Gesundheitsförderung und Prävention durch Bewegung

 
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Gesundheitsförderung und Prävention durch Bewegung
Gesundheitsförderung und Prävention
durch Bewegung
Andreas M. Nieß1, 2
1 Innere Medizin V, Abteilung Sportmedizin, Universitätsklinikum Tübingen
2 Interfakultäres Forschungsinstitut für Sport und körperliche Aktivität, Universität Tübingen

04.05.20
© UNIVERSITÄTSKLINIKUM TÜBINGEN.
Gesundheitsförderung und Prävention durch Bewegung
Agenda

                                             Evidenz

             Epidemiologische Studien
       Mechanismen körperlicher Aktivität
      Individuelle Dosis-Wirkungsbeziehung

2
Gesundheitsförderung und Prävention durch Bewegung
Körperliche Aktivität und Krankheitsrisiko
       – Die historische Entwicklung

                 Inzidenz der KHK

    Morris et al. (1953) Lancet 265: 1111-20   Wen et al. Lancet (2011) 378: 1244-1253

3
Gesundheitsförderung und Prävention durch Bewegung
Epidemiologische Evidenz
                  All cause                                       All cancer

                                                                                                                          Lancet (2011) 378: 1244-1253

                                                                                             N = 416.175 Personen
                                                                                                199.265 Männer, 216.910 Frauen

           Cardiovascular disease                            Diabetes mellitus               Gruppen körperlicher Aktvität (MET-Std. / Woche):

                                                                                             inaktiv:           < 3.75
                                                                                             gering:            3.75 – 7.49
                                                                                             mittlere:          7.49 – 16.49 (z.b. 2.5 Std. Walking)
                                                                                             hohe:              16.49-25.49
                                                                                             Sehr hohe:         > 25.49 (e.g. >3.5 hrs. Jogging)

Inactive    Low    Medium High   Very high       Inactive   Low    Medium High   Very high
                                         Activity level
Gesundheitsförderung und Prävention durch Bewegung
Epidemiologische Evidenz - Subgruppenanalyse

               Wen et al. (2011) Lancet 378: 1244-1253
Gesundheitsförderung und Prävention durch Bewegung
Epidemiologische Evidenz - Gesamtaktivität

Kyu et al. (2016) BMC 354: j3857
Gesundheitsförderung und Prävention durch Bewegung
Quant               0.64 (0.52–0.79)                         40.6              5
                                                                                                   Walking time    Combined Between
                                                                                                              Dose Response All studies Physical
                                                                                                                                         0.71 (0.59–0.84)
                                                                                                                                                  Activity 44.7   7 of
                                                                                                                                                           and Risk
                                Epidemiologische Evidenz                                                                                                  Coronary
                                                                                                                                                            Quant Heart   Disease
                           .2
                                                                                                                                                                   0.67 (0.57–0.79)                                           37.2              5
                                1     2      3     4                                      5                                                                            A Meta-Analysis
                                      Category of Leisure−time Physical Activity                                                          Men                All studies 0.63 (0.34–1.17)                                     76.9              2
792                        - Circulation
                             Koronare Herzerkrankung
                                         August 16, 2011 -
                  Figure 1. Plot of the relative risks of coronarySattelmair
                                                                    heart diseaseetbyal
                                                                                                                   Jacob Sattelmair, MSc, ScD; Jeremy Pertman, MS; Eric L. Ding, ScD; Harold W. Kohl III, PhD;
                                                                                                 Physical Activity and Coronary Heart Disease
                                                                                                                                           WilliamQuant
                                                                                                                                                   Haskell, PhD;0.63
                                                                                                                                                                 I-Min(0.34–1.17)
                                                                                                                                                                       Lee, MBBS, ScD 76.9          2                                           791
                  category of leisure-time physical activity. All study categories                                                                                                Circulation (2011) 124: 789-795
                                                                                                              Background—No reviews have quantified the specific amounts of physical activity required for lower risks of coronary
                                                                                                                                       Women                 All studies 0.65 (0.55–0.76)                                      0
                                                                                                                heart disease when assessing the dose-response relation. Instead, previous reviews have used qualitative estimates such         4
                  were standardized to 5 categories for ease of comparison. The                                 as low, moderate, and high physical activity.
                  size of the data point corresponds to the study size; the larger                                                                        Quant              0.64 (0.54–0.76)                          0               3
                                                                                                         Plots          of     the     dose-response                       relation            between                  quantitative
                                                                                                              Methods and Results—We performed an aggregate data meta-analysis of epidemiological studies investigating physical
                                                                                                 Table. Pooled Relative Risks of Coronary Heart Disease Comparing
                                                                                                                activity and primary prevention of CHD. We included prospective cohort studies published in English since 1995. After                  es
                  the dot is, the larger the sample size is. Dashed lines indicate
       1

                                                                                                  Walking
                                                                                                     mates     pace LTPA         Combined             All studies 0.53        per (0.43–0.66)                          0
                                                                                                                reviewing 3194 abstracts, we included 33 studies. We used random-effects generalized least squares spline models for   3
                                                                                                             andofLowest                   in kilocalories                             week and CHD                                 risk                 (
                  1

                                                                                                                                                                                                                                 14 –22
                  studies with physical activity categorized quantitatively; solid               Highest                              Physical          Activity Categories
                                                                                                                trend estimation to derive pooled dose-response estimates. Among the 33 studies, 9 allowed quantitative estimates of
                                                                                                                leisure-time physical activity. Individuals who engaged in the equivalent of 150 min/wk of moderate-intensity
                  lines, studies with physical activity categorized categorically.                   comparisons; 9 studies),                             Quantincluding     0.51 (0.35–0.74)
                                                                                                                                                                                           a trend line                0 derived       2             fro
       .9

                                                                                                                leisure-time physical activity (minimum amount, 2008 US federal guidelines) had a 14% lower coronary heart disease
                                                                                                                                                                                    Relative                                      Studies,
                                                                                                                risk (relative risk, 0.86; 95% confidence interval, 0.77 to 0.96) compared with those reporting no leisure-time physical
                                                                                                                                     Men1-stage       All studies
                                                                                                     random effects,                                             GLST0.53            (0.42–0.67)
                                                                                                                                                                                 spline              analysis          0 for 2both sex
                                                                                                                activity. Those engaging in the equivalent of 300 min/wk of moderate-intensity leisure-time physical activity (2008 US
       .8

                                                                                                                                                                                                            2
                                                                                                 Type of Activity                    Sex                Studies                 Risk (95% CI)                      I,%                n*
                  .8

                                                                                                                federal guidelines for additional benefits) had a 20% (relative risk, 0.80; 95% confidence interval, 0.74 to 0.88) lower

      for women (based on population norms for weight). These intervals                              combined, isWomen               shown All         instudies
                                                                                                                                                               Figure 2. Pooled results indicated                                      1
                                                                                                                risk. At higher levels of physical activity, relative risks were modestly lower. People who were physically active at levels
                                                                                                                lower than the minimum recommended amount also had significantly lower risk of coronary heart disease. There was
                                                                                                                                                                                                                                                         t
                                                                                                 LTPA                           Combined All studies 0.74 (0.69 – 0.78) 28.3                                                         26
             .7
 Relative Risk

      were used as a guide to extend analyses to higher levels of LTPA to fit                        expectedPAinverse
                                                                                                  Occupational                   Combined      relation
                                                                                                                                                      All studies   between             LTPA and0CHD4risk. Ind
                                                                                                                                                                             0.84 (0.79–0.90)
                                                                                                                a significant interaction by sex (P!0.03); the association was stronger among women than men.
           Relative Risk

                                                                                                              Conclusions—These findings provide quantitative data supporting US physical activity guidelines that stipulate that “some
      the available data; higher doses were assigned to balance model                                                                                     Quant              0.71 (0.63–0.80) 39.8
                                                                                                                physical activity is better than none” and “additional benefits occur with more physical activity.” (Circulation. 2011; 9
                                                                                                     viduals who met                 Men the All        basicstudiesguideline0.87 (0.81–0.99)    had a 14%             0         lower 3        risk
       .6
                 .6

                                                                                                                124:789-795.)
      parsimony and goodness of fit.                                                                                                Men
         In a sensitivity analysis, we examined lower doses of physical activity                     CHD thanKeythose           Words:
                                                                                                                                  Women      whoAll
                                                                                                                                         coronary heart    studies
                                                                                                                                                      Allengaged
                                                                                                                                                          disease
                                                                                                                                                             studies
                                                                                                                                                                             0.78
                                                                                                                                                                    ! exercise      (0.73–0.82)
                                                                                                                                                                              in! meta-analysis
                                                                                                                                                                                   no       LTPA                (RR,  0 ! women
                                                                                                                                                                                                      ! physical activity
                                                                                                                                                                                                                               0.86; 15
                                                                                                                                                                                                                                       1 95% C
.5

                                                                                                     0.77 to                                              Quant              0.79 (0.72–0.86)                         0                 5
      (eg, 275 kcal/wk for both sexes combined) to test the statement in the                      Transport       PA 0.96),            whereas
                                                                                                                                 Combined                    those
                                                                                                                                                      Allof studies    heartwho
                                                                                                                                                                             0.87       metreviews
                                                                                                                                                                                     (0.74–1.02)      theor advanced81.0               4 guideli
                                                                                                          A      lthough  prevalence and  incidence rates    coronary            in numerous                     meta-analyses.       Although   all re-
                                                                                                                                                                                                                                         2– 8

                                                                                                                 disease (CHD) mortality have declined since the 1960s,          views agree that physical activity is associated with a 20% to
      2008 US guidelines that, in addition to recommending levels of physical                                                     Women              All
                                                                                                                                                      in thestudies   States 0.67   (0.61–0.74)                    12.5              11hasto
       .4

                                                                                                     haditareisliving
                                                                                                                aestimated
                                                                                                                      20%          lower
                                                                                                                                      million peoplerisk          (RR,         0.80;              95% of CHD, CI,            0.74                  0.88
                  .4

                                                                                                                            that "17
                                                                                                                                     Men              All studies
                                                                                                                                                              United
                                                                                                                                                                             0.9330%
                                                                                                                                                                                     (0.85–1.02)
                                                                                                                                                                                       lower risk
                                                                                                                                                                                                                    25.9
                                                                                                                                                                                                                    no work
                                                                                                                                                                                                                        7,8    to date
                                                                                                                                                                                                                                       3 designated
      activity, says, “All adults should avoid inactivity. Some physical activity                                      with CHD in 2010. Coronary heart disease causes           quantitative assessments of the amount of physical activity
                                                                                                                                               1

                                                                                                     Additionally                  lower          risks
                                                                                                          "425 000 annual deaths in the United States,    Quant
                                                                                                                                                              making it the 0.64
                                                                                                                                                                 ofand moderate     (0.52–0.79)
                                                                                                                                                                                 required
                                                                                                                                                                                               magnitude
                                                                                                                                                                                            for these lower risks, 40.6      were5 toobserv
                                                                                                                                                                                                                       referring instead    qualitative
                                                                                                                                  Women               All studies      char- 0.74    (0.57–0.97)
                                                                                                                                                                                          of physical activity 73.2  (eg, high versus2 low). Public
       .3

      is better than none, and adults who participate in any amount of activity                           leading cause of mortality   nationwide. Identifying
                                                                                                                                                         1                       levels                                                                8

      gain some health benefits.”9                                                                   among
                                                                                                 Walking
                                                                                                  Total   for publicthose
                                                                                                            time health and        withmedicine.
                                                                                                                                Combined       higherAll studies physical
                                                                                                          acterizing modifiable risk factors for CHD remain important
                                                                                                         PA                      Combined
                                                                                                                                  clinical            All studies            0.74foractivity
                                                                                                                                                                             0.71health
                                                                                                                                                                                    (0.59–0.84)
                                                                                                                                                                                     (0.62–0.90)
                                                                                                                                                                                      health benefits havelevels;  44.7 eg, there
                                                                                                                                                                                                                 relied0 on individual 3           was
                                                                                                                                                                                                                                        7studies rather
                                                                                                                                                                                         guidelines on the amount of physical activity required
                  .2

                                                                                                                                                                                 than a systematic assessment of the overall evidence.                     9

         We also assessed prespecified potential interaction by geographic                           25%Thelower         Clinicalrisk       for
                                                                                                                                   Perspective
                                                                                                                                     Men            those
                                                                                                                                                   on
                                                                                                                                                      All
                                                                                                                                                          795 active
                                                                                                                                                       p Quant
                                                                                                                                                             studies
                                                                                                                                                                             0.67atMany
                                                                                                                                                                the primary 0.79
                                                                                                                                                                                        5andearlytimes
                                                                                                                                                                                    (0.57–0.79)
                                                                                                                                                                                     (0.59–1.07)                the37.2the
                                                                                                                                                                                                   studies that assessed
                                                                                                                                                                                                                    18.9  basic        2 guidelin
                                                                                                                                                                                                                                        5 physical
                                                                                                                                                                                                                              relation between
       0 1 (North
      region    550 America,
                          1100 2     1650 Middle
                                    Europe,        3
                                                 2200                   4
                                                            2750adjustment
                                                         East),       3300       3850
                                                                                for        5
                                                                                          4400
                                                                                    confound-
                                                                                                                    independent role of physical activity in                     activity         CHD dichotomized      participants according  to their
                             Category   of Leisure−time   Physical Activity                          Amongprevention ofpersons
                                                                                                                                    Men      who
                                                                                                                           CHD is well established
                                                                                                                                                     All  were
                                                                                                                                                    and has
                                                                                                                                                           studies      physically
                                                                                                                                                              been assessed
                                                                                                                                  Women All studies 0.66 (0.44–0.99)         0.63   (0.34–1.17)
                                                                                                                                                                                 activity levels (eg,active        76.9at
                                                                                                                                                                                                       active versus inactive);
                                                                                                                                                                                                                       0
                                                                                                                                                                                                                               half
                                                                                                                                                                                                                                  however,the
                                                                                                                                                                                                                                       22            bas
                                                                                                                                                                                                                                            more recent

      ing (multivariate,Leisure−time
                             multivariatePhysical      Activity (Kcal/wk)
                                               inclusive    of intermediates), and CHD
                                                                                                     guideline level (275 kcal/wk),0.63                                        we(0.34–1.17)
                                                                                                                                                                                        found a 14%                76.9 lower                   risk
   Figure
Figure       1.
         2. Plot
      outcome   Plot  of
                 (fatal,   the
                    withnonfatal,relative
                            spline combined)risks
                                      (smoothed    of   coronary
                                                    using
                                                        fit) GLST
                                                             and 95% heart    disease
                                                                     splineconfidence   by
                                                                              models, evalu-      Nonspecific PA Combined AllQuant                           studies                                                                   12
                                                                                                                Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.

   category  P of  leisure-time      physical     activity.   All  study    categories               CHD (RR, 0.86;               Women95%                CI, 0.760.65         to 0.97).
                                                                                                                Received November 28, 2010; accepted June 2, 2011.
intervals
      ating(CIs)   of relative
                values              risks
                         for interaction    of   coronary
                                             terms              heart
                                                     with indicator     disease
                                                                        variables.   by kilo-
                                                                                     We  were     All studies                    Combined            All
                                                                                                                                                      All studies
                                                                                                                                                             studies 0.75 (0.55–0.76)(0.71–0.79) 47.6                 0              33†4
                                                                                                                From the Department of Epidemiology, Harvard School of Public Health, Boston, MA (J.S., J.P.); Channing Laboratory, Department of Medicine,
                                                                                                              Brigham and Women’s Hospital and Harvard Medical School, Department of Nutrition, Harvard School of Public Health, Boston, MA (E.L.D.); Division
   were   standardized       to   5 categories      for   ease   of  comparison.       The
calories
   size  of
           pertoweek
      unable
            the
                  assessof
                  data   point
                              leisure-time
                          potential    interaction
                                  corresponds
                                                  physical      activity
                                                      by age (!65
                                                     to  the   study
                                                                      or !65
                                                                       size;
                                                                            (LTPA).
                                                                               the
                                                                                  yearsGLST
                                                                                        of age
                                                                                    larger
                                                                                                         Using GLST spline Quant                           models,0.64         we(0.54–0.76)
                                                                                                                                                                                       observed                    significant          3 intera
                                                                                                              of Epidemiology, Genetics and Environmental Health Sciences, University of Texas Health Science Center–Houston, Department of Kinesiology and

                                                                                                                                                                                                                      0
                                                                                                              Health Education, University of Texas at Austin (H.W.K.); Stanford Center for Research in Disease Prevention, Stanford Medical School, Stanford, CA

    7
indicates   generalized
      at baseline)             least squares.
                     or race (white,     black, other) because there was insufficient                LTPA indicates leisure-time physical activity; I , percentage of variation          2
                                                                                                              (W.H.); Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Department of

   the dot is, the larger the sample size is. Dashed lines indicate                                  tion
                                                                                                 Walking      by sex
                                                                                                            pace
                                                                                                  across studies
                                                                                                                                 (P"0.03).
                                                                                                                                Combined
                                                                                                                                   is due to All
                                                                                                                                                          Figure
                                                                                                                                                           studies 3
                                                                                                              Epidemiology, Harvard School of Public Health, (I.-M.L.).
                                                                                                                Guest Editor for this article was Gregory Y.H. Lip, MD.
                                                                                                                            that                      heterogeneity
                                                                                                                                                                                shows
                                                                                                                                                                             0.53   (0.43–0.66)
                                                                                                                                                                                rather
                                                                                                                                                                                                   trend lines from
                                                                                                                                                                                            than chance;0 All studies,                  3 gende
                                                                                                                The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.110.
Gesundheitsförderung und Prävention durch Bewegung
Epidemiologische Evidenz
          - Typ 2 – Diabetes -
                                                                                     Diabetologia (2016) 59: 2527-2545
    Risikoreduktion pro 10 MET-Stunden pro Woche

                                                   Dosis an körperlicher Aktivität        Risikoreduktion

                                                   Pro 10 MET-Stunden/Woche               13% (95% CI 11 – 16%)

                                                   150 min moderat
                                                   11.25 MET-Stunden/Woche                26% (95% CI 20 – 31%)

                                                   300 min moderat                        36% (95% CI 27 – 46%)

                                                   60 MET-Stunden/Woche                   53%

8
Gesundheitsförderung und Prävention durch Bewegung
Epidemiologische Evidenz
- Neoplastische Erkrankungen -
 n = 1.44 Mio. Teilnehmer

 In 13 von 26 Tumorentitäten geringeres
 Risiko unter körperlicher Aktivität

 Bei 7 Tumorentitäten
 Risikoreduktion > 20%

                                          Moore et al. (2016) JAMA Intern Med 176: 816–825
Gesundheitsförderung und Prävention durch Bewegung
Epidemiologische Evidenz
- Sitzen und Sterblichkeitsrisiko -

                                            Lancet (2016) 388: 1302-1310

                                      STERN Nr. 16 20-04-2015
Epidemiologische Evidenz
- Inaktivität und Seelische Gesundheit
                                         Lancet Psychiatry (2020) 7: 262-271
„Polypill“ Körperliche Aktivität

                                        td.)
      Physical activity retard (12 MET-S

                     http://www.healthexpress.eu/de
Wirkmechanismen körperlicher Aktivität
        - Insulinresistenz -                                                                       Diabetes (1992) 41: 1091-1099
                                                       Wiederholte
                              Insulin                 Muskelkontraktion

                                                       ATP → ADP + P
            Insulinrezeptor                              Metformin
                                                 2 ADP → ATP + AMP

                                            AMP-aktivierte Kinase ­

                    GLUT-4

          Glukose              GLUT-4:
                               Glukosetransporter-4         Abbildung: nach König et al. Dtsch Z Sportmed (2006) 57: 242 – 247
Wirkmechanismen körperlicher Aktivität
                        - Kardiovaskuläre Erkrankungen –

Koronare Arteriosklerose im 12-monatigen Follow-up

                                                     Schuler et al. (2018) Eur Heart J 34: 1790–1799
Wirkmechanismen körperlicher Aktivität - Krebserkrankungen -

                                                    (2016)   23, 554–562

                                     Natürliche
                                     Killerzellen
Wirksamkeit körperlicher Aktivität
     - Qualitative Aspekte

     Kraft vs. Ausdauertraining

          Nieß & Thiel (2017) Diabetologie 12: 112-126

          Adapted from Pollok et al., 2001; Mandic et al., 2012
                       Fagard et al. 2006
Wirksamkeit körperlicher Cardio-metabolic risk factors adaptations in HIIE and MICT: A meta-analysis
Aktivität - Qualitative Aspekte                              VO2max

                                                             Flow-mediated Dilation

                                                             BMI

                                                             Body Mass

                                                             Body Fat
              Exerc Sport Sci Rev (2008) 36: 58-63           Systolic Blood Pressure

                                                             Diastolic Blood Pressure

                                                             HDL

                                                             LDL

                                                             Triglycerides

                                                             Total Cholesterol

                                                             C-reactive Protein

                                                             Fasting Insulin

                                                             Fasting Glucose

                                                             HbA1c

                                                             HOMA-IR

                            Mattioni et al. (under review)
Individuelle Trainierbarkeit

        Maximale Sauerstoffaufnahme                        Belastungs-Herzfrequenz          Nüchtern-Insulin

        n = 720
        Mean response: +384 ±202 ml VO2.

Bouchard & Rankinen (2001) Med Sci Sports Exerc 33: S446                             Bouchard et al. (2012) PLoS ONE 7: e37887

18
Individuelle Trainierbarkeit
                                                                                                                                                                                           PLoS ONE (2012) 7: e37887

                                                                                                                                        13,3%
Anteil Non-Responder (%)

                                                          8,3%

                                                                                                                                                                        Anteil Non – Responder für    1 RF: 31%
                                                                                                                                                                                                      2 RF: 6%
                            HERITAGE HERITAGE   DREW   INFLAME STRRIDE MARYLAND JYVASKYLA Total   HERITAGE HERITAGE   DREW   INFLAME STRRIDE MARYLAND JYVASKYLA Total
                                                                                                                                                                                                     3-4 RF: 0,8%
Anteil Non-Responder (%)

                                                                                                                                12,2%
                                                            10,3%

                            HERITAGE HERITAGE   DREW   INFLAME STRRIDE MARYLAND JYVASKYLA Total   HERITAGE HERITAGE   DREW   INFLAME STRRIDE MARYLAND JYVASKYLA Total
Individuelle Trainierbarkeit

                               n = 202 Personen mit Typ-2-Diabetes

                               9-monatiges Trainingsintervention
                               3-5 x Ausdauer-/Kraft-/Kombitraining/Woche
                                          bei 50-80% VO2peak

20
Individuelle Trainierbarkeit
     J Physiol (2017) 595: 3377-3387
                                       Alles nur eine Frage der Dosis ?

                                            Gabriel & Zierath (2017) Cell Metabol 25: 1000-1011

21
Vom vom Trainingsreiz zur Trainingsanpassung

Reiz                      mechanischer               metabolischer                neuronaler          hormoneller
                                                                                                                           Modulatoren:

Auslenkung                  z.B. ­Tension       ¯O2 ¯ATP/AMP ­Laktat ­FFA ROS­ ­Ca 2+
                                                                                                                            Stressresponse
Homöostase
                           z.B.    MAPK        HIF-1a      AMPK          PPARag            PGC-1a      NFAT
Signaling
                                                                                                                            Genetics
                            Zellkern
                                                                                                                            Epigenetics
Transkription

Translation

                  z.B. Muskelfaser-                 Fettsäure-/Glukose             Mitochondriale           Gefäßwachstum
                       Transformation                Stoffwechsel                    Biogenese               -regulation

       modifiziert nach: M. Flück (2006) J Exp Biol 209: 2239 • Hood et al. (2006) J Exp Biol 209: 2265 • Yan et al. (2011) J Appl Physiol 110: 264
Zusammenfassung

Große Evidenz zur Wirksamkeit körperlicher Aktivität aus epidemiologische Studien
mit Hinweisen zu Dosis-Wirkungsbeziehung (Gruppeneffekte) als robuste Basis für
Empfehlungen zur aktivitätsbasierten Prävention

Wachsende Erkenntnisse zu den zugrundeliegenden Mechanismen körperlicher Aktivität
bei der Risikoreduktion mit präzisierenden Hinweisen zur Dosis-Wirkungsbeziehung und
Reizqualität sowie unter entitätsspezifischen Gesichtspunkten

Individuelle Dosis-Wirkungsbeziehung körperlicher Aktivität als „offene Flanke“ in der
aktivitätsbezogenen Prävention mit der Notwendigkeit des Verfolgens interdisziplinärer
Forschungsansätze

23
Vielen Dank für Ihre
Aufmerksamkeit

04.05.20
© UNIVERSITÄTSKLINIKUM TÜBINGEN.
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