Arterial stiffness is an important biometric in predicting cardiovascular diseases, since mechanical properties serve as indicators of several pathologies such as e.g. atherosclerosis. Shear Wave Elastography (SWE) could serve as a valuable non-invasive diagnostic tool for assessing arterial stiffness, with the technique proven efficient in large homogeneous tissue. However the accuracy within arterial applications is still uncertain, following the lack of proper validation. Therefore, the aim of this study was to assess the accuracy of SWE in arterial phantoms of poly(vinyl alcohol) cryogel by developing an experimental setup with an additional mechanical testing setup as a reference method. The two setups were developed to generate identical stress states on the mounted phantoms, with a combination of axial loads and static intraluminal pressures. The acquired radiofrequency-data was analysed in the frequency domain with retrieved dispersion curves fitted to a Lamb-wave based wave propagation model. The results indicated a significant correlation between SWE and mechanical measurements for the arterial phantoms, with an average relative error of 10 % for elastic shear moduli in the range of 23 to 108 kPa. The performed accuracy quantification implies a satisfactory performance level and as well as a general feasibility of SWE in arterial vessels, indicating the potential of SWE as a future cardiovascular diagnostic tool.

The risk of having a disability increases with advancing age and as the life expectancy is growing worldwide, the number of people living with disability is expected to increase, as well as the number of years lived with disability. Low back pain and sarcopenia are health problems that present a higher prevalence with aging. While low back pain is a symptom, sarcopenia is considered a geriatric syndrome. However, both issues constitute a significant health burden in older adults. Although there are many research studies investigating low back pain, the participation of older adults is often missing from these studies, preventing the generalization of the findings to this population, and leaving some questions unanswered. On the other hand, sarcopenia is a new research field with gaps to fill and flaws to correct. Questions related to low back pain management in older adults, the inclusion of this population in clinical trials, the presence of association between sarcopenia and low back pain and questions pertaining the diagnosis and measurement of sarcopenia have yet to be fully addressed by researchers. The broad aim of this thesis therefore was to contribute to a better understanding concerning low back pain and sarcopenia in older adults by performing studies in these key research areas. Different interventions are presented in clinical practice guidelines for the treatment of low back pain. However, these recommendations are based on clinical trials investigating young and middle-aged adults and as a result, the recommendations do not encompass older adults. Therefore, a systematic review was performed with the objective of assessing the effectiveness of interventions for low back pain in older adults ≥ 60 years (Chapter 3). Eligible studies were identified via searches in Medline, EMBASE, CINAHL, LILACS, PEDro, and Cochrane CENTRAL. A total of 18 randomized controlled trials fulfilled the eligibility criteria and the results from eight trials were pooled in a meta-analysis to test the effectiveness of complementary health approaches (i.e., manual therapy, acupuncture, mindfulness, yoga). Evidence about interventions to manage non-specific low back pain in older adults was found to be weak. Very low to moderate quality evidence showed that complementary health approaches, percutaneous electrical nerve stimulation, education, exercise, or pharmacological agents did not produce a clinically significant reduction in pain and disability at short and intermediate terms compared to sham, usual care, or minimal intervention. Interventions were often not well described and the risk of bias was moderate (average of 6.4 on the 10-point PEDro Scale (SD = 1.44)). Evidence about interventions for non-specific low back pain in older adults is limited and new studies are highly likely to change these results. Participation of older adults in clinical trials pertaining to the management of low back pain has been limited. Usually, the exclusion of older adults from clinical trials is based solely on an arbitrary age limit. Therefore, an investigation concerning the potential increased inclusion of older adults in upcoming clinical trials was conducted (Chapter 4). Chapter four presents an analysis of the International Clinical Trial Registry Platform database from the World Health Organization performed to verify the participation of older adults in registered clinical trials. A total of 167 clinical trial protocols for low back pain with registration dates from January 2015 through November 2018 were planning to recruit participants older than 65 years. However, only five registered trials (2.99%; pooled sample = 169 participants) were designed to target this population specifically. The exclusion of older participants was not formally justified and imposed through an arbitrary upper-age limit in 93.6% of the protocols. Most studies planning to include older adults were interested in pharmacologic interventions, devices/technology, and physical rehabilitation, and were to be carried out in developed regions. However, older adults with low back pain will continue to be under-investigated in clinical trials for low back pain in the near future. Although a slight increase in the participation of older adults in clinical trials was observed, the improvement is small and some questions still need an answer. Therefore, a survey investigating whether researchers recognize the exclusion of older adults from clinical trials, its impact, and justifications to support this exclusion was realized (Chapter 5). All attendees of the 2017 International Back Forum were invited by email to answer an electronic survey about their opinions regarding participation of older adults in clinical trials for low back pain. Approximately 90% of those who answered the questionnaire were engaged with back research, with more than a half having done or doing a clinical trial for low back pain. Most of the respondents believed that older people are excluded from clinical trials for low back pain and that exclusion based solely on age is not justifiable. About two thirds of the respondents reported that the exclusion of older people from clinical trials can impose a barrier in offering evidence-based interventions to this population. More researchers are planning to include older adults in their current/future trials compared to their previous work. An increase in the investigation of older adults in clinical trials is expected in the future which may optimize the development of evidence-based interventions for this population. As early evidence suggests an association between sarcopenic markers and low back pain, the association between the diagnosis of sarcopenia and low back pain still needs to be investigated (Chapter 6). Therefore, a study investigating the association between sarcopenia using different diagnosis criteria and low back pain in older adults was performed. Data from 12,646 older adults (50.1% men, 49.9% women) ≥ 65 years of age that participated in the Canadian Longitudinal Study on Aging (CLSA) were analyzed. The prevalence of low back pain in the past 12 months as well the prevalence of sarcopenia assessed through different definitions, and the number of comorbidities and depressive symptoms were included in the analysis. Associations between sarcopenia, comorbidities and lifestyle factors with low back pain were examined using multivariate logistic regressions. Prevalence of low back pain was 16.3% and the prevalence of sarcopenia varied among sarcopenia definitions and the presence of low back pain. Participants with low back pain had higher prevalence of pre-sarcopenia and sarcopenia compared to those without low back pain based on the International Working Group on Sarcopenia (x2 = 20.25, p < 0.001) and the Foundation National Institute of Health definitions (x2 = 13.83, p < 0.001). The odds of having low back pain was higher among those with sarcopenia based on the Foundation National Institute of Health criterion (OR 1.28, 95%CI 1.0-1.64). These results suggest that sarcopenia may influence low back pain in older adults and future studies should consider to test whether the association between sarcopenia and low back pain is causal. Current clinical practice guidelines recommend to divide patients with low back pain in specific subgroups to provide a targeted intervention. However, despite older adults presenting specific age-related characteristics that could classify them as a subgroup, this population has been neglected. Sarcopenia is a muscle disease affecting older adults and is diagnosed with the presence of a reduction in muscle strength and muscle quantity/quality. Although low back pain has been shown to be associated with muscle dysfunction, the role of sarcopenia in relation to low back pain is unknown. An experiment comparing sarcopenic markers (grip strength and gait speed), muscle activity and elasticity between older adults with and without chronic low back pain was conducted (Chapter 7). The anticipatory activity of transversus abdominis muscle during the rapid arm abduction test, transversus abdominis muscle elasticity, grip strength and gait speed were collected from a group of older adults (≥ 60 years) with chronic low back pain (≥ 3 months) and the results compared with a control group of matched older adults without low back pain. Participants with chronic low back pain presented with a reduction in the sarcopenic markers compared with the controls: grip strength (mean difference (MD) = 5.3Kg, 95%CI = 1.5-9.0, p = 0.006), gait speed (MD = 0.21m/s, 95%CI = 0.10-0.31, p<0.001), as well as a delay in activation of transversus abdominis (p = 0.002). A delay in transversus abdominis muscle activation, and a reduction in muscle strength and gait speed were observed in older adults with chronic low back pain compared to subjects without back complaints. These findings show an association between muscle dysfunction and chronic low back pain in older adults. Although the definition of sarcopenia was recently updated establishing muscle strength as the key criteria surpassing the role of muscle mass, there remains confusion regarding its diagnosis and the comparison of estimates is problematic. Therefore, a systematic review assessing how sarcopenia is measured and defined in population-based studies was performed. Chapters 8 and 9 describe the protocol of a systematic review and the full systematic review respectively. The databases Medline, EMBASE, CINAHL, Web of Science (Core Collection), and Google Scholar were searched for observational population-based studies reporting prevalence of sarcopenia in community dwelling older adults. Descriptive statistics were used to present data pertaining to sarcopenia definition and measurement tools, and the quality-effects model for meta-analysis of pooled prevalence. Results found seven different operational definitions of sarcopenia and a variety of measurement tools applied to assess the sarcopenic markers: muscle mass, muscle strength and physical performance. The prevalence of sarcopenia varied between the definitions, with general estimates ranging from 5% based on the European Working Group on Sarcopenia in Older People (EWGSOP1) criterion to 17% with the International Working Group on Sarcopenia criterion. The use of different measurement tools to assess muscle mass, strength and physical performance resulted in variations within definitions ranging from 1 to 7%, 1 to 12% and 0 to 22%, respectively. The criteria used to define sarcopenia, as well as the measurement tools used to assess sarcopenic markers has an influence in the prevalence of sarcopenia. The establishment of a unique definition for sarcopenia, the use of methods that guarantee an accurate evaluation of muscle mass, and the standardization of measurement tools are necessary to allow a proper diagnosis and comparison of sarcopenia prevalence among populations.

京都大学 / 0048 / 新制・課程博士 / 博士(人間健康科学) / 甲第19970号 / 人健博第38号 / 新制||人健||3(附属図書館) / 33066 / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 杉本 直三, 教授 精山 明敏, 教授 黒田 知宏 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

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Magnetic resonance imaging is a non-invasive imaging modality that is used to produce detailed images of soft tissues within the human body. Typically, MRI scanners used in the clinical setting are high field systems because they have a magnetic field strength greater than 1.5 Tesla. The high magnetic field offers the benefit of high spatial resolution and high SNR. However, low filed systems can also produce high resolution MR images with the added benefit of imaging stiffer samples. In this study, a low field 0.5 T MR system was used to image various samples to demonstrate the capability of the low field system in acquiring MR images with resolution comparable to high field systems. Furthermore, the MR system was modified to one capable of performing low field MR Elastography (MRE), a technique that can non-destructively measure the mechanical properties of soft samples. Agarose gel phantom of 0.5% wt. and 1.0% wt. were used to validate the MRE system. Additionally, a rat brain was used to assess the sensitivity of the MRE system in measuring the mechanical properties of small tissues. The results illustrated that the low field MR system can acquire high resolution images and provide sufficient tissue contrast (e.g through long TE times (80 ms), which is not possible with high field systems). MRE results on gel phantoms illustrated the capability of the low field system to accurately measure the mechanical properties and the MRE testing of rat brain demonstrated the potential of the system to study biological tissues. Finally, the capability of low field MRI and MRE to assess the growth of tissue engineered bone has the potential to transform the field of tissue engineering.

Genom att generera mer information om hälsenan i form av dess elasticitet kan förhoppningsvis fler slutsater nås gällande diagnostik och behandling. Elastografi med hjälp av ultraljud skulle kunna vara en metod för att bidra med denna information. För att utföra detta anpassades en mjukvara utifrån ett grundläggande basprogram för elastografimätningar, utvecklat av företaget Verasonics, för att kunna utföra elastografi av hälsenan genom programmering i matlab. Tidigare undersökningsmetoder för elastografi är utvecklade för större organ, varför anpassningen innebar att använda metoder som även ger tillförlitlig information för mindre organ. För att göra detta anpassades först mjukvaran för en mindre fantom med liknande djup som hälsenan. När det konstaterats att skjuvningsvågor genererats på rätt avstånd kunde sedan mätningar göras på hälsenan. Genom att bestämma hastigheten av de genererade skjuvningsvågorna kunde sedan skjuvmodulen, följt av elasticitetsmodulen, beräknas för vävnaden. Denna bestämdes först genom grupphastigheten av skjuvningsvågorna, vilket är den metod som används vid större organ, följt av fashastigheten av skjuvningsvågorna vilket tar hänsyn till vågens dispersion. Detta gav då hälsenans elasticitetsmodul enligt grupphastighet samt fashastighet som sedan kunde jämföras. Slutligen gick det att konstatera att elasticitetsmodulen kommer att variera beroende på vilken typ av hastighet denna härleds från. Detta indikerar då på att sjuvningsvågen interagerar med organets gränsyta vilket orsakar dispersion. / Generating more information about the achilles tendon, such as its elasticity, will hopefully lead to more conclusions and results within both diagnostics as well as treatment. Elastography by ultrasound could be a method to contribute with this information. To do so, a basic software,provided and developed by the company Verasonics for elastography was specialized to fit the achilles tendon by programing in matlab. Earlier methods to perform elastography are developed for larger organs, hence the adjustment will include methods that acquire trustworthy information from smaller organs. To do so the adjustment of the software was first made to work on a smaller phantom with similar symmetry as the achilles tendon. When it was confirmed that shear waves were generated at the correct distance this enabled further measurements on the achilles tendon. By deciding the speed of the generated shear waves the shear modulus, followed by the elastic modulus, could then be estimated for the tissue. This was first decided by the group velocity of the shear waves, as the usual method done on larger organs, followed by the phase velocity that also takes dispersion in mind. The result could then be used to obtain the elastic modulus of the achilles tendon based on group and phase velocity for further comparison.The conclusion was then that the elastic modulus will depend on what kind of velocity it is derived from. This indicates that the shear wave interacts with the organ's boundaries which causes dispersion.

This thesis is comprised of two studies. The objective of the first study was to find the frequency response and stiffness of the biceps brachii muscle group during recovery from exercise induced damage and to determine whether these data could be used to track muscle recovery by correlating changes in the frequency response with changes in muscle stiffness. Stiffness moduli were collected using Shear Wave Elastography (SWE) which were then applied to a proportional first mode frequency analysis. Data were collected for the muscle stiffness and frequency response for fifteen subjects (25.6 +- 4.5). By comparing the proportion of the square root of the SWE results, the variation in stiffness showed a less than 2 Hz change in first mode resonance for the control group. Frequency response results for the control group agreed with the modified SWE results and the proportion analysis. SWE results for the damage protocol group showed an average increase of 4 Hz. Frequency response results for the damage protocol group were sorted into three categories: three subjects had a change in frequency of peaks of at least 4 Hz in the positive direction; four subjects had an increase in amplitude, but no change in frequency of peaks; three subjects showed mixed responses like fewer resonance peaks, variable amplitudes, changes in peak bandwidth. This research allowed for the documentation of the in-vivo frequency response of the biceps brachii muscle. We believe that the frequency response of a muscle group may be used in the future to evaluate recovery from exercise induced damage. Lessons learned were also recorded for helping future studies in their efforts using an SLDV with human body testing.The second study focused on finding the effects on the surface velocity of tissue above and below a region of the lower leg wrapped in an elastic band when excited by an external source. Ten male subjects between the ages of 18-25 were seated in a chair with one foot placed on a vibrating platform. Two excitation frequencies were separately applied while three points along the leg were measured. A repeatability analysis, using results without the leg wrap, showed a 6.5%, 2.5%, and 10.5% variance in the x-, y-, and z-directions respectively, applying a 20 Hz frequency. With a 40 Hz frequency, the variations were 24%, 23.8%, and 28.4% respectively. A change in displacement of +38% and +10% occurred above the knee in the x-direction with 40 Hz and in the y-direction with 20 Hz, respectively. A change in displacement of -20% occurred below the knee in the x-direction with 20 Hz. A change in displacement of -24% occurred below the wrap location in the y-direction with 40Hz. With a confidence interval of 93%, surface velocity of the tissue located above the wrap increased, while the surface velocity of the tissue below the wrap decreased.

Patient-reported outcomes are important in nonalcoholic fatty liver disease (NAFLD). Pruritus is of special interest for evolving therapies with farnesoid X receptor (FXR) agonists. The aim of this study was to investigate the prevalence of pruritus in a real-life NAFLD cohort and analyze associations with anxiety and depression. Pruritus was assessed using a visual analogue- (VAS) and 5-D itch-scale (5-D). Anxiety and depression were evaluated by Beck’s-Depression-Inventory (BDI) and the Hospital Anxiety and Depression Scale (HADS-A, HADS-D). An optimal logistic regression model was found with a stepwise procedure to investigate variables associated with pruritus. In total, 123 NAFLD patients were recruited. VAS and 5-D were highly correlated (Spearman’s correlation coefficient 0.89). Moderate/severe pruritus was reported in 19% (VAS) and 21% (5-D) of patients. Anxiety and depression were present in 12% and 4% (HADS-A and HADS-D, respectively) and 12% (BDI) of cases. There was a significant association between VAS and BDI (p = 0.019). The final multivariate model for 5-D included diabetes mellitus (OR 4.51; p = 0.01), BDI (OR 5.98; p = 0.024), and HADS-A (OR 7.75; p = 0.011). One-fifth of NAFLD patients reported moderate or severe pruritus. 5-D was significantly associated with diabetes mellitus, depression, and anxiety. These findings should be tested in larger populations and considered in candidates for treatment with FXR agonists.

Aim: This study aims to assess the association of biomechanical characteristics of carotid walls and carotid intima-media thickness (IMT), as assessed by ultrasound, when incorporated into prediction models for coronary CT plaque burden in both people living with HIV (PLWH) and HIV-negative control individuals. Methods: In this cross-sectional study, 164 participants (mean age 57 years ± 8 years; 134 males) with low to intermediate cardiovascular risk were recruited from the ongoing prospective Canadian HIV and Aging Cohort Study (CHACS). Among the 164 recruited participants, a total of 154 individuals (mean age, 56.5 years ± 7.55 years; 83 PLWH, 54%; 137 males; 88%) were evaluated. Ten participants were excluded due to unavailable coronary plaque data. The mean time interval between coronary CT and carotid ultrasound per participant was 7.69 ± 20.1 months. Using ultrasound, cumulated axial strain, cumulated shear strain, cumulated axial translation, cumulated lateral translation, and IMT of the common and internal carotid arteries were measured. Participants also underwent cardiac CT for coronary plaque assessment. Univariate and multivariate Poisson regression analyses with robust variance were performed to identify independent associations of cardiovascular risk factors, IMT, and elastography parameters with coronary plaque presence. Receiver operating characteristic (ROC) curve analysis and the area under the curve (AUC) were used to compare different prediction models for coronary plaque presence. Results: The study included 83 PLWH and 71 controls (N=154). The median 10-year Framingham risk score was 12% [IQR, 8 - 16] in PLWH and 9% [IQR, 7 - 15] in controls (p = 0.045). In the PLWH group, coronary plaques were observed in 55 participants (61.1%) compared to 42 (56.8%) in the non-HIV control group (p = .46). Carotid IMT and all elastography features for both the internal and common carotid arteries were similar between PLWH and healthy volunteers. 4 After adjusting for cardiovascular risk using multivariate Poisson regression, smoking exposure was significantly associated with coronary plaque presence on CT (prevalence ratio 1.10, 95% CI 1.04 – 1.13, p < 0.001). No significant associations were found with other coronary artery disease risk factors or HIV status in multivariate analysis. Carotid elastography parameters and carotid intima-media thickness were not associated with coronary atherosclerosis after adjustment. AUC analyses did not reveal any significant differences in predictive accuracy between models when adding either elastography parameters, IMT, or both elastography parameters and IMT results to the cardiovascular risk factor model, with AUC ranging from 0.647 to 0.681 in all models. Conclusion: In our study, models incorporating carotid elastography and IMT did not enhance the prediction of coronary plaque presence in PLWH or controls, compared to models including only traditional cardiovascular risk factors. Key words: HIV, computed tomography, angiography, us elastography, atherosclerosis / Objectif: Évaluer l’association des caractéristiques biomécaniques des parois carotidiennes et de l'épaisseur intima-média (EIM) « Intima-media Thickness » (IMT) carotidienne, telles qu'évaluées par échographie, lorsque celles-ci sont incluses dans les modèles de prédiction de la charge de plaque coronarienne évaluée par tomodensitométrie (CT) chez les personnes vivant avec le VIH (PVVIH) et les personnes contrôles séronégatives. Méthodes : Dans notre étude transversale, 164 participants (âge moyen 57 ans ± 8 ans ; 134 hommes) présentant un risque cardiovasculaire faible/intermédiaire ont été recrutés, provenant tous de l’étude prospective Cohorte canadienne VIH et vieillissement (CHACS, Canadian HIV an Aging Cohort Study). Parmi les 164 participants recrutés, un total de 154 participants (âge moyen, 56.5 ans ±7.55 ans; 83 PPLWH, 54 %; 137 hommes; 88%) ont été évalués. Dix participants ont été exclus en raison de données de plaques non disponibles. L’intervalle de temps moyen entre le CT et l’élastographie carotidienne était de 7.7 ± 20.1 mois Avec l’imagerie par ultrasons, nous avons mesuré la déformation axiale cumulée, la déformation de cisaillement cumulée, la translation axiale cumulée, la translation latérale cumulée et l'IMT des artères carotides commune et interne. Les participants ont également subi une tomodensitométrie cardiaque pour l'évaluation de la plaque coronarienne. Des analyses de régression de Poisson univariées et multivariées avec une variance robuste ont été réalisées pour identifier comment les facteurs de risque cardiovasculaire, les paramètres IMT et élastographie sont indépendamment associés à la présence de plaque coronarienne. La fonction d’efficacité du récepteur (« caractéristique de fonctionnement du récepteur ») (ROC, receiver operating characteristic) et l'analyse de l'aire sous la courbe (AUC, area under the curve) ont également été utilisées pour comparer différents modèles de prédiction de la présence de plaque coronarienne. Résultats: Il y avait 83 PVVIH et 71 contrôles (N=154). Le score médian de risque de Framingham sur 10 ans était de 12% [IQR, 8 - 16] chez les PLWH and de 9% [IQR,7 -15] chez les témoins (p = 0.045). Dans le groupe PVVIH, des plaques coronaires étaient présentes chez 55 participants (61,1 %) contre 42 (56,8 %) dans le groupe contrôle non VIH (p = 0,46). 2 Après ajustement pour les facteurs de risque cardiovasculaire, on note que le tabagisme est associé à la présence de plaque coronarienne (ratio de prévalence 1.10, 95% CI 1.04 – 1.13, p < 0.001). Aucune autre association significative n’a été démontré avec d’autres facteurs de risque cardiovasculaire, ou avec le statut VIH, dans les analyses multivariées. L’analyse multivariée démontre que l'ajout des données d’IMT ou d’élastographie n'augmente pas la précision des modèles, au-delà du modèle n’incluant que les facteurs de risque traditionnels. Les analyses des courbes ROC et AUC n'ont montré aucune différence significative dans la précision prédictive entre les modèles qui incluent les paramètres d'élastographie, d'IMT et les facteurs de risque cardiovasculaire, versus les modèles qui n’incluent que les facteurs de risque cardiovasculaire, avec des AUC allant de 0,65 à 0,68. Conclusion: Dans notre étude, les modèles incluant l'élastographie carotidienne et l'IMT n'ont pas montré d’augmentation de la prédiction de la présence de plaque coronarienne chez les PVVIH ou les contrôles, en comparaison aux modèles incluant uniquement les facteurs de risque traditionnels.

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