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Background: This study evaluated, as a snapshot, the variability in quantification and image quality (IQ) of the clinically utilized PET [ 18 F]FDG whole-body protocols in Finland using a NEMA/IEC IQ phantom permanently filled with 68 Ge., Methods: The phantom was imaged on 14 PET-CT scanners, including a variety of models from two major vendors. The variability of the recovery coefficients (RC max , RC mean and RC peak ) of the hot spheres as well as percent background variability (PBV), coefficient of variation of the background (COV BG ) and accuracy of corrections (AOC) were studied using images from clinical and standardized protocols with 20 repeated measurements. The ranges of the RCs were also compared to the limits of the EARL 18 F standards 2 accreditation (EARL2). The impact of image noise on these parameters was studied using averaged images (AVIs)., Results: The largest variability in RC values of the routine protocols was found for the RC max with a range of 68% and with 10% intra-scanner variability, decreasing to 36% when excluding protocols with suspected cross-calibration failure or without point-spread-function (PSF) correction. The RC ranges of individual hot spheres in routine or standardized protocols or AVIs fulfilled the EARL2 ranges with two minor exceptions, but fulfilling the exact EARL2 limits for all hot spheres was variable. RC peak was less dependent on averaging and reconstruction parameters than RC max and RC mean . The PBV, COV BG and AOC varied between 2.3-11.8%, 9.6-17.8% and 4.8-32.0%, respectively, for the routine protocols. The RC ranges, PBV and COV BG were decreased when using AVIs. With AOC, when excluding routine protocols without PSF correction, the maximum value dropped to 15.5%., Conclusion: The maximum variability of the RC values for the [ 18 F]FDG whole-body protocols was about 60%. The RC ranges of properly cross-calibrated scanners with PSF correction fitted to the EARL2 RC ranges for individual sphere sizes, but fulfilling the exact RC limits would have needed further optimization. RC peak was the most robust RC measure. Besides COV BG , also RCs and PVB were sensitive to image noise., (© 2023. The Author(s).)

Therapeutic angiogenesis induced by gene therapy is a promising approach to treat patients suffering from severe coronary artery disease. In small experimental animals, adeno-associated viruses (AAVs) have shown good transduction efficacy and long-term transgene expression in heart muscle and other tissues. However, it has been difficult to achieve cardiac-specific angiogenic effects with AAV vectors. We tested the hypothesis whether AAV2 gene transfer (1 × 10 13  vg) of vascular endothelial growth factor B (VEGF-B186) together with immunosuppressive corticosteroid treatment can induce long-term cardiac-specific therapeutic effects in the porcine ischemic heart. Gene transfers were delivered percutaneously using direct intramyocardial injections, improving targeting and avoiding direct contact with blood, thus reducing the likelihood of immediate immune reactions. After 1- and 6-month time points, the capillary area was analyzed, myocardial perfusion reserve (MPR) was measured with radiowater positron emission tomography ([ 15 O]H 2 O-PET), and fluorodeoxyglucose ([ 18 F]FDG) uptake was used to evaluate myocardial viability. Clinical chemistry and immune responses were analyzed using standard methods. After 1- and 6-month follow-up, AAV2-VEGF-B186 gene transfer failed to induce angiogenesis and improve myocardial perfusion and viability. Here, we show that inflammatory responses attenuated the therapeutic effect of AAV2 gene transfer by significantly reducing successful transduction and long-term gene expression despite the efforts to reduce the likelihood of immune reactions and the use of targeted local gene transfer methods., (© 2022. The Author(s).)

Background: Very recently, cognitively normal, middle-aged adults with severe obstructive sleep apnea (OSA) were shown to have regional cortical amyloid-β deposits. In the normal brain, amyloid tracer (e.g., [11C]-PiB) uptake is observed in white matter (WM) but not in cortical gray matter (GM), resulting in clear GM-WM contrast. There are no reports on possible changes in this contrast in severe OSA., Objectives: Evaluate changes in the global [11C]-PiB GM-WM contrast and study if factors reflecting clinical and imaging characteristics are associated with them., Design and Setting: Cross-sectional imaging study., Participants: 19 cognitively intact middle-aged (mean 44 years) patients with severe OSA (Apnea-Hypopnea Index >30/h), carefully selected to exclude any other possible factors that could alter brain health., Measurements: Detailed neuroimaging (amyloid PET, MRI). Signs of possible alterations in amyloid tracer GM-WM contrast and kinetics were studied with static and dynamic [11C]-PiB PET and WM structures with detailed 3.0T MRI., Results: Static [11C]-PiB PET uptake showed significantly decreased GM-WM contrast in 5 out of 19 patients. This was already clearly seen in visual evaluation and also detected quantitatively using retention indexes. Dynamic imaging revealed decreased contrast due to alterations in trace accumulation in the late phase of [11C]-PiB kinetics. Decreased GM-WM contrast in the late phase was global in nature. MRI revealed no corresponding alterations in WM structures. Importantly, decreased GM-WM contrast was associated with smoking (p = 0.007) and higher Apnea-Hypopnea Index (p = 0.001)., Conclusions: Severe OSA was associated with decreased GM-WM contrast in amyloid tracer uptake, with significant correlation with clinical parameters of smoking and AHI. The results support and further extend the current understanding of the deleterious effect of severe OSA on proper amyloid clearance, possibly reflecting dysfunction of the brain glymphatic system., Competing Interests: None of the authors have any financial or other substantial COI that might be construed to influence the results or interpretation of the manuscript. Salla Ylä-Herttuala: No conflict of interest; Mikko Hakulinen: No conflict of interest; Pekka Poutiainen: No conflict of interest; Jyrki Lötjönen: No conflict of interest; Mervi Könönen: No conflict of interest; Heidi Gröhn: No conflict of interest; Ritva Vanninen: No conflict of interest; Hanna Mussalo: No conflict of interest; Tomi Laitinen: No conflict of interest; Esa Mervaala: No conflict of interest.

Vascular endothelial growth factor B (VEGF-B) is an interesting therapeutic candidate for coronary artery disease. However, it can also cause ventricular arrhythmias, potentially preventing its use in clinics. We cloned VEGF-B isoforms with different receptor binding profiles to clarify the roles of VEGFR-1 and Nrp-1 in angiogenesis and to see if angiogenic properties can be maintained while avoiding side effects. VEGF-B constructs were studied in vivo using adenovirus (Ad)-mediated intramyocardial gene transfers into the normoxic and ischemic porcine heart (n = 51). It was found that the unprocessed isoform VEGF-B186R127S is as efficient angiogenic growth factor as the native VEGF-B186 in normoxic and ischemic heart. In addition, AdVEGF-B186R127S increased myocardial perfusion reserve by 22% in ischemic heart without any side effects. AdVEGF-B127 (VEGFR-1 and Nrp-1 ligand) and AdVEGF-B109 (VEGFR-1 ligand) did not induce angiogenesis. Thus, VEGF-B186 is angiogenic only before its proteolytic processing to VEGF-B127. Only the VEGF-B186 C-terminal fragment was associated with arrhythmias., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Background: Spinal surgeries are the leading causes for patient settlement issues. Recent European Medical Device Regulations aims to reduce complications by enforcing that surgical tools are validated before clinical use. Human cadavers are favored in preclinical use, but due to anatomic variance, decay, and scarce supply, alternative synthetic and animal models are used. This study evaluates the fidelity and validity of porcine models in training and assessment of microsurgical decompressive techniques in the lumbar spine., Methods: Anatomic dimensions of 10 human and 5 young pig spines were assessed from computed tomography images. Novel "en bloc" fresh-frozen ex vivo porcine model tissues' fidelity and validity for decompressive surgery was evaluated by 3 expert neurosurgeons, in comparison with other models., Results: The pigs' anatomic dimensions were on average 11% smaller than in humans. The pigs' L4-L5 was most alike humans, and the highest similarity was in lamina and spinous process widths, and the skin to posterior longitudinal ligament distance. Dimensional variability was higher in humans (F = 19.06-0.56, P < 0.05). The pigs' tissues were felt as good as living patients and better than cadavers for skin, fascia, bone, facets, ligamentum flavum, and dura, but poor for vessels (experts' intraclass correlation coefficient = 0.696-0.903). The pig models' validity for assessing drills' adverse features (friction, jitter, heating, and soft tissue trauma) was reported to be unanimously excellent., Conclusion: Pigs are representative for assessing microsurgical decompression techniques in the lower lumbar spine. The novel "en bloc" pig model can be an asset for industries and clinicians during assessment and training of new spinal techniques., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The suggested association between severe obstructive sleep apnea (OSA) and risk of Alzheimer's disease (AD) needs further study. Only few recent reports exist on associations between brain amyloid-β (Aβ) burden and severe OSA in middle-aged patients., Objective: Examine the possible presence of cortical Aβ accumulation in middle-aged patients with severe OSA., Methods: We performed detailed multimodal neuroimaging in 19 cognitive intact patients (mean 44.2 years) with severe OSA (Apnea-Hypopnea Index >30 h-1). Known etiological factors for possible Aβ accumulation were used as exclusion criteria. Aβ uptake was studied with [11C]-PiB-PET, glucose metabolism with [18F]-FDG-PET, and structural imaging with 3.0T MRI., Results: When analyzed individually, in [11C]-PiB-PET a substantial number (∼32%) of the patients exhibited statistically significant evidence of increased cortical Aβ uptake based on elevated regional Z-score values, mostly seen bilaterally in the precuneus and posterior cingulum regions. Cortical glucose hypometabolism in [18F]-FDG-PET was seen in two patients. MRI did not show structural changes suggestive of AD-related pathology., Conclusion: Increased [11C]-PiB uptake was seen in middle-aged cognitively intact patients with severe OSA. These findings are similar to those described in cognitive unimpaired older OSA patients. The changes in cortical Aβ uptake suggest that severe OSA itself may predispose to alterations related to AD already in middle-age. Aβ clearance may be compromised without simultaneous evidence of metabolic or structural alterations. The results emphasize the importance of early diagnostics and proper treatment of severe OSA in cognitively intact middle-aged subjects, possibly diminishing the individual risk for later cognitive dysfunction.

Since 1989, the Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE, n = 14220) Study has followed long-term changes of bone mineral density (BMD) and body composition in women with GE Lunar devices. During the course of OSTPRE, the dual-energy X-ray absorptiometry device had to be replaced by a newer model. Then, it was essential to determine whether systematic measurement differences in BMD and body composition will occur. As a part of the OSTPRE study, BMD was measured in 54 women, whereas body composition was determined in 55 women, aged 27-71, by using both the GE Healthcare Lunar Prodigy and iDXA narrow-angle fan beam densitometers during the same visit. The total body fat mass (FM) and lean body mass (LBM) results of these scanners showed a high linear correlation (r = 0.981-0.994, p < 0.0001). However, the mean total body FM and LBM values measured by iDXA were on average 2.3% (0.5 kg, 95% confidence interval: 0.3-0.7 kg) higher and 0.8% (0.3 kg, 95% confidence interval: 0.1-0.6 kg) lower, respectively, than those measured by Prodigy. Inclusion of local soft tissue measurements (total body LBM, legs/android FM) improved the agreement of total body, total hip, and lumbar spine BMD values between the devices but not femoral neck BMD agreement. Equations, based on linear regression analyses, were derived to minimize differences between the instruments. Then, the differences in BMD and body composition measurements were negligible between Prodigy and iDXA. Using correction equations enables an objective comparison of longitudinal BMD and body composition measurements., (Copyright © 2016 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Aim: Cardiac resynchronization therapy (CRT) is a treatment for patients with end-stage heart failure. However, two-thirds of the patients are nonresponders. Evaluation of left ventricular mechanical dyssynchrony may help in finding patients who will benefit from CRT. Dyssynchrony can be evaluated by the phase analysis method in myocardial perfusion imaging (MPI) or with cardiac ultrasound. The aim of this study was to investigate the reproducibility of phase analysis parameters in MPI and echocardiographic parameters in the evaluation of left ventricular mechanical dyssynchrony. In particular, the influence of BMI on reproducibility was studied., Methods and Results: Twenty-one patients underwent an ECG-gated MPI scan. Acquisition was repeated after the rest image. The patients were also studied twice with transthoracic echocardiography. Of MPI phase analysis parameters bandwidth, histogram SD and entropy% were highly reproducible in the pooled population: Cronbach's α 0.927-0.967 and intraclass correlation (ICC) 0.868-0.967, (P<0.001 for all). However, the reproducibility of bandwidth and SD was poorer in patients with BMI≥29 kg/m group (α 0.203 and -0.055; ICC 0.106 and -0.027, NS for both) than in those with BMI<29 kg/m (α 0.984 and 0.980; ICC 0.968 and 0.961, P<0.001 for both). In contrast, BMI had no obvious influence on the reproducibility of global longitudinal strain in echocardiography., Conclusion: Parameters reflecting mechanical dyssynchrony were found to be well reproducible. However, this study indicates that phase analysis results may be less reproducible in patients with high BMI, whereas global longitudinal strain in echocardiography seems to be less critical for a patient's BMI.

In long-term prospective studies, dual-energy X-ray absorptiometry (DXA) devices need to be inevitably changed. It is essential to assess whether systematic differences will exist between measurements with the new and old device. A group of female volunteers (21-72 years) underwent anteroposterior lumbar spine L2-L4 (n = 72), proximal femur (n = 72), and total body (n = 62) measurements with the Prodigy and the iDXA scanners at the same visit. The bone mineral density (BMD) measurements with these two scanners showed a high linear association at all tested sites (r = 0.962-0.995; p < 0.0001). The average iDXA BMD values were 1.5%, 0.5%, and 0.9% higher than those of Prodigy for lumbar spine (L2-L4) (p < 0.0001), femoral neck (p = 0.048), and total hip (p < 0.0001), respectively. Total body BMD values measured with the iDXA were -1.3% lower (p < 0.0001) than those measured with the Prodigy. For total body, lumbar spine, and femoral neck, the BMD differences as measured with these two devices were independent of subject height and weight. Linear correction equations were developed to ensure comparability of BMD measurements obtained with both DXA scanners. Importantly, use of equations from previous studies would have increased the discrepancy between these particular DXA scanners, especially at hip and at spine.

Purpose: We aimed to provide comprehensive data on and reference values for cardiorespiratory fitness, respiratory function and hemodynamic responses during and after maximal cycle ergometer test in children., Methods: The participants were a population sample of 140 children (69 girls) aged 9-11 years. Heart rate (HR) and systolic blood pressure (SBP) were measured from pre-exercise rest to the end of recovery. Respiratory gases were measured directly by the breath-by-breath method. Peak workload, HR changes, peak oxygen uptake (VO2), peak oxygen pulse (O2 pulse), peak respiratory exchange ratio (RER) and the lowest ratio of ventilation and carbon dioxide output (VE/VCO2) during the exercise test in girls and boys were presented according to their distributions in 5 categories., Results: HR decreased more during 4-min recovery in boys than in girls (76 vs. 67 beats/min, p < 0.001), whereas SBP decrease was similar in boys and girls (30 vs. 22 mmHg, p = 0.66). Boys had a higher peak VO2 per weight [51.9 vs. 47.6 ml/kg/min, p < 0.001] and per lean mass [67.3 vs. 63.0 ml/kg/min, p < 0.001] than girls. Peak O2 pulse per lean mass was higher in boys than in girls (0.34 vs. 0.31 ml/kg/beat, p < 0.001). There was no difference in the lowest VE/VCO2 during the test between boys and girls (28 vs. 29, p = 0.18)., Conclusions: The indicators of cardiorespiratory fitness were better in boys than in girls. These data enable the evaluation of cardiorespiratory function during and after maximal exercise test and the detection of children with abnormal values.

Objective and Methods: We compared InBody720 segmental multifrequency bioimpedance analysis (SMF-BIA) with Lunar Prodigy Advance dual-energy X-ray absorptiometry (DXA) in assessment of body composition among 178 predominantly prepubertal children. Segmental agreement analysis of body compartments was carried out, and inter-relationships of anthropometric and other measures of body composition were defined. Moreover, the relations of different reference criteria for excess body fat were evaluated., Results: The prevalence of excess body fat varies greatly according to the used criteria. Intraclass and Pearson's correlations between SMF-BIA and DXA were >0·92 in total body and >0·74 in regional measures. SMF-BIA underestimated percentage body fat (%BF) and fat mass (FM), and overestimated lean mass (LM) and percentage LM with significant offset trend bias. Higher adiposity increased offsets, and overall agreement was poorer in girls. On average, %BF offsets (girls/boys) and limits of agreement (LA) were 3·9/1·6% [(-)1·4-9·2%/(-)3·4-6·7%]. Interestingly percentage offsets of fat content (%BF: 18·9/10·1%, FM: 18·8/11·1%) showed no significant bias trends indicating that the corresponding absolute methodological offset depends on the amount of fat content. The smallest percentage offset was found with LM: 4·3/0·1%, referring offset (LA) of 0·88/0·03 kg (±2·05/±1·71 kg). Correspondingly, segmental LM had poorer agreement than total body LM. All anthropometrics except for the waist-to-hip ratio showed strong correlations (r = 0·76-0·95) with abdominal and total body fat., Conclusion: Segmental multifrequency bioimpedance analysis is precise enough for total-LM analysis and had also sufficient trueness for total body composition analysis to be used in epidemiological purposes. There is need to generate scientifically and clinically relevant criteria and reference values for excess body fat., (© 2013 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.)

A real-time ultrasound measurement system for tablet compression monitoring is introduced. The measurement system was tested in actual manufacturing environment and found to be capable of measuring the ultrasound response of the tabletting process from bulk to tablet. The tablet sets were compressed and the ultrasound measurements were conducted as implemented in eccentric single station tabletting apparatus in through transmission geometry. The speed of sound and ultrasound spectrum was measured during dynamic compression for microcrystalline cellulose/paracetamol tablets. The ultrasound system introduced in this study was found to be suitable for tabletting process monitoring as the mechanical properties of compressed tablets can be estimated during compression using the ultrasound system. In addition, it was found that the ultrasound was sensitive to the mixing time of magnesium stearate and the concentration of paracetamol. Thus, ultrasound measurements made during the compression can be used to monitor the tablet formation process., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Respiratory and cardiac motion artefacts impair the quality and reliability of medical imaging, particularly in nuclear medicine. At worst, the interpretation of distorted images may lead to inadequate or unnecessary treatment. Image artefacts can be minimized by gating the image acquisition according to respiratory phase and cardiac contractions. However, currently there are no clinically established dual-gating methods in nuclear medicine imaging. The aim of this study is to validate a previously determined optimized bioimpedance measurement configuration against traditional respiratory and cardiac measurement systems in 12 volunteers. High agreement and excellent correlations (r = 0.944-0.999) were found between respiratory peak-to-peak amplitudes as well as temporal respiratory and cardiac intervals. Above all, good quality respiratory and cardiac gating signals were obtained from all test subjects with a fairly regular sinus rhythm. Importantly, both signals were acquired simultaneously with a single device. Due to the simplicity of this inexpensive method, the technique has high potential to be adopted for dual-gating in clinical practice in the future.

Unlabelled: About 75% of patients suffering from osteoporosis are not diagnosed. This study describes a multi-site bone ultrasound method for osteoporosis diagnostics. In comparison with axial dual energy X-ray absorptiometry (DXA), the ultrasound method showed good diagnostic performance and could discriminate fracture subjects among elderly females., Introduction: Axial DXA, the gold standard diagnostic method for osteoporosis, predicts fractures only moderately. At present, no reliable diagnostic methods are available at the primary health care level. Here, a multi-site ultrasound method is proposed for osteoporosis diagnostics., Methods: Thirty elderly women were examined using the ultrasound backscatter measurements in proximal femur, proximal radius, proximal and distal tibia in vivo. First, we predicted the areal bone mineral density (BMD) at femoral neck by ultrasound measurements in tibia combined with specific subject characteristics (density index, DI) and, second, we tested the ability of ultrasound backscatter measurements at proximal femur to discriminate between individuals with previously fractured hips from those without fractures. Areal BMD was determined by axial DXA., Results: Combined ultrasound parameters, cortical thickness at distal and proximal tibia, with age and weight of the subject, provided a significant estimate of BMD(neck) (r = 0.86, p < 0.001, n = 30). When inserted into FRAX (World Health Organization fracture risk assessment tool), the DI indicated the same treatment proposal as the BMD(neck) with 86% sensitivity and 100% specificity. The receiver operating characteristic analyses, with a combination of ultrasound parameters and patient characteristics, discriminated fracture subjects from the controls similarly as the model combining BMD(neck) and patient characteristics., Conclusions: For the first time, ultrasound backscatter measurements of proximal femur were conducted in vivo. The results indicate that ultrasound parameters, combined with patient characteristics, may provide a means for osteoporosis diagnostics.

Background: Hip resurfacing arthroplasty (HRA) is considered a bone-preserving procedure and may eliminate proximal femoral stress shielding and osteolysis. However, in addition to implant-related stress-shielding factors, various patient-related factors may also have an effect on bone mineral density (BMD) of the proximal femur in patients with HRA. Thus, we studied the effects of stem-neck angle, demographic variables, and physical functioning on the BMD of the proximal femur in a one-year follow-up., Methods: Thirty three patients (9 females and 24 males) with a mean (SD) age of 55 (9) years were included in the study. BMD was measured two days and 3, 6, and 12 months postoperatively and 10 regions of interest (ROI) were used. Stem-neck angle was analyzed from anteroposterior radiographs., Results: Three months postoperatively, BMD decreased in six out of 10 regions of interest (ROI) on the side operated on and in one ROI on the control side (p<0.05) compared to the second postoperative day. At 12 months, BMD had increased in 7 ROIs on the operated side and one ROI on the control side (all p<0.001). Correlation was found between the stem-neck angle and BMD in ROIs 2, 3, 7, and 9 (r=0.36-0.61). In multiple regression analysis, stem-neck angle, age, sex, body mass index, and walking distance did not explain the BMD changes., Conclusions: After an early drop, the BMD of the upper femur was restored and even exceeded the preoperative level at one year follow-up. From a clinical standpoint, the changes in BMD in these HRA patients could not be explained by stem-neck angle or patient related factors.

Unlabelled: This study employed microCT to investigate whether image resolution affects bone structural parameters differently in healthy normal and osteoporotic trabecular bone. With increasing image voxel size, the originally detected differences between sample groups diminished. The results suggest that structural differences may not be reliably detected with clinical scanners., Introduction: Structural parameters of bone reflect its health status, but are highly dependent on the image resolution. We hypothesized that image resolution affects bone structural parameters differently in normal and osteoporotic trabecular bone., Methods: Human trabecular bone samples from the iliac crest and the knee were analyzed (normal n = 11, osteoporotic n = 15) using a high-resolution microCT (14 or 18 µm voxel sizes). Images were re-sampled to voxel sizes 1-16 times larger than the original image and thresholded with global or local adaptive algorithms. Absolute and normalized values of each structural parameter were calculated, and the effect of decreasing image resolution was compared between the normal and osteoporotic samples., Results: Normal and osteoporotic samples had different (p < 0.05) absolute bone volume fractions. However, the normalized values showed that the osteoporotic samples were more prone to errors (p < 0.05) with increased voxel size. The absolute values of trabecular number, trabecular separation, degree of anisotropy, and structure model index were different between the groups at the original voxel size (p < 0.05), but at voxel sizes between 60 and 110 µm, those differences were no longer significant., Conclusions: The results suggest that structural differences between osteoporotic and normal trabecular bone may not be reliably detected with clinical CT scanners providing image voxel sizes above 100 µm.

An ultrasound measurement system for tablet defect detection is introduced. The measurement system was implemented in an eccentric single station tabletting apparatus, where ultrasound transducers were placed inside the upper and lower punches. These instrumented punches were then used to measure the speed of sound and ultrasound attenuation values in both intact and defective tablets made from dibasic calcium phosphate, microcrystalline cellulose and lactose monohydrate. Ultrasound attenuation was found to be a very sensitive method to discriminate defective tablets from intact ones. In addition, it was found that the determined ultrasound attenuation was different between all three materials used in this study, which indicates that different materials could be distinguished from one another by this detection method., (Copyright © 2010 Elsevier B.V. All rights reserved.)

The strength as well as the acoustic properties of trabecular bone are determined by its structure and composition. Consequently, tissue structure and compositional properties also affect the ultrasound propagation in bone. The diagnostic potential of ultrasound has not been fully exploited in clinical quantitative ultrasound devices. The aim of this study was to investigate the ability of quantitative ultrasound pulse-echo imaging, conducted over a broad range of frequencies (1 to 5 MHz), to predict the mechanics, composition and microstructure of trabecular bone. Ultrasound reflection and backscatter parameters correlated significantly with the ultimate strength of the trabecular bone and the bone volume fraction (r=0.76-0.90, n=20, p<0.01). Ultrasound backscatter associated significantly (independently of bone structure or mineral content) with the collagen content of the bone matrix (r=0.75, r(adjusted)=0.66, p<0.01). Interestingly, the applied ultrasound frequency seemed to relate the sensitivity of ultrasound backscatter to different properties of trabecular bone. At frequencies ranging from 1 to 3.5 MHz, the ultrasound backscatter associated significantly with the tissue mechanical and structural parameters. At 5MHz, the composition of the bone matrix was a more significant determinant of the measured backscatter. This study provides useful information for optimizing the use of pulse-echo measurements, and thereby further emphasizes the diagnostic potential of the ultrasound backscatter measurements of trabecular bone.

The composition of bone marrow is influenced by many factors, such as age and diseases. The present numerical study investigates the contribution of marrow on the acoustic measurements of trabecular bone. Cylindrical bone samples (n = 11), extracted from three anatomical sites of human cadaver knees, were imaged with a high-resolution microtomography (microCT). Three-dimensional finite difference time domain (FDTD) models (Wave 3000 Pro 2.2, Cyberlogic Inc., NY, USA) were created using the segmented microCT images of each sample. First, we evaluated the effect of voxel size on the computer resource requirements, morphological parameters and acoustic simulations. Second, the effect of bone marrow on ultrasonic measurements was assessed. The simulations were repeated with two voxel sizes before and after substitution of bone marrow (i.e., fat) with water. The voxel size of the FDTD mesh controlled the fine structure of the modeled calcified matrix and significantly affected the simulation results. However, present simulations showed that the effect of bone marrow on ultrasound parameters can be reliably simulated with the applied voxel sizes of 72 and 90 microm. Ultrasound attenuation and speed were found (p < 0.01) to decrease and increase, respectively, when bone marrow was substituted with water. Moreover, reflection from the surface of the sample increased (p < 0.01) and backscatter from internal structures decreased (p < 0.01) after removal of marrow. The effect of bone marrow on the acoustic properties was stronger in samples with low bone volume fraction. The present results indicate that the amount and quality of bone marrow significantly influence the acoustic properties of trabecular bone. Possible interindividual differences in the composition of bone marrow may increase uncertainty in clinical ultrasound diagnostics of osteoporosis. Importantly, the effect is most significant in osteoporotic low-density bone.

Quantitative ultrasound has been suggested for screening of osteoporosis. Most commercial ultrasound devices are based on the through-transmission measurement of calcaneus, which is not a typical fracture site. In contrast to through-transmission measurements, reflection and backscattering measurements may be conducted at typical fracture sites such as vertebra and proximal femur. At these regions, soft tissues overlying bones affect reliability of the measurements. In this study, a novel dual-frequency ultrasound (DFUS) pulse-echo technique is introduced for reduction of the errors induced by soft tissues. First, DFUS was validated using elastomer samples. For further validation, human trabecular bone samples (n = 25) covered with heterogeneous soft tissues were measured at frequencies of 2.25 MHz and 5.0 MHz. The DFUS technique reduced (p < 0.01) the mean error induced by soft tissue from 58.6% to -4.9% and from 127.4% to 23.8% in broadband ultrasound backscattering and integrated reflection coefficient (at 5.0 MHz), respectively. To conclude, the DFUS, being the first ultrasound technique capable of determination of the composition and thickness of the soft tissue overlying the bone, may enhance the accuracy of clinical ultrasound measurements. Thereby, DFUS shows a significant clinical potential.

The aim of this study was to investigate the effects of tablet porosity and particle size fraction of compacted Starch acetate powders, with and without model drug caffeine, on acoustic properties of tablets. The ultrasound velocity was determined from the transmission measurements. Tablets of starch acetate (SA DS 2.7) powder with two particle size fractions of 0-53 and 0-710 microm were compressed with a compaction simulator. Porosities of tablets varied in the range from 12% to 43% for both particle size fractions. Strong associations were found between the ultrasound velocity and physical properties of the tablets such as porosity and particle size fraction. Interestingly, ultrasound velocity was practically insensitive to inclusion of the model drug caffeine with the concentrations used. Based on this study ultrasound transmission method is a potential non-destructive tool for studying structural changes of tablets and other solid dosage forms.

In clinical applications, ultrasound parameters are measured as an average value over a region of interest (ROI) or as a value at a single measurement point. Due to natural adaptation to loading conditions, trabecular bone is structurally, compositionally and mechanically heterogeneous and anisotropic. Thus, spatial variation of ultrasound parameters within ROI may contain valuable information on the mechanical integrity of trabecular bone. However, this issue has not been thoroughly investigated. In the present study, we aimed at investigating the significance of the spatial variation of ultrasound parameters for the prediction of mechanical properties of human trabecular bone. For this aim, parametric maps of apparent integrated backscattering (AIB), integrated reflection coefficient (IRC), speed of sound (SOS), average attenuation (AA) and normalized broadband ultrasound attenuation (nBUA) were calculated for femoral and tibial bone cylinders (n = 19-20). Further, the effect of time window length on the AIB, variation of AIB within ROI and association between AIB and bone mechanical properties were characterized. Based on linear correlation analysis, spatial variation of AIB, assessed as standard deviation of measurements within ROI, was a strong predictor of bone ultimate strength (r = -0.82, n = 19, p < 0.01). Further, the time window length affected absolute values of AIB and strength of correlation between AIB and bone ultimate strength. Interestingly, linear combination of mean IRC and spatial variation of AIB within ROI was the strongest predictor of bone ultimate strength (r = 0.92, n = 19, p < 0.01). In conclusion, our findings suggest that the measurement of two-dimensional parametric maps of ultrasound parameters could yield information on bone status not extractable from single point measurements. This highlights the potential of parametric imaging in osteoporosis diagnostics.

Mechanical properties of bone are determined not only by bone mineral density (BMD), but also by tissue trabecular structure and organic composition. Impedance spectroscopy has shown potential to diagnose trabecular bone BMD and strength, however, the relationships between organic composition and electrical and dielectric properties have not been systematically investigated. To investigate these issues organic composition of 26 human trabecular bone samples harvested from the distal femur and proximal tibia was determined and compared with relative permittivity, loss factor, conductivity, phase angle, specific impedance and dissipation factor measured at wide range (50 Hz to 5 MHz) of frequencies. A strong linear correlation was found between the relative permittivity at 1.2 MHz and trabecular bone fat content (r = -0.85, p<0.01, n=26). On the other hand, relative permittivity measured at 200 Hz served as a good predictor of water content (r = 0.83). Phase angle, specific impedance and especially conductivity were strongly related to the trabecular bone dry density and water content (|r| > or = 0.69). Variation in bone tissue collagen content was strongly related to the relative permittivity measured at 1.2 MHz (r = 0.64), but only moderately to other parameters. Glycosaminoglycan content showed no significant relations with any investigated electrical parameters. The present study indicates that if the trabecular bone composition is known, the relationships presented in this study could facilitate calculation of current field distribution, e.g. during electrical stimulation of osteogenesis. On the other hand, our results suggest that permittivity measured at low (<1 kHz) or high (>100 kHz) frequencies could be used, e.g. during implant surgery, for prediction of trabecular bone water or fat contents, respectively.

In osteoporosis, changes in tissue composition and structure reduce bone strength and expose it to fractures. The current primary diagnostic technique, i.e., dual energy X-ray absorptiometry, measures areal bone mineral density (BMD) but provides no direct information on trabecular structure or organic composition. Although still poorly characterized, ultrasound techniques may bring about information on bone composition and structure. In this study, relationships of 2.25-MHz ultrasound speed, attenuation, reflection and backscattering with composition of human trabecular bone (n=26) were characterized experimentally, as well as by using numerical analyses. We also determined composition of the trabecular sample (fat and water content, bone volume fraction) and that of the calcified matrix (mineral, proteoglycan and collagen content of trabeculae). In experimental analyses, bone volume fraction and mineral content of the calcified matrix were the only determinants of BMD. Further, bone volume fraction served as the strongest determinant of ultrasound parameters (r=0.51-0.87). In numerical simulations, density and mechanical properties of the calcified matrix systematically affected ultrasound speed, attenuation, reflection and backscattering. However, partial correlation coefficients revealed only low associations(|r|

Techniques for quantitative magnetic resonance imaging (MRI) have been developed for non-invasive estimation of the mineral density and structure of trabecular bone. The R*(2) relaxation rate (i.e. 1/T*(2)) is sensitive to bone mineral density (BMD) via susceptibility differences between trabeculae and bone marrow, and by binarizing MRI images, structural variables, such as apparent bone volume fraction, can be assessed. In the present study, trabecular bone samples of human patellae were investigated in vitro at 1.5 T to determine the ability of MRI-derived variables (R*(2) and bone volume fraction) to predict the mechanical properties (Young's modulus, yield stress and ultimate strength). Further, the MRI variables were correlated with reference measurements of volumetric BMD and bone area fraction as determined with a clinical pQCT system. The MRI variables correlated significantly (p < 0.01) with the mechanical variables (r = 0.32-0.46), BMD (r = 0.56) and bone structure (r = 0.51). A combination of R*(2) and MRI-derived bone volume fraction further improved the prediction of yield stress and ultimate strength. Although pQCT showed a trend towards better prediction of the mechanical properties, current results demonstrate the feasibility of combined MR imaging of marrow susceptibility and bone volume fraction in predicting the mechanical strength of trabecular bone and bone mineral density.

Microstructural changes, such as reduction of trabecular thickness and number, are characteristic signs of osteoporosis leading to diminished bone strength. Electrical and dielectric parameters might provide diagnostically valuable information on trabecular bone microstructure not extractable from bone mineral density measurements. In this study, structural properties of human trabecular bone samples (n=26) harvested from the distal femur and proximal tibia were investigated using the computed microtomography (microCT) technique. Quantitative parameters, e.g. structural model index (SMI) or trabecular bone volume fraction (BV/TV), were calculated. In addition, the samples were examined electrically over a wide frequency range (50 Hz-5 MHz) using a two-electrode impedance spectroscopy set-up. Relative permittivity, loss factor, conductivity, phase angle, specific impedance and dissipation factor were determined. Significant linear correlations were obtained between the dissipation factor and BV/TV or SMI (|r| 0.70, p<0.01, n=26). Principal component analyses, conducted on electrical and structural parameters, revealed that the high frequency principal component of the dissipation factor was significantly related to SMI (r=0.72, p<0.01, n=26). The linear combination of high and low frequency relative permittivity predicted 73% of the variation in BV/TV. To conclude, electrical and dielectric parameters of trabecular bone, especially relative permittivity and dissipation factor, were significantly and specifically related to a trabecular microstructure as characterized with microCT. The data gathered in this study constitute a useful basis for theoretical and experimental work towards the development of impedance spectroscopy techniques for detection of bone quality in vitro or in special cases of open surgery.

In trabecular bone, the interrelationships of electrical and dielectric properties with mechanical characteristics are poorly known. Information on these relations is crucial for evaluation of the diagnostic potential of impedance techniques. In this study, electrical and dielectric properties, i.e. permittivity, conductivity, phase angle, loss factor, specific impedance and dissipation factor of human trabecular bone samples (n=26, harvested from the distal femur and proximal tibia) were characterized in a wide frequency range (50 Hz-5 MHz). Mechanical properties, i.e. Young's modulus, ultimate strength, yield stress, yield strain and resilience of the samples (n=20) were determined by using destructive compressive testing. Subsequently, measurements of electrical and dielectric properties were repeated after mechanical testing. The measurements were also repeated for the control samples (n=6) that were not mechanically tested. Electrical, dielectric or mechanical properties showed no significant differences between the intact femoral and tibial samples. The electrical and dielectric parameters as well as the linear correlations between the dielectric and electrical parameters with mechanical parameters were strongly frequency dependent. At the frequency of 1.2 MHz, the relative permittivity showed the strongest linear correlations with the Young's modulus (r=0.71, p<0.01, n=20) and ultimate strength (r=0.73, p<0.01, n=20). Permittivity and dissipation factor showed statistically significant changes after mechanical testing. Our results suggest that the measurements of low frequency electrical and dielectric properties may provide information on the mechanical status of trabecular bone and, possibly, may even help to diagnose bone microdamage. In the future, these measurement techniques may be further developed for use during open surgery, such as bone grafting or total hip replacement surgery.

In dual energy x-ray absorptiometry (DXA) the photon attenuation is assumed to be similar in soft tissue overlying, adjacent to and inside the measured bone. In the calcaneal dual energy x-ray laser (DXL) technique, this assumption is not needed as attenuation by soft tissues at the local bone site is determined by combining DXA and heel thickness measurements. In the present study, 38 subjects were measured with DXL Calscan, Lunar PIXI and Lunar DPX-IQ DXA instruments and Hologic Sahara ultrasound instrument, and the performance and agreement of the instruments were analysed. Furthermore, numerical simulations on the effect of non-uniform fat-to-lean tissue ratio within soft tissue in heel were conducted. In vivo short-term precision (CV%, sCV%) of DXL Calscan (1.24%, 1.48%) was similar to that of Lunar PIXI (1.28%, 1.60%). Calcaneal areal bone mineral densities (BMD, g cm(-2)) measured using DXL Calscan and Lunar PIXI predicted equally well variations in BMD of femoral neck (r2 = 0.63 and 0.52, respectively) or lumbar spine (r2 = 0.61 and 0.64, respectively), determined with Lunar DPX-IQ. BMD values measured with DXL Calscan were, on average, 19% lower (p < 0.01) than those determined with Lunar PIXI. Interestingly, the difference in BMD values between instruments increased as a function of body mass index (BMI) (r2 = 0.17, p < 0.02) or heel thickness (r2 = 0.37, p < 0.01). Numerical simulations suggested that the spatial variation of soft tissue composition in heel can induce incontrollable inaccuracy in BMD when measured with the DXA technique. Theoretically, in contrast to DXA instruments, elimination of the effect of non-uniform soft tissue is possible with DXL Calscan.

Interrelationships of trabecular bone electrical and dielectric properties with mechanical characteristics and density are poorly known. While electrical stimulation is used for healing fractures, better understanding of these relations has clinical importance. Furthermore, earlier studies have suggested that bone electrical and dielectric properties depend on the bone density and could, therefore, be used to predict bone strength. To clarify these issues, volumetric bone mineral density (BMDvol), electrical and dielectric as well as mechanical properties were determined from 40 cylindrical plugs of bovine trabecular bone. Phase angle, relative permittivity, loss factor and conductivity of wet bovine trabecular bone were correlated with Young's modulus, yield stress, ultimate strength, resilience and BMDvol. The reproducibility of in vitro electrical and dielectric measurements was excellent (standardized coefficient of variation less than 1%, for all parameters), especially at frequencies higher than 1 kHz. Correlations of electrical and dielectric parameters with the bone mechanical properties or density were frequency-dependent. The relative permittivity showed the strongest linear correlations with mechanical parameters (r > 0.547, p < 0.01, n = 40, at 50 kHz) and with BMDvol (r = 0.866, p < 0.01, n = 40, at 50 kHz). In general, linear correlations between relative permittivity and mechanical properties or BMDvol were highest at frequencies over 6 kHz. In addition, a significant site-dependent variation of electrical and dielectric characteristics, mechanical properties and BMDvol was revealed in bovine femur (p < 0.05, Kruskall-Wallis H-test). Based on the present results, we conclude that the measurement of electrical and dielectric properties provides quantitative information that is related to bone quantity and quality.

Haemophilus influenzae type b capsular polysaccharide-diphtheria toxoid conjugate vaccine has recently been shown to be capable of inducing antibodies to H. influenzae in infants. In an evaluation of its clinical efficacy, 60,000 children were enrolled in an open trial in Finland. Children born on odd-numbered days between October 1, 1985, and September 30, 1986, received the vaccine at 3, 4, 6, and 14 months; those born on even-numbered days served as controls. The geometric mean antibody titer measured in a cohort of 99 children rose from a prevaccination level of 0.08 microgram per milliliter at three months of age to 0.42 microgram per milliliter at seven months. Only minor adverse reactions were reported. Up to February 1987, two cases of invasive H. influenzae infection had occurred among the children who had received three doses of vaccine, whereas 12 cases had occurred among the controls (P = 0.0005 by Poisson one-tailed test). The rate of short-term (average follow-up time, five months) protection provided by this conjugate vaccine in infancy was thus 83 percent.