However unlike the sought crystal acceleration effect

However, unlike the sought crystal acceleration effect (9), the curve distortion is determined only by the deviation from the exact Bragg condition at the entry time t0 of neutron to crystal, but not by variation of the deviation during the time-of-flight through the crystal.
So the position (t0) of the maximum and the maximum intensity N(t0) of the scanning curve (see Fig. 2) in the absence of the crystal acceleration effect will be some functions of deviation ∆B(t0), depending on the crystal speed v(t0):

For further consideration and comparison with the experimental results expressions (10) and (11) can be expanded by Taylor series over v(t0) about the point v(t0)=0 (i.e., ). Taking into account that the crystal speed was significantly less than the typical Bragg widths, it is enough to leave expansion terms up to second order over v(t0):
where A, B, C, N0, N1 and N2 are the free parameters depending on to be found from experiment.
As it follows from (9), the crystal acceleration effect contains a term phase-shifted with respect to the false effect (12) by the value of ωτ/2. This shift is approximately equal to π/4 for our experimental conditions. Furthermore, the presence of acceleration effect does not change the intensity of the line, but gives its additional shift. Thus, there is a phase shift between the time dependencies of and that represents the crystal acceleration effect.

Results and discussion
An example of experimental dependence of the line positions on its maximal intensity () is shown in Fig. 4. In the absence of the acceleration effect a bijection between the maximum positions and the intensities should be observed, shown by a dashed line. The presence of the neutron chemokine receptor antagonist change after passage through the accelerating crystal leads to the dependence () described with a closed curve like Lissajous figure, where the figure square is determined by the crystal acceleration effect. Curved arrows in Fig. 4 show the sweep direction over time. The relation between a line shift in units of the crystal temperature and a change in the neutron energy is given by the following expression:

The splitting marked by arrows in Fig. 4 corresponds to ∆E ≅ 5neV.
Examples of the time dependencies of the scanning curve maximum position are shown in Fig. 5 for different deviations T13 from the Bragg condition. Those are the results of fitting the experimental curves under the assumption that the maximum position is determined by a sum of two effects: see formulae (12) and (9).
Dependence of the maximum value for an energy change (9) due to the acceleration effect on the deviation from the neutron Bragg energy for working crystal (temperature difference T13) is shown in Fig. 6. Measurements were carried out at two different crystal oscillation amplitudes, corresponding to v0 ≅ 3mm/s and v0 ≅ 1.5mm/s (see Eq. (6)). Curves show the results of approximating the experimental points by the theoretical curve (9). Thus, one can see that the neutron energy change after passage through accelerating crystal can reach ∼20neV.
The mean potential energy of a neutron–crystal interaction (see Eq. (5)) can be obtained from the experimental dependence shown in Fig. 6, because that is actually a derivative of function (5) (see Eq. (6)). One should take into account that far from the Bragg condition the correction to the mean interaction potential due to the presence of g-harmonic tends to zero (see Eq. (4)), and so neutron refraction will be determined only by the average potential V0. The result of the interaction potential reconstruction for neutrons moving in a crystal with energies close to the Bragg one is shown in Fig. 7. It is easy to see that the relative change of the neutron energy by several units of 10–5 leads to the variation of the interaction neutron–crystal potential by ±20%.

The features of refraction of a neutron wave moving in a crystal close to the Bragg condition has been studied. The energy dependence of refractive index was shown to exhibit an evident resonance shape in the vicinity of the Bragg energy with the corresponding Bragg (Darwin) width (for thermal and cold neutrons ∆E/E ≅ 10−5). The variation of the interaction potential of the neutron with the crystal in this energy range can reach about ±20%.

Meanwhile the new imaging mode of

Meanwhile, the new imaging mode of annular bright-field scanning transmission chemokine receptor antagonist microscopy (ABF-STEM) has enabled imaging of extremely light elements, such as hydrogen and lithium atomic columns [37–41]. Furthermore, direct imaging of the organic frameworks in the CuPcCl16 crystal with ABF- and LAADF-STEM had been reported in 2012 [42]. However, illuminating conditions cannot be assigned independently to processes for focusing and acquiring image. The STEM mode is particularly disadvantage to low-dose observation owing to the fixed illuminating condition during focusing, unless minimum-dose-system (MDS) [43] is optimized for STEM imaging. Thus, it is still necessary to improve and explore imaging possibilities for organic molecules by HRTEM. It is desirable for there to be many choices of imaging modes available for soft materials like organic crystals. The combination of Zernike phase plate and AC-HRTEM can be also a powerful technique for direct imaging of soft materials [44,45]. However, ideal phase plates have not been developed so far, so it is impossible to get high-resolution image without any artifacts by the current stage.


Results and discussion

Our results demonstrated that the direct imaging of light elements with AC-HRTEM is very sensitive to the defocus value and specimen thickness. The thickness range permitted for AC-HRTEM imaging was restricted considerably, as compared with ABF-STEM imaging [42]. The imaging mode should be set to either AC-HRTEM or ABF-STEM according to the type of specimen. AC-HRTEM imaging can be applied to a wider variety of organic materials if a novel sample preparation technique can be developed that reduces the damage during the thinning process.


In general, images or maps reconstructed from automated Electron Backscatter Diffraction (EBSD) data provide an excellent way to characterize the orientation aspects of polycrystalline microstructures [1]. This technique is also referred to as Orientation Imaging Microscopy or OIM [2]. However, some EBSD maps can be noisy, with a large fraction of non-indexed or mis-indexed points in the scan grid. Noisy maps generally arise when patterns are too noisy for the automated band detection and indexing algorithms to work reliably. Noisy patterns can arise for various reasons, for example highly deformed materials and fine-grained materials tend to produce patterns of lower quality due to resolution limitations related to the size of the interaction volume and the fine scale of the structure in such materials. Another source of noise is the EBSD camera itself. While higher speed data collection is desirable, the camera settings often required to achieve higher speeds – higher gain and shorter exposure times – can lead to degraded pattern quality. While the band detection (i.e. the Hough Transform) and indexing routines can overcome quite a lot of noise in the patterns, the reliability of these algorithms begins to diminish as was recognized early in the development of the automated technique [3,4].
Various post-processing approaches have been developed to try and cleanup the orientation data in an attempt to improve the fidelity of the EBSD maps relative to the underlying microstructure [5,6]. These techniques tend to lead to high levels of artifacts as the fraction of non-indexed or incorrectly indexed points becomes large. Often, scan fidelity can be improved by adjusting various parameters during offline re-scanning of the the data using EBSD patterns recorded during the original online scan. For example, image processing can be applied to the saved patterns in order to improve the indexing, mistakes made in defining the crystallographic structure parameters used in indexing can be corrected, the pattern center calibration improved and Hough Transform parameters better optimized for the patterns collected. Such adjustments allow the patterns to be re-indexed to improve on the original results.

br Conflict of interest statement br Acknowledgements br Introduction

Conflict of interest statement


Lameness originating from the stifle joint is relatively common in cattle (Ducharme et al., 1985; Pentecost and Niehaus, 2014). The complex arrangement of osseous, articular, fibro-cartilaginous and ligamentous structures and the biomechanics of the stifle joint during motion as well as hereditary factors in certain breeds were suggested to be predisposing factors in stifle lameness (Ducharme et al., 1985). Disorders of the bovine stifle include fractures, septic arthritis, traumatic arthritis with injuries of the menisci, collateral, meniscal and/or cruciate chemokine receptor antagonist and osteoarthritis (Hurtig, 1985; Munroe and Cauvin, 1994; Gaughan, 1996; Trostle et al., 1997; Tryon and Farrow, 1999).
Radiography, ultrasonography, magnetic resonance tomography (MRT) and computed tomography (CT) have been used in bovine orthopaedics (Kofler et al., 2014). The bovine stifle joint has been thoroughly examined with radiography and ultrasonography (Kofler, 1999; Siegrist and Geissbuehler, 2011) but radiography provides little information on soft tissue structures and ultrasonography is limited to bone surfaces. CT and MRT are valuable diagnostic imaging modalities, but their use in cattle is limited to advanced veterinary clinics due to the high cost and the need for general anaesthesia (Lee et al., 2009; Ehlert et al., 2011; Nuss et al., 2011).
Arthroscopy and arthrotomy offer valuable information for diagnosis and treatment of stifle joint injuries (Hurtig, 1985; Plesman et al., 2013). Arthroscopy is superior to arthrotomy because of the minimal damage to the peri-articular soft tissues, multiple joint approaches, smaller incisions, short operative times, improved intra-articular visibility, enhanced cosmetic appearance, and rapid recovery (Honnas et al., 1993; Necas et al., 2002). In addition, arthroscopy allows examination of structures within the joint that are inaccessible with routine arthrotomy (Honnas et al., 1993; Lardé and Nichols, 2014); however, arthroscopy is not widely used in cattle due to cost and availability, so its use is limited to valuable cows and breeding bulls (Lardé and Nichols, 2014).
The bovine stifle consists of the femoropatellar (FP), medial femorotibial (MFT), and lateral femorotibial (LFT) joints (Dyce and Wensing, 1971; Ashdown and Done, 1984; Nickel et al., 1985; Desrochers et al., 1996; Lopez et al., 1996; Budras et al., 2003; Dyce et al., 2010). The FP and MFT joints always communicate, while the MFT and LFT joints communicate in 57% of bovine stifles (Desrochers et al., 1996).
The cranial arthroscopic approach to the stifle joint has been reported in cattle (Hurtig, 1985; Munroe and Cauvin, 1994; Lardé and Nichols, 2014; Nichols and Anderson, 2014), horse (Martin and McIlwraith, 1985; Moustafa et al., 1987; Vinardell et al., 2008), dog (Marino and Loughin, 2010), South American camelids (Pentecost et al., 2012) and sheep (Modesto et al., 2014). Although the caudal approaches to the femorotibial (FT) joints have been described in horses (Watts and Nixon, 2006) and sheep (Modesto et al., 2014), reports on the arthroscopic evaluation of the caudal FT pouches in bovine are lacking. Consequently, the objective of the current study was to develop a satisfactory technique for arthroscopic examination of the FT and FP joints in cattle and to establish a protocol for exploration and characterization of the cranial and caudal aspects of the FT joints to provide a detailed systematic description of the intra-articular structures of the bovine stifle joint.

Materials and methods


The present study described the surgical technique and normal findings of the arthroscopic approaches to the chemokine receptor antagonist cranial and caudal compartments of the stifle joint in cattle. Arthroscopic visualization of the MFT, LFT and FP joints was accomplished in a systematic order through a craniomedial single skin incision. The anatomical landmarks used to insert the scope into the MFT joint were similar to those used in South American camelids (Pentecost et al., 2012), sheep (Modesto et al., 2014) and cattle (Nichols and Anderson, 2014). During the anatomical study, palpation and identification of the medial and middle patellar ligaments, tibial plateau and patellar apex allowed localization of the craniomedial skin portal. However, it was difficult to palpate the collateral ligaments and the lateral patellar ligament was completely blended with the biceps femoris tendons, thus making localization of the craniolateral portal difficult. Similar findings were reported in the horse (Vinardell et al., 2008), sheep (Modesto et al., 2014) and cattle (Nichols and Anderson, 2014).

The surplus of the National fund

The surplus of the National fund continues to increase every year. From the time of the creation of the National fund, the major revenue was non-tax (sales of property and agricultural lands), but every year the tax-revenue share is becoming a larger portion of the total revenue of the National fund (Fig. 4).
Davis et al. (2001) suggest measuring the effectiveness of the oil revenue fund by its effect on the relationship between the government expenditure and resource export earnings. The data shows a possible positive correlation between Kazakhstan\’s government expenditure and export of oil (Fig. 5). Also, the correlation looks stronger before 2001, while from 2001 on (after creation of the National fund), government expenditure looks less correlated with oil exports.
Nevertheless, there is a strong relationship between the government\’s revenue and expenditure with oil prices (Fig. 6).
An economy\’s dependency on oil resources can be measured in two ways (Liuksila, Garcia, & Bassett, 1994): external dependency shows how a country relies on oil exports to obtain foreign exchange (the share of oil export to total export), while fiscal dependency on the other hand, measures how the public sector relies on oil revenues (the share of oil taxes to total fiscal revenue). Data which is necessary to calculate external dependency of Kazakhstan is available, but oil revenue of Kazakhstan, which is needed to calculate fiscal dependency, is not available. That is why payments of oil and gas companies to the government of Kazakhstan from National Reports on the implementation of the extractive industry transparency initiative in Kazakhstan 2005–2011 (available at were used as approximate data. These reports provide payments of selected oil, gas and mining companies. During the chemokine receptor antagonist 2005–2008 payments by oil and gas companies are not separated from payments by mining companies. From 2009 only tax payments to the budget from the oil and gas companies (excluding mining companies) were used. Since in 2005 only payments of 38 oil, gas and mining companies available, while in 2006–2011 payments of 103–170 oil, gas and mining companies are available, we calculated fiscal dependency over the period 2006–2011. Oil revenue is divided between the government budget and the National fund. That is why total fiscal revenue was calculated as a sum of government revenue and payments of oil companies which were deposited into the National fund. Employing these measurements and plotting the share of Kazakhstan\’s oil exports to its total exports against the share of oil revenue to total revenue shows that Kazakhstan has a high external oil dependency (Fig. 7). About 70 percent of export earning and 40 percent of the fiscal revenue can be definitively associated with the economic activities of the oil sector. For comparison, Fig. 8, based on the work of Liuksila et al. (1994) shows that Nigeria, Saudi Arabia and Venezuela, which are also oil-dependent countries, have over 60 percent external and fiscal dependency (Fig. 8).
As is the case for most oil-producing countries, Kazakhstan has benefited from the upward trend in oil prices that is largely attributable to the strong demand for energy products over the past few years. A simple test of correlation depicted in the graph below affirms the positive correlation between Kazakhstan\’s GDP and the world oil price and between Kazakhstan\’s GDP and the country\’s oil production (Figs. 9 and 10).
The portion of fund\’s revenue in Kazakhstan\’s total revenue is constantly increasing (Fig. 11).

Theoretical analysis

Empirical work


In 1997, Zbigniew Brzezinski who once served as President Jimmy Carter\’s National Security Advisor published his seminal book The Grand Chessboard: American Primacy and Its Geostrategic Imperatives with the goal of formulating a long-term strategy for US foreign policy in the post-Cold War period. The central argument of the book was that the US primacy in the world depended foremost on its success in maintaining political, economic and military dominance over the Eurasian supercontinent, which Brzezinski presumptuously depicted as “the chief geopolitical prize for America”. Such a bold assertion, however, was actually based on the self-confidence of the US policymakers of the period who boasted a strong political standing and powerful economy at home and an unequalled political, economic, military and cultural influence abroad in the immediate aftermath of the Cold War.

Another weakness of the model

Another weakness of the model is the physical barrier presented by the transwell insert, which both restricts access of virus particles to the basolateral surface of the chemokine receptor antagonist and may also limit the amount of cell membrane available for infection. To counter this, we designed a protocol where the transwell contained 200μl more fluid than required for hydrodynamic balance, attempting to induce a convective flow from the well into the insert. While this would not allow direct comparison of infection from the apical and basolateral surfaces, it should at least provide a reproducible system that could allow relative comparisons between different cell types and different viruses. For interpretation of these results, however, we can conclude that there was sufficient virus particle access to the basolateral side to observe if infection was possible. Furthermore, in some cases transgene expression from the basolateral side was greater than from the apical surfaces despite the lower numbers of particles present, suggesting real biological differences over and above and assay limitations. The transwell insert, which has pores 1µm in diameter, also mimics some of the initial physical barriers faced by oncolytic virus entering tumour tissues from tumour-infiltrating blood vessels, such as multiple layers of vascular endothelial and smooth muscle cells with tumour-dependent intercellular pore cutoff sizes (Hobbs et al., 1998; Russell et al., 2012).
The therapeutic efficacy of oncolytic viruses depends not only on their ability to translocate and infect the outermost, exposed surfaces of a tumour, but also to spread through the tumour mass in order to reach poorly perfused areas deep within the tumour microenvironment (Miller et al., 2016). Our study suggested that, regardless of the surface of entry, progeny EnAd virus particles are released predominantly via the apical surface. For many adenoviruses, this corresponds well to the natural route of spread through the apical surface of polarised lung or intestinal epithelia. Barriers to release from the basolateral surface of polarised cells, such as underlying extracellular matrix or neighbouring cells, physically bias the release of virus particles from lysed cells toward the apical surface.
For viruses delivered via the bloodstream this could provide a useful mechanism for directional infection through the first tumour cells encountered, allowing access of progeny virus to the lumens of tumour pseudo-glans, and thereby facilitating apical infection of all the tumour cells bordering that glans. In addition, small assemblies of penton base and fibre, known as penton dodecahedrons (PtDd), are released from cells infected with DSG-2-binding group B adenoviruses (serotypes 3, 7, 11, and 14) and bind to DSG-2 on epithelial cells (Wang et al., 2015, 2011b; Yumul et al., 2016), triggering an intracellular MAPK-mediated signalling cascade that ultimately results in the activation of the matrix metalloprotease ADAM17 and cleavage of the extracellular domain of DSG-2 (Wang et al., 2015). This cleavage triggers transient opening of epithelial junctions and exposure of lateral surface receptors for virus attachment. This, in turn, may lead to better virus spread into solid tumours (Yumul et al., 2016). Though other factors, such as the prevailing cytokine milieu, also play important roles in determining the efficiency of viral infection in the tumour microenvironment, one of the first encountered barrier of intravenously administered viruses is the basolateral surface of tumour cells facing the blood vessel. Such mechanisms of directional infection and cell-to-cell spread for oncolytic viruses may be essential for their success in treatment of primary and metastatic cancers.

Funding information
SLC is supported by a chemokine receptor antagonist postdoctoral scholarship from the Ministry of Higher Education Malaysia and the Universiti Putra Malaysia. The authors would like to gratefully acknowledge support from Cancer Research UK, programme Grant no. C552/A17720. The funders has no role in study design, data collection and interpretation, or submission of the manuscript for publication.

br Multiple linear regression analysis

Multiple linear regression analysis using all variables as factors (Model 1) demonstrated that weight, BMI, and tidal volume were independently associated with the bilateral excursion of the diaphragms (all P < 0.05) after adjusting for other clinical variables, including age, gender, smoking history, height, VC, %VC, FEV1, FEV1%, and %FEV1. There were no significant associations between the excursion of the diaphragms and variables including age, gender, smoking history, height, VC, %VC, FEV1, FEV1%, and %FEV1 (Table 4). Additionally, a multiple linear regression model using age, gender, BMI, tidal volume, VC, FEV1, and smoking history as factors (Model 2) was also fit as a sensitivity analysis, taking into account the correlation among variables (eg, BMI, height, and weight; VC and %VC; FEV1, FEV1%, and %FEV1). Model 2 (Supplementary Data S1) gave results consistent with Model 1 (Table 4): higher BMI and higher tidal volume were independently associated with the increased bilateral excursion of the diaphragms (all P < 0.05). The adjusted R2 in Model 1 was numerically higher than that in Model 2 (right, 0.19 vs. 0.16, respectively; left, 0.16 vs. 0.13, respectively).


Our study determined the average excursion of the diaphragms during tidal breathing in a standing position in a health screening center cohort using dynamic chest radiography (“dynamic X-ray phrenicography”). These findings are important because they provide reference values of diaphragmatic motion during tidal breathing useful for the diagnosis of diseases related to respiratory kinetics. Our study also suggests that dynamic X-ray phrenicography is a useful method for the quantitative evaluation of diaphragmatic motion with a radiation dose comparable to conventional posteroanterior chest radiography (22).

Our study demonstrated that the average excursions of the bilateral chemokine receptor antagonist during tidal breathing (right: 11.0 mm, 95% CI 10.4 to 11.6 mm; left: 14.9 mm, 95% CI 14.2 to 15.5 mm) were numerically less than those during forced breathing in previous studies using other modalities 2; 7 ;  8. Using fluoroscopy, Alexander reported that the average right excursion was 27.5 mm and the average left excursion was 31.5 mm during forced breathing in the standing position in 127 patients (2). Using ultrasound, Harris et al. reported that the average right diaphragm excursion was 48 mm during forced breathing in the supine position in 53 healthy adults (7). Using MR fluoroscopy, Gierada et al. reported that the average right excursion was 44 mm and the average left excursion was 42 mm during forced breathing in the supine position in 10 healthy volunteers (8). The difference in diaphragmatic excursion during tidal breathing versus forced breathing is unsurprising.

Our study showed that the excursion and peak motion speed of the left diaphragm are significantly greater and faster than those of the right. With regard to the excursion, the results of our study are consistent with those of previous reports using fluoroscopy in a standing position 2 ;  3. However, in the previous studies evaluating diaphragmatic motion in the supine position, the asymmetric diaphragmatic motion was not mentioned 7 ;  8. The asymmetric excursion of the bilateral diaphragm may be more apparent in the standing position, but may not be detectable or may disappear in the supine position. Although we cannot explain the reason for the asymmetry in diaphragmatic motion, we speculate that the presence of the liver may limit the excursion of the right diaphragm. Regarding the motion speed, to the best of our knowledge this study is the first to evaluate it. The faster motion speed of the left diaphragm compared to that of the right diaphragm would be related to the greater excursion of the left diaphragm.

br The purpose of this article is to demonstrate how

The purpose of this article is to demonstrate how these principles and assessments can be applied in practice to inform policy choices of OIR, AWR, Approve, or Reject. Two case studies that explore situations in which OIR or AWR might be particularly relevant and challenging have been selected for this purpose. We describe each checklist point of assessment and examine how each of the assessments might be informed on the basis of the type of evidence and analysis currently available and what additional information and/or analyses might be required.

Case Studies

The two case studies selected are 1) enhanced external counterpulsation for chronic stable chemokine receptor antagonist (EECP), and 2) clopidogrel for the management of patients with non–ST-segment elevation acute coronary syndromes (CLOP). The cost-effectiveness of EECP and clopidogrel has been examined previously as part of the National Institute for Health Research Health Technology Assessment program and the National Institute for Health and Care Excellence (NICE) Multiple Technology Appraisal, respectively [11]; [12] ;  [13]. The existing methods of appraisal have been taken as the accepted starting point. A range of additional information was sought and further analysis conducted to inform the sequence of assessment and judgments required when completing the OIR/AWR checklist.

EECP is a noninvasive procedure used to provide symptomatic relief from stable angina. The analysis compares EECP (adjunct to standard therapy) with standard therapy alone. Randomized controlled trial (RCT) evidence suggests an improvement in health-related quality of life with EECP at 12 months. To characterize the uncertainty associated with possible longer durations of treatment effect, formal elicitation of expert clinical judgment was undertaken. This provided an estimate of the probability, with uncertainty, of a patient continuing to respond to treatment with EECP in subsequent years [12].

EECP is expected to be cost-effective but with potentially significant irrecoverable costs. These irrecoverable costs include both 1) capital costs of equipment and 2) large initial per-patient treatment costs, combined with a chronic condition in which a decision not to treat a particular patient can be changed at a later date when the results of research become available or other events occur. Consequently, these irrecoverable costs might influence the type of guidance; for example, OIR rather than Approve [9].

CLOP (used for up to 12 months) in combination with low-dose aspirin was recommended by NICE after a multiple technology appraisal for patients with non–ST-segment-elevation acute coronary syndrome who presented with a moderate to high risk of ischemic events (TA80 in 2004 and updated in 2010 in CG94) [14] ;  [15]. AWR was considered during the appraisal of CLOP. Four alternative treatment durations of CLOP of 12, 6, 3, and 1 month were compared with standard therapy (with low-dose aspirin). CLOP is expected to be cost-effective with no significant irrecoverable costs and illustrates a number of important characteristics, including 1) the impact of other sources of uncertainty (price change following patent expiry) on the value of research, and 2) interpretation of multiple alternatives.

Assessments Required

Point 1—Is the Technology Expected to Be Cost-Effective?

The sequence of assessment starts with cost-effectiveness and expected impact on population net health effect (NHE) [16] ;  [17]. This requires information about prevalence and future incidence of the population and a judgment about the time horizon over which the technology will be used [6]. The scale of the population NHE and how it accumulates over time are important for subsequent assessments; for example, the NHE for current patients must be compared with the benefits to future patients and the significance of irrecoverable opportunity costs of initially negative NHE must be determined.

br We found that higher BMI and

We found that higher BMI and higher tidal volume were independently associated with the increased excursions of the bilateral chemokine receptor antagonist by both univariate and multivariate analyses, although the strength of these associations was weak. We cannot explain the exact reason for the correlation between BMI and the excursion of the diaphragm. However, a previous study showed that BMI is associated with peak oxygen consumption (23), and the increased oxygen consumption in an obese participant may affect diaphragmatic movement. Another possible reason is that lower thoracic compliance due to higher BMI may cause increased movement of the diaphragm for compensation. Regarding the correlation between tidal volume and excursion of the diaphragm, given that diaphragmatic muscle serves as the most important respiratory muscle, the result is to be expected. Considering our results, the excursion evaluated by dynamic X-ray phrenicography could potentially predict tidal volume.

Our study has several limitations. First, we included only 172 volunteers, and additional studies on larger participant populations are required to confirm these preliminary findings. Second, we evaluated only the motion of the highest point of the diaphragms for the sake of simplicity, and three-dimensional motion of the diaphragm could not be completely reflected in our results. However, we believe that this simple method would be practical and more easily applicable in a clinical setting.


The time-resolved quantitative analysis of the diaphragms with dynamic X-ray phrenicography is feasible. The average excursions of the diaphragms are 11.0 mm (right) and 14.9 mm (left) during tidal breathing in a standing position in our health screening center cohort. The diaphragmatic motion of the left is significantly larger and faster than that of the right. Higher tidal volume and BMI are associated with increased excursions of the bilateral diaphragm.

AcknowledgmentsThe authors acknowledge the valuable assistance of Hideo Ogata, MD, PhD, Norihisa Motohashi, MD, PhD, Misako Aoki, MD, Yuka Sasaki, MD, PhD, and Hajime Goto, MD, PhD, from the Department of Respiratory Medicine; Yuji Shiraishi, MD, PhD, from the Department of Respiratory Surgery; and Masamitsu Ito, MD, PhD, Atsuko Kurosaki, MD, Yoichi Akiyama, RT, Kenta Amamiya, RT, and Kozo Hanai, RT, PhD, from the Department of Radiology, Fukujuji Hospital, for their important suggestions. The authors also acknowledge the valuable assistance of Alba Cid, MS, for editorial work on the manuscript. Yoshitake Yamada, MD, PhD, is a recipient of a research fellowship from the Uehara Memorial Foundation.

Appendix. Supplementary DataThe following is the supplementary data to this article:
To view the video inline, enable JavaScript on your browser. However, you can download and view the video by clicking on the icon belowVideo S1.
 A representative video of sequential chest radiographs obtained by chest dynamic radiography for the motion of the diaphragms (“dynamic X-ray phrenicography”). A board-certified radiologist placed a point of interest (red point) on the highest point of each diaphragm on the radiograph at the resting end-expiratory position. These points were automatically traced by the template-matching technique throughout the respiratory phase. Based on locations of the points on sequential radiographs, the vertical excursions and the peak motion speeds of the bilateral diaphragm were calculated (Fig 2c).Help with MP4 filesOptionsDownload video (1042 K)
Data S1.
 Multivariate analysis of associations between the excursions and participant demographics using age, gender, BMI, tidal volume, VC, FEV1, and smoking history as factors (Model 2).Help with DOCX filesOptionsDownload file (23 K)

The bilateral diaphragm is the most important respiratory muscle. Diaphragmatic dysfunction is an underappreciated cause of respiratory difficulties and may be due to a wide variety of issues, including surgery, trauma, tumor, and infection (1). Several previous studies have evaluated diaphragmatic motion using fluoroscopy 2; 3; 4 ;  5, ultrasound 6 ;  7, magnetic resonance (MR) fluoroscopy (dynamic MR imaging [MRI]) 8; 9; 10; 11 ;  12, and computed tomography (CT) 13; 14; 15 ;  16. However, the data of the previous studies using ultrasound, MR fluoroscopy, or CT were obtained in a supine position 6; 7; 8; 9; 10; 11; 12; 13; 14; 15 ;  16, not in a standing position. Also, while the data of the previous studies using fluoroscopy were obtained in a standing position, the data were assessed under forced breathing 2 ;  3, not under tidal or resting breathing. Thus, diaphragmatic motion in a standing position during tidal breathing remains unclear, even though it is essential for understanding respiratory physiology in our daily life. Furthermore, the evaluation of diaphragmatic motion using fluoroscopy, ultrasound, dynamic MRI, or CT has not been used as a routine examination because of limitations, including high radiation dose, small field of view, low temporal resolution, and/or high cost.

chemokine receptor antagonist br Figure thinsp xA Flow diagram of the

Figure 1. Flow diagram of the study population.Figure optionsDownload full-size imageDownload high-quality image (83 K)Download as PowerPoint slide

Imaging Protocol of Dynamic Chest Radiology (“Dynamic X-Ray Phrenicography”)

Posteroanterior dynamic chest radiography (“dynamic X-ray phrenicography”) was performed using a prototype system (Konica Minolta, Inc., Tokyo, Japan) composed of an FPD (PaxScan 4030CB, Varian Medical Systems, Inc., Salt Lake City, UT, USA) and a pulsed X-ray generator (DHF-155HII with Cineradiography option, Hitachi Medical Corporation, Tokyo, Japan). All participants were scanned in the standing position and instructed to breathe normally in a relaxed way without deep inspiration or expiration (tidal breathing). The exposure conditions were as follows: tube voltage, 100 kV; tube current, 50 mA; pulse duration of pulsed X-ray, 1.6 ms; source-to-image distance, 2 m; additional filter, 0.5 mm Al + 0.1 mm Cu. The additional filter was used to filter out soft X-rays. The exposure time was approximately 10–15 seconds. The pixel size was 388 × 388 µm, the matrix size was 1024  × 768, and the overall image area was 40 × 30 cm. The gray-level range of the images was 16,384 (14 bits), and the signal intensity was proportional to the incident exposure of the X-ray detector. The dynamic image data, captured at 15 frames/s, were synchronized with the pulsed X-ray. The pulsed X-ray prevented excessive chemokine receptor antagonist exposure to the subjects. The entrance surface dose was approximately 0.3–0.5 mGy.

Image Analysis

The diaphragmatic motions on sequential chest radiographs (dynamic image data) during tidal breathing were analyzed using prototype software (Konica Minolta, Inc.) installed in an independent workstation (Operating system: Windows 7 Pro SP1; Microsoft, Redmond WA; CPU: Intel Core i5-5200U, 2.20 GHz; memory 16 GB). The edges of the diaphragms on each dynamic chest radiograph were automatically determined by means of edge detection using a Prewitt Filter 18 ;  19. A board-certified radiologist with 14 years of experience in interpreting chest radiography selected the highest point of each diaphragm as the point of interest on the radiograph of the resting end-expiratory position (Fig 2a). These points were automatically traced by the template-matching technique throughout the respiratory phase (Fig 2b, Supplementary Video S1), and the vertical excursions of the bilateral diaphragm were calculated (Fig 2c): the null point was set at the end of the expiratory phase, that is, the lowest point (0 mm) of the excursion on the graph is the highest point of each diaphragm at the resting end-expiratory position. Then the peak motion speed of each diaphragm was calculated during inspiration and expiration by the differential method (Fig 2c). If several respiratory cycles were involved in the 10 to 15-second examination time, the averages of the measurements were calculated.

Figure 2. Representative sequential chest radiographs and the graphs of excursion and peak motion of the diaphragms obtained by chest dynamic radiography (“dynamic X-ray phrenicography”). (a) Radiograph of the resting end-expiratory position. (b) Radiograph of the resting end-inspiratory position. (c) Graph showing the vertical excursions and the peak motion speeds of the bilateral diaphragm. A board-certified radiologist placed a point of interest (red point) on the highest point of each diaphragm on the radiograph at the resting end-expiratory position (a). These points were automatically traced by the template-matching technique throughout the respiratory phase (double arrows in b) (Supplementary Video S1); red double arrow indicates the vertical excursion of the right diaphragm and blue double arrow indicates that of the left diaphragm. Based on locations of the points on sequential radiographs, the vertical excursions and the peak motion speeds of the bilateral diaphragm were calculated (c). The lowest point (0 mm) of the excursion on the graph indicated that the highest point of each diaphragm was at the resting end-expiratory position (ie, null point was set at the end-expiratory phase) (c). (Color version of figure is available online.)Figure optionsDownload full-size imageDownload high-quality image (305 K)Download as PowerPoint slide