Aspirin use for cancer prevention: A systematic review of public, patient and healthcare provider attitudes and adherence behaviours

We undertook a systematic review to synthesise the data on attitudes and behaviour towards the use of aspirin for cancer prevention, and healthcare providers' attitudes towards implementing aspirin in practice. Searches were carried out across 12 databases (e.g. MEDLINE, EMBASE). We used the Mixed Methods Appraisal Tool to evaluate study quality, and conducted a narrative synthesis of the data. The review was pre-registered (PROSPERO: CRD42018093453). Thirty-eight studies were identified. Uptake and adherence data were all from trials. Trials recruited healthy participants, those at higher risk of cancer, and those with cancer. Four studies reported moderate to high (40.9–77.7%) uptake to an aspirin trial among people who were eligible. Most trials (18/22) reported high day-to-day adherence (≥80%). Three trials observed no association between gender and adherence. One trial found no association between adherence and colorectal cancer risk. Three studies reported moderate to high (43.6–76.0%) hypothetical willingness to use aspirin. Two studies found that a high proportion of healthcare providers (72.0–76.0%) perceived aspirin to be a suitable cancer prevention option. No qualitative studies were identified. The likelihood that eligible users of aspirin would participate in a trial evaluating the use of aspirin for preventive therapy was moderate to high. Among participants in a trial, day-to-day adherence was high. Further research is needed to identify uptake and adherence rates in routine care, the factors affecting aspirin use, and the barriers to implementing aspirin into clinical care.

Despite many countries having national cancer screening programmes, few have implemented guidance recommending aspirin for cancer prevention. The US Preventive Services Taskforce recommends aspirin for colorectal cancer prevention among adults aged 50-69 who have ≥10% 10-year cardiovascular disease risk (Bibbins-Domingo, 2016). In the UK, the National Institute of Health and Care Excellence recommends daily aspirin for people with Lynch syndrome (National Institute for Health and Clinical Excellence (NICE), 2020), and in Australia aspirin is recommended for the public aged 50-70 (Cancer Council Australia, 2019). Guideline implementation depends on informed uptake, high adherence, and understanding the barriers to achieving these goals. However, deciding whether to use preventive therapy can be a complex choice for patients, and for their healthcare providers prescribing it. The benefits of aspirin need to be considered in relation to its side-effects, as even low doses can increase the risk of gastrointestinal bleeding, ulcers and, in more rare cases, haemorrhagic stroke (Lanas and Scheiman, 2007;Cuzick et al., 2015).
Studies have investigated the barriers and facilitators to using breast cancer preventive therapy. The evidence suggests the factors associated with increased uptake include having children (Hackett et al., 2018), higher objective risk , higher cancer-related worry (Bober et al., 2004;Holmberg et al., 2017), and fewer concerns about the side-effects (Bober et al., 2004;Thorneloe et al., 2019;Rondanina et al., 2008). Women with lower educational qualifications, depression and those who are older are also less likely to adhere to the medication . Prospective studies have also identified a positive association between healthcare provider recommendation and patients' use of breast cancer preventive therapy (Bober et al., 2004;Holmberg et al., 2017). To our knowledge, no review has examined decisionmaking in the context of aspirin for cancer prevention among potential users of aspirin and healthcare providers.
We undertook a systematic review to synthesise the quantitative and qualitative data on uptake and adherence behaviours related to aspirin for cancer prevention, investigate the factors affecting decisions to use aspirin, and examine healthcare providers' attitudes towards implementing aspirin in clinical care.

Search strategy
We first conducted a search of the literature in March 2018, and reran the searches in February 2020. Searches were conducted in the following databases from inception to February 2020: MEDLINE; EMBASE; CINAHL; Cochrane Library (CENTRAL and Cochrane Database of Systematic Reviews); Database of Abstracts of Reviews of Effects (DARE); NHS Economic Evaluation Database; Pan Health Technology Assessment (HTA) Database; HTA Database (Wiley); PubMed; ProQuest Dissertation and Theses A&I; and Web of Science Core Collection. We also searched the International Clinical Trials Registry Platform (ICTRP) and Clinical trials.gov, and the websites of Cancer Research UK and canc er.gov for any ongoing trials. After identifying relevant conference abstracts, trials, and dissertations, we searched for the peer-reviewed articles of these studies. Search terms were developed for the concepts: aspirin, cancer and prevention by an information specialist (RR) and project team members using subject headings and free text terms (see supplementary appendix for search strategies). We did not apply date limits or methodological filters to the searches.
We stored and de-duplicated the records in EndNote X9, and screened them using the management software Covidence. To find additional papers, we searched the reference lists of included studies and relevant reviews. The review was pre-registered (PROSPERO number: CRD42018093453), and PRISMA guidelines for reporting were followed throughout (Moher et al., 2009).

Study selection
We included both quantitative and qualitative peer-reviewed studies, which provided empirical data and recruited individuals aged 18 or over. Studies were included if they reported rates of uptake and/or adherence to aspirin (at any dose) for primary or secondary prevention (i.e. preventing recurrence) of cancer. Additionally, we included articles which reported patient, public or healthcare provider attitudes towards using aspirin for cancer prevention. We deviated from the preregistration by including quantitative studies exploring individuals' perceptions about taking aspirin for cancer prevention, instead of only qualitative data. Articles on the same trial were included if they provided additional data, such as adherence at longer follow up. We excluded articles reporting adherence on a smaller sub-sample from an included trial.
As we were only interested in attitudes and behaviour data in the context of aspirin for cancer prevention, we excluded studies where aspirin was not used/prescribed for the primary purpose of cancer prevention. For example, we excluded studies using aspirin for the primary purpose of cardiovascular disease prevention/management, and case control and cohort studies if aspirin was not being used for the primary purpose of cancer prevention. Non-peer reviewed studies and reviews were also excluded. We excluded by hand non-English language studies as we did not have the resources to translate.
Screening of the titles and abstracts was completed by two authors (RJT, KEL), and two authors (RR, LHH) duplicated screening for 20% of articles. Discrepancies were resolved with a third reviewer (SGS). Two authors (RJT, KEL) screened the full text articles, and second reviewers (LHH, KEL) duplicated screening for 20% of articles. The review was managed in Covidence.

Data extraction
Two authors (RJT, KEL) extracted the study data using Excel, and 45% (17/38) of a random sample of articles were verified by second reviewers (RR, KEL) to ensure consistency (Shea et al., 2017). We extracted data on study characteristics; sample characteristics; aspirin dose; timing; uptake level; adherence method; adherence definitions; follow-up time; day-to-day adherence; persistence adherence; and factors associated with uptake, day-to-day adherence and/or persistence. Additionally, we extracted data reporting attitudes towards aspirin for cancer prevention.
Uptake rates were defined as the proportion of individuals who were offered aspirin and took the first dose (Vrijens et al., 2012). To calculate uptake to a clinical trial, we calculated the proportion of eligible participants who enrolled on the trial. The denominator was the number of eligible participants offered the trial, with ineligible participants excluded from the calculation. We classified participants who declined trial participation for unknown reasons as declining to take part. We defined day-to-day adherence as the extent to which people took the medication as prescribed (Vrijens et al., 2012). Data could be continuous (0-100% of medications) or categorical (proportion classified as adherent). We defined persistence as the length of time between uptake and last dose (Vrijens et al., 2012). Studies reporting the proportion of participants who completed the trial, without explicit reference to the medication, were excluded. We included both self-report and objective adherence measures.

Quality assessment
We used the Mixed Method Appraisal Tool (MMAT) to assess methodological quality (Pluye and Hong, 2014). MMAT is reliable (Pace et al., 2012), and has been used in a review examining decision-making in breast cancer preventive therapy . For each study design (qualitative, quantitative RCTs, non-randomised quantitative studies, quantitative descriptive studies, mixed methods studies), there was a quality checklist consisting of 5 items. All items were categorised as 'Yes ', 'No', or 'Can't tell'. RCTs received a quality assessment score ranging from 0 to 4, as the criterion 'Did the participants adhere to the assigned intervention?' (2.5) was removed due to adherence being a review outcome. All other study types received a score 0-5. The MMAT guidance recommended study teams agreed on an acceptable dropout rate for the criterion 'Are there complete outcome data? ' (2.3, 3.3). We decided a priori that an article would qualify as 'Yes' if they reported a dropout rate of ≤30% participants (Pluye and Hong, 2014;Furlan et al., 2009). One author (KEL) assessed the quality of all articles, with over 35% (14/38) of a random sample of articles verified by a second author (LHH) to ensure consistency. Any discrepancies were resolved with a third author (SGS).

Synthesis of the evidence
To determine if a meta-analysis was appropriate we considered whether the included studies were sufficiently similar on the domains of participants (setting), intervention, comparison and outcomes (Ryan and Cochrane Consumers and Communication Review Group, 2016). There was substantial heterogeneity, for example there was high variations in the doses of aspirin prescribed (intervention), assessments of adherence (outcomes), and the participant population (setting). Within subgroups, few studies used the same setting, intervention, and outcome. Therefore, we concluded that a meta-analysis was inappropriate for our review due to the high heterogeneity. Instead we conducted a narrative synthesis, with findings tabulated (Petticrew and Roberts, 2006). We organised the studies into categories and synthesised the findings (Petticrew and Roberts, 2006). Where possible, comparisons were made between studies on the setting (trial vs. routine care), sample population, aspirin dose/frequency, and healthcare provider population. Across the different categories, we also examined if there was a relationship between year of study, and age of the sample, on the review outcomes.

Results
We identified 17,344 papers, of which 11,258 papers remained after duplicates were removed (Fig. 1). After screening titles and abstracts, we excluded 10,061 articles. We screened 1197 full text articles, 37 studies met the eligibility criteria, and one study was identified by backwards citation searching. A total of 38 studies were included.

Uptake of aspirin
Four studies reported data on uptake of participants to an aspirin clinical trial Rexrode et al., 2000;Hull et al., 2018;Jankowski et al., 2018), and all investigated aspirin for primary cancer prevention (Table 1). No studies were identified reporting uptake rates in routine care. All studies were RCTs Rexrode et al., 2000;Hull et al., 2018;Jankowski et al., 2018), and of mixed quality with scores ranging from one  to four  on the MMAT. Three studies (75%) recruited participants at higher risk of developing cancer Hull et al., 2018;Jankowski et al., 2018), and one (25%) recruited a healthy population sample . The dose and frequency of prescribed aspirin varied, from 100 mg every alternative day  to 325 mg administered daily . Rates of uptake among eligible people to an aspirin trial were moderate to high (40.9-77.7%) Rexrode et al., 2000;Hull et al., 2018;Jankowski et al., 2018).
Rates of uptake to an aspirin trial did not appear to increase or decrease over time. For example, the oldest study conducted in 2000 reported an uptake rate of 61.2% , while two studies conducted in 2018 reported uptake rates of 40.9%  and 77.7% . A trial with a mean sample age of 65 years observed lower rates of uptake among eligible people (40.9%) , compared with studies with a mean sample age of 58 (65.5-77.7%) Jankowski et al., 2018). No studies examined the demographic, psychological or clinical factors associated with uptake. No studies compared different aspirin doses and uptake. See supplementary Table 1 for the proportion of participants who enrolled onto the trial, with the dominator the number of participants offered the trial (i.e. inclusive of ineligible participants).
There was no clear evidence of a relationship between dose and dayto-day adherence. In an RCT of high-risk participants, lower adherence was reported among those taking 650 mg of aspirin (79.0% adherent), compared with those taking aspirin at 325 mg (100.0% adherent) and 81 mg (93.0% adherent) . Three other studies reported adherence rates across different doses of aspirin and identified few differences Baron et al., 2003;Falk et al., 2012). We also observed no pattern between when the study was conducted (older vs. newer studies) and day-to-day adherence.
Persistence was reported by 52% (15/29) of studies Jankowski et al., 2018;Cook et al., 2013;Frommel et al., 1997;Lipton et al., 1982;Roop et al., 2013;Ruffin et al., 1997;Sample et al., 2002a;Sandler et al., 2003;Liesenfeld et al., 2016;Baron et al., 2003;Burn et al., 2013;Pommergaard et al., 2016;Sample et al., 2002b;Garland et al., 2019). Measurements of persistence varied from average number of months/years participants were taking the medication Cook et al., 2013;Sandler et al., 2003;Burn et al., 2013), to increase in bleeding time ). Short-term persistence (i.e. weeks, months) was high (83.3-100.0%) Ruffin et al., 1997;Sample et al., 2002a;Liesenfeld et al., 2016;Garland et al., 2019). The proportion of participants reporting long-term persistence (i.e. years) varied. Three RCTs, all recruiting participants with colorectal adenomas, examined persistence at three years Baron et al., 2003;Pommergaard et al., 2016). One RCT observed high levels of persistence, with 93.6% of participants still taking at least 50% of the medication at year three . In contrast, two trials reported low to moderate levels of persistence, with 38.6% and 66.8% of participants completing the three-year medication Pommergaard et al., 2016). No pattern was observed between the year the study was conducted and persistence with aspirin. Additionally, no pattern was observed between participants' age and persistence with aspirin. For example, both a trial with a mean sample age of 31 , and a trial with a mean age of 66 reported high levels of persistence (≥90%) .
Four studies examined factors associated with day-to-day adherence. A non-randomised trial of healthy participants found self-report measures to be significantly associated with higher adherence (73.0% adherent), than the objective measure of MEMS (44.0% adherent) . Two RCTs and one non-randomised trial observed no association between adherence and gender Benamouzig et al., 2001;Benamouzig et al., 2003). In an RCT of participants with history of colorectal adenomas, no association was found between adherence and being at higher risk of recurrence, when compared with those at lower risk . No other factors associated with day-to-day adherence or persistence were reported.
Mixed results were observed for an association between participants' demographic characteristics and whether they would use aspirin for cancer prevention. A US survey examined the relationship between healthy participants' characteristics and intentions to use aspirin Table 1 Characteristics of articles reporting uptake rates to a clinical trial involving the use of aspirin for cancer prevention (n = 4). Key: RCT = Randomised Control Trial; MMAT = Mixed Methods Appraisal Tool; n * = number of participants enrolled at the beginning of the study; Eligible participant trial uptake** = proportion of eligible individuals who enrolled on the trial, excluding participants who were ineligible.    . Higher intentions were significantly associated with being male, black ethnicity, older age, history of polyps, and being a smoker . Another survey recruiting Barrett's oesophagus patients found higher education and younger age to be significantly associated with higher willingness to use aspirin in the univariable analysis . However, this association was not significant in the multivariable analysis . Two studies also found no evidence of a relationship between demographic factors and willingness to use aspirin Nguyen et al., 2019). Mixed evidence was also observed for the relationship between participants' current aspirin use and whether they would use aspirin for cancer prevention Nguyen et al., 2019). Participants with increased self-efficacy, response efficacy, barriers and perceived susceptibility to developing colorectal cancer were significantly more likely to report higher intentions to use aspirin . Some of the barriers found to be significantly and positively associated with intentions included participants' believing their doctor would want them to take aspirin, and believing most people Table 3 Characteristics of articles reporting public, patient and healthcare provider attitudes towards using or recommending aspirin for cancer prevention (n = 8). Key: n * = number of participants who took part in the study; HCP = Healthcare provider; GP = General Practitioner; LS = Lynch Syndrome; BO = Barrett's Oesophagus; PPI = Proton Pump Inhibitor; CRC = Colorectal Cancer; ND = No Data.

Study and location
their age were being told to take aspirin . Participants who believed there was low evidence for using aspirin for cancer prevention reported significantly lower intentions . No clear relationship was observed between year of study and attitudes towards aspirin. Two papers examined publics' willingness to use aspirin, with the 2019 Australian study finding higher willingness (>70%) , than a US-based study conducted in 2009 (43.6%) . However, among two US studies, one conducted in 2008 found higher willingness among patients with Barrett's oesophagus (76.0%) , compared with a 2015 study examining willingness among the same patient population (53.0%) .

Healthcare providers
Three studies reported healthcare providers' attitudes towards aspirin for cancer prevention Chen et al., 2017;Das et al., 2008) (Table 3). All studies were of medium MMAT quality (3/5). Samples consisted of gastroenterologists Das et al., 2008), genetics professionals , colorectal surgeons  and general practitioners . Two studies reported data on healthcare providers' attitudes towards the use of aspirin for patients at higher risk of cancer (Lynch syndrome, Barrett's oesophagus) Das et al., 2008). In both studies, a high proportion of healthcare provider respondents (72.0-76.0%) perceived aspirin to be a suitable cancer prevention option Das et al., 2008).
A UK survey of general practitioners found willingness to prescribe aspirin was higher at lower doses, with 91.3% willing at 100 mg, 81.8% willing at 300 mg, and 62.3% willing at 600 mg . General practitioners were significantly more willing to prescribe aspirin at 600 mg if they had >10 years' professional experience, were aged ≥50, had greater awareness of the preventive effects of aspirin, and if they had seen a Lynch syndrome patient in clinic (range, odds ratio: 1.44 to 1.58) . There was evidence to suggest profession may influence willingness, with general practitioners who had a special interest in family history significantly less willing to prescribe aspirin (odds ratio: 0.41) . An Australian survey also found that a higher proportion of gastroenterologists (41/49, 83.7%) and genetic professionals (49/59, 83.1%) perceived aspirin to be effective for cancer prevention, than colorectal surgeons (47/73, 64.4%) . Across all three studies, we did not observe a pattern between year of study and healthcare providers' attitudes towards aspirin for preventive therapy Chen et al., 2017;Das et al., 2008).

Discussion
In this systematic review investigating attitudes and behaviour towards aspirin for preventive therapy, we found moderate to high levels of uptake to an aspirin clinical trial among people who were eligible to participate. A large proportion of participants in trials reported high levels of adherence on a day-to-day basis. At short-term follow up, most people were still taking aspirin for cancer prevention. However, there was mixed evidence observed for long-term persistence with aspirin. Given that aspirin is recommended to be taken regularly for several years for a cancer preventive benefit (Bibbins-Domingo, 2016; National Institute for Health and Clinical Excellence (NICE), 2020), persistence among users of aspirin should be investigated further.
In contrast to the more extensive behavioural research conducted in breast cancer preventive therapy (Hackett et al., 2018;Smith et al., 2016;Bober et al., 2004;Holmberg et al., 2017;Thorneloe et al., 2019;Rondanina et al., 2008), minimal research has examined the factors associated with use of aspirin for cancer prevention. In our review, we only identified four studies reporting any factors associated with adherence, and none with uptake. Additionally, no qualitative studies were identified. Several studies investigated willingness or intention to use aspirin, which was found to be moderately high among members of the public and those at higher cancer risk. The demographic, clinical and psychological factors associated with willingness and intentions were also investigated, but evidence was either limited or conflicting. While observational studies were eligible, we only identified trials reporting uptake and adherence data, which presents generalisability issues. Trial participants may be more motivated to use aspirin than those in routine care, and frequent follow-ups may have increased adherence rates. Previous research has also observed that people at lower socioeconomic status (Gross et al., 2005) and those from an ethnic minority group (Du et al., 2006) are less likely to participate in cancer trials. Furthermore, the decision to participate in a trial would not have been just a consideration of aspirin, but also other agents being simultaneously investigated. The four trials reporting uptake data were also evaluating esomeprazole, vitamin E, folate, and eicosapentaenoic acid alongside aspirin. Members of the public may be less familiar with these agents, which may have negatively affected their decision to participate in the trial.
In our review, we identified studies conducted across multiple decades (1982 to 2019). However, official guidance recommending the use of aspirin for colorectal cancer prevention has only recently been introduced (2016 onwards) (Bibbins-Domingo, 2016; National Institute for Health and Clinical Excellence (NICE), 2020; Cancer Council Australia, 2019). While we did not find an increase over time in trial uptake and adherence, future trials may observe higher rates of uptake and adherence as official guidance becomes more widely known among the public and healthcare providers. Furthermore, in the future we may observe an increasing trend in positive attitudes towards aspirin for preventive therapy.
Despite searching for studies using aspirin for secondary cancer prevention, most articles investigated aspirin for primary prevention. Our review findings should be applied with caution to a secondary prevention context. Patients who have previously had cancer may have different motivations for taking aspirin than those offered aspirin for primary prevention. Healthcare providers may also have less positive views towards aspirin for secondary cancer prevention, as a lower number of secondary prevention trials have been conducted compared with primary prevention (Langley et al., 2011). However, there is a large ongoing trial in the adjuvant setting (Add-Aspirin trial), which will provide further evidence on the effects of regular aspirin use in patients with non-metastatic breast, colorectal, gastro-oesophageal, and prostate cancer (Coyle et al., 2016).
Relevant studies have been published following our search cut-off date that contribute further to our knowledge in this topic area. Similar to our review findings, the ASPIRED trial, investigating aspirin for colorectal cancer prevention, found that most participants reported high levels of day-to-day adherence to aspirin at dose of 81 mg (79% reported 95-100% adherence) and 325 mg (91% reported 95-100% adherence) (Drew et al., 2020). Furthermore, a recent qualitative study was published exploring healthcare professionals' views on the Australian guidance recommending aspirin for colorectal cancer prevention for the public (Milton et al., 2021).

Directions for future research
Overall, we found that the likelihood that eligible users of aspirin would participate in a trial that requires randomization to aspirin for cancer prevention was between 40.9 and 77.7%. Researchers developing a trial in this area should take these findings into consideration when planning and designing their study. While clinical guidelines in the US, Australia and the UK recommend aspirin for colorectal cancer prevention (Bibbins-Domingo, 2016; National Institute for Health and Clinical Excellence (NICE), 2020; Cancer Council Australia, 2019), it is currently unknown if people initiate and adhere to aspirin in routine care. To date, only studies reporting data on intentions and willingness to use aspirin have been published. As intentions do not always translate into behaviour (Sheeran and Webb, 2016), further research should investigate how people form a decision to initiate and adhere to aspirin for preventive therapy, and the support they may need.
Despite searching for studies investigating aspirin for any cancer prevention, the vast majority of identified studies focused on gastrointestinal cancer risk reduction. As the evidence base is stronger for gastrointestinal cancer prevention, we may expect lower rates of uptake, adherence and acceptability for other cancers (e.g. breast, lung, prostate). Research should investigate further rates of uptake and adherence of, and attitudes towards, aspirin for the prevention of nongastrointestinal cancers.
Previous research has found higher uptake of breast cancer preventive therapy among women with fewer concerns about its side-effects (Thorneloe et al., 2019;Rondanina et al., 2008). While there are several reported side-effects to using aspirin (Lanas and Scheiman, 2007;Cuzick et al., 2015), it is currently unknown the relationship between participants' side-effects, perceived or experienced, in relation to aspirin and their rates of uptake and adherence. We recommend that future research should investigate the relationship between these factors further.
The recent Australian qualitative study reported that healthcare providers viewed primary care physicians as having the most important role in the implementation of guidance recommending aspirin for cancer prevention (Milton et al., 2021). We recommend that future research aiming to examine decision-making in the context of aspirin for cancer prevention should focus on the primary care setting. In our review, we found moderately high levels of willingness among general practitioners to prescribe aspirin to patients with Lynch syndrome. Factors that may be influencing willingness include the aspirin dose, professional background, and awareness of the cancer preventive benefits of aspirin.
The review had limitations. Due to time and resource constraints, the literature was limited to English language articles, and second reviewers only duplicated screening, data extraction, and quality assessment for a proportion of articles (20-45%). Our review excluded studies that did not use or prescribe aspirin for the primary purpose of cancer prevention, such as the ASPREE trial which had fatal and non-fatal cancer as a secondary endpoint (McNeil et al., 2018). However, in clinical practice consideration to use aspirin is likely to factor in both its use as a form of cancer preventive therapy and other outcomes, such as cardiovascular disease prevention. Uptake rates to a clinical trial were also strongly affected by the approach used to calculate uptake. For example, as reported in supplementary Table 1, when we calculated rates of uptake to a trial with the denominator all people who were approached about the trial, including those who were ineligible to participate, uptake rates were much lower. More standardised and transparent reporting of uptake data is warranted to compare across cohorts.

Conclusions
Overall, we found that most people who were eligible and offered participation in an aspirin trial accepted. The majority of participants also reported a good level of adherence on a day-to-day basis. We found high levels of short-term aspirin persistence, but evidence was mixed for long-term persistence. No studies examined uptake and adherence in routine care, and minimal research investigated the factors associated with using aspirin. Overall, we found that there is substantial scope for research into the barriers and facilitators to implementing aspirin for preventive therapy into clinical care.

Collaborators
This work is on behalf of the Aspirin for Cancer Prevention Group  Smith [grant number NIHR300588]. SGS also acknowledges funding support from a Yorkshire Cancer Research University Academic Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Disclosure
RJT has received honorarium from Novartis. All remaining authors declare no conflicts of interest.

Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.