Acceptability and compliance of atenolol tablet, compounded paste and compounded suspension prescribed to healthy cats

Abstract

This study was designed to evaluate the cats’ acceptance and compliance of the owners and cats towards an extemporaneously prepared palatable compounded atenolol (paste and suspension) formulation in comparison to the commercially obtained tablet, in a randomised, cross-over study design.The three formulations were prescribed twice daily for 6 days to 13 healthy privately-owned cats of 13 different owners, with varying levels of experience in medicating cats. Daily compliance was evaluated via an owner-completed diary, completed after each dose administered. Owner’s experience and preference of the formulation was evaluated via questionnaires given prior to, at the end of each treatment protocol, and upon completion of the study. Although compounded suspension was association with fewest missed doses, the majority of cat owners expressed a preference for the divided tablet. Atenolol tablets, compounded paste and suspension acceptance and compliance were comparable. Further work is now required to assess the amount and stability of the active ingredient and the robustness of the paste and suspension formulations prior to any bioavailability comparisons between the formulations.

Introduction

Drug compliance in human medicine is generally described as the adherence of patients to their prescribed medication.^1,2 Grave and Tanem ³ defined drug compliance in veterinary medicine as the extent to which owners adhere to instruction when giving prescribed drugs to their animals. To date, drug compliance in veterinary medicine has been reported to range from 44–55%, ⁴ while a wider range (5–96%) was reported for human compliance. ¹ Drug compliance may be improved in veterinary medicine if the treatment regime is easily incorporated into owners’ daily routine and if the owner is made aware of the risks and rationale for the selected treatment.^1,5,6 In human medicine, drug compliance declines when the formulation is difficult to administer.^7,8 Compounded medications are used in veterinary medicine to enhance administration or if a suitable formulation or drug is not registered for veterinary species.

Atenolol, a β₁-adrenoceptor blocker, is a good example of a drug that is not registered for animal use but is commonly prescribed to treat cats with hypertrophic cardiomyopathy (HCM). ⁹ However, the commercially available human tablet (25 mg or 50 mg) must be divided to provide a twice-daily administration of 6.25–12.5 mg/cat, which is inconvenient for long-term therapy. Compounded transdermal delivery systems, ¹⁰ applied to the inner ear, have been investigated, but inconsistent absorption has resulted in unpredictable physiological responses. ¹¹ Atenolol is a moderately hydrophilic drug, thus making it less suitable drug for transdermal application because it may not cross the stratum corneum easily without a suitable skin penetration enchancer. ¹¹ Furthermore, frequent grooming behaviour in cats allows only a limited area of transdermal application as an adverse reaction owing to ingestion maybe a concern. Therefore, different oral formulations are still a useful alternative to ensure compliance of this medication in cats.

The aim of this study was to quantitatively and qualitatively assess, via questionnaire and owner-completed daily diaries, the compliance associated with atenolol in the form of a paste, suspension (both extemporaneously prepared compounded formulations by the authors) and the commercially-available divided tablet.

Materials and methods

Animals

Healthy adult neutered cats were sourced from staff and students of The University of Queensland School of Veterinary Science. Inclusion suitability was assessed by physical examination, haematology and serum biochemistry, urinalysis profile, indirect Doppler blood pressure measurement, echocardiography and electrocardiography. Only healthy cats were used to ensure treatments were not administered to cats with underlying disease to avoid exacerbation. All tests were performed without sedation with the exception of echocardiography, which was performed following subcutaneous administration of hydromorphone (0.1 mg/kg) and acepromazine (0.1 mg/kg). ¹² Exclusion criteria included cats weighing over 6 kg, any abnormalities in the haematology and serum biochemistry, urine specific gravity <1.030, systolic blood pressure >180 mmHg, ¹³ and echocardiographic or electrocardiographic examination outside the limits of normal as defined by Kittleson and Kienle ⁹ suggesting heart disease, concurrent illness or ongoing health problem. Only one cat was chosen from a multi-cat household to avoid biased results or potential repeated feedback. Written owner consent was obtained as required by The University of Queensland Animal Ethics Committee, which approved this investigation (AEC approval number: SVS/040/09).

Study design and drug administration

Cats were administered three different oral atenolol formulations in a randomised, cross-over design. The formulations comprised: a commercially-available atenolol tablet(Noten 50 mg; Alphapharm Pty. Ltd., Carole Park, NSW Australia); an extemporaneously prepared compounded oral paste (applied to the oral mucous membranes); and an extemporaneously prepared compounded oral suspension. Each cat was administrated a 12.5-mg dose of each formulation q12h for 6 consecutive days (12 doses) with 8 days washout between each formulation. The owners were instructed (verbally and via written take-home instructions) on administration techniques of each formulation before undertaking the treatment protocol.

Briefly, upon medicating, the cat’s cheekbone was gently grasped from above and head tilted slightly to the back. The divided tablet was held between the index finger and thumb of the right hand. The middle finger of the tablet-giving hand was use to pry the lower jaw down and the tablet was then ‘popped’ into the back of the throat — beyond the base of the tongue — mouth closed and cat’s head returned back to its normal position. Similar handling and positioning of the cat’s head was applied with suspension administration. An accurate measured suspension in the syringe was administered slowly into the side of the cat’s mouth and directly onto the tongue. As for the paste administration, the head was tilted to the back or side. Either side of the gum was exposed. The calculated bolus paste placed on the index finger was smeared onto the gums or premolar teeth or on the upper palate of the oral cavity.

Oral formulation

Preparation of atenolol tablet

Each atenolol tablet was manually divided into four equal parts using a scalpel blade. Divided tablets were kept stored protected from light at room temperature (20–25°C) before being provided to the cat owners.

Preparation of compounded oral atenolol paste and suspension formulations

A non-controlled pilot investigation on different cats not included in the current study (n = 7; results not shown) was conducted and identified beef and pork flavour as a suitable flavouring agent for the compounded formulation. The flavouring agent was prepared by crushing and drying (60°C for ~60 min) a commercial cat liver treat (Love’em purrfect, Liver Treats, Somersby, NSW Australia) passed through a 710 µm mesh sieve before being added to the compounded formulation. The extemporaneously prepared compounded atenolol (paste and suspension) formulation was made in 150 ml batches of 25 mg/ml atenolol.

The compounded atenolol paste was prepared by gradually adding 8 g of hydroxypropyl methylcellulose (HPMC, Methocel E10M Premium CR Grade; Colorcon Asia Pacific, Pte Ltd., Merchant Square, Singapore) to 50 ml of distilled water that had been boiled and allowed to cool to 80–90^°C. A high-speed stirrer (UltraTurrax; C-Mag HP101 Katherm, IKA Works, Wilmington, NC, USA) was used to obtain an opaque white mixture and was then stirred manually with a spatula to remove excess froth, before a further 150 ml distilled water was added. The mixture was immediately stirred by spatula to facilitate gelation. ¹⁴ The HPMC transparent gel (4% w/w) was allowed to equilibrate to room temperature, before 3.75 g atenolol powder (analytical grade; Sigma-Aldrich, St Louis, MO, USA), was gradually added and thoroughly mixed using a spatula. The flavouring agent (15 g) and 1.8 g of 5.9% sodium saccharin [food grade, (Sugarless Australia Pty. Ltd., Chipping Norton, Australia, to counteract the characteristic bitterness of the atenolol] were then added and mixed to produce a light brown paste. The paste was rested at room temperature for 30 min to allow bubbles formed to rise to the top. Paste was then loaded into 3 ml disposable syringes, capped and wrapped with aluminum foil to protect from light.

The compounded atenolol suspension was prepared by adding atenolol powder (3.75 g), 51 g polyethylene glycol (PEG 4500, technical grade; BDH Laboratory Supplies, Poole, UK), flavouring agent (15 g) and sodium saccharin (1.8 g) to 50 ml of distilled water and shaken vigorously. The volume was made up to 150 ml with distilled water and mixed further. Aliquots of 10 ml were dispensed into amber glass bottles.

Both the compounded paste and suspension made were immediately stored at −20^°C and owners were instructed to thaw and store at 4^°C for administration.

Owners’ compliance/cats’ acceptance

The formulations were assigned in a randomised, cross-over design to avoid potential bias associated with improving owner skill of administration and ‘learned’ cat acceptance over the three treatment protocols.

Prior to the study, each owner was asked to complete a short-answer and multiple-choice questionnaire, which provided objective data about the owner, cat and medication experience. Additional questionnaires were completed by owners at the end of each treatment protocol and at the end of study to provide subjective and objective feedback on their experience.

Each owner was given a diary requiring their response immediately after each dose administrated twice daily for the duration of 6 days treatment protocol. Here, owners were asked to log the time of treatment (Table 1) and briefly record information on a score sheet with five questions [one question as a yes/no (Table 2),with space for written comments, and four questions were scored on scale of 1–5 (Table 3)] regarding the ease of administration, their perceived success of administration, wastage of formulation and their cat’s acceptance of the medication at each dosage in the diary. Acceptance was based on the definition provided by Thombre, ¹⁵ as cats will not normally voluntarily accept medication, so acceptance can be gauged on how easily or difficult (eg, struggling during restraint, owner being scratched) it was when the drug was administered.

Table 1.

Owner compliance in administration of formulation evaluated from the diary

Compliance parameter	Formulation	Number of times (%)		P-value for difference compared with tablet	Odds ratio (95% CI)	Probability of outcome occurring
		Yes	No
Number of doses given	Tablet	146 (93.6)	10 (6.4)
	Compounded paste	150 (96.2)	6 (3.8)	0.42	1.70 (0.46–6.40)	0.94
	Compounded suspension	154 (98.7)*	2 (1.3)	0.01	5.30 (1.63–17.10)	0.96 0.99
Owner-estimated consumption success	Tablet	141 (90.4)	15 (9.6)			0.90
	Compounded paste	138 (88.5)	18 (11.5)	0.71	0.82 (0.28–2.38)	0.88
	Compounded suspension	145 (92.9)	11 (7.1)	0.43	1.40 (0.60–3.25)	0.93
Time of administration	Tablet	98 (67.1)	48 (32.9)			0.67
	Compounded paste	99 (66.0)	51 (34.0)	0.91	0.95 (0.39–2.31)	0.66
	Compounded suspension	99 (64.3)	55 (35.7)	0.77	0.88 (0.38–2.04)	0.64
Interval between doses	Tablet	74 (58.7)	52 (41.3)			0.59
	Compounded paste	81 (60.9)	52 (39.1)	0.70	1.09 (0.69–1.74)	0.54
	Compounded suspension	75 (54.0)	64 (46.0)	0.50	0.82 (0.47–1.45)	0.61

Compliance parameter evaluation for each formulation:

Number of doses given = number of times the owner gave the dose prescribed (ie, dose q12h for 6 days)

Owner-estimated consumption success = number of times the owner successfully administered medication with the correct dose prescribed

Time of administration = number of times the owner administered medication within ± 30 min of the prescribed time

Interval between doses = number of times the owner adhered to the 12 h dosage interval

^*Significantly different (P <0.05) of the number of times (%) compounded paste and suspension compared with tablet. The ‘probability of outcome occurring’ indicates, for example, that the probability of the cat receiving the total number of doses given was 0.94 (94%) if the medication was given in tablet formulation and 96% if given as compounded paste.

CI = confidence interval.

Table 2.

Owners’ observations during administration of the formulations evaluated from the questionnaire (palatability and behavioural change) and diary (wastage) at the end of each formulation prescribed

Evaluation of formula	Formulation	Number of times (%)		P-value for difference compared with tablet	Odds ratio (95% CI)	Probability of outcome occurring
		Yes	No
Palatability	Tablet	8 (61.5)	5 (38.5)			0.58
	Compounded paste	9 (69.2)	4 (30.8)	0.65	0.94 (0.73–1.21)	0.57
	Compounded suspension	10 (76.9)	3 (23.1)	0.40	0.89 (0.68–1.17)	0.55
Behavioural Change	Tablet	7 (53.8)	6 (46.2)			0.59
	Compounded paste	9 (69.2)	4 (30.8)	0.40	0.89 (0.69–1.16)	0.57
	Compounded suspension	7 (53.8)	6 (46.2)	1.00	1.00 (0.81-1.23)	0.59
Wastage	Tablet	5 (38.5)	8 (61.5)			0.62
	Compounded paste	7 (53.8)	6 (46.2)	0.30	0.91 (0.75–1.09)	0.59
	Compounded suspension	5 (38.5)	8 (61.5)	1.00	1.00 (0.83–1.21)	0.62

Questions for evaluation of the oral formulation asked at the last dose of each formulation:

Palatability = did your cat appear to like the taste of the oral formulation?

Behavioural change = were there changes of behaviour after medicating your cat?

Question for evaluation of the oral formulation asked at each dose of administration:

Wastage = was there any wastage of the formulation supplied to you?

^*Significantly different (P < 0.05) of the number of times (%) compounded paste and suspension compared with tablet. The ‘probability of outcome occurring’ indicates, for example, that the probability of the cat was observed to like the taste (palatability) was 0.58 (58%) if the medication was given in tablet formulation and 57% if given as compounded paste

CI = confidence interval.

Table 3.

Evaluation obtained from the diary after each dose administered by the owners for all the formulations, which were measured on a Likert scale of 1–5

Parameter	Formulation	Mean	SD	Median	Range	P-value for difference compared with tablet
Owner enjoy	Tablet	2.86	0.86	3	2–5
	Compounded paste	2.74	0.77	3	1–5	0.71
	Compounded suspension	2.78	0.64	3	1–4	0.70
Difficulty	Tablet	2.21	1.15	2	1–5
	Compounded paste	2.31	0.93	2	1–5	0.74
	Compounded suspension	2.07	0.81	2	1–5	0.68
Cat enjoy	Tablet	3.32	0.86	3	1–5
	Compounded paste	3.07	0.72	3	1–5	0.36
	Compounded suspension	3.07	0.66	3	1–4	0.22
Cat compliance	Tablet	2.14	1.09	2	1–5
	Compounded paste	2.32	0.93	2	1–5	0.60
	Compounded suspension	2.14	0.81	2	1–5	0.99

Questions for evaluation of the oral formulation asked after each dose administered for each formulation:

Owner enjoy (owner enjoyment) = did you enjoy the medicating session?

(1, love; 2, like; 3, neutral; 4, dislike; 5, hate)

Difficulty = how difficult was it for you to give the medication?

(1, very easy; 2, easy; 3, average; 4, difficult; 5, very difficult)

Cat enjoy (owner’s perception cat enjoyment) = did your cat enjoy the medicating session?

(1, love; 2, like; 3, neutral; 4, dislike; 5, hate)

Cat compliance = rate cat’s compliance in receiving medication?

(1, very good; 2, good; 3, average; 4, bad; 5, very bad)

^*Significantly different (P<0.05) of the mean of compounded paste and compounded suspension compared with tablet. No significant different in any of the parameter analysed.

SD = standard deviation.

Statistical analysis

Compliance with medication according to drug formulation (tablet, compounded paste or suspension) was compared using the four outcome measures: whether or not the dose was actually given, whether all of the doses given were actually consumed by the cat, whether the dose was given at the prescribed time (±30 min), and whether the interval between doses was >12 h. Data where the outcome was dichotomous was analysed using logistic regression with drug formulation as the explanatory variable. Results are presented as odds ratios with ‘tablet’ as the reference category. Owner enjoyment, difficulty of administration, owner’s perception cat enjoyment and cat compliance, which were measured on a scale of 1–5, were analysed using general linear models (SPSS genlin; SPSS Inc., Chicago, IL, USA) with log link to adjust for the non-normality of the data and repeated measurements for individual cats. All statistical analyses were performed using SPSS 16 (SPSS). If not indicated otherwise, analysed data were presented as mean (SEM). The level of significance was set to 5%.

Results

Twenty-eight cats were identified as clinically normal for study inclusion. However, 15 cats were excluded based on echocardiographic (n = 5), biochemical (n = 5) abnormalities or being part of a multi-cat household (n = 5). Therefore, 13 cats and 13 different owners were enrolled in the study. The 13 (eight males and five females) cats had a mean ± SD (range) bodyweight of 5.04 ± 0.63 (range 3.74–5.90) kg and age of 4.3 ± 2.8 (range 1–9) years. Breeds included: domestic shorthair (n = 8), domestic longhair (n = 2), Persian (n = 1), Siamese (n = 1) and Russian blue (n = 1). Cats were described by their owners as being 50% indoor and 50% outdoor (n = 8) or strictly indoor (n = 5). All cats had a prior history of tablet administration by owners, which was quantified as having received either <10 tablets (n = 7) or >10 tablets (n = 6). Response to tablet administration in the past was rated by each cat’s owner as easy (n = 3), intermediate (n = 8), and difficult (n = 2).

Owners reported previously owning cats for an average of 16 (range 1–30) years. Owner’s tablet administration technique was reported as being obtained from their professional career (eg, as veterinarians or veterinary nurses), self-learned from having many cats as pets, or being educated by veterinarians during consultation. Owners exhibited varying levels of prior experience in administering tablets and were grouped based on this estimated number of total tablets administered to any cat: beginner (<10 tablets; n = 5), novice (10–40 tablets; n = 2), intermediate (41–80 tablets; n = 2) and expert (>80 tablets; n = 4). Most owners (n = 8) rated themselves as having good skill in the administration of tablets, average (n = 4) and poor (n = 1) skill. Prior to the study, owners rated their compliance, as it related to administration of tablets to their cat, as good (n = 10) and average (n = 3).

At completion of the study, owners revealed in the questionnaire that they adhered better to the dose, rate and frequency of compounded suspension (P<0.05) than the other two formulations. Owners’ compliance was further objectively evaluated from the diary (Tables 1–3). A small proportion (3.8%; n = 18) of medications failed to be given as directed because owners were not at home, the dose was forgotten or the cat went missing. There was no significant difference (P = 0.42) in the proportion of doses actually given between the compounded paste and tablet; however, owners administered a greater proportion (P = 0.01) of the compounded suspension, compared to the tablet, which correlated with their opinions given at the end of the study.

Overall, 9.4% (n = 44) of the medications administered were not consumed entirely by cats during administration (ie, medication was spat out, evidence of suspension droplets, some paste remained on the fur around the cat’s mouth and owner’s finger). There was no difference in the amount of medication successfully administered by owners between compounded paste and suspension compared to tablet (Table 1).

The compliance with dosing interval also varied, with 34.2% (n = 154) of medications not given on time and 42.2% (n = 168) of medications not administered within the 12 h interval. There was no difference between formulations as to whether cats received their medications on time or with an interval of >12 h between doses (Table 1).

Prior to the study, the majority of owners, particularly from the beginner and expert groups, felt that an alternative to a tablet would be preferable for long-term administration of medication to their cat. These owners had experience in administration of pastes (n = 10) and/or suspensions (n = 4) prior to study. However, the percentage of preference reduced from 69.2% to 46.2% upon completion of the study (Figure 1).

Figure 1.

Preference of alternative formulation (compounded paste and/or compounded suspension) compared witht ablet chosen by each group of owner (left) prior to study and (right) end of the study

The owners reported no difference (P >0.05) in palatability, wastage and behavioural changes of cats with the administration of compounded paste and suspension compared to the tablet (Table 2).

An evaluation of the mean score of owner enjoyment, owner difficulty, owner’s perception of cat enjoyment and cat compliance on each session with the compounded paste and suspension were not significantly different (P >0.05) compared with the tablet (Table 3).

A comparison between the compounded paste and suspension formulations show that there were no differences (P >0.05) in the ability of the owner to obtain an accurate dose, the confidence in their ability to administer an accurate amount of medication or the method of administration.

Discussion

The present study demonstrated that compliance between an extemporaneously prepared, compounded atenolol paste or suspension and the commercially-available tablet were comparable. Owner and cat compliance were superior with the suspension, although at the end of the study the tablet was the preferred formulation for long-term administration.

Measurement of compliance by direct (eg, measurements of drugs in blood and urine excretion, measurements of biological or inert markers) or indirect (eg, therapeutic outcomes, clinical opinions, interviews, filling of prescriptions, pill counts, microelectronic monitors) methods is possible in human and veterinary medicine, but no ‘gold standard’ exists.^1,2,7,16 Such studies have been conducted in dogs for short courses of medication^3,16 but are lacking in cats, particularly for long-term administration. The current study questionnaire design may be relatively subjective, but relied on direct and indirect questions to evaluate compliance in a realistic setting (the home). Moreover, these tests were easy to conduct, inexpensive and permitted pet owners to express problems encountered or their observation during drug administration.^7,17

A feature of the current study were the strategies^3,6,18,19 adopted to minimise owners’ non-compliance, including written agreement and demonstration of medicine administration a self-assessment questionnaire and a diary for more objective evaluation of owner compliance. Pet compliance was enhanced by adding flavour to the compounded formulations, similar to procedures employed by pharmaceutical companies to mask the taste and odour of the drug.^15,20 Palatability tests are standard in industry to determine acceptance and preference of a formulation^15,17 and is an important factor to consider when developing extemporaneously prepared formulations for cats. Similarly, palatability is an important factor in drug compliance for children, where the acceptability and ease of medication is greatly affected by its taste.^8,19

The majority of recruited cats were rated to possess good compliance with tablet administration by their owner prior to the study. Most of the cats exhibited a good nature and behaviour; however, two were observed to occasionally display aggression and one would hide. Those cats that were identified as difficult to medicate belonged to owners in the expert group, where they occasionally strategies to administer tablets, including the conventional ‘poke down’ method, aid of a pill- popper or hiding the tablet in a small amount of food. Most owners in this study had limited experience with paste or suspension formulations and initially appeared supportive of an alternative formulation for long-term administration. However, this preference was reversed at the completion of the study, particularly owners from the expert group, with tablets indicated as being quicker, easier, more familiar (based on prior experience) and resulting in less wastage. This result could be biased as most of the cats included in this study were described as easy-to-pill and well behaved during administration. However, most owners indicated that a suspension would be preferable if the tablet size was large and the cat was not compliant.

A major cause of non-compliance is owner related,^5,21 which is relatively common and likely related to lifestyle and commitments of the owner. ³ Owner compliance in the current study (96.2%) was much higher than what had been reported previously. ¹⁸ However, despite this, 34.2% of the cats’ doses were not given at the correct time and 42.2% of the cats’ doses were not given within the optimum time period for efficacy, which, depending on the drug, can be crucial for efficacy and/or to minimise adverse effects.^1,16

An important outcome of the current study was that cats were more likely to get medicated properly with an accurate amount of dose if the drug was a compounded suspension. Owners preferred tablets for long-term administration, as they were familiar with the technique. However, cats are notoriously independent, less accustomed to being restrained and can be aggressive if upset,^15,22 so ease of administration is an important consideration in extemporaneously prepared compounded oral formulations for this species.^15,20 Compounded suspensions may be a viable alternative to tablets for cats requiring long-term medication. In contrast, although there were no significant differences observed between the owner and the owner’s perception of the cat’s enjoyment during the medication sessions, some owners appeared to have difficulty with repeated administration of the compounded paste. Comments received were that it was difficult to smear onto the gum without staining the fur, was messier and took longer for the cats to consume the total dose (although applying paste medications to the commissures of the lips can be an accepted method of administering medications to cats). Furthermore, following paste administration, cats were observed to have increased grooming, with one cat being reported as being more affectionate than normal and some cats exhibited mild hypersalivation, reduced appetite, occasional vomiting and increased water intake. These observations were unlikely to be associated with flavour, as the suspension and paste were similar in this aspect. As this study specifically compared compliance following orally-administered formulations, application of any paste to the lip commissures was avoided; this may be assisted by the use of pre-loaded syringes, similar to the method of suspension administration. We also found that cats that did not initially like the use of the syringe seemed to learn and accept the dose by this method as the study progressed.

To assist in drug delivery, drugs have been compounded for veterinary medicinal use for many years. It is important to consider that although extemporaneously prepared oral compounded veterinary medications allow some potentially useful drugs that are not registered for veterinary use or may allow reformulation of available preparations to facilitate compliance, these compounded medications are not subject to the same rigid controls required for registration. ²³ Therefore, they may be associated with adverse effects ²⁴ or lack of efficacy ¹¹ if not carefully manufactured. Veterinarians must carefully monitor any extemporaneously prepared compounded formulation they prescribe for safety and efficacy, particularly if the active drug has a low therapeutic index.

In conclusion, compliance of extemporaneously prepared compounded atenolol (paste and suspension) formulations was comparable to the commercially-available tablet when administered to cats. Most owners reported that they preferred the tablet formulation at the end of the study, although this may have been related to familiarity with this dosage form. There was a significantly better compliance in terms of prescribed doses actually given with the suspension formulation, which may be useful for long-term therapy, particularly in non-compliant cats. Future investigations are necessary to identify suitable longer-acting (ie, once daily) medications or if alternative routes, such as transdermal medication, are viable, to determine if these will improve compliance.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest

The authors declare that there is no conflict of interest