Visits to the emergency department by community-dwelling people with dementia during the first 2 waves of the COVID-19 pandemic in Ontario: a repeated cross-sectional analysis
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* Laura C. Maclagan
* Xuesong Wang
* Abby Emdin
* Aaron Jones
* R. Liisa Jaakkimainen
* Michael J. Schull
* Nadia Sourial
* Isabelle Vedel
* Richard H. Swartz
* Susan E. Bronskill

## Abstract

**Background:** Community-dwelling people with dementia have been affected by COVID-19 pandemic health risks and control measures that resulted in worsened access to health care and service cancellation. One critical access point in health systems is the emergency department. We aimed to determine the change in weekly rates of visits to the emergency department of community-dwelling people with dementia in Ontario during the first 2 waves of the COVID-19 pandemic compared with historical patterns.

**Methods:** We conducted a population-based repeated cross-sectional study and used health administrative databases to compare rates of visits to the emergency department among community-dwelling people with dementia who were aged 40 years and older in Ontario during the first 2 waves of the COVID-19 pandemic (March 2020–February 2021) with the rates of a historical period (March 2019–February 2020). Weekly rates of visits to the emergency department were evaluated overall, by urgency and by chapter from the *International Statistical Classification of Diseases and Related Health Problems, 10th Revision*. We used Poisson models to compare pandemic and historical rates at the week of the lowest rate during the pandemic period and the latest week.

**Results:** We observed large immediate declines in rates of visits to the emergency department during the COVID-19 pandemic (rate ratio [RR] 0.50, 95% confidence interval [CI] 0.47–0.53), which remained below historical levels by the end of the second wave (RR 0.88, 95% CI 0.83–0.92). Rates of both nonurgent (RR 0.33, 95% CI 0.28–0.39) and urgent (RR 0.51, 95% CI 0.48–0.55) visits to the emergency department also declined and remained low (RR 0.68, 95% CI 0.59–0.79, RR 0.91, 95% CI 0.86–0.96), respectively. Visits for injuries, and circulatory, respiratory and musculoskeletal diseases declined and remained below historical levels.

**Interpretation:** Prolonged reductions in visits to the emergency department among people with dementia during the first 2 pandemic waves raise concerns about patients who delay seeking acute care services. Understanding the long-term effects of these reductions requires further research.

People with dementia are susceptible to adverse events associated with disruptions in health care and social supports caused by the COVID-19 pandemic.1–3 Before the pandemic, research had shown that care fragmentation and lower continuity of care were associated with increased risks of visits to the emergency department by people with dementia.4 People with dementia frequently visit the emergency department for care, often to address concerns such as injuries, behavioural changes and other symptoms of dementia, adverse drug reactions and for caregiver reassurance. Although many physicians shifted to virtual care provision during the COVID-19 pandemic to enable continuity of care, people with dementia faced challenges accessing such care, including lack of access to technology or a support person to assist them.5,6 In addition, there are concerns that the social isolation and cancellation of health and social services that resulted from pandemic restrictions have worsened behavioural and psychological symptoms for people with dementia, which may necessitate appropriate access to in-person health care services.1

The emergency department is an important care setting for persons with dementia;7 however, there are little data regarding changes in rates of visits to the emergency department among people with dementia during the COVID-19 pandemic. Studies across several jurisdictions have noted large declines in visits to emergency departments by the general population during the pandemic,8–13 including for both urgent and nonurgent visits. Lower rates of visits to the emergency department for urgent conditions are concerning because they may result from people who avoid or delay seeking necessary care, or from barriers to care, which may lead to exacerbations of chronic conditions and increased risks of longer-term complications. Describing changes in the rates of visits to the emergency department during the pandemic by urgency and diagnoses among people with dementia will aid in understanding the initial effect of the pandemic and longer-term implications for patterns of use of health systems and outcomes in this vulnerable population. Therefore, we aimed to determine the change in weekly rates of visits to the emergency department of community-dwelling people with dementia in Ontario, by urgency and diagnosis, during the first 2 waves of the COVID-19 pandemic compared with historical patterns.

## Methods

### Study design

We conducted a repeated cross-sectional study using linked population-based health administrative databases in Ontario. We followed the Reporting of Studies Conducted Using Observational Routinely-Collected Data (RECORD) guideline.14

### Data sources

We obtained data on visits to the emergency department from the Canadian Institute for Health Information’s National Ambulatory Care Reporting System Database, which captures records for all visits in Ontario. We used the Ontario Registered Persons Database to obtain demographic information (e.g., age, sex and date of death, if applicable) and eligibility for health insurance. Details of other administrative databases used in this study can be found in Appendix 1, Table S1, available at [www.cmajopen.ca/content/10/3/E610/suppl/DC1](http://www.cmajopen.ca/content/10/3/E610/suppl/DC1). These data sets were linked using unique encoded identifiers and analyzed at ICES, an independent, nonprofit research institute whose legal status under Ontario’s health information privacy law allows it to collect and analyze health care and demographic data, without consent, for health system evaluation and improvement

### Study population

We identified community-dwelling people with Alzheimer disease and related dementias (dementia) in Ontario who were aged 40–110 years and who were eligible for provincial health insurance at the start of each week (index date). We excluded people who were not residents of Ontario and those with invalid death dates. We also excluded those who did not have contact with the Ontario health system in the 5 years before the index date to ensure we identified people who had active use of the provincial health plan. We identified people who resided in long-term care homes at each weekly index date using an established algorithm15 and excluded them, as they are likely to have different patterns of emergency department use compared with community-dwelling older adults.

We used data from the week of Mar. 1, 2020, to the week of Feb. 21, 2021, to define the first 2 waves of the COVID-19 pandemic in Ontario (pandemic period). We used data from the week of Mar. 3, 2019, to the week of Feb. 23, 2020, to define the historical period. Data for the cohort were extracted in September 2021.

We identified a patient’s dementia status using a validated health administrative data algorithm that requires at least 1 hospital admission for dementia, at least 3 physician visits for dementia within 2 years (at least 30 d apart) or at least 1 prescription for a cholinesterase inhibitor. This algorithm has been shown to have a sensitivity of 79.3% and a specificity of 99.1% for the detection of dementia when validated against a primary care electronic medical record reference standard.16

We measured patient characteristics including age, sex, rural residence, neighbourhood income quintile and time since case ascertainment using health administrative databases as of the date of the visit to the emergency department. We defined rural residence as having a Rurality Index for Ontario value greater than 40. We defined neighbourhood income quintiles using postal code linkage to Statistics Canada Census data (2016; [https://www150.statcan.gc.ca/n1/pub/92-154-g/92-154-g2017001-eng.htm](https://www150.statcan.gc.ca/n1/pub/92-154-g/92-154-g2017001-eng.htm)). For people with more than 1 visit to the emergency department during the pandemic or historical period, we analyzed individual characteristics as of the date of the first emergency department visit in each period. History of 16 common chronic conditions, likely to be associated with the need for care in the emergency department, was assessed using health administrative data algorithms. We defined a history of chronic conditions, according to Mondor and colleagues,20 as including acute myocardial infarction (AMI), osteoarthritis, rheumatoid arthritis, asthma, cancer, cardiac arrhythmia, heart failure, chronic obstructive pulmonary disease, coronary syndrome (excluding AMI), dementia, diabetes, hypertension, mood, anxiety, depression and other nonpsychotic disorders, other mental illnesses, osteoporosis, renal failure and stroke (excluding transient ischemic attack).

### Outcomes

We evaluated emergency department visits (including visits by people who were later admitted to hospital) overall and also stratified by urgency and diagnostic groupings. We defined urgency using the Canadian Triage and Acuity Scale (CTAS) (1–3, urgent/emergent; 4–5, less urgent/nonurgent). 17 We evaluated diagnoses using the diagnosis code listed as the “main problem,” which represents the most clinically important reason for the patient’s visit.18 We defined diagnostic groupings using the Canadian version of the *International Statistical Classification of Diseases and Related Health Problems, 10th Revision* (ICD-10-CA) chapter headings, which cluster related diagnoses and conditions. Specific diagnosis codes, within chapter headings, were also evaluated separately. We were interested in ICD-10-CA codes that occurred more commonly for people with dementia7,19 (e.g., fall-related and non-fall-related injuries, dementia or delirium, adverse drug reactions and urinary tract infections; see Appendix 1, Table S2 for ICD-10-CA codes).

### Statistical analysis

We compared sociodemographic and clinical characteristics of people with dementia who presented to the emergency department at least once during the historical and pandemic periods using standardized differences, with differences less than 0.10 indicating imbalance. Among people with at least 1 emergency department visit, we calculated the mean (standard deviation [SD]) and median (interquartile range [IQR]) number of emergency department visits during each period. We calculated weekly rates of emergency department visits per 100 people.

We used Poisson models to estimate rate ratios (RRs) and 95% confidence intervals (CIs), comparing rates of emergency department visits at the week of the lowest rate during the pandemic period and the latest week during the pandemic period with equivalent weekly rates during the historical period. The latest weekly rate is as of the week of Feb. 21, 2021 (pandemic period) and the week of Feb. 23, 2020 (historical period). The models included a single predictor variable for the period (pandemic v. historical) and an offset term for number of people with dementia alive and living in the community at the start of each week. We conducted all analyses using SAS 9.4 (SAS Institute Inc.).

### Ethics approval

The use of the data in this project is authorized under Section 45 of Ontario’s *Personal Health Information Protection Act* and does not require review by a Research Ethics Board.

## Results

We identified 58 852 unique people with dementia who visited the emergency department during the pandemic period and 67 611 unique people who visited the emergency department during the historical period (Figure 1, Table 1). We found that people with dementia who visited the emergency department during the pandemic showed characteristics similar to those presenting during the historical period (mean age 81.4 v. 81.3 yr, standardized difference [Std. Diff.] < 0.01; 56.8% v. 57.4% female, Std. Diff. 0.01). Both groups had a high but similar prevalence of multiple chronic conditions (5 or more chronic conditions: 77.6% v. 75.7%, Std. Diff. 0.04). People who presented to the emergency department during the pandemic were more likely to be admitted to an inpatient facility (35.1% v. 29.7%, Std. Diff. 0.12). People with dementia who visited the emergency department during the pandemic also were likely to experience repeated emergency department visits compared with the historical period (3 or more visits: 24.9% v. 29.0%, Std. Diff. 0.09).

![Figure 1:](http://www.cmajopen.ca/https://www.cmajopen.ca/content/cmajo/10/3/E610/F1.medium.gif)

[Figure 1:](http://www.cmajopen.ca/content/10/3/E610/F1)

Figure 1: 
Flow diagram showing selection of the population of community-dwelling people with dementia who visited the emergency department during the COVID-19 pandemic and historical periods in Ontario. We defined the pandemic period as the week of Mar. 1, 2020, to the week of Feb. 21, 2021. We defined the historical period as the week of Mar. 3, 2019, to the week of Feb. 23, 2020. Note: ED = emergency department.

View this table:
[Table 1:](http://www.cmajopen.ca/content/10/3/E610/T1)

Table 1: 
Characteristics of community-dwelling people with dementia who had at least 1 visit to the emergency department in Ontario, by COVID-19 pandemic and historical periods (2019–2021)

The rate of visits to the emergency department during the first week of the pandemic period (week of Mar. 1, 2020) was 2.17 per 100 people, which declined to 1.20 visits per 100 people at the week of the lowest rate (week of Mar. 29, 2020) (Figure 2, Table 2). We observed a 50% decline in visit rates at the week of the lowest rate (RR 0.50, 95% CI 0.47–0.53) (Table 3). These rates increased over time but remained 12% below historical levels by the end of the second wave (RR 0.88, 95% CI 0.83–0.92).

![Figure 2:](http://www.cmajopen.ca/https://www.cmajopen.ca/content/cmajo/10/3/E610/F2.medium.gif)

[Figure 2:](http://www.cmajopen.ca/content/10/3/E610/F2)

Figure 2: 
Weekly rates of visits to the emergency department overall and by urgency among community-dwelling people with dementia during the historical and COVID-19 pandemic periods in Ontario. We defined the pandemic period as the week of Mar. 1, 2020, to the week of Feb. 21, 2021. We defined the historical period as the week of Mar. 3, 2019, to the week of Feb. 23, 2020. Note: The red line represents the beginning of the first COVID-19 pandemic wave in Ontario.

View this table:
[Table 2:](http://www.cmajopen.ca/content/10/3/E610/T2)

Table 2: 
Rates of visits to the emergency department among community-dwelling people with dementia during the COVID-19 pandemic and historical period* in Ontario, by urgency and chapter from the *International Statistical Classification of Diseases and Related Health Problems, 10th Revision* (2019–2021)

View this table:
[Table 3:](http://www.cmajopen.ca/content/10/3/E610/T3)

Table 3: 
Rate ratios for visits to the emergency department among community-dwelling people with dementia in the COVID-19 pandemic period and the historical period in Ontario, by urgency and chapter from the *International Statistical Classification of Diseases and Related Health Problems, 10th Revision* (2019–2021)

### Rates by urgency

We found that the rates for emergency department visits for nonurgent and urgent conditions fell by as much as 67% (RR 0.33, 95% CI 0.28–0.39) and 49% (RR 0.51, 95% CI 0.48–0.55), respectively, compared with rates before the pandemic. Although we observed rebounds in visit rates for both nonurgent and urgent visits over time, by the end of the study period, rates remained significantly below historical levels (RR 0.68, 95% CI 0.59–0.79, RR 0.91, 95% CI 0.86–0.96), respectively.

### Rates by diagnostic grouping

We noted the highest rates of emergency department visits for the following ICD-10-CA diagnostic groupings: signs, symptoms, and abnormal clinical and laboratory findings, injuries and poisoning, and circulatory and respiratory diseases (Figure 3). Together, these chapter headings accounted for 60% of all the visits to the emergency department by people with dementia. Rates of visits for these diagnostic groupings declined and failed to return to historical levels by the end of the study period (Table 3). Rates of visits to the emergency department for musculoskeletal diseases, genitourinary diseases, mental and behavioural disorders, and digestive and nervous system diseases initially declined but returned to historical levels by the end of the study period.

![Figure 3:](http://www.cmajopen.ca/https://www.cmajopen.ca/content/cmajo/10/3/E610/F3.medium.gif)

[Figure 3:](http://www.cmajopen.ca/content/10/3/E610/F3)

Figure 3: 
Weekly rates of emergency department visits by ICD-10-CA chapter* among community-dwelling people with dementia during the historical and pandemic periods in Ontario. Historical rates shown are from January 2019 to February 2020. Pandemic rates shown are from March 2020 to February 2021. Note: ICD-10-CA = Canadian version of the *International Statistical Classification of Diseases and Related Health Problems, 10th Revision*. The red line represents the beginning of the first COVID-19 pandemic wave in Ontario. *Selected ICD-10-CA chapters are shown for the main presenting diagnosis.

### Rates by dementia-associated conditions

We observed large immediate declines in visits to the emergency department for dementia, delirium, signs and symptoms involving cognition, and adverse drug reactions, but all rebounded to historical levels by the end of the study period (Table 3). Rates of visits for cardiac diseases (i.e., AMI, stroke and heart failure) declined and remained below historical levels by the end of the study period (RR 0.58, 95% CI 0.44–0.78). Rates of influenza, pneumonia and chronic lower respiratory infections declined and remained 41% below historical levels (RR 0.59, 95% CI 0.45–0.77).

## Interpretation

During the first 2 waves of the COVID-19 pandemic, we observed large and rapid declines in weekly rates of visits to the emergency department among community-dwelling people with dementia. Rates for both urgent and nonurgent conditions declined and did not return to historical levels by the end of the second wave. Rates of visits to the emergency department for key diagnostic groupings, including injuries, and circulatory, genitourinary and respiratory diseases, also declined and remained below historical levels by the end of the second wave, whereas rates of visits for mental and behavioural disorders declined initially but rebounded to historical levels. Our findings highlight that by the end of the second wave, use of the emergency department among people with dementia had not returned to prepandemic levels and raise concerns regarding the receipt of timely care for urgent and acute conditions.

The size of decline in visits to the emergency department that we observed was similar to that previously found in adults (40%–65%) in the general population in Canada8–10 and the United States.11–13 Declines in rates of visits are likely due to a constellation of factors including both a reluctance to present to the emergency department (e.g., fear of infection as well as policies preventing care partners from accompanying persons with dementia into the emergency department) and a potentially decreased need for emergency department care during the pandemic (e.g., fewer injuries owing to lower levels of activity, lower levels of other circulating viruses). Although our findings are not surprising given what is known about the pandemic, the sequelae of decreased access are just now emerging, and it is helpful to characterize the size of the issue in people with dementia.

Although few studies have evaluated visits to the emergency department by urgency during the pandemic, we found similar declines in visits for both urgent and nonurgent conditions.21,22 Lower rates of visits for nonurgent conditions may represent conditions that were treated at home or by other health care providers (either in person or virtually). Sustained periods of decline in nonurgent visits may be a positive finding and reflect the provincial expansion of the provision of virtual care. Related work from our group has documented the rapid shift to virtual family physician care among people with dementia during the COVID-19 pandemic.23 Although virtual care provides benefits to patients with dementia including convenience, there are challenges with conducting cognitive assessments virtually that may necessitate in-person care.5 It is difficult to determine to what extent visits to the emergency department may have been avoided by seeking virtual care from primary care and other providers.24 A 2020 study involving community-dwelling people with dementia and their caregivers who were recruited from an activity day centre for older adults in Hong Kong showed that telehealth interventions improved mental health and reduced caregiver burden among people with dementia during the pandemic.25 This may point to the opportunity for virtual care to address gaps in care for people with dementia and avoid presentation to the emergency department.

Lower rates of visits to the emergency department for diagnoses that require urgent acute care such as circulatory diseases and injuries are concerning because this may reflect care that was forgone or delayed, which could lead to poor outcomes. Other population-based studies have also shown similar declines in visits to the emergency department for diagnoses that require urgent care, such as fall-related injuries, during the COVID-19 pandemic.26,27 Appropriate messaging by health care practitioners and public health officials is necessary to ensure all patients feel secure coming to the emergency department to receive timely acute care services. This may be especially important for people with dementia who are vulnerable to decline and have high levels of comorbid chronic conditions. Similar to several studies during the pandemic,13,28,29 we noted increases in the proportion of visits to the emergency department for which patients were admitted to hospital. Although we did not observe any other differences in patient characteristics at admission to the emergency department, this finding likely represents admissions because of COVID-19, as well as possibly more severe or delayed presentations among higher-urgency visits to the emergency department.

We observed declines in visits to the emergency department across key diagnostic groupings (e.g., circulatory diseases and injuries) as has been found in other studies.12,30,31 Rates of the visits for these conditions remained below historical levels by the end of the second wave. We found declines for visits to the emergency department for cardiac diseases similar to those for AMI and stroke reported in a US study involving older adults (18%–28%). It is unlikely that the decline in rates of AMI and stroke observed represent true declines but may represent hesitancy or delays in seeking care. There is evidence that mortality for AMI increased during the COVID-19 pandemic, possibly because of delays in seeking treatment, which underscores the need for additional surveillance and public health messaging for patients not to delay seeking care.

We also observed sustained declines in rates of visits for respiratory diseases, whereas results in other studies have been mixed. Increases seen in other studies may have been due to SARS-CoV-2 infections. Although reductions in visits for influenza, pneumonia and chronic lower respiratory infections that we observed and those found in several other studies likely reflect low circulating levels of respiratory viruses because of public health measures.

We found that visits to the emergency department for mental and behavioural disorders (i.e., delirium) showed declines but rebounded by the end of the second wave. Studies involving the general populations in the US and Australia have shown smaller declines but have also shown rebounds to at or above historical levels. Other studies have noted increased rates of visits for anxiety and substance use disorders.11,12,32,33 Qualitative studies have shown an increased burden of behavioural and psychosocial symptoms among people with dementia and their care partners during the pandemic, which is likely associated with social isolation and service cancellation owing to pandemic-related restrictions.1,34 Thus, the decline in visits to the emergency department that we observed for mental and behavioural disorders is unlikely to reflect a true decreased burden but may reflect people who did not present to health care providers for treatment and increased burden on care partners in managing these issues at home or management via care that has shifted to other settings (e.g., virtual physician or community care). Family physicians may have provided virtual support for behavioural and psychological symptoms in people with dementia during the pandemic. Ongoing reductions in social support services, including day programs, support groups and other in-person services, during the pandemic35 may have contributed to the rapid rebound in rates of visits to the emergency department for mental and behavioural disorders among people with dementia and underscore the importance of the emergency department in caring for patients with these concerns.

### Limitations

Some limitations to our study should be noted, such as the lack of information on behavioural symptoms of dementia and severity of cognitive impairment, which may have helped understand the reasons for presentation to the emergency department. Furthermore, although validated in a primary care sample, the dementia ascertainment is not a clinical diagnosis and there is potential for misclassification.

Although we excluded persons residing in long-term care homes (publicly funded facilities that provide 24-h nursing support for people who can no longer live independently), we were unable to distinguish those who resided in private retirement homes from the broader community-dwelling population in the administrative data holdings. Retirement homes are privately paid and provide housing for older adults who require less care than persons residing in long-term care homes. Owing to their congregate nature, people living in these settings may have experienced different patterns of use of the emergency department because of provincial pandemic restrictions on visitors or an increased likelihood of SARS-CoV-2 infection.36 We were also unable to identify whether people with dementia lived alone or with a spouse or care partner.

### Conclusion

We observed large declines in visits to the emergency department overall and for both urgent and nonurgent conditions during the first 2 waves of the COVID-19 pandemic among community-dwelling people with dementia, which did not return to historical levels by the end of the second wave. We also found declines in visits for conditions that required urgent care such as fall-related injuries and circulatory diseases, which raises concerns about people with dementia receiving adequate and immediate acute care. Future research might evaluate long-term outcomes associated with the sustained reductions in emergency department use during the pandemic.

## Acknowledgements

The authors thank the Research on Organization of Healthcare Services for Alzheimer’s (ROSA) team for their contributions, specifically the patients and care partners for sharing their experiences, which led to the development of ideas for the manuscript, as well as Geneviève Arsenault-Lapierre, Laura Rojas-Rozo and Mary Henein for facilitating these exchanges with the partners. The authors also acknowledge the support of the Canadian Consortium on Neurodegeneration in Aging (CCNA). The CCNA is supported by a grant from the Canadian Institutes of Health Research with funding from several partners.

## Footnotes

*   **Competing interests:** None declared.

*   This article has been peer reviewed.

*   **Contributors:** Laura Maclagan and Susan Bronskill conceived and designed the work; contributed to the acquisition, analysis and interpretation of the data; and drafted the manuscript. Xuesong Wang performed the statistical analysis. Abby Emdin, Aaron Jones, R. Liisa Jaakkimainen, Michael Schull, Nadia Sourial, Isabelle Vedel and Richard Swartz contributed to the interpretation of the data for the work. All of the authors revised the manuscript critically for important intellectual content, gave final approval of the version to be published and agreed to be accountable for all aspects of the work.

*   **Funding:** This study was supported by the Ontario Neurodegenerative Disease Research Initiative (ONDRI) through the Ontario Brain Institute, an independent nonprofit corporation, funded partially by the Ontario government. This study also received funding from the Canadian Institutes of Health Research (CIHR VR5-172692). This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and the Ministry of Long-Term Care.

*   **Data sharing:** The data set from this study is held securely in coded form at ICES. While legal data-sharing agreements between ICES and data providers (e.g., health care organizations and government) prohibit ICES from making the data set publicly available, access may be granted to those who meet prespecified criteria for confidential access, available at [https://www.ices.on.ca/DAS](https://www.ices.on.ca/DAS) (email: das{at}ices.on.ca). The full data set creation plan and underlying analytic code are available from the authors upon request, understanding that the computer programs may rely upon coding templates or macros that are unique to ICES and are therefore either inaccessible or may require modification.

*   **Disclaimer:** This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health (MOH) and the Ministry of Long-Term Care (MLTC). The opinions, results and conclusions reported in this article are those of the authors and are independent from the funding sources. No endorsement by ICES or the MOH and the MLTC is intended or should be inferred. Parts of this material are based on data and information compiled and provided by Canadian Institute for Health Information (CIHI). However, the analyses, conclusions, opinions and statements expressed in the material are those of the author(s), and not necessarily those of CIHI. The analyses, conclusions, opinions and statements expressed herein are solely those of the authors and do not reflect those of the funding or data sources; no endorsement is intended or should be inferred. The authors thank IQVIA Solutions Canada Inc. for use of their Drug Information File.

*   **Supplemental information:** For reviewer comments and the original submission of this manuscript, please see [https://www.cmajopen.ca/content/10/3/E610/suppl/DC1](https://www.cmajopen.ca/content/10/3/E610/suppl/DC1).

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is noncommercial (i.e., research or educational use), and no modifications or adaptations are made. See: [https://creativecommons.org/licenses/by-nc-nd/4.0/](https://creativecommons.org/licenses/by-nc-nd/4.0/)

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