely due to a lower testosterone level (Figure 3A).


To determine the female sniffing behavior associated with the above candidate compounds, two female lemurs (the same indi- viduals as in Figures 1F and 1G) were presented with cotton pads that contained different amounts of dodecanal, 12-methyltride- canal, or tetradecanal for 2 min and the sniffing duration was measured at the RIEB.

No increase in sniffing duration was observed for dodecanal, whereas significant increases were observed for 12-methyltridecanal and tetradecanal at amounts greater than 490 and 300 ng, respectively (Figure 4A).

A measurement of 490 ng of 12-methyltridecanal is equivalent to 20-100 mL of breeding-season secretion.

These results suggest A B that 12-methyltridecanal and tetradeca- nal are key compounds in the male ante- brachial glandular secretions that elicit attractive behaviors among female lemurs during the breeding season.


Finally, the effect of the above candidate aldehyde com- pounds was examined in relatively more natural and social conditions in an indoor enclosure at the JMC (Figure 4B).

To determine whether females were interested in these alde- hydes, they were presented with cotton pads that contained different amounts of dodecanal, 12-methyltridecanal, or tetra- decanal for 5 min (Figure 4B).

In the breeding season, no in- crease in the total number of sniffing events per trial, or the to- tal sniffing duration per trial, was observed for each compound, whereas conspicuous increases were observed for the three-compound mixture (Figure 4B, upper panel).

Moreover, the duration of females' responses to any single compound was not different from their response to the control solution, whereas females sniffed significantly longer at mix- tures with concentrations of 3-10 ppm for 10 mL solutions, which is equivalent to a 3 to 30 mL breeding-season secretion.

On the other hand, females in the nonbreeding season were not interested in these compounds (Figure 4B, lower panel).

These results support the hypothesis that the identified C12 and C14 aldehydes are key compounds in male antebrachial ll Current Biology 30, 2131-2138, June 8, 2020 2135 Report glandular secretions that elicit attraction behaviors of female lemurs during the breeding season.


Despite the results of many studies indicating intraspecies chemical communications among primates, no research where the phero- mone-like molecules were identified had been published.

This was partially due to the complexity of volatile compounds contained in body odors or secretions and the difficulty of performing reliable behavioral experiments in primates.

This study used lemurs, with unique exocrine scent glands and a specific marking behavior, to successfully identify volatile long-chain aldehydes that increased A B during the breeding season in a testos- terone-dependent manner and appeared to be major male-specific odorants involved in female attraction during the lemur-breeding season.

It is conceivable that the identified C12 and C14 aldehydes are putative sex pheromones that aid male-female interactions among lemurs.


There have been several reports of GC- MS analyses of secreting glands in lemurs.

Hayes et al. [ 15] reported that anogenital gland secre- tions contained long-chain alcohols and esters that showed sex differences.

Scordato et al. [ 9] reported that brachial secre- tions were thick and viscous, containing squalene and choles- terol derivatives, whereas labial and scrotal secretions contained organic acids and esters.

They also determined that antebrachial secretions were highly volatile and contained fewer compounds than other glands [9].

Boulet et al. [ 14] reported 338 and 203 semiochemicals in labial and scrotal secretions, respectively.

None of these studies, however, reported the specific com- pounds that are involved in sexual communication.


Three C12 and C14 aldehydes identified in this study have not previously been detected in the secretions of lemurs or in any secreting ll 2136 Current Biology 30, 2131-2138, June 8, 2020 Report gland of other primate species (Mandrillus sphinx [22]; Callithrix jacchus [23]).

There are, however, some reports of these com- pounds being detected in animals other than primates.

Dodeca- nal, tetradecanal, and 12-methyltridecanal have been reported to exist in lamb wool [24] and were suggested to be involved in the recognition of newborn sheep by their mothers.

Tetradecanal is known as a sex pheromone in mantis and Helicoverpa assulta [25, 26].

Thus, although the identified aldehydes are novel find- ings in primate species, long-chain fatty aldehydes appear to be used as communication tools widely throughout the animal kingdom.


It has been reported that the volatile composition of male brachial gland secretions correlates with testosterone level [9, 20].

Consistently, testosterone administration in the 9-year-old male during the nonbreeding season resulted in an increase in the amount of the C12 and C14 aldehydes that were secreted.

We also observed that the volume of antebrachial gland secre- tions increased in both the breeding season and the testos- terone-effective period.

In contrast, the seasonal change in the amount of C12 and C14 aldehyde secretion from the 17-year- old male was small.


The reproductive age of ring-tailed lemurs starts at 2-4 years [27, 28].

The mean (±SD) lifespan of females was 4.9 ± 4.9 years and the longest was 20 years.

Male lemurs rarely live beyond 10 years in the wild, although the maximum lifespan in captivity has been recorded as 37 years among females and 35 years among males [29].

Therefore, the 9- and 17-year-old male subjects of this study could be stratified into prime adult and old age, respectively, and the testosterone- dependent change is a signal from young reproductive males toward females.


On the female side, young females are inter- ested in males' secretions during the breeding season, whereas old females that have passed their reproductive age equally snif- fed secretions during the breeding and nonbreeding seasons (data not shown).

Therefore, both young reproductive males and females appear to benefit from their mating choice, and sub- sequent reproductive behaviors demonstrated during the breeding season by males are associated with the production of testosterone-dependent C12 and C14 aldehydes, which females sense.


Can we say that the identified C12 and C14 aldehydes in lemurs are pheromones?

The classical definition of a pheromone is a sub- stance that is secreted by an individual and received by a second individual of the same species (conspecific) to induce a specific re- action, such as a stereotyped behavior or endocrinological change.

The identified C12 and C14 aldehydes seem to support this definition.

Future studies on behaviors or endocrine changes might help us to argue more explicitly about whether the identified C12 and C14 aldehydes in lemurs are sex pheromones.

Nonethe- less, the identification of key volatiles used in sexual communica- tions among lemurs introduces a way to better understand chem- ical communications among primates.


Detailed methods are provided in the online version of this paper and include the following:


Pheromones mediate a wide range of functions across the animal kingdom [1], and such chemosensory communication is especially widespread among mammals [2].


In a recent paper in Current Biology, Shirasu, Ito et al. [ 3] describe the results of a series of chemical and behavioral studies that identified three aldehyde odors released from the wrist gland of ring-tailed lemurs (Lemur catta) that could represent the first identified sex pheromones in male primates.


Observations of a captive group and controlled presentations of isolated male scent samples showed captive female lemurs sniffing antebrachial scent marks longer on average during the breeding season.


Comparison of the chemical profiles of antebrachial secretions between breeding- and non-breeding-season samples revealed three aldehydes putatively responsible for the female response, the concentration of one of these subsequently shown to increase following testosterone injection of one male.


Average sniffing duration of two females increased slightly with increasing concentrations of two of the three aldehydes in one experiment, and so did the response of seven other females to swabs with mixtures of the three compounds, compared to individually presented aldehydes.


From these results, the authors conclude that “it is conceivable that the identified C12 and C14 aldehydes are putative sex pheromones that aid male–female interactions among lemurs.”


Here, I argue that, in fact, more data are needed to determine whether antebrachial marking and these substances are actually involved in mediating the attractiveness of males to females during the breeding season.