Emergency Medicine

Emergency presentations of older patients living with frailty: Presenting symptoms compared with non-frail patients

a b s t r a c t

Background and objective: Symptoms may differ between frail and non-frail patients presenting to Emergency De- partments (ED). However, the association between frailty status and type of presenting symptoms has not been investigated. We aimed to systematically analyse presenting symptoms in frail and non-frail older emergency pa- tients and hypothesized that frailty may be associated with Nonspecific complaints (NSC), such as generalised weakness.

Methods: Secondary analysis of a prospective, single centre, observational all-comer cohort study conducted in the ED of a Swiss tertiary care hospital. All presentations of patients aged 65 years and older were analysed. At triage, presenting symptoms and frailty were systematically assessed using a questionnaire. Patients with a Clin- ical Frailty Scale (CFS) > 4 were considered frail. Presenting symptoms, stratified by frailty status, were analysed. The association between frailty and generalised weakness was tested by logistic regression.

Results: Overall, 2?416 presentations of patients 65 years and older were analysed. Mean age was 78.9 (SD 8.4) years, 1?228 (50.8%) patients were female, and 885 (36.6%) patients were frail (CFS > 4). Generalised weakness, dyspnea, localised weakness, speech disorder, loss of consciousness and gait disturbance were recorded more often in frail patients, whereas chest pain was reported more often by non-frail patients. Generalised weakness was reported as presenting symptom in 166 (18.8%) frail patients and in 153 (10.0%) non-frail patients. Frailty was associated with generalised weakness after adjusting for age, gender and elevated National Early Warning Score 2 (NEWS) >= 3 (OR 1.19, CI 1.10-1.29, p < 0.001).

Conclusion: Presenting symptoms differ in frail and non-frail patients. Frailty is associated with generalised weak- ness at ED presentation.

(C) 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://

creativecommons.org/licenses/by-nc-nd/4.0/).

  1. Introduction

Frailty is an age-related condition characterized by a decline in phys- iological capacity across several organ systems, which results in a higher vulnerability to stressors and unfavourable outcomes [1-3]. Frailty is de- fined either by a phenotype [4] or by assessing the cumulative deficit in patients older than 65 years [5]. However, there is no universal defini- tion for frailty [1,2,6]. Independent of the definition used, functional im- pairment is a core component of frailty [7], and generalised weakness may contribute to functional impairment [8,9]. Disease presentation of older adults in the Emergency Department (ED) setting, for example with delirium, appears to be associated with frailty status [2,10].

* Corresponding author.

E-mail addresses: [email protected] (N.R. Simon), [email protected] (A.S. Jauslin), [email protected] (R. Bingisser), [email protected] (C.H. Nickel).

Presenting symptoms have been previously investigated in older ED patients in retrospective analyses [11-13]. It is known that older adults often present with nonspecific or atypical symptoms and undergo a more complex work-up when presenting to the ED [12,14-16].

In addition, nonspecific complaints (NSC) are predictive of adverse outcomes, such as a higher rate of admission, increased use of resources and a longer ED-length-of-stay as well as mortality [15,17,18]. However, it is unclear, whether frail older patients – representing about 31% to 44% of the older ED population [19-21] – may account for these findings. It has been suggested that frail patients often present with NSC such as generalised weakness [2,22,23].

There is, however, no systematic analysis of presenting symptoms in frail older ED patients, and no formal investigation on the association of frailty with NSC. We therefore intended to compare presenting symp- toms of frail and non-frail older patients in a consecutive cohort of older ED patients. Furthermore, we aimed to investigate to what extent age, frailty and disease severity are associated with the presence of NSC such as generalised weakness.

https://doi.org/10.1016/j.ajem.2022.06.046

0735-6757/(C) 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

  1. Methods
    1. Study design, population and inclusion criteria

This is a secondary analysis of a prospective, single centre, observa- tional all-comer cohort study conducted at the Emergency Department (ED) of the University Hospital Basel, a tertiary care centre with approx- imately 54?000 annual ED visits.

Consecutive patients presenting to the ED between March 18th and May 20th, 2019, were included 24 h a day, 7 days a week. All participat- ing patients or their legally authorised representatives gave verbal consent. The study was conducted according to the principles of the Declaration of Helsinki and approved by the local ethics committee (http://eknz.ch; project-ID: 236/13; and the amendment PB_2019-00008).

For this analysis, a consecutive cohort of patients aged 65 years and older were included. Exclusion criteria were unwillingness to partici- pate and insufficient ability to communicate with the study personnel (e.g. treatment in the resuscitation bay, coma, intoxication, and lan- guage barrier).

    1. Data acquisition

Patients underwent formal triage by the Emergency Severity Index [24] and their presenting symptoms were systematically recorded, as previously described [25]. Vital signs, such as heart rate, blood pres- sure, body temperature, respiration rate, peripheral oxygen saturation, level of consciousness and new confusion as assessed by the ACVPU scale (alert, acute confusion, verbal, pain, unresponsive; C, V, P and U denote altered mental status) were routinely assessed at triage and re- corded by the study personnel. Vital signs were used for the calculation of the National Early Warning Score 2 (NEWS) [26]. Patients were approached by a member of the study team, specifically trained medical students, for information about the study. In case of participation, pa- tients were first asked “what are your symptoms right now?”. The study personnel then asked, “Do you have any other symptoms?” up to a maximum of three times, if more symptoms were conveyed. An- swers were recorded in the case report form (CRF) containing a predefined list of 35 symptoms: feeling feverish, skin rash, headache, dizziness, acute visual disorder, acute hearing disorder, Nasal discharge, dysphagia, cough, expectoration, dyspnea, chest pain, abdominal pain, nausea, vomiting, diarrhoea, obstipation, dysuria, back pain, neck pain, Arm pain, leg pain, joint pain, flank pain, joint swelling, Leg swelling, loss of consciousness, numbness, localised weakness, gait disorder, speech disorder, Loss of appetite, sleeping disorder, generalised weak- ness, and fatigue. Other symptoms were recorded in a free text field in the CRF. Second, patients were asked “which of the symptoms you just reported is the most important to you?” (“chief complaint”). If they were uncertain, the study team supported them by mentioning the definition of chief complaint (“your reason for seeking care or atten- tion”). If no answer could be given, no chief complaint was reported. Ad- ditionally, patients were asked, if they suffered from falls in the previous 12 months before presentation. Answers were recorded either as no fall, one fall, or two or more falls.

All data were recorded immediately on machine-readable CRFs. They were subsequently scanned, and data were cleaned in two steps, first by ED administration (handwriting issues) and subsequently by an external company (Swiss Post(R)) which was responsible for transfer- ring the data to the database. Patients’ baseline characteristics, such as age, gender, ESI triage level, disposition, and diagnoses at ED discharge, were imported from the patients’ electronic health record , pro- vided by Protec Data(R), Boswil, Switzerland.

The CFS was used to assess patients’ frailty level from 1 to 9 (1 very

fit, 2 well, 3 managing well, 4 vulnerable, 5 mildly frail, 6 moderately

frail, 7 severely frail, 8 very severely frail, 9 terminally ill) at ED presen- tation. It has been validated in adults aged 65 years and older. Each frailty level comes with a short description and a pictograph [27]. All el- igible patients were assigned a frailty level according to the German ver- sion of the Clinical Frailty scale [19]. For this analysis, levels of CFS were grouped in 1-4 being “non-frail”, and 5-9 being “frail”. Patients without CFS level assessed were excluded.

    1. Statistical analysis

Descriptive statistics are presented as counts and frequencies for cat- egorical data and mean (standard deviation) for metric variables. Group comparisons were done using Student’s t-test for means, and for cate- gorical data chi-squared tests, or exact Fisher tests in cells with expected frequencies below n = 5.

Logistic regressions were used to calculate odds ratios (OR), 95% Confidence Intervals (CI), and p-values, and were adjusted for age, gen- der and elevated NEWS >=3. A p-value <0.05 was considered significant. All significant and non-significant variables were left in the final models. All evaluations were done using the statistical software R version 4.0.3 (2020-10-10) [28].

  1. Results
    1. Baseline characteristics

Of 7?859 ED visits screened, 550 were not enrolled (e.g. due to denial of general consent). Of all 7?309 presentations, 4?850 patients <65 years and 43 presentations with lacking CFS were excluded. The final study population consisted of 2?416 ED patients aged 65 years and older, 885 (36.6%) of which were frail (CFS > 4). The inclusion procedure is shown in Fig. 1. Mean age was 78.9 (SD 8.4) years, 1?228 (50.8%) pa- tients were female. Of all frail patients, 293 (44.9%) presented with a NEWS >=3, as compared to 293 (24.0%) of all non-frail patients. Frail pa- tients presented more often with altered mental status (n = 160, 18.1%), as compared to non-frail patients (n = 38, 2.5%). The prevalence of altered mental status, stratified by CFS level, is shown in Fig. 2. A pos- itive history of falls (at least one fall in the last 12 months) was found in 362 (41.6%) of all frail patients and in 425 (28.2%) of all non-frail pa- tients. Baseline characteristics are presented in Table 1.

    1. Most common presenting symptoms

All 35 predefined presenting symptoms stratified by frailty status are presented in Table 2.

In frail patients, the five most common presenting symptoms were

1) generalised weakness (n = 166, 18.8%), 2) dyspnea (n = 131,

14.8%), 3) dizziness (n = 104, 11.8%), 4) leg pain (n = 96, 10.8%), and

5) back pain (n = 84, 9.5%).

In non-frail patients, the five most common symptoms were 1) dizzi- ness (n = 207, 13.5%), 2) dyspnea (n = 163, 10.6%), 3) chest pain (n = 160, 10.5%), 4) generalised weakness (n = 153, 10.0%), and 5) headache (n = 146, 9.5%).

    1. Disparities in presenting symptoms between frail and non-frail patients

Generalised weakness, dyspnea, localised weakness, speech disor- der, loss of consciousness, and gait disturbance were recorded more often in frail patients than in non-frail patients. In contrast, chest pain was significantly more common in non-frail patients (see Table 2).

A similar distribution of symptoms was seen when analysing the

patients’ chief complaints.

Table 1

Characteristics of frail versus non-frail patients.

All (n = 2?416)

Frail (CFS > 4)

Non-frail (CFS <=

4)

P

N

(n = 885)

(n = 1?531)

Age, mean (SD)

78.9

(8.4)

82.3

(8.3)

76.9

(7.9)

<0.001

2416

Female gender, n (%)

1?228

(50.8)

488

(55.1)

740

(48.3)

0.001

2416

ESI, n (%)

<0.001

2416

1

96

(4.0)

60

(6.8)

36

(2.4)

2

877

(36.3)

353

(39.9)

524

(34.2)

3

1?153

(47.7)

424

(47.9)

729

(47.6)

4

269

(11.1)

46

(5.2)

223

(14.6)

5

21

(0.9)

2

(0.2)

19

(1.2)

NEWSa >= 3

586

(31.3)

293

(44.9)

293

(24.0)

<0.001

1871

Heart rate (bpm), mean (SD)

83.4

(18.7)

84.9

(19.3)

82.5

(18.3)

0.003

2397

Systolic BP (mmHg), mean (SD)

142.0

(25.6)

138.5

(26.8)

144.0

(24.7)

<0.001

2389

Diastolic BP (mmHg), mean (SD)

79.0

(15.8)

77.0

(17.2)

80.1

(14.7)

<0.001

2387

Temperature, (?C), mean (SD)]

36.8

(0.8)

36.8

(0.9)

36.7

(0.7)

0.048

2120

Oxygen saturation (%), mean (SD)

96.3

(3.4)

95.7

(4.1)

96.6

(2.9)

<0.001

2394

Respiratory rate (RR), mean (SD)

17.3

(4.6)

18.1

(5.0)

16.9

(4.3)

<0.001

2250

ACVPU, n (%)

<0.001

2412

A

2?214

(91.8)

723

(81.9)

1?491

(97.5)

CVPUb

198

(8.2)

160

(18.1)

38

(2.5)

History of falls in the last 12 months, n (%)

<0.001

2376

Zero

1?589

(66.9)

507

(58.3)

1?082

(71.8)

One

545

(22.9)

233

(26.8)

312

(20.7)

Two or more

242

(10.2)

129

(14.8)

113

(7.5)

Medication per day, mean (SD)

5.4

(4.5)

6.9

(4.8)

4.6

(4.1)

<0.001

2381

Total number of symptoms, mean (SD)

2.2

(1.3)

2.3

(1.4)

2.1

(1.3)

0.005

2416

Disposition, n (%)

<0.001

2416

Outpatient

902

(37.3)

186

(21.0)

716

(46.8)

Inpatient

1?514

(62.7)

699

(79.0)

815

(53.2)

The table comprises all patients analysed aged 65 years and older at time of ED-presentation, as well as frail patients (CFS 5-9) and non-frail patients (CFS 1-4).

CFS = Clinical Frailty Scale, SD = standard deviation, ESI = emergency severity index, NEWS = National Early Warning Score, bpm = beats per minute, BP = blood pressure, mmHg = millimetres of mercury, RR = respiratory rate per minute, ACVPU = alert, acute confusion, verbal, pain, unresponsive.

a Including the assessment of level of consciousness, as measured by the ACVPU-scale. C denotes acute confusion.

b C, V, P and U denote altered mental status.

Fig. 1. Inclusion procedure of patients who presented to the ED. ED = Emergency Department, CFS = Clinical Frailty Scale.

Image of Fig. 2

Fig. 2. Prevalence of altered mental status stratified by CFS level. The figure illustrates the prevalence of altered mental status at emergency presentation in patients aged 65 years and older, stratified by CFS level (CFS 1: 0%, CFS 2: 1.4%, CFS 3: 2.5%, CFS 4: 3.5%, CFS 5: 8%, CFS 6: 12.3%, CFS 7: 19.1%, CFS 8: 51.6%, CFS 9: 18.8%). The error bars display 95% confidence intervals. Altered mental status was assessed by the ACVPU scale. C, V, P and U denote altered mental status.

CFS = Clinical Frailty Scale, ACVPU = alert, acute confusion, verbal, pain, unresponsive.

    1. Association of generalised weakness with frailty

Generalised weakness was found in 166 (18.8%) frail and in 153 (10.0%) non-frail patients (p < 0.001).

The prevalence of generalised weakness, as stratified by frailty level is shown in Fig. 3. In a multivariable logistic regression model, adjusted for age, gender and NEWS >=3, increasing frailty levels were associated with generalised weakness (CFS: OR 1.19 per CFS level, CI 1.10-1.29, p < 0.001). An elevated NEWS >=3 was associated with generalised weakness at ED presentation (OR 1.61, CI 1.21-2.14, p = 0.001). No associations between generalised weakness and age, and generalised weakness and gender were observed (age: OR 1.00, CI 0.98-1.01, p = 0.705; female gender: OR 1.08, CI 0.82-1.42, p = 0.598). These results are presented in Table 3.

  1. Discussion

The main findings of the study are that certain disparities exist be- tween presenting symptoms in frail as compared to non-frail older ED patients, as well as the association of generalised weakness with frailty at presentation, after adjustment for age, gender, and NEWS. Further- more, the overall probability of weakness as presenting symptom rises with higher frailty levels, but not in a linear association. Prevalence of symptoms, though generally comparable between frail and non-frail patients, showed significant differences regarding generalised weak- ness, dyspnea, localised weakness, speech disorder, loss of conscious- ness and gait disturbance – all of which are more prevalent in frail patients. In contrast, chest pain is the only symptom significantly more prevalent in non-frail patients. Furthermore, frail patients pre- sented more often with an elevated NEWS >=3, with a history of falls, and with altered mental status.

We can only speculate on the reasons for the association between frailty and nonspecific complaints, particularly generalised weakness, a

possible explanation being the frail patients’ chronic symptoms, or al- tered physiology and perception in frail patients. Little is known on pre- senting symptoms in frail older patients in acute care [29], but generalised weakness was described as a possible warning sign of in- creasing vulnerability in frailty development [30]. In addition, weakness, in terms of poor hand grip strength, is one of the five components of the frailty phenotype model [4]. Even though there is no universal consensus on how to define and assess frailty [1,2,6,31], our findings in this emer- gency cohort support the concept that generalised weakness is closely associated with frailty, independent of the definition used.

Generalised weakness was previously shown to be associated with

adverse outcomes such as hospitalisation and mortality [25,32]. Similar results were found for the combination of generalised weakness with other presenting symptoms [33]. Weakness can be considered a non- specific complaint [32,34,35]. However, there is no uniform definition of NSC and several frameworks for the selection of patients presenting with NSC exist [15,32,36,37].

Nonspecific complaints such as generalised weakness are common emergency presentations [15,25,32]. The prevalence of weakness may depend on how it is noted at presentation. Using systematic interviews, 14% of all ED patients reported generalised weakness [25], which is comparable to the data presented. In contrast, retrospective studies found a much lower prevalence of generalised weakness, ranging from 2% to 6% [11,12,32]. Possibly, disagreements on presenting symp- toms between patients and physicians are more pronounced in nonspe- cific complaints – with an observed tendency of emergency physicians to suppress or even withhold such symptoms [38]. Patients presenting with a high number of symptoms at presentation are of higher complex- ity [17]. Therefore, emergency physicians tend to focus on specific and most obvious complaints [3]. Furthermore, generalised weakness is often reported in combination with other symptoms [33].

In summary, we found evidence for the hypothesis of an association of frailty with nonspecific complaints, at least for generalised weakness,

Table 2

Presenting symptoms of emergency patients stratified by frailty status.

Table 3

Multivariable logistic regression model for the association with generalised weakness.

All

(n = 2?416)

Frail

(CFS > 4)

(n = 885)

Non-frail P (CFS <= 4)

(n = 1?531)

OR CI P

Age, y 1.00 0.98-1.01 0.705

Female gender 1.08 0.82-1.42 0.598

Generalised weakness, n (%)

319

(13.2)

166

(18.8)

153

(10.0)

<0.001

Dizziness, n (%)

311

(12.9)

104

(11.8)

207

(13.5)

0.235

Dyspnea, n (%)

294

(12.2)

131

(14.8)

163

(10.6)

0.003

Leg pain, n (%)

236

(9.8)

96

(10.8)

140

(9.1)

0.198

Headache, n (%)

220

(9.1)

74

(8.4)

146

(9.5)

0.372

Abdominal pain, n (%)

219

(9.1)

83

(9.4)

136

(8.9)

0.738

Chest pain, n (%)

214

(8.9)

54

(6.1)

160

(10.5)

<0.001

Back pain, n (%)

211

(8.7)

84

(9.5)

127

(8.3)

0.353

Nausea, n (%)

207

(8.6)

68

(7.7)

139

(9.1)

0.269

Joint pain, n (%)

170

(7.0)

59

(6.7)

111

(7.3)

0.647

Fatigue, n (%)

157

(6.5)

68

(7.7)

89

(5.8)

0.087

Arm pain, n (%)

142

(5.9)

45

(5.1)

97

(6.3)

0.242

Vomiting, n (%)

141

(5.8)

55

(6.2)

86

(5.6)

0.608

Cough, n (%)

128

(5.3)

46

(5.2)

82

(5.4)

0.942

Feeling feverish, n (%)

121

(5.0)

47

(5.3)

74

(4.8)

0.673

Speech disorder, n (%)

99

(4.1)

57

(6.4)

42

(2.7)

<0.001

Localised weakness, n (%)

94

(3.9)

58

(6.6)

36

(2.4)

<0.001

Numbness, n (%)

93

(3.9)

38

(4.3)

55

(3.6)

0.451

Loss of consciousness, n (%)

85

(3.5)

42

(4.8)

43

(2.8)

0.018

Diarrhoea, n (%)

85

(3.5)

26

(2.9)

59

(3.9)

0.288

Gait disturbance, n (%)

78

(3.2)

38

(4.3)

40

(2.6)

0.033

Flank pain, n (%)

62

(2.6)

18

(2.0)

44

(2.9)

0.261

Dysuria, n (%)

61

(2.5)

18

(2.0)

43

(2.8)

0.301

Loss of appetite, n (%)

58

(2.4)

22

(2.5)

36

(2.4)

0.944

Leg swelling, n (%)

56

(2.3)

19

(2.2)

37

(2.4)

0.776

Expectoration, n (%)

48

(2.0)

16

(1.8)

32

(2.1)

0.743

Neck pain, n (%)

44

(1.8)

11

(1.2)

33

(2.2)

0.145

Joint swelling, n (%)

42

(1.7)

10

(1.1)

32

(2.1)

0.115

Obstipation, n (%)

36

(1.5)

15

(1.7)

21

(1.4)

0.647

Acute hearing disorder, n (%)

32

(1.3)

12

(1.4)

20

(1.3)

1.000

Sleeping disorder, n (%)

25

(1.0)

9

(1.0)

16

(1.1)

1.000

Skin rash, n (%)

22

(0.9)

7

(0.8)

15

(1.0)

0.804

Dysphagia, n (%)

20

(0.8)

7

(0.8)

13

(0.9)

1.000

Nasal discharge, n (%)

14

(0.6)

3

(0.3)

11

(0.7)

0.365

Acute visual disorder, n (%)

13

(0.5)

2

(0.2)

11

(0.7)

0.143

NEWS >=3 1.61 1.21-2.14 0.001

CFS (per level) 1.19 1.10-1.29 <0.001

Multivariable logistic regression model. This model shows the association of age, gender, NEWS and increasing frailty levels with generalised weakness.

NEWS = National Early Warning Score, CFS = Clinical Frailty Scale, OR = odds ratio, CI = 95% confidence interval.

which can be considered as the cardinal nonspecific complaint. The mechanism of this association cannot be elucidated with this study. In order to investigate the cause-and-effect relationship of weakness with frailty, further studies should therefore investigate onset, time- course, and change from baseline that prompted ED presentation. Po- tential hypotheses on weakness-associated frailty include weakness as a hallmark of the frailty-phenotype, or weakness as a modifier regarding adverse outcomes and illness trajectories [33,39]. Nonetheless, in clinical practice, the occurrence of NSC in older ED patients should prompt screening for geriatric syndromes such as delirium or fall risk [10,40-42].

    1. Strengths and limitations

The table comprises all 35 predefined symptoms of patients aged 65 years and older at time of ED-presentation, stratified by frailty status. Symptoms are ordered by descending frequency. This information was available for all 2?416 patients.

CFS = Clinical Frailty Scale.

A strength of this study is the highly standardised setting with a standardised binary questionnaire and a list of 35 predefined symp- toms. However, this might as well be a limitation since the number of all possible symptoms exceeds the list of 35 predefined symptoms. The list of symptoms has not undergone a formal process of validation but has been used for other studies. Additionally, history of a recent fall was not counted as a “presenting symptom” for obvious reasons. Leg pain and back pain, which were among the five most common pre- senting symptoms of frail patients, might be indirect indicators of falls as reason of presentation. Importantly, we did not investigate whether

Image of Fig. 3

Fig. 3. Prevalence of generalised weakness stratified by CFS level. The figure illustrates the prevalence of generalised weakness in emergency patients aged 65 years and older, stratified by CFS level (CFS 1: 2.8%, CFS 2: 5.4%, CFS 3: 11.6%, CFS 4: 11.7%, CFS 5: 20%, CFS 6: 17.4%, CFS 7: 16%, CFS 8: 20.3%, CFS 9: 37.5%). The error bars display 95% confidence intervals.

CFS = Clinical Frailty Scale.

weakness was acute, chronic or transient, but only asked for its presence at presentation [43]. In addition, representations were not considered. Generalisability is limited due to the monocentric study design. In addition, the chosen study period of nine weeks between March and May 2019 may be subject to seasonal bias. Variables for the assessment of comorbidities (such as the Charlson Comorbidity Index) were not available for our study population. Therefore, associations with comor- bidity could not be analysed. However, there is a need for an updated comorbidity index that will aid in emergency research [44]. In addition, frailty, disability and comorbidity should be considered as different entities [45]. Lastly, since the Clinical Frailty Scale is validated only for older age, patients younger than 65 years of age were excluded [27].

  1. Conclusion

This study shows certain disparities between presenting symptoms in frail as compared to non-frail ED patients, as well as an association of generalised weakness with frailty at presentation. However, this as- sociation is not linear, and we can only speculate on the underlying pathophysiology.

Funding

This work was supported by scientific funds from the University Hospital of Basel. The funder had no role in the design, data collection, data analysis, manuscript preparation and/or publication decisions.

Author contributions statement

Conception and design, C.H.N., R.B., A.S.J., N.R.S.; data analysis N.R.S.; Data interpretation, C.H.N., R.B., A.S.J, N.R.S.; drafting of the paper, C.H.N., N.R.S.; critical revisions, C.H.N., R.B., A.S.J., N.R.S.

All authors have approved to the final version of this manuscript.

Data availability statement

Data sharing requests will be forwarded to the ethics committee. In case of acceptance of the request, the data can be shared in a fully anonymised form.

Credit authorship contribution statement

N.R. Simon: Writing – original draft, Methodology, Formal analysis, Conceptualization. A.S. Jauslin: Writing – review & editing. R. Bingisser: Writing – review & editing, Methodology, Data curation, Conceptualiza- tion. C.H. Nickel: Writing – review & editing, Writing – original draft, Supervision, Methodology, Conceptualization.

Declaration of Competing Interest

The authors declare no conflict of interest.

Acknowledgements

The bio-statisticians Andreas Schotzau, MSc. math., and Nikolai Hodel, MSc. epidemiology, provided statistical support. We thank the study staff involved in data collection for their valuable contributions and the University Hospital of Basel supporting the study financially and logistically.

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