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Abstract
Objective To assess the prevalence of vision impairment, hearing impairment and dual sensory impairment (DSI) as combination of vision and hearing impairment, in association with cognitive dysfunction in a population aged 85+ years.
Methods The cross-sectional population-based Ural Very Old Study, conducted in rural and urban Bashkortostan, Russia, between 2017 and 2020, included a detailed ocular and systemic examination with assessment of moderate to severe vision impairment (MSVI)/blindness (best-corrected visual acuity <6/18), moderate to severe hearing loss (MSHL) and cognitive function.
Setting A rural and urban area in Bashkortostan, Russia.
Participants Out of 1882 eligible individuals aged 85+ years, 1526 (81.1%) individuals participated.
Primary and secondary outcome measures Prevalence of vision, hearing and DSI and cognitive dysfunction.
Results The study included 731 (47.9%) individuals (mean age 88.1±2.7 years; median 87 years, range 85–98 years) with measurements of MSVI/blindness, MSHL and cognitive function. The prevalence of MSVI/blindness, MSHL, DSI and dementia were 51.8% (95% CI 48.2% to 55.5%), 33.1% (95% CI 29.7% to 36.5%), 20.5% (95% CI 17.8% to 23.5%) and 48.2% (95% CI 44.5% to 51.8%), respectively. Lower cognitive function score was associated with lower visual acuity (p<0.001) and higher hearing loss score (p=0.03), after adjusting for older age (p=0.001), rural region of habitation (p=0.003), lower educational level (p<0.001) and higher depression score (p<0.001). Higher dementia prevalence was associated with higher MSHL prevalence (OR 2.18 95% CI 1.59 to 2.98; p<0.001), higher MSVI/blindness prevalence (OR 2.09, 95% CI 1.55 to 2.81; p<0.001) and higher DSI prevalence (OR 2.80, 95% CI 1.92 to 4.07; p<0.001).
Conclusions In this very old, multiethnic population from Russia, DSI (prevalence 20.5%), as compared with hearing impairment (OR 2.18) and vision impairment alone (OR 2.09), had a stronger association (OR 2.80) with dementia. The findings show the importance of hearing and vision impairment, in particular their combined occurrence, for dementia prevalence in an old population.
- Epidemiology
- Ophthalmology
- Dementia
Data availability statement
Data are available upon reasonable request.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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Strengths and limitations of this study
A population-based recruited multiethnic study sample of individuals aged 85+ years and living in rural and urban region in Bashkortostan, Russia, was ophthalmologically and systemically examined.
Vision was tested as best-corrected visual acuity; hearing loss was assessed with the help of a standardised questionnaire; and cognitive function was examined applying the Mini Mental Test.
Limitations of the study include a relatively low participation rate of 47.9%, and hearing impairment was not phonometrically measured.
Strengths of the study are the high age of the study participants, the combination of a multitude of examinations in the area of ophthalmology, hearing loss and internal medicine, and performance in Russia for which public health information has been relatively scarce so far.
Introduction
Due to growth and ageing of the population, the role of dementia as major cause of the global burden of disease has further gained importance during the past decades.1 In view of estimations of further rising trends in the global prevalence of dementia and taking into account the absence of any evidence-based therapy with a major impact on the course of the disease, detection of risk factors of dementia and reduction of their influence are of thus major importance.2 3 In the 2020 update to the Lancet Commission report on dementia, about 40% of dementia was attributed to 12 major modifiable risk factors.2 These included hearing impairment among other factors such as lower level of education, arterial hypertension, obesity, smoking, depression, physical inactivity, social isolation, diabetes mellitus, alcohol consumption, head injury and air pollution. Although vision impairment was associated with a higher risk of dementia in some investigations which showed an up to eight times higher risk of dementia for visually impaired individuals, the association between vision impairment and dementia has remained unclear so far.4–7 In particular, the effect of a combined occurrence of vision impairment with hearing impairment as dual sensory impairment (DSI) has not fully been explored and recognised as a risk factor for cognitive dysfunction yet. Using data from the US National Health and Ageing Trends Study, a recent nationally representative cohort study of community-dwelling Medicare beneficiaries aged 65+ years revealed that self-reported functional vision impairment, self-reported functional hearing impairment, and combined self-reported vision and hearing impairment had adjusted cross-sectional HRs of dementia of 1.89, 1.14 and 2.00, respectively.8 Similar results were obtained during a follow-up of 7 years for the incidence of dementia.
The strengths of some of previous studies were that they addressed sensory impairment and cognitive function and their association by using objective measures of sensory functions, and that they analysed nationally representative and longitudinal data with a relatively long follow-up.8–10 Some of the previous investigations, however, had limitations such as being based on self-reported impairment in vision and hearing, including Medicare beneficiaries as a subgroup of the total population in the case of Kuo's study, and not being focused on the very old population.11 We therefore conducted the present population-based study on individuals aged 85+ years who underwent measurements of visual acuity and cognitive function and assessment of hearing loss. In addition, we performed the study in Russia, a world region for which population-based data on DSI and cognitive dysfunction have only scarcely been available so far, and which is one of the world regions with a relatively fast ageing of the population.12 13
Methods
The Ural Very Old Study (UVOS) is a population-based study performed in the rural region in the Karmaskalinsky District in a distance of 65 km from the capital Ufa and in the urban region of Kirovskii in Ufa in the Republic of Bashkortostan, Russia.14 15 The study was conducted between November 2017 and December 2020. In the situation of individuals who were not able to understand the meaning of the consent, the closest relative was informed and consented. Inclusion criteria were the age of 85+ years and living in the study regions. The Republic of Bashkortostan has a population of about 4.07 million people, and it is geographically located in the west of the southern Ural Mountains, about 1300 km east of Moscow. Its capital, Ufa, is an economic, scientific and cultural centre and has a population of 1.1 million inhabitants including Russians, Bashkirs, Tatars, Ukrainians and other ethnicities.
Out of 1882 eligible inhabitants aged 85+ years and living in the study regions, the study consisted of 1526 (81.1%) participants including inhabitants of retirement or nursing homes. The urban group (1238 (81.3%) out of 1523 individuals) and the rural group (288 (80.2%) out of 359 individuals) did not differ significantly in the participation rate. Based on the census performed in Russia in 2010, age and gender distributions in the study population did not vary markedly from the Russian population aged 85+ years, with a marked preponderance of women.16
Using a bus, the study participants were brought from their homes to the Ufa Eye Institute, where a team of about 20 trained technicians and ophthalmologists performed all examinations. Those individuals who were unable to come to the hospital underwent the interview and all examinations, which could be performed outside of the hospital, in their homes. The series of examinations included a standardised interview by trained social workers with almost 300 questions on the socioeconomic background, diet, smoking, alcohol consumption, physical activity, quality of life and quality of vision, history of any type of injuries and interpersonal violence, and health assessment questions.14 All questions were taken from standardised interviews published in the literature, such as the Centre for Epidemiologic Studies Depression Scale scoresheet and the Folstein test.16–21 The physical examinations consisted of the measurement of the anthropomorphic parameters, arterial blood pressure and pulse rate. Using blood samples taken under fasting conditions, we measured the serum concentrations of transaminases, bilirubin, blood lipids, glucose, creatinine, haemoglobin and others and performed a blood cell count. We applied the Guidelines for Accurate and Transparent Health Estimates Reporting (statement guidelines).22 The UVOS design was similar to the design of the Ural Eye and Medical Study, which has been described in detail previously.14
Besides other ocular examinations, we measured best-corrected visual acuity (BCVA), expressed in logarithm of the minimal angle of resolution and determined the ocular axial length by sonography. Using the WHO criteria, we defined moderate to severe vision impairment (MSVI) as a BCVA of <6/18 but ≥3/60 in the better eye or binocularly, and blindness as a BCVA of <3/60 in the better eye or binocularly.
Hearing loss was assessed by a series of 11 standardised questions, 10 of which were derived from the ‘Hearing Handicap Inventory for the Elderly Screening Version (HHIE-S)’.23–26 The prevalence of self-reported hearing loss as a binary variable was assessed by the single question ‘Do you experience a hearing loss?’ The questions could be answered by ‘no’ (0 points), ‘sometimes’ (2 points) and ‘yes’ (4 points). The total hearing loss score was the sum of the points of all questions of the questionnaire and could range between 0 points and 44 points. The amount of hearing loss was assessed by the hearing loss score. The HHIE-S had been applied in previous investigations.23–25 The diagnostic performance of the HHIE-S against five definitions of hearing loss as assessed by pure-tone audiometry had been explored in a previous study revealing sensitivities ranging between 53% and 72% and specificities from 70% to 84%, depending on the definition of hearing loss.27 Based on the WHO hearing impairment grading system, we defined mild hearing impairment (‘No problems in quiet but may have real difficulty following conversation in noise’) by a hearing loss score of 11–17; moderate hearing impairment (‘May have difficulty in quiet hearing a normal voice and has difficulty with conversation in noise’) by a hearing loss score of 18–24; moderately severe hearing impairment (‘Needs loud speech to hear in quiet and has great difficulty in noise’) by a hearing loss score of 25–31; severe hearing impairment (‘In quiet, can hear loud speech directly in one’s ear, and, in noise, has very great difficulty’) by a hearing loss score of 32–38; and profound hearing impairment (‘Unable to hear and understand even a shouted voice whether in quiet or noise’) by a hearing score of 39–44.27 28 We defined DSI as MSVI/blindness combined with moderately severe or more severe hearing impairment (grade 3+). Cognitive function was assessed using the Mini-Mental Status Examination Scale.18
Using a statistical software package (SPSS for Windows V.25.0), we determined the demographic characteristics of the study population (presented as mean±SD) and assessed the prevalence of MSVI/blindness, hearing impairment and DSI (presented as mean and 95% CIs). We performed a regression analysis as univariate analysis with the cognitive function score as dependent variable, followed by a multivariable analysis that included as independent variables all those parameters which were significantly associated with the cognitive function score in the univariate analysis. Finally, we conducted a binary regression analysis of the relationships between the prevalence of cognitive dysfunction, vision impairment, hearing impairment and DSI. We calculated the standardised regression coefficient beta, the non-standardised regression coefficient B, ORs and the 95% CIs. All p values were two-sided and considered statistically significant when the values were less than 0.05.
Patient and public involvement
Patients or the public were not involved in the design, conduct, reporting or dissemination plans of our research.
Results
Out of 1526 individuals primarily participating in the UVOS, the present investigation included 731 (47.9%) individuals (530 (72.5%) women and 201 (27.5%) men) for whom measurements and data of BCVA, hearing loss and cognitive function were available (tables 1 and 2). The individuals with assessment of vision loss, hearing loss and cognitive function as compared with the individuals without these examinations did not vary significantly in age (88.1±2.7 years vs 88.5±3.0 years, p=0.10), level of education (4.6±2.1 vs 4.4±2.1, p=0.08), sex (p=0.10) and ethnic background (Russian vs non-Russian) (p=0.06).
Characteristics of the participants of the Ural Very Old Study
Anthropometric data (mean±SD; median, range; 95% CI) of the participants of the Ural Very Old Study
Out of the 731 study participants, 342 (46.8%, 95% CI 43.2% to 50.4%) individuals fulfilled the definition of MSVI, and 37 individuals (5.1%, 95% CI 3.5% to 6.7%) fulfilled the definition of blindness in the better eye or under binocular conditions. The combined prevalence of MSVI and blindness was 51.8% (95% CI 48.2% to 55.5%). The mean hearing loss score was 19.5±15.4 (median 22, range 0–44). Out of the 731 study participants, 291 (39.8%) had a normal hearing score; 55 (7.5%) had mild hearing impairment (grade 1); 143 (19.6%) individuals had moderate hearing impairment (grade 2); 66 (9.0%) persons had moderately severe hearing impairment (grade 3); 58 individuals (7.9%) had severe hearing impairment (grade 4); and 118 (16.1%) had profound hearing impairment (grade 5). DSI, defined as MSVI/blindness combined with moderately severe hearing impairment grade 3+, was present in 150 (20.5%, 95% CI 17.8% to 23.5%) individuals.
The mean cognitive function score obtained in the Mini Mental Test was 22.2±6.4 (median 24, range 0–30). Stratified by the category of cognitive dysfunction, 399 individuals had a cognitive range between 24 and 30; 162 participants had a score ranging between 19 and 23; for 137 individuals, the score ranged between 10 and 18; and 33 participants had a score of less than 10 (table 3). In univariate analysis, a higher cognitive score was associated with younger age (p<0.001), urban region of habitation (p<0.001), higher level of education (p<0.001), lower hearing loss score (p<0.001), higher body mass index (p=0.002), longer waist (p<0.001) and hip (p=0.003) circumference, higher prevalence of alcohol consumption (p=0.02), higher number of meals taken daily (p<0.001), higher number of days per week with fruit intake (p<0.001), higher serum concentration of triglycerides (p=0.02), urea (p=0.03), higher leucocyte blood cell count (p=0.02), lower diastolic blood pressure (p=0.005), lower depression score (p<0.001), a lower State Trait Anxiety score (p<0.001), and with the ocular parameters of better BCVA (p<0.001), longer ocular axial length (p=0.04) and lower prevalence of dry eye (p=0.02). It was not significantly associated with sex (p=0.15), Russian versus non-Russian ethnicity (p=0.20), body height (p=0.07), body weight (p=0.09), waist:hip circumference ratio (p=0.09), current smoking (p=0.56), systolic (p=0.75) and mean (p=0.15) blood pressures, prevalence of arterial hypertension (p=0.11), serum concentration of glucose (p=0.78), creatinine (p=0.48), haemoglobin (p=0.19) and erythrocyte count (p=0.22), and with the ocular parameter of refractive error (p=0.80).
Demographic data of the study population stratified by the category of cognitive dysfunction
In multivariable analysis, we first dropped due to collinearity the parameter of the anxiety score (variance inflation factor 4.9). Due to lack of statistical significance, we then dropped the parameters of prevalence of alcohol consumption (p=0.96), number of days with fruit intake (p=0.77), dry eye prevalence (p=0.82), leucocyte blood cell count (p=0.78), waist circumference (p=0.80), diastolic blood pressure (p=0.65), ocular axial length (p=0.53), number of meals taken daily (p=0.15), hip circumference (p=0.42), serum concentration of triglycerides (p=0.05) and body mass index (p=0.05). In the final model, higher cognitive function score was associated with younger age (p=0.001), urban region of habitation (p=0.003), higher level of education (p<0.001), lower BCVA (p<0.001), higher hearing loss score (p=0.03) and higher depression score (p<0.001) (table 4). If the BCVA and hearing loss score were replaced by the prevalence of DSI, a lower prevalence of the latter was associated with a higher cognitive function score (beta −0.11, B −1.70, 95% CI −2.66 to –0.74; p=0.001).
Associations (multivariable analysis) between the cognitive function score assessed in the Mini-Mental test and other parameters
In a reverse manner, a higher prevalence of MSVI was associated with a lower cognitive function score (OR 0.93, 95% CI 0.90 to 0.97; p=0.001), after adjusting for older age (OR 1.20, 95% CI 1.10 to 1.30; p<0.001), higher mean arterial blood pressure (OR 1.02, 95% CI 1.001 to 1.03; p=0.04), longer axial length (OR 1.27, 95% CI 1.04 to 1.55; p=0.02) and lower prevalence of previous cataract surgery (OR 0.46, 95% CI 0.30 to 0.70; p<0.001). A higher prevalence of hearing loss (grade 3+) correlated with lower cognitive function score (OR 0.95, 95% CI 0.92 to 0.97; p<0.001) after adjusting for older age (OR 1.08, 95% CI 1.01 to 1.14; p=0.02) and higher depression score (OR 1.02, 95% CI 1.01 to 1.04; p=0.01). In multivariable analysis, a higher prevalence of DSI was associated with a lower cognitive function score (OR 0.94, 95% CI 0.91 to 0.98; p=0.001), after adjusting for older age (OR 1.16, 95% CI 1.08 to 1.24; p<0.001), rural region of habitation (OR 2.32, 95% CI 1.51 to 3.56; p<0.001) and higher depression score (OR 1.03, 95% CI 1.01 to 1.06; p<0.002). In that model, the prevalence of DSI was not significantly associated with sex (p=0.08). If the depression score was dropped, the association with a higher anxiety score became significant (OR 1.03, 95 CI 1.01 to 1.05; p=0.001).
If cognitive dysfunction was defined by Mini Mental Test score of <24, 332 (45.4%, 95% CI 41.8% to 49.0%) study participants fulfilled the definition. A higher prevalence of cognitive dysfunction was associated (univariate analysis) with a higher hearing loss grade (OR 1.13, 95% CI 1.08 to 1.27; p<0.001), with a higher prevalence of hearing loss of grade 3+ (OR 2.18, 95% CI 1.59 to 2.98), with a higher prevalence of MSVI/blindness (OR 2.09, 95% CI 1.55 to 2.81; p<0.001) and a higher prevalence of a DSI (OR 2.80, 95% CI 1.92 to 4.07; p<0.001).
Discussion
In our ethnically mixed study population with an age of 85+ years from Bashkortostan, Russia, the prevalence of MSVI/blindness, moderately severe hearing loss and DSI were 51.8%, 33.1% and 20.5%, respectively. In multivariable analysis, a higher prevalence of all three variables was associated with a lower cognitive function score and higher cognitive dysfunction prevalence. After adjusting for age, region of habitation, educational level and depression score, a lower cognitive function score was associated with worse BCVA and a higher hearing loss score. As a corollary, the risk of cognitive dysfunction increased by 2.18 for the presence of moderately severe or more advanced hearing loss, by 2.09 for the presence of MSVI/blindness, and by 2.80 for the presence of DSI.
The findings made in our study on a population aged 85+ years cannot directly be compared with the observations made in many previous studies, since previous investigations usually did not include a sufficient number of participants in that age category, and since hearing impairment, vision impairment and cognitive dysfunction have rarely been assessed together. In their study on the prevalence of DSI and its relationship with dementia in community-dwelling Medicare beneficiaries, Kuo and colleagues found an 1.9-fold, 1.1-fold and 2.0-fold increase in the cross-sectional hazard of dementia for self-reported functional vision impairment, hearing impairment and DSI, respectively.11 Despite differences in the assessment of sensory impairment (self-reported vs measurements), study design (nationally representative sample of Medicare beneficiaries aged 65+ years vs population-based recruitment of 85+ years old) and study region (USA vs urban and rural Russia), the figures reported by Kuo and associates are similar to those found in our study, with a higher cross-sectional risk of dementia for the presence of DSI as compared with the presence of vision impairment or hearing impairment taken separately. Kuo and colleagues additionally observed that sensory impairment was associated with an increased incidence of dementia during over 7 years of follow-up. The results of our study also agree with other investigations, such as a longitudinal study of older US adults from the Health and Retirement Study which reported higher hazards of incident dementia for individuals with self-reported visual impairment, hearing impairment and DSI as compared with individuals without such impairments.29–32 In the study conducted by Hwang and colleagues, functional DSI as compared with vision impairment or hearing impairment alone was more strongly associated with all-cause dementia during a follow-up of 8 years in a group of highly educated and mostly white elderly adults.30 In the English Longitudinal Study of Ageing, individuals with poor and moderate self-reported hearing had a 57% and 39% higher hazard of incident dementia during a follow-up of 9 years, respectively.31 The finding of a concurrence of vision impairment and cognitive impairment concurs also with the results of precent meta-analyses.33 34
A reason for the association between impairment in vision and hearing and cognitive dysfunction may be a sensory impairment-related reduction in external stimuli for cognitive activities, in addition to an increased risk of social isolation, depression and reduced physical activity.35–37 All these factors have been known to increase the risk of cognitive dysfunction and dementia.2 Another reason may be an increase in cognitive load in individuals with sensory impairments since more cognitive resources may be needed for the support of the visual and hearing function. It may lead to a lack of remaining resources for cognitive tasks.37–39 One of the reasons for a higher risk of cognitive dysfunction for DSI as compared with vision impairment or hearing impairment alone could be that individuals with hearing impairment tend to perform lip reading what depends on sufficient vision. In addition, individuals with DSI have a limited ability to compensate for a single sensory impairment by employing functioning of an unimpaired sensory system. Besides these causal relationships, other factors leading to the co-occurrence of sensory impairment and cognitive dysfunction could be a common mechanism, such as microvascular changes, leading to sensory impairment and cognitive dysfunction, and the possibility of a sensory impairment as a sequel of cognitive dysfunction, such as in the situation of patients with cognitive dysfunction and cataract who may not have the means, support or willingness for cataract surgery to be performed.
Assuming at least a partially causative relationship between sensory impairment and cognitive dysfunction, we found that any improvement in vision or hearing impairment by providing correcting glasses and hearing aids and performing cataract surgery could be meaningful.40–43 To cite an example, the pilot study of the Ageing and Cognitive Health Evaluation in Elders trial suggested a slowing of memory decline by treatment of hearing impairment.41 Another example may be providing simple reading glasses. In the population-based Beijing Eye Study, higher cognitive function was associated with a lower amount of undercorrection of refractive error after adjusting for younger age, rural region of habitation, educational level, occupation, depression score, BCVA and history of cardiovascular disorder.44 Correspondingly, individuals wearing glasses for correction of their refractive error as compared with subjects without glasses showed a significantly higher cognitive score. These results also fit with observations made in a study by Rogers and Langa, who reported that in an 8.5-year follow-up study, poor vision at baseline was associated with incident dementia.45 Simple, cheap treatment of refractive errors by providing adequate eyeglasses not only may increase the quality of life but also may potentially provide cost-effective prophylaxis of cognitive dysfunction and dementia.
The reason for the association between a higher cognitive function score and urban region of habitation may be the higher level of education in the cities and other lifestyle-associated parameters. Policy implications of our findings may be, among others, to further increase the frequency of cataract surgeries in Russia, to provide best correcting glasses to correct refractive errors including presbyopic refractive error, to provide hearing aids to address hearing loss, and to prevent hearing loss by adequate protective measures at the working place and in daily life.
The limitations of our study have to be considered. First, we did not measure presenting visual acuity, so that we could not assess the prevalence of undercorrection of refractive error. Second, the participation rate in our study was 47.9%, a figure considerably lower than those for other population-based studies. It may have introduced a selection bias, in particular since individuals with marked dementia could not participate in the study. In view of the relatively high age of 85+ years as inclusion criterion, the study may give, however, some information about the prevalence of vision and hearing impairment and their combined occurrence in that age group. In addition, the main goal of our study was to examine not the prevalence of vision and hearing impairment but their relationship with cognitive function. Third, we did not phonometrically measure hearing impairment, but the study participants underwent an interview with standardised questions about their subjective hearing capacity. The validity of these questions of the HHIE-S had been assessed in previous investigations.18–20 Fourth, our study had a cross-sectional design so that only cross-sectional associations could be examined; however, longitudinal cause–effect relationships could not be explored. Fifth, the study could not include those individuals with an advanced stage of dementia, which did not allow taking part in the interview and in the examinations. Strengths of our study were that it was the first population-based study on the prevalence of DSI as well as their relationship with cognitive function in the age group of 85+ years with a relatively large study sample size, and the inclusion of a multitude of systemic parameters.
In conclusion, in this very old multiethnic population from Bashkortostan, Russia, vision impairment, hearing impairment and DSI as combination of both were relatively common and were associated with cognitive dysfunction. Assuming a causal relationship, providing hearing aids and glasses for distant and reading vision and cataract surgery may potentially be measures to reduce the impact of cognitive dysfunction by reducing some of its risk factors.
Data availability statement
Data are available upon reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by the ethics committee of the Academic Council of the Ufa Eye Research Institute (ethical Committee #N 3, dated 16 March 2015), in agreement with the Declaration of Helsinki. All study participants signed an informed written consent. The participants gave informed consent to participate in the study before taking part.
References
Footnotes
Contributors Design of the study: MMB, GMK and JBJ; examination of participants: MMB, GMK, EMR, IAR, AAF, AMT, NIB, KRS, AVG, IPP, DFY, NEB and NAN; examination of clinical images and data collection: MMB, GMK, EMR, IAR, AAF, AMT, SP-J, NIB, KRS, AVG, IPP, DFY, NEB, NAN and JBJ; statistical analysis: SP-J and JBJ; funding: MMB and JBJ; writing the first draft: SP-J and JBJ; approval of final draft: MMB, GMK, EMR, IAR, AAF, AMT, SP-J, NIB, KRS, AVG, IPP, DFY, NEB, NAN and JBJ. guarantors are MMK, JJB.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.