Frailty: Pathophysiology, Theoretical and Operational Definition(s), Impact, Prevalence, Management and Prevention, in an Increasingly Economically Developed and Ageing World

The twentieth and presently twenty-first centuries have been characterized by accelerating medical, pharmacological, and technological advances [1‒3]. In the context of population demographics, one of the most significant outcomes of these advances is the exponential increase in overall population, and the relatively rapid increase in life expectancy [4, 5]. These increases can be partially attributed to improvements in public health that have resulted in a profound reduction in global child mortality rates; with an increasing proportion of the population now living to sexual maturity [3, 6, 7]. However, increases in life expectancy have also occurred in the later part of life, albeit to a relatively lesser extent, in the increased population of older adults [4, 5] (Fig. 1).

Closely succeeding these increases in life expectancy, another demographic phenomenon has been observed: a substantial reduction in global fertility rates, particularly in developed countries. With most of the developed world now below the population replacement rate of 2.1 births per female for several consecutive decades [9, 10]. The combination of these two demographic phenomena has resulted in a growing, yet increasingly ageing population throughout the developed world; and even in the developing world, the onset of these changes are beginning to be observed [9, 10].

In Europe, current demographic trends indicate that by the year 2030 almost one in six of the European population will be aged 60 years or older, and the number of older people will grow to 247 million by 2050; representing a 35% increase from 2017, with one in four older adults being over 85 by 2040 [11]. The social and economic impacts of this epidemiological transition have yet to be fully experienced, as dependency ratios remain relatively stable, as the increase in the older population is, to an extent, offset by the reduction in youth dependency [5, 12]. However, if present trends persist, over time, dependency ratios in developed countries may shift as the absolute and relative number of those entering older age increases, while the absolute and relative number of those entering from youth dependency to workforce participation decreases [12]. When taken in conjunction with progressive declines in physical activity throughout all stages of the lifespan, this leaves this increasing population of older adults particularly susceptible to the development of disease and comorbidities associated with a lack of physical activity and an increase in sedentary behaviour [13‒15]. This alone, irrespective of future dependency ratios, will have substantial personal and economic impacts as life expectancy increases, while the proportion of the lifespan spent without disease and disability fails to keep pace, or potentially deceases; as has been observed with a number of lifestyle-mediated non-communicable diseases in recent decades [16]. It is in this context that frailty, particularly in older age, has been described as “without question, one of the most serious public health challenges we will face in this coming century” ([17] p. 1376).

Frailty is a multidimensional and dynamic condition, theoretically defined as “a state of increased vulnerability, resulting from age-associated declines in reserve and function across multiple physiologic systems, such that the ability to cope with every day or acute stressors is compromised” ([18]p. 1, [19]) (Fig. 2).

Although declines in physiological reserve are associated with senescence in the normal ageing process, frailty is an extreme consequence of this process, where this decline is accelerated and homeostatic responses begin to fail [21‒23]. Frailty is a common and clinically significant condition among older adults [24]. This is predominantly due to its association with adverse health outcomes, such as hospitalization, falls, disability, and mortality [19, 20, 24‒28]. All older adults are susceptible to the risk of developing frailty, and even their younger counterparts [29, 30]. However, this risk is significantly increased with increases in chronological age, in the presence of comorbidities, low physical activity, poor dietary intake, and low socio-economic status, among a number of other factors (Fig. 3) [19, 31‒35].

While frailty is a dynamic condition, with the possibility of bidirectional transition between frailty states [28, 37, 38], this transition is more commonly progressive [39]. This is largely due to the association of frailty with a plethora of adverse health outcomes, which can often lead to a spiral of decline. As frailty progresses, interventions to mitigate, manage, or reverse this decline become increasingly difficult to implement, both from practical and physiological perspectives [39, 40]. The relative prevalence of frailty in older adults may be reduced with future improvements in treatment, particularly those identified as effective at mitigating the onset of frailty [17]. However, irrespective of this, the absolute prevalence and overall burden of frailty are projected to increase dramatically in the coming decades as the population ages [36]. Perhaps of most concern in this regard, is that several longitudinal birth cohort studies have reported increases in the relative prevalence of frailty among more contemporary generations of older adults, when compared to their generational predecessors [41‒43].

Although there is a general consensus regarding the theoretical definition of frailty as a multidimensional and dynamic condition characterized by a loss of reserve across multiple physiological systems which collectively result in a compromised resilience to cope with stressors [17‒20, 36, 44‒50]. Presently, there is no one universally utilized or accepted operational definition for the classification of frailty [27, 51, 52]. However, there are a number of valid operational definitions which exist, i.e., definitions which take into consideration the multidimensional nature of the condition (face and content validity) and have been specifically validated for the assessment of frailty: either through their predictive validity regarding negative health outcomes associated with frailty, or their concurrent validity with existing validated frailty tools [53, 54]. The most commonly utilized and well-regarded of these operational definitions are the Fried frailty phenotype [19], and the Frailty Index (FI) [55‒57]. The Fried frailty phenotype proposes that frailty be defined as a clinical syndrome in which three or more of the five following criteria are present: unintentional weight loss (≥10 lbs in the past year), self-reported exhaustion, weakness (grip strength), slow walking speed, and low physical activity (active kcals expended per week) [19] (Table 1).

The FI proposes that frailty should be operationally defined on a spectrum utilizing a mathematical model which considers frailty in regard to the accumulation of deficits. In this model, deficits represent any symptom, sign, disability, or laboratory measurement regarded as abnormal. The FI score is assessed as the accumulative proportion of these potential deficits that are present. Typically, the list of deficits ranges from approximately 30–70 items related to various aspects of health and well-being [45]. Although these are among the most commonly utilized operational definitions of frailty, there are also a number of other valid operational definitions which are frequently employed (Table 2).

Further to these validated operational definitions, proxy indicators of frailty are also commonly utilized, such as unidimensional measures of physical function, e.g., the Short Physical Performance Battery (SPPB) [77], Timed Up and Go (TUG) [78], Upper-Extremity Function (UEF) frailty index [79], gait speed [80], and hand grip strength [81]. These measures are associated with frailty and may even possess concurrent validity with existing frailty tools, or predictive validity regarding negative health outcomes associated with frailty. However, they lack the content validity regarding assessment of the multidimensional nature of the condition to be regarded themselves as valid operational definitions. Although strong arguments have been made regarding the pragmatic utility of these tools within various settings and circumstances [82].

Similarly, there are a number of other tools, such as the geriatric 8 questionnaire (G-8) [83], identification of seniors at risk (ISAR) [84], vulnerable elderly survey (VES-13) [85], frailty index for elders (FIFE) [86], frailty risk score [87], hospital frailty risk score [88], and PRISMA 7 [89], which serve as proxy indicators of frailty through identifying “frailty risk,” often with the suggestion of further more comprehensive evaluation. However, they are not valid operational definitions which definitively distinguish between frail, pre-frail, or robust classification states.

Recently, an alternative approach, separating itself from the phenotypic and accumulation of deficits models, has proposed a focus on intrinsic capacity, i.e., a composite measure of all physical and mental resources which an individual can draw from to overcome environmental, physical, and psychological challenges [90]. The development of this construct was initially supported by the World Health Organization, however, it remains to be empirically validated [90, 91]. While the construct of intrinsic capacity is in its theoretical and operational infancy, it may provide a new paradigm for future exploration, closely aligned with that of frailty research [92].

Presently, one of the major weaknesses in the frailty field is not only a lack of a single standardized operational definition, but also the common utilization of non-validated iterations of the above definitions. This produces a detrimental effect on both the internal and external validity of such studies, resulting in a reduced capacity for accurate evaluation and comparison; even between studies which report to be utilizing the same operational definition [93‒95]. A recently published brief standard checklist for studies reporting frailty data has attempted to address this through outlining, and proposing solution to, some of these persistent issues within the literature, including: (1) studies often report participants as frail without a frailty assessment; (2) studies often claim to utilize validated operational definitions for the classification of frailty, however, adapt these definitions, or classification criteria, which resulted in the definitions becoming not only non-standardized, but also non-validated; (3) the use of the nomenclature for different operational definitions of frailty vary widely, even among studies utilizing the same operational definition; (4) often, useful data regarding prevalence of frailty (such as pre-frailty, a sex breakdown of frailty, or occasionally the overall prevalence of frailty itself) are not reported. To address these issues, the following checklist is proposed: (1) accurate citation of the validation study for the specific operational definition utilized for the classification of frailty; (2) accurate use of the nomenclature of the operational definition of frailty utilized in accordance with the initial validation study to maintain reliability and validity, or prominent subsequent study establishing the nomenclature; (3) reporting of the number of frail, pre-frail (if applicable), and robust participants; (4) a sex breakdown of the number of frail, pre-frail, and robust participants [96].

In this regard, the academic field of frailty is somewhat lacking a desired order and uniformity. This is likely the manifestation of the multidimensional and heterogenous nature of frailty as a combination of a multitude, and often different array, of phenomena which can result from many differential causes and pathways [20]. The breadth of proposed frailty definitions is a manifestation of this complexity. Ultimately,what may be required regarding progress towards the establishment of a universally accepted operational definition, in addition to exploration of emerging constructs [90‒92, 97], is mathematical modelling of large longitudinal datasets which can identify frailty through an abundance of potential multidimensional pathways over time, as it relates to the dynamic ability to cope with acute stressors over these periods. However, to date a universally accepted operational definition for the classification of frailty remains elusive, despite the utility this may provide in the future.

Although the exact prevalence of frailty within geriatric populations is poorly defined due to the lack of a single standardized operational definition, there are a number of systematic reviews and meta-analyses which have attempted to provide well-evidenced estimates of the prevalence of frailty among older adults within a variety of settings [96, 98‒105]. An enhanced understanding regarding the prevalence of a condition within a specific setting has a number of important consequences; including the enhanced ability to contribute towards improvements in the planning and orientation of organizational structures and resources, to meet population needs. This is especially the case regarding the tailoring of service provision within particular settings to the needs of service users. Specifically regarding frailty, this includes for example the provision of exercise rehabilitation services within settings for this population; with physical activity and exercise proposed to offer the best form of treatment for frail older adults [106].

Presently, there are several systematic reviews and meta-analyses which have examined the prevalence of frailty in various cohorts of community-dwelling older adults [98‒101, 105] (Table 3). In the single review which examined the overall prevalence of frailty within this population, the pooled prevalence of frailty was 10.7%. However, the reported prevalence of frailty within the studies comprising this review ranged from 4.0 to 59.1%; largely due to inclusion of proxy indicators of frailty, and to a lesser degree the lack of a single standardized operation definition [105]. In the remaining four systematic reviews/meta-analyses of the prevalence frailty in various specific cohorts of community-dwelling older adults, the overall pooled prevalence of frailty ranged from 7.4% among community-dwelling older adults in Japan, to 68% among the overall population of undernourished community-dwelling older adults [100, 101]. Along a similar line of inquiry, a recent systematic review and meta-analysis found the global incidence of frailty, and pre-frailty, among community-dwelling older adults (aged ≥60 years) to be 43.4, and 150.6 per 1,000 person-years respectively [107].

As previously described by Doody et al. [108], presently there are no well-evidenced pooled estimates of the overall prevalence of frailty among older adults in assisted living facilities. Although, it could be postulated that this prevalence would likely be higher than that of community-dwelling older adults, given that older adults within assisted living facilities typically tend to be chronologically older, and often exhibit a greater number of comorbidities and a reduced functional capacity than their community-dwelling counterparts. However, these differences routinely become non-significant once standardized for age [109]. Additionally, the estimated prevalence of frailty, and pre-frailty, in nursing homes (where qualified nursing care is required, in addition to care assistance) is approximately 52.3%, and 40.2%, respectively [104]. As such, the prevalence of frailty in assisted living facilities likely lies somewhere in between that of community-dwelling older adults and nursing home residents, given the inherent nature of these respective settings and the demographics of the individuals who occupy them. However, presently, there appears a lack of individual studies which have examined the prevalence of frailty specifically within assisted living facilities.

A recently published systematic review and meta-analysis produced the first well-evidenced pooled estimates of the prevalence of frailty among geriatric hospital inpatients [98]. This review found that approximately 47.4% (95% CI 43.7–51.1%) of all geriatric hospital inpatients are frail; and another 25.8% (95% CI 22.0–29.6%) pre-frail. Prevalence varied significantly based on age, clinical population, morbidity, ward type, and the operational definition utilized for the classification of frailty [98]. The authors noted that the overall pooled prevalence estimate of frailty of 47.4% reported within this review, placed the prevalence of frailty among geriatric inpatients between that reported for community-dwelling older adults at 10.7% [105], and older adults in nursing homes at 52.3% [104]; outlining an increase in the relative prevalence of frailty with progression through the healthcare system [98]. Further the authors noted the overall pooled prevalence of pre-frailty of 25.8% was lower than that reported for both community-dwelling older adults at 41.6% [105], and nursing home residents at 40.2% [104]; while the combined prevalence estimates of both frailty and pre-frailty increased from 52.3% among community-dwelling older adults, to 73.2% among geriatric inpatients, and to 92.5% among nursing home residents. The authors concluded that this underscores differences in the relative prevalence of frailty status between community, and hospital inpatient settings, are the result of an increase in the relative prevalence of frailty, and similar decreases in the relative prevalence of pre-frailty and robustness. However, differences in the relative prevalence of frailty status between hospital inpatient and nursing home settings, appear primarily the result of a relative increase in the prevalence of pre-frailty, and decrease in the prevalence of robustness [98].

The overall pooled frailty, and pre-frailty, prevalence estimates of 47.4% (95% CI: 43.7–51.1%), and 25.8% (95% CI: 22.0–29.6%) reported within this review were consistent with estimates of a systematic review and meta-analysis examining the prevalence of frailty and pre-frailty among hospitalized older adults in several studies which also assessed undernutrition risk, at 47% (95% CI: 37–57%) and 36% (95% CI: 29–44) respectively [110]. Similarly, the pooled prevalence estimates of frailty on acute wards of 51.1% (95% CI: 35.9–66.2%), and among all acute hospital inpatients of 47.3% (95% CI: 42.8–51.8%) were outlined to be relatively consistent with findings of a recent scoping review, which reported a median frailty prevalence of 49% (range 34–69%) in acute care hospital settings [111]. Further, this review reported no significant differences in the prevalence of frailty stratified by sex. The authors noted that this contrasts systematic reviews and meta-analysis regarding the prevalence of frailty among community-dwelling older adults [98, 99, 105]. However, further noted these findings are consistent with systematic reviews and meta-analysis among other clinical populations of older adults such as nursing home residents [104]; concluding that these findings further contribute to the evidence that sex differences in the prevalence of frailty among community-dwelling older adults may dissipate among clinical geriatric populations [98].

Frailty is associated with a myriad of adverse health outcomes, which have both personal and economic consequences. Among these adverse outcomes include the increased occurrence of falls, fractures, worsening mobility, disability, cognitive decline, dementia, depression, hospitalization, institutionalization, and mortality [69, 112‒117]. Moreover, frailty has been consistently shown to be associated with increased healthcare cost and usage [118‒120]. For example, a cross-sectional analysis of approximately 2,600 older adults aged ≥60 years in Germany found that the mean 3-month healthcare expenditure was almost sixfold higher among the frailest participants (five positive Fried frailty phenotype criteria), at € 3,659, compared to the least frail participants (no positive Fried frailty phenotype criteria), at € 642 [121]. A subsequent 3-year longitudinal analysis of over 1,600 older adults within the same cohort found that progression from a non-frail to a frail state was associated with an average of 54%–101% increase in healthcare cost in those with 3, and 4 or 5 positive frailty criteria respectively; including a 200% increase in inpatient costs from those who transitioned from non-frail (no positive Fried frailty phenotype criteria) to low levels of frailty (three positive Fried frailty phenotype criteria) [122]. Similarly, a recent analysis of 5,300 community-dwelling older adults aged ≥60 years in China, found frailty to be an independent predictor of increased health expenditure [118]. However, the impact of frailty on an individual’s life extends further than the clinical manifestation or economic impact of these adverse health outcomes, with frailty additionally being associated with a reduced quality of life, and loneliness [123, 124].

While at the individual level there is evidence of the association between socio-economic status and frailty onset and progression [34], at the societal level the association between economic variables and frailty is less well evidenced. Preliminary research into this area has shown the prevalence of frailty in the community to be correlated with national economic indicators such as gross domestic product (GDP) per capita purchasing power parity (PPP) and healthcare expenditure per capita PPP. However, noted that more research is needed to better understand the relationship between macroeconomic indicators and the prevalence of frailty [125]. A recent systematic review and meta-analysis found no association between the prevalence of frailty among geriatric hospital inpatients and GDP per capita PPP, or healthcare expenditure per capita PPP [98]. The authors postulated it possible that these associations, while present in the community, are not present in inpatient hospital settings, and that given the inherent nature of hospital inpatient settings, i.e., institutions for chronically or acutely unwell patients, such association may be more sensitive among community-dwelling older adults. However the authors noted more large-scale and comprehensive studies are required in a variety of settings as a limitation of these ana­lyses was that included studies were predominantly from economically developed countries due to limited evidence presently from low-income countries [98, 103]. The authors further noted that while it has been postulated that increases in economic prosperity may limit the prevalence and burden of frailty [129], these findings bring this postulation into question, and as such reliance of non-direct intervention such as economic development to improve the prevalence and burden of frailty on health systems alone, appear to be misplaced, and suggests the need for more direct interventions to address the burden of frailty among this population [98].

Presently, care plans specifically for frail individuals have yet to be extensively developed or assessed. However, there are several proposed treatments and care pathways involved in the prevention, treatment, and management of frailty. Initial establishment of agreed goals of care may be assisted in clinical settings in particular by a comprehensive geriatric assessment, which can provide a framework from which to develop a management and intervention plan for frail individuals. Further, as frailty progresses patients will develop different care needs, and require different forms of care, often in different settings (Table 4).

Regular physical activity and exercise have been shown to provide a degree of protection against multiple components of frailty in both sexes, at all stages of the condition, and all stages of the life cycle [126, 127]. Further, exercise interventions have been proposed as potentially offering the best form of treatment for frail older adults [106], with promising results in a variety of settings and geriatric populations [128, 129], and even shown to mediate the reversal of frailty in some cases [130, 131]. However, more research is needed to determine the feasibility and efficacy of exercise interventions in different settings and clinical populations [25, 131].

Regular physical activity and exercise have been shown to consistently improve cognition, physical function, sarcopenia (low muscle quantity, strength, and performance), and mood in both non-frail and frail older adults [126]. While inactivity is a modifiable risk factor for frailty onset and progression, physical activity and exercise are known to improve function across multiple physiological systems, including the muscle, heart, brain, endocrine system, and inflammation response [132]. In this regard, exercise can improve function in all physiological systems known to be dysregulated with the onset and progression of frailty [133]. However, while there is evidence of the benefits of exercise regarding the prevention, treatment, and potential reversal of frailty, it is universally noted that there needs to be more studies within this area to truly assess the feasibility and efficacy of exercise in frail geriatric populations within different settings, and particularly in clinical settings [25, 134]. Further, to increase external validity of such studies, particularly those among clinical cohorts, it is imperative that prospective studies attempt to recruit as representative a sample as possible, so that feasibility and efficacy assessments are extrapolatable to real-world settings. In this regard for example, a recent systematic review examining exclusion rates in 305 randomized controlled trials involved in the treatment of 31 physical conditions, reported that a quarter of all trials excluded 89% of patients with the specific condition to be treated within that trial, while half excluded 77.1% of patients with the condition. Those excluded were primarily attributed to advanced age, and those with significant comorbidity and co-prescription; characteristics which are ubiquitous among those treated in clinical practice [135]. Though it is often required to exclude certain cohorts to define the clinical population and control for confounding factors, particularly with regard to exercise interventions which pose a low likelihood of contraindication, it is essential that representative samples are examined, which among frail older adults, and particularly in certain settings, invariably includes those with significant comorbidities and polypharmacy.

Exercise, or exercise and nutrition interventions combined, have been shown to be capable of reversing frailty [130, 131, 136], or limiting its progression [137, 138], among cohorts of community-dwelling older adults.

The implementation of exercise interventions in nursing home settings has been shown to be effective in improving strength, gait speed, and balance in older adults residing in these settings [139, 140]. Further, individualized and progressive multicomponent exercise interventions at a moderate intensity have been shown to be effective in the prevention of falls, and the reduction of frailty and mortality among older nursing home residents [129].

As previously described by Doody et al. [141], acute hospital admission for older adults is associated with further loss of physical activity and represents a period of increased susceptibility to sarcopenia and frailty [142]. Frailty is associated with longer stay and increased rates of mortality in hospitalized older adults, as well as serving as a predictor of readmission [143, 144]. As such there is a crucial need to examine the feasibility of such interventions within this setting, and whether these interventions can be effectively implemented to improve the health of frail older populations in inpatient hospital ward settings. Preliminary evidence has shown some success in the implementation of exercise interventions to reverse functional decline among general geriatric inpatient populations [145, 146], and walking during hospitalization has been shown to be associated with a shorter length of stay [147]. However, to date, presently, there are no studies which have attempted to assess the feasibility or efficacy of such an intervention in operationally defined frail participants with more significant initial impairments.

There are several research directions which are pertinent to the advancement of the understanding of frailty and the promotion of healthy longevity among the increasing global population of older adults. More generally within the frailty field, further work towards a universally accepted operational definition of the construct, to practically complement the theoretical definition [18], is of paramount interest to the field. Additionally, the association between frailty and other related composite measures such as allostatic load [148‒150] and intrinsic capacity [90, 92], and the potential utilization of these constructs as inexpensive proxy measures for biological ageing (identified through associations with the pattern of DNA methylation at different cytosine-phospho-guanine sites which correlate with mortality and time [151, 152], morbidity and lifespan [153‒156], and the pace of ageing [157]) is of interest for future research. The initial validation of cost-effective assessments as valid proxy measures of biological ageing may allow for a better understanding of ageing, not only in economically developed nations, but also throughout the globe, and especially among less economically developed areas of the world. The lack of data in these regions in particular will become increasingly important from a global perspective, given that these are the regions of the world projected to undergo the largest population growth in the coming century (e.g., the population of sub-Saharan Africa is projected to grow 298% from 2017 to 2100, from 1.03 to 3.07 billion), while conversely, many economically developed regions are projected to experience marked population decline (e.g., Europe’s population is projected to decline 19.2% from 2017 to 2100, from 758 to 613 million, and China’s population is projected to decline 48% over the same period, from 1.41 billion to 732 million) [158].

Further, as frailty is a relatively new concept, particularly as an operationally defined one, with most studies cited within this review published in the past 20 years, the potential change in frailty over time, particularly as it relates to national policy directives, and economic indicators are of interest for future research. Although at the individual level there is evidence of the association between socio-economic status and the frailty onset and progression [34], at the societal level, the association between economic variables and frailty is less well evidenced. More large-scale and comprehensive research is needed in this regard to better understand this relationship between macroeconomic indicators and the prevalence of frailty in a variety of settings. Further, more comprehensive systematic analyses of this association between frailty and national economic indicators among community-dwelling older adults, older adults in residential care settings, and hospitalized older adults, may help to further elucidate this relationship within relevant settings.

Regarding the provision of well-evidenced estimates of the prevalence of frailty within various settings, presently, there are no currently published well-evidenced pooled estimates of the prevalence of frailty among older adults residing in assisted living facilities. Further research is required to elucidate the prevalence of frailty among older adults in these settings. Further, adapted exercise interventions among frail hospital and intermediate-care patients are also of interest for future research. Particularly, the continuation of these activities and assessments following patient discharge from hospital over a prolonged period, and the impact on these activities on measures of multidimensional health and other health-related outcomes, such as readmissions, and cost-effectiveness. Exercise interventions have been shown to be effective at reducing functional decline among general hospital inpatients during hospitalization [145]; however, to date no research has been conducted among specifically frail inpatients, or providing continuity of the interventions, post-inpatient discharge. Further, adapted exercise interventions may also be ideally suited within more stable clinical environments, such as those of intermediate-care facilities, assisted living facilities, nursing homes, or hospital at home settings.

Frailty and healthy longevity have become increasingly important fields of research, which, if present global demographic trends persist, will continue to grow in importance as the world’s population ages. Further elucidation of frailty, and its exploration in the context of emerging constructs, is pertinent to the advancement of frailty research and the promotion of healthy longevity among the increasing population of older adults.

The authors have no conflicts of interest to declare.

This review was supported by the European Commission Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement (675003); of which Dr. Paul Doody was a Marie Sklodowska-Curie doctoral research fellow; Professor Anna Whittaker, Professor Janet Lord, and Professor Carolyn Greig doctoral supervisors; and Professor Anna Whittaker the grant’s principal investigator. The funding source had no role in the design, conduct, or reporting of the review, or the decision to publish the manuscript.

Dr. Paul Doody is the guarantor and lead reviewer. Dr. Paul Doody drafted the initial manuscript with supervision, input, and feedback from Professor Anna Whittaker, Professor Carolyn Greig, and Professor Janet Lord. All the authors have read and approved the final manuscript.