Clinical Definition of Camptocormia in Parkinson's Disease

Abstract

Background

Clinical key aspects of camptocormia in patients with idiopathic Parkinson's disease (PD) await further definition.

Methods

Based on a self‐assessment of PD patients, we performed an observational study, asking patients with subjectively felt involuntary forward bending to return a questionnaire and provide photographs showing their axial disorder. Forty‐two matched PD patients without subjective signs of camptocormia were recruited as controls.

Results

The stooped posture of patients with advanced PD without camptocormia is characterized by a forward bending angle of always less than 30 degrees. Of the 145 camptocormia patients in our study, 70% had an angle ≥30 degrees. The patients with a more‐severe forward bending angle were more severely affected in daily life than those with an angle of less than 30 degrees. Back pain was more frequent (81% vs. 43%) and more severe in PD patients with camptocormia than in controls. Back diseases in camptocormia PD patients were also significantly more frequent than in the PD control patients (55% vs. 26%). Camptocormia is a relevant burden in everyday life. Seventy‐seven percent of patients needed walking aids and 85% reported specific disabilities attributed to camptocormia (e.g. increased risk of falling, dyspnea, problems in eating or swallowing).

Conclusions

Camptocormia cannot be clinically defined based on the forward bending angle alone, but an angle larger than 30 degrees is only found in camptocormia. Back pain is an essential aspect of camptocormia in PD. Back diseases can be seen as a risk factor in these patients.

Camptocormia is an involuntary, marked flexion of the thoracolumbar spine apparent during standing or walking and resolving in the supine position; it is mostly found in movement disorders, particularly Parkinson's disease (PD).1, 2, 3 Although the clinical syndrome of camptocormia is universally accepted and meanwhile defined by characteristic myopathological4 and radiological5 changes of the paravertebral muscles, an unambiguous clinical definition of camptocormia is lacking. In some publications, a UPDRS III‐item 28 ≥ 2 is used for definition,6 but in most studies, camptocormia is defined on the basis of the angle of bending. However, neither the degree of the angle nor the method of evaluation has been agreed on. A wide range of forward bending angles of between 15 and 45 degrees is currently used to define camptocormia.1, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 Highly differing prevalence rates between 3% and 17.6% may reflect the uncertainties in the characterization of camptocormia in PD.7, 8, 9, 18 For definition, camptocormia needs to be distinguished from the frequently found stooped posture in PD. Further clinical aspects, apart from the forward bending angle, are even more undefined. It remains unclear whether camptocormia is regularly associated with back pain or with diseases of the vertebral column.1, 9, 10 Also still to be determined is the disease burden associated with camptocormia in daily life. The aim of this current study is to characterize the clinical presentation of camptocormia based on the self‐assessment of a large group of PD patients.

Patients and Methods

Camptocormia Patients

We conducted an observational study supported by the German Parkinson's disease patient organisation (dPV, Deutsche Parkinson Vereinigung e.V.) with approximately 22,000 members, who kindly published our comprehensive camptocormia questionnaire in their members journal. Patients were asked to use the questionnaire to self‐assess their camptocormia. Our evaluation included those patients who complained of a substantial, subjective, forward bending of the trunk, who returned a completed questionnaire and who provided two photographs showing themselves from the front and from the side in a standing position to document the extent of the axial disorder. Participants were asked to stand in their usual posture and try not to correct their body position. Photos were made showing the person in full length wearing clothes that allowed a clear view of the body contour. We asked in our questionnaire, in addition to biographical data and information concerning the type and severity of PD syndrome, for a detailed description of the postural abnormality. This included the extent of the forward bending, its duration, age at onset, occurrence of fluctuations or modifying factors, whether there were any special limitations or the need of adjuvant because of camptocormia, as well as whether back diseases were present. We also asked about impairment of daily activities attributed to the bent‐forward trunk and to back pain, both of which were rated on a Likert scale ranging from 1 to 10 points (higher numbers indicating a greater impairment). Presence of back pain was noted as frequent, occasionally, infrequent, and none. Localization of back pain was given as cervical, thoracic, lumbar sacral, or extended when it covered more than one of the named regions of the spine.

Patients with dropped head (isolated axial disorder of head position) or Pisa syndrome (as solely lateral deviation or predominately lateral deviation), as well as patients with nonidiopathic PD syndrome, were excluded from further analysis.

Control Group

We recruited a control group of PD patients without camptocormia, group matched to the camptocormia questionnaire patients for sex, age, PD duration, and equivalent levodopa dosage. Candidates for our study were found in our department's database, from which we identified patients suffering from advanced idiopathic PD (iPD) who were clinically characterized and video documented during an l‐dopa test. The control patients denied to suffer from camptocormia or a subjective feeling of forward bending. They were asked for the same clinical information as the camptocormia questionnaire patients (e.g. occurrence of back pain and back diseases).

All participants of our study gave their informed consent, and the ethics committee of the medical faculty of Kiel University (Kiel, Germany) approved the protocol.

Standardized Assessment of the Forward Bending Angle

For both groups, photos were used to determine the angle of forward bending of the trunk. As indicated in Figure 1A, the angle was measured between a line from the lateral malleolus to the sacroilical joint and a second line from the sacroiliac joint to the processus spinosus of C7. Two independent raters performed the angle assessments. They were blinded to subjects' group (i.e. controls or study patients). Their assessment was considered to agree if the difference in their rating of the angle was less than 5 degrees. In case of a disagreement, a consensus decision was made. As an additional aspect, laterodeviation was defined as any clear alteration from the normally horizontal line between the shoulders, assessed on photos showing the patient from the front. However, in these patients, the clearly predominant axial deviation was the forward bending, and not lateral bending, as in a Pisa syndrome. On the basis of our photo material, a further assessment of rotational aspects of the axial disorder was not possible.

Figure 1.

(A) Method of angle assessment. (B) Camptocormia angle in the control group (gray) and photo‐documented questionnaire patients complaining of camptocormia (black). It is evident that there is a (sub)group that can clearly be separated from PD patients without the subjective complaint of camptocormia and another (sub)group of PD patients with the subjective complaint of camptocormia, but who have a forward bending angle similar to the control PD patients without camptocormia.

The Limit of Stooped Posture in PD

We determined the range of forward bending angles in our control patients. A sample size of 42 subjects was considered to reflect the distribution of the angle of the trunk in PD patients with advanced disease. We chose three standard deviations (SDs) from the mean bending angle of controls as a cut‐off criterion to distinguish the stooped posture frequently found in PD from camptocormia.

Statistical Analysis

Comparisons between the examined patient groups were performed using a two‐sample Wilcoxon's rank‐sum test (also known as the Mann‐Whitney U test) or Fisher's exact test in the case of categorical data (R statistics; http://www.r-project.org/). Correlations and inter‐rater agreement were tested by nonparametric Spearman's rank‐correlation tests. A P≤0.05 was classified as significant.

Results

Questionnaires were returned by 278 patients (107 females and 171 males; average age: 72.3 years with a ±SD of 6.8 years). Thirty‐seven patients (12 females, 25 males; average age: 73.3 years ±SD 5.5) were excluded because they had axial disorders other than camptocormia (dropped head or Pisa syndrome), as indicated by the photos, or had been diagnosed with non‐iPD. Furthermore, 96 questionnaire PD patients (40 females, 56 males; average age: 72.7 years ±SD 7.7) were excluded because they did not send any photo material with the questionnaire. One hundred forty‐five PD patients (55 women, 90 men; mean age: 71.8 years ±SD 6.4) fulfilled the inclusion criteria. We called this group the “photo‐documented questionnaire PD patients” (Fig. 2).

Figure 2.

Flow chart showing the classification of the returned questionnaires and the definition of subgroups.

The Bending Angle in Advanced PD

As indicated in Table 1, the forward bending angle in the OFF state of the PD control participants was 14.3 degrees (±SD 5.0). The mean of the angle in the ON state (11.0 degrees ±SD 5.5) was slightly, but significantly, lower than in the OFF state. In none of the control patients was the angle in the ON state higher than in the OFF state. The Shapiro‐Wilk's normality test of the distribution of bending angles did not differ from a normal distribution (P = 0.59). The mean plus 3 SDs (29.3–30 degrees) is used as a cut‐off criterion for the normal stooped posture of advanced PD. None of the PD patients in the control group showed a forward bending angle of more than 25 degrees in the OFF state (see Fig. 1B). We conclude that angles above 30 degrees are not found in patients with PD without subjective complaints of camptocormia.

Table 1.

Statistical data of the photodocumented questionnaire PD patients, the group of patients with a bending angle of ≥30 degrees, the overlap group (<30 degrees), and the PD control group

	Photo‐Documented Questionnaire PD Patients			Control PD Patients Without Camptocormia (n = 42) (Mean, SD)	P Value (Con vs. ≥30 Degrees)	P Value (Con vs. <30 Degrees)	P Value (<30 vs. ≥30 Degrees)
	Total Group (n = 145)	Bending Angle ≥30 Degrees (n = 102) (Mean, SD)	Bending Angle <30 Degrees) (n = 43) (Mean, SD)
Sex	Female: 55 (38%) Male: 90 (62%)	Female: 34 (33%) Male: 68 (67%)	Female: 21 (49%) Male: 22 (51%)	Female: 14 (33%) Male: 28 (67%)	1	0.188	0.093
Age (years)	71.8 (±6.4)	70.9 (±5.8)	73.9 (±7.2)	70.0 (±4.6)	0.14	0.002*	0.022*
Duration of PD (years)	11.5 (±5.8)	11.8 (±5.9)	10.9 (±5.7)	13.0 (±4.5)	0.13	0.04	0.43
l‐dopa equivalent dose (mg)	788.4 (±334.4) (n.a. = 36)	818.3 (±337.8) (n.a. = 21)	702.1 (±314.4) (n.a. = 15)	887.7 (±390.6)	0.48	0.049*	0.13
Assessed forward bending angle (degrees)a	43.1 (±21) (n.a. = 6)	53.0 (±14.8)	15.8 (±5.6) (n.a. = 6)	14.3 (±5.0) (n.a. = 5)	<0.001*	0.17	n.d.
Frequencies of occurrence of back pain	Frequent: 117 (81%) Occasionally: 18 (13%) Infrequent: 6 (4%) No = 3 (2%)	Frequent: 87 (86%) Occasionally: 10 (10%) Infrequent: 2 (2%) No = 2 (2%)	Frequent: 30 (70%) Occasionally: 8 (19%) Infrequent: 4 (9%) No = 1 (2%)	Frequent: 18 (43%) Occasionally: 8 (19%) Infrequent: 8 (19%) No = 8 (19%)	<0.001*	0.0188*	0.058
Back pain rating scale 1–10 (points)	5.8 (±1.9) (n.a. = 6)	6.1 (±1.7) (n.a. = 3)	5.2 (±2.2) (n.a. = 3)	4.5 (±2.7) (n.a. = 2)	<0.001*	0.197	0.033*
Age at the beginning of camptocormia (years)	67.1 (±7.3) (n.a. = 6)	66.5 (±6.45) (n.a. = 3)	68.5 (9) (n.a. = 3)	—	—	—	0.206
Duration of PD at the beginning of camptocormia (years)	6.9 (5.5) (n.a. = 5)	7.4 (±5.5) (n.a. = 3)	5.6 (±5.4) (n.a. = 2)	—	—	—	0.122
Duration of camptocormia (months)	54.9 (±42.6) (n.a. = 5)	52.8 (±38.1) (n.a. = 3)	60 (±51.9) (n.a. = 2)	—	—	—	0.539
Rating scale for impairment attributed to camptocormia in daily life 1–10 (points)	6 (±2.1) (n.a. = 1)	6.6 (±1.7)	4.4 (±2.1) (n.a. = 1)	—	—	—	<0.001*

For continuous data, the nonparametric Wilcoxon's test was used to assess group differences, and for count data, we used the Fisher's exact test. * P≤0.05.

^aAll camptocormia angles were determined on the basis of photos, and the control participants were evaluated in the OFF state. The angle of the two camptocormia subgroups was defined in this article and is therefore not tested.

Con, control group; n.a., not available; n.d., not done.

Forward Bending Angle of the Questionnaire Patients

The bending angle of the photo‐documented patients was 43.1 degrees (±SD 21) and differed strongly from the control group (14.3 degrees ±SD 5; P = 0.0001). Overall inter‐rater reliability for the assessment of the forward bending angle showed a very good agreement (ρ = 0.91; P < 0.001). The mean difference between the two raters was 2 degrees. Among the 145 patients with the subjective complaint of camptocormia, 43 had a forward bending angle within the normal range of PD and 102 had a larger angle than 30 degrees (see Fig. 1B). Table 1 summarizes the clinical data. PD patients subjectively complaining of camptocormia, but with a forward bending angle of less than 30 degrees, are called the “overlap‐group” here. We compared the whole group of photo‐documented questionnaire PD patients with the PD controls and also compared the two camptocormia subgroups.

Clinical Characterization of the Questionnaire and the Control Patients

As indicated in Table 1, the majority of the camptocormia patients suffered from advanced PD (PD duration: 11.5 years ±SD 5.8; l‐dopa equivalent dosage: 788.4 mg ±SD 334.4). Duration of camptocormia was 54.9 months (±SD 42.6). The 145 photo‐documented patients were slightly older than the controls (71.8 vs. 70.0 years; P = 0.028), but the l‐dopa equivalent dosage and PD duration were not different. The questionnaire patients with a bending angle <30 degrees were significantly older than those ≥30 degrees, but there were no statistical differences in PD duration, l‐dopa dosage, age at onset, and duration of camptocormia (see Table 1).

Of the PD patients with ≥30‐degree camptocormia, 31% showed an aspect of laterodeviation in their forward bending, as opposed to 8% in the overlap group with an angle <30 degrees. This did not correlate with any of the measured variables, with the single exception of a longer duration of PD in the patients with laterodeviation than the questionnaire patients without laterodeviation (P = 0.02).

The Burden of Camptocormia

The mean impairment of activities in daily life attributed to camptocormia was rated 6.6 on a 10‐point scale for the patients with ≥30‐degree forward bending angle compared to 4.4 in the overlap group (P < 0.001). Bending angle seems to influence overall impairment and pain attributed to camptocormia: In the photo‐documented questionnaire group, bending angle correlated positively with the score of back pain (ρ = 0.26; P = 0.003) and the score of daily impairment (ρ = 0.48; P < 0.001). A significant correlation between angle and daily impairment (ρ = 0.33; P < 0.001) was also found in the group ≥30 degrees, but not in the group <30 degrees.

Back pain is more frequent in camptocormia than in control patients (Fig. 3A). PD patients with ≥30‐degree camptocormia had significantly more‐frequent back pain than control patients (86% vs. 43%), whereas in the overlap group 70% of the patients suffered from frequent back pain (see Table 1). The mean pain rating scale score was significantly higher (6.1 points ±SD 1.7) for ≥30‐degree camptocormia patients than for the control patients (4.5 points ±SD 2.7) and for patients in the overlap group (5.2 points ±SD 2.2). In the whole group and both subgroups, back pain and daily impairment were significantly correlated (rho between 0.49 and 0.56; P < 0.001).

Figure 3.

(A) Frequency of back pain, (B) localization of back pain, (C) frequency of back diseases for ≥30‐degree camptocormia patients, the overlap (<30 degrees), and control group patients. (D) Need of walking aids in ≥30‐degree camptocormia patients and the overlap (<30‐degree) group.

Localization of back pain was mostly accentuated in the lumbar sacral region in the group of ≥30‐degree camptocormia patients, with 74% versus 56% in the overlap group and 50% in the control group. Although in the overlap group the highest proportion suffered from extended back pain (33% vs. 23% in the ≥30‐degree group and 21% in the control group), frequency of cervical and thoracic back pain seemed not to differ between the three groups (Fig. 3B).

As shown in Figure 3C, a history of diseases of the spine (disc herniation, osteoarthritis, fractures, surgical procedures, etc.) was reported more often (59%) by ≥30‐degree camptocormia patients than by controls (26%; P < 0.001) and the overlap group (45%; P = 0.106).

Ninety percent of patients with a forward bending angle of ≥30 degrees used walking aids because of their camptocormia, compared to 40% in the overlap group (Fig. 3D). Use of wheelchairs and orthoses were not statistically different in the two groups.

Of the ≥30‐degree patients, 93% reported specific disabilities related to camptocormia as opposed to 67% in the overlap group: Seventy‐seven percent of ≥30‐degree patients complained of the risk of falling (compared to 53% in the overlap group), 39% reported dyspnoea (compared to 16%), and 15% reported stomach problems, difficulties in eating, problems with swallowing, or weight loss (compared to 0% in the overlap group).

Discussion

Camptocormia would be intuitively defined according to the forward bending angle. However, despite our large cohort of PD patients, who presented with camptocormia based on the subjective complaint of involuntary forward bending, we are unable to provide convincing evidence for a threshold angle defining camptocormia. Nevertheless, we found that the stooped posture of PD without camptocormia does not present with an angle exceeding 30 degrees, and hence forward bending above this angle can be regarded as a diagnostic feature of camptocormia. However, less severely forward angles do not exclude camptocormia. Patients with the subjective complaint of camptocormia and an angle of less than 30 degrees were less affected in daily life by the camptocormia than those with an angle exceeding 30 degrees. We propose a definition and additional criteria for the clinical diagnosis of camptocormia in PD (Table 2).

Table 2.

Clinical criteria for camptocormia in PD

Camptocormia is an axial postural disorder that persists for a longer period (more than 3 months) with a subjectively perceived involuntary flexion of the trunk while walking, standing, or sitting, but which resolves in the supine position. Diseases of the spine cannot explain the forward bending.

Additional characteristics: The bending angle is mostly ≥30 degrees, but can present below <30 degrees, which is within the normal range of stooped posture in PD. The severity of camptocormia depends on the camptocormia angle. It is strongly associated with constant or frequent lumbar sacral back pain. Walking aids or other supports are necessary because of the axial disorder. Related daily activities are impaired because of the disturbed axial posture. The arms are held in a backward position for balancing (back‐swept wing sign). Typical individual complaints associated with camptocormia include, for example, inability to drive a car because the patient cannot look backward or sit upright, inability to carry objects in front of the body, or difficulties looking people in the eye. Pre‐existing back diseases are more frequent.

The Camptocormia Angle and its Relation to Clinical Symptoms

So far, the problem of angle measurement has not been addressed, or if methods of measurement have been described,15, 16 they have not been formally assessed for reliability. Here, we propose a simple, but reproducible, method to measure the forward bending angle with a high inter‐rater reliability. In our study, we have documented the severity of camptocormia with photographs. This might underestimate the severity of the syndrome because some patients try to minimize their axial disorder while being photographed, though they are usually unable to maintain a more‐upright position for long. Pragmatically, we suggest standardizing the procedure by requiring 3 minutes of free standing before the patient is photographed to reduce the possible bias of underestimating the angle.

Despite the weaknesses of all measurement methods, we made several interesting observations with our practical approach. The angle of forward bending alone is not sufficient to define camptocormia. A forward bending angle of more than 30 degrees is not found in advanced PD, so that such severe angles can thus be used to definitely define these patients as camptocormia cases. At the same time, we found that PD patients with a forward bending angle of less than 30 degrees may also suffer from camptocormia, and therefore the subjective complaint of involuntary forward bending remains the key criterion for camptocormia. Our data show that two‐thirds of our patients with a forward bending angle of <30 degrees had already reported at least one specific disability related to camptocormia, and that back pain had already become relevant in these patients compared to PD controls. Further studies would have to characterize the clinical features of these patients in more detail.

In one‐third of our camptocormia PD patients, we observed a laterodeviation similar to the 29% and 25% of the patients described in earlier studies.1, 10 However, we could not find statistically relevant differences between camptocormia patients with and without laterodeviation, the only exception being that patients with laterodeviation had had PD significantly longer. The relation between laterodeviation and camptocormia still remains to be explored. Some researchers tried to differentiate camptocormia in an upper and a lower type.16 These subtypes do not influence our method of angle assessment; therefore, we did not refer to it in the current analysis.

The severity of camptocormia has not been addressed so far. We assessed severity using subjective measures, numerical analog scales to measure the impairment of activities in daily life attributed to camptocormia, and a scale to assess back pain. We found that the patient group with a camptocormia angle of less than 30 degrees is less affected in daily life by camptocormia than the group with a more‐severe forward bending ≥30 degrees. Moreover, the camptocormia angle is correlated with the degree of impairment in daily life as well as with severity of back pain. Thus, the severity of camptocormia depends on the forward bending angle.

An interesting finding of this study is the high prevalence and severity of back pain in the camptocormia and overlap group compared to controls. Most of the camptocormia studies so far have not addressed the topic of back pain; or camptocormia has even been regarded as painless.1 In our cohort, 87% of the PD patients with a forward bending angle of ≥30 degrees reported frequent back pain of moderate strength, mostly located in the lumbar sacral spine, a finding similar to some other studies.8, 10 Comparisons with the control patients demonstrated that back pain is an issue in PD itself, as also reported by several researchers.19, 20, 21 According to our data, the location of back pain is similar in PD patients with and without camptocormia. The major difference lies in the frequency of pain and, to a lesser extent, in the pain severity.

Overall, the existing data indicate that back pain is an essential feature of camptocormia in PD. The significant correlation in our study between back pain and level of impairment in the activities of daily life indicates that pain treatment is an important therapy target.

Back Diseases and Camptocormia

Frequency of back diseases was significantly higher for the PD patients with a forward bending angle ≥30 degrees compared to the PD control group in our cohort, but not for the overlap group with an angle <30 degrees. In a previous study, we found back diseases preceding camptocormia in 53% of PD camptocormia patients.11 Djaldetti et al.1 and Lepoutre et al.8 reported similar figures (63% and 65%) in camptocormia patients with relevant pathological radiological findings in the spine, whereas Umemura et al.6 found, in 38% of the camptocormia PD patients, spinal bone deformities. Tiple et al.9 could show a significant association of camptocormia and past vertebral surgery even after adjusting for relevant demographic and clinical variables. Thus, most of the studies show that back diseases are more frequent in PD camptocormia patients and therefore may be a risk factor. Our observation that camptocormia patients with <30 degrees did not have a previous history of back disease needs to be studied in a larger, better‐controlled patient population.

The Clinical Definition of Camptocormia

The present findings may help to further specify the definition of camptocormia. Current definitions mainly rely on the forward bending angle of the torso as a defining criterion.2 Understandably, no consensus can be reached in the literature if a 15‐, 30‐, or 45‐degree angle is sufficient, and they are all used to distinguish between camptocormia and stooped posture. However, our findings show that the bending angle alone cannot be used as the defining criterion. Therefore, we propose that the definition of camptocormia needs to include typical subjective complaints,22 as well as the further characteristics given in Table 2. Prospective studies are needed to assess whether the proposed pathological and imaging criteria can further delineate the condition. Studies on the natural course of camptocormia need to focus specifically on patients with a bending angle below 30 degrees to find out whether this is a more benign variant or an early stage of the disease.

Limitations

Aside from the control group and the photo material sent by participants in the questionnaire, all information used for the analysis was based on the questionnaire itself and was not cross‐checked by other data sources (e.g., patient files or a direct physical examination). Because of the exploratory manner of our evaluation, we do not apply any corrections for multiple comparisons in the statistical analysis. This certainly can produce some oversensitivity. However, in this study, our objective was to evaluate potential factors and properties for camptocormia. The set of diagnostical criteria is therefore, to a certain extent, preliminary and has to be verified in further studies.

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.

N.G.M.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B

O.G.: 1B, 1C, 2A, 2B, 2C, 3B

J.H.: 1B, 1C, 3B

A.W.: 2A, 2B, 2C, 3B

W.J.S.‐S.: 1A

G.D.: 1A, 1B, 3B

Disclosures

Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest: The authors report no sources of funding and no conflicts of interest.

Financial Disclosures for previous 12 months: N.G.M. received a travel grant from UCB and a lecture fee from Merz Pharmazeuticals and Bayer. O.G. received a lecture fee from UCB. W.J.S.‐S. received institutional funding from the Alberta Prion Research Institute and the Alberta Livestock and Meat Agency, Canada, the BMG, the DFG, and the dPV. G.D. has received lecture fees from Almirall and Desitin and has been serving as a consultant for Boston Scientific. He received royalties from Thieme publishers. He is a government employee and receives, through his institution, funding for his research from the German Research Council, the German Ministry of Education and Health and Medtronic.