3D-SPACE Sequence Research Articles

Assessment of pituitary micro-lesions using 3D sampling perfection with application-optimized contrasts using different flip-angle evolutions

The aim of this study was to explore the value of three-dimensional sampling perfection with application-optimized contrasts using different flip-angle evolutions (3D-SPACE) sequence in assessment of pituitary micro-lesions. Coronal 3D-SPACE as well as routine T1- and dynamic contrast-enhanced (DCE) T1-weighted images of the pituitary gland were acquired in 52 patients (48 women and four men; mean age, 32 years; age range, 17-50 years) with clinically suspected pituitary abnormality at 3.0 T, retrospectively. The interobserver agreement of assessment results was analyzed with K-statistics. Qualitative analyses were compared using Wilcoxon signed-rank test. There was good interobserver agreement of the independent evaluations for 3D-SPACE images (k = 0.892), fair for routine MR images (k = 0.649). At 3.0 T, 3D-SPACE provided significantly better images than routine MR images in terms of the boundary of pituitary gland, definition of pituitary lesions, and overall image quality. The evaluation of pituitary micro-lesions using combined routine and 3D-SPACE MR imaging was superior to that using only routine or 3D-SPACE imaging. The 3D-SPACE sequence can be used for appropriate and successful evaluation of the pituitary gland. We suggest 3D-SPACE sequence to be a powerful supplemental sequence in MR examinations with suspected pituitary micro-lesions.

Atherosclerosis imaging using 3D black blood TSE SPACEvs2D TSE

To compare 3D Black Blood turbo spin echo (TSE) sampling perfection with application-optimized contrast using different flip angle evolution (SPACE) vs 2D TSE in evaluating atherosclerotic plaques in multiple vascular territories. The carotid, aortic, and femoral arterial walls of 16 patients at risk for cardiovascular or atherosclerotic disease were studied using both 3D black blood magnetic resonance imaging SPACE and conventional 2D multi-contrast TSE sequences using a consolidated imaging approach in the same imaging session. Qualitative and quantitative analyses were performed on the images. Agreement of morphometric measurements between the two imaging sequences was assessed using a two-sample t-test, calculation of the intra-class correlation coefficient and by the method of linear regression and Bland-Altman analyses. No statistically significant qualitative differences were found between the 3D SPACE and 2D TSE techniques for images of the carotids and aorta. For images of the femoral arteries, however, there were statistically significant differences in all four qualitative scores between the two techniques. Using the current approach, 3D SPACE is suboptimal for femoral imaging. However, this may be due to coils not being optimized for femoral imaging. Quantitatively, in our study, higher mean total vessel area measurements for the 3D SPACE technique across all three vascular beds were observed. No significant differences in lumen area for both the right and left carotids were observed between the two techniques. Overall, a significant-correlation existed between measures obtained between the two approaches. Qualitative and quantitative measurements between 3D SPACE and 2D TSE techniques are comparable. 3D-SPACE may be a feasible approach in the evaluation of cardiovascular patients.

Systematical Radiologic Comparison of 3D-T2W MR Sequences for Cranial Nerve Imaging at 3 T

Background and Purpose: With the technology of magnetic resonance improving, more intricate details of the intracranial anatomy can be visualized. We investigated the visibility and anatomic features of the normal cranial nerves, using high-resolution 3D-SPACE imaging. Materials and Methods: The subjects, 24 healthy volunteers without neurological diseases, all underwent magnetic resonance examination at 3 T using a 32-channel coil to visualize the cisternal segments of the cranial nerves. Two different sequences were used including: conventional 3D-TSE (voxel size, 0.7×0.7×0.7 mm) and 3D-SPACE (voxel size, 0.7×0.7×0.7 mm). The visibilities of the cranial nerves were graded as “distinct,” “probable,” and “blurred” using a qualitative scale of certainty; the Fisher exact χ2 test was used. Results: The display rates on the 3D-SPACE images were 85.41% for IV, 87.50% for IX, 79.16% for X, 72.91% for XI, and 68.75% for XII, compared with display rates of 43.75% for IV, 66.66% for IX, 33.33% for X, 45.83% for XI, and 39.58% for XII on the 3D-TSE images. No statistical difference was observed between the 2 sequences in the detection of some cranial nerves including II, III, V, VI, VII, and VIII (P>0.05). However, there was statistically significant difference in detection of other cranial nerves including IV, IX, X, XI, and XII (P<0.05). For these cranial nerves, their origins and paths were displayed more clearly by the 3D-SPACE sequence. Conclusions: The 3D-SPACE sequence combined with a 32-channel coil demonstrated the cisternal segments of the cranial nerves suitability within acceptable scan times.

AB1471-HPR The reliability and validity of a novel MRI-based tool for the evaluation of forefoot bursae in patients with rheumatoid arthritis: The “FFB-score”

BackgroundWe recently demonstrated forefoot bursae (FFB) are a clinically important feature in patients with rheumatoid arthritis (RA)1. However, there is a need for an observer-independent, reliable and valid method of...

3D fat-saturated T1 SPACE sequence for the diagnosis of cervical artery dissection

This study aims to demonstrate the added value of a 3D fat-saturated (FS) T1 sampling perfection with application-optimised contrast using different flip angle evolutions (SPACE) sequence compared to 2D FS T1 spin echo (SE) for the diagnosis of cervical artery dissection. Thirty-one patients were prospectively evaluated on a 1.5-T MR system for a clinical suspicion of acute or subacute cervical artery dissection with 3D T1 SPACE sequence. In 23 cases, the axial 2D FS T1 SE sequence was also used; only these cases were subsequently analysed. Two neuroradiologists independently and blindly assessed the 2D and 3D T1 sequences. The presence of recent dissection (defined as a T1 hyperintensity in the vessel wall) and the quality of fat suppression were assessed. The final diagnosis was established in consensus, after reviewing all the imaging and clinical data. Overall sensitivity and specificity were 0.929 and 1 for axial T1 SE, and 0.965 and 0.945 for T1 SPACE (P > 0.05), respectively. The two readers had excellent agreement for both sequences (k = 1 and 0.8175 for T1 SE and T1 SPACE, respectively; P > 0.05). The quality of the fat saturation was similar. Very good fat saturation was obtained in the upper neck. Multiplanar reconstructions were very useful in tortuous regions, such as the atlas loop of the vertebral artery or the carotid petrous entry. 3D T1 SPACE sequence has a shorter acquisition time (3min 25s versus 5min 32s for one T1 SE sequence) and a larger coverage area. 3D T1 SPACE sequence offers similar information with its 2D counterpart, in a shorter acquisition time and larger coverage area.

Ligaments of the Lisfranc joint in MRI: 3D-SPACE (sampling perfection with application optimized contrasts using different flip-angle evolution) sequence compared to three orthogonal proton-density fat-saturated (PD fs) sequences

To compare the detection rate and visibility of the ligaments in the Lisfranc joint with a single 3D (-SPACE) MR sequence and three orthogonal PD fat-saturated sequences. Thirty-one asymptomatic feet and 15 patients with posttraumatic pain in the Lisfranc joint were evaluated with a 3D-SPACE-sequence (0.5 mm section thickness, acquisition time 10:22 min, secondary reformations) and three orthogonal PD fs sequences (2 mm section thickness, 9:20 min). The Lisfranc-ligament, the dorsal and plantar tarsometatarsal ligaments (TMT), the dorsal, interosseous, and plantar intermetatarsal ligaments (IMT) (24 ligaments for each foot) were assessed. In asymptomatic feet, 692 ligaments were detected with the SPACE sequence, thereof 90.6 % exhibited normal signal, and most (96.9 %) were completely visible on one single image. A total of 659 ligaments were detected with the PD fs sequence, thereof 86.6 % yielded normal signal, and 28.5 % were completely visible on one single image. In patients, 327 ligaments were detected with SPACE, thereof 50.6 % appeared completely visible with high signal. On PD fs, 308 ligaments were detected, 42.2 % of the ligaments had high signals. The ligaments of the Lisfranc joint are better detected with a single 3D-SPACE sequence and secondary reformations than with three orthogonal PD fs sequences.

SLAP tears: diagnosis using 3-T shoulder MR arthrography with the 3D isotropic turbo spin-echo space sequence versus conventional 2D sequences

The aim of this study was to determine the accuracy and reliability of shoulder magnetic resonance (MR) arthrography with three-dimensional (3D) isotropic intermediate-weighted turbo spin-echo (TSE) sampling perfection with application-optimised contrasts using different flip angle evolution (SPACE) in the diagnosis of superior labrum anterior-to-posterior (SLAP) lesions compared with two-dimensional (2D) TSE at 3.0 T. MR arthrograms, including 2D TSE and 3D TSE-SPACE, in 87 patients who underwent arthroscopy were retrospectively analysed by two reviewers for the presence and type of SLAP lesions. Sensitivity and specificity were compared using McNemar's test, and inter-observer agreement was calculated using Cohen's kappa. Receiver operating characteristic (ROC) curve analyses were performed. The mean sensitivity, specificity and accuracy were 90%, 85% and 86% for 2D TSE, and 81%, 86% and 85% for 3D TSE-SPACE respectively, with no statistically significant differences. Inter-observer agreements were substantial in 2D TSE (κ = 0.76) and 3D TSE-SPACE (κ = 0.68). The areas under the ROC curves were 0.92 for 2D TSE and 0.90 for 3D TSE-SPACE, which were not significantly different. MR arthrography with 3D TSE-SPACE showed comparable accuracy and substantial inter-observer agreement for the diagnosis of SLAP lesions.

Supraspinatus tendon tears at 3.0 T shoulder MR arthrography: diagnosis with 3D isotropic turbo spin-echo SPACE sequence versus 2D conventional sequences

To assess the diagnostic performance of shoulder MR arthrography with 3D isotropic fat-suppressed (FS) turbo spin-echo sequence (TSE-SPACE) for supraspinatus tendon tears in comparison with 2D conventional sequences at 3.0T. The study was HIPAA-compliant and approved by the institutional review board with a waiver of informed consent. Eighty-seven arthroscopically confirmed patients who underwent 3.0T shoulder MR arthrography with 2D sequences and 3D TSE-SPACE were included in a consecutive fashion from March 2009 to February 2010. Two reviewers independently analyzed 2D sequences and 3D TSE-SPACE. Sensitivity, specificity, accuracy, and interobserver agreement (κ) were compared between 2D sequences and 3D TSE-SPACE for full-thickness and partial-thickness supraspinatus tendon tears together and for partial-thickness supraspinatus tendon tears alone. There were 33 full-thickness tears and 28 partial-thickness tears of supraspinatus tendons. For full-thickness and partial-thickness supraspinatus tendon tears together, the mean sensitivity, specificity, and accuracy of both readers were 96, 92, and 94% on 2D sequences and 91, 84, and 89% on 3D TSE-SPACE. For partial-thickness supraspinatus tendon tears alone, the mean sensitivity, specificity, and accuracy were 95, 92, and 94% on 2D sequences and 84, 85, and 84% on 3D TSE-SPACE. There was no statistical difference between 2D sequences and 3D TSE-SPACE. Interobserver agreements were almost perfect on 2D conventional sequences and substantial on 3D TSE-SPACE. Compared with 2D conventional sequences, MR arthrography using 3D TSE-SPACE was comparable for diagnosing supraspinatus tendon tears despite limitations in detecting small partial-thickness tears and in discriminating between full-thickness and deep partial-thickness tears.

Evaluation of spontaneous third ventriculostomy by three-dimensional sampling perfection with application-optimized contrasts using different flip-angle evolutions (3D-SPACE) sequence by 3 T MR imaging: Preliminary results with variant flip-angle mode

This prospective study aimed to evaluate the use of three-dimensional sampling perfection with application-optimized contrasts using different flip-angle evolutions (3D-SPACE) in the diagnosis of spontaneous third ventriculostomy (STV) and to compare it with phase-contrast cine magnetic resonance imaging (PC-MRI). PC-MRI and 3D-SPACE images were obtained in 15 patients with hydrocephalus for evaluation of STV as well as in 10 control cases. The presence of STV was evaluated visually by two experienced radiologists on both PC-MRI and 3D-SPACE images, and the results were statistically compared. There was a strong correlation between PC-MRI and SPACE scores for both readers (correlation coefficient [r]=0.784; P=0.001). There was also a good correlation between PC-MRI scores and consensus-based results. Interobserver reliabilities were strong for all STV scores. In addition, there was excellent correlation between 3D-SPACE scores and consensus-based results (first reader's kappa value: 0.87; second reader's kappa value: 1). 3D-SPACE can provide morphological-physiological information for the evaluation of STV with no need for additional PC-MRI analysis or other sequences. As a non-invasive test, it can also be included among the first line of choices of MRI sequences for patients with obstructive hydrocephalus.

Dynamic Magnetic Resonance Imaging of the Cervical Spine with High-Resolution 3-Dimensional T2-Imaging

Imaging of the cervical spine in functional positions has so far been limited to conventional X-ray examinations or the scarcely available open magnetic resonance imaging (MRI). An MRI compatible positioning device allows MRI examinations in various positions and even in motion. In combination with high-resolution T2-weighted MRI it allows detailed functional imaging of the cervical spine and nerve roots. To evaluate the utility of this method a population of patients from a clinical study was examined 5 years after anterior cervical discectomy and fusion (ACDF). A total of 32 patients (median age 51.5 years, 15 female, 17 male) were examined after a median interval of 64.3 months from ACDF including 16 patients with a titanium cage and 16 with autologous bone graft. The prototype of an MR compatible positioning device (NeuroSwing) was used for MRI of the cervical spine in functional positions on a 1.5 T MRI unit (Siemens Avanto). A real-time true fast imaging with steady-state precession (FISP) sequence [6 mm, TR 704, TE 1.3 ms, matrix 256 x 207, field of view (FoV) 22 cm] was used for monitoring of flexion up to 45° and extension up to 40° or until patient discomfort. A sagittal T2 sampling perfection with application optimized contrast using different flip angle evolution sequence (SPACE sequence, 0.9 mm isotropic voxels, TR 1770, TE 186 ms, matrix 320 x 318, FoV 28 cm) and an axial true FISP sequence (3 mm slices, TR 194, TE 1.9 ms, matrix 256 x 256, FoV 22 cm) were used for imaging in the end positions. Using the motorized positioning device and a real-time true FISP sequence, imaging of the cervical spine in flexion and extension motion was possible in a quality suitable to observe changes in the alignment of vertebral bodies, the width of the spinal canal and the spinal cord itself. The 3D T2-weighted SPACE sequence yielded high quality and resolution images in the maximum flexion and extension positions. Compared to primary axial T2 true FISP slices, axial reconstructions of the T2 SPACE sequence were found to be clearly less affected by metal artifacts with the additional benefit of multiplanar and transforaminal reconstructions. The combination of a mechanical positioning device and a high-resolution 3D T2-weighted sequence (SPACE) on a conventional 1.5 T MRI allows kinematic imaging of the cervical spine as well as high-resolution imaging in the end positions, even in the presence of metal implants. In this proof of concept study a good visualization of narrowing of the spinal canal in functional positions could be achieved, showing the potential of MRI in functional positions for clinical and research applications.

Evaluation of Aqueductal Stenosis by 3D Sampling Perfection with Application-Optimized Contrasts Using Different Flip Angle Evolutions Sequence: Preliminary Results with 3T MR Imaging

Diagnosis of AS and periaqueductal abnormalities by routine MR imaging sequences is challenging for neuroradiologists. The aim of our study was to evaluate the utility of the 3D-SPACE sequence with VFAM in patients with suspected AS. PC-MRI and 3D-SPACE images were obtained in 21 patients who had hydrocephalus on routine MR imaging scans and had clinical suspicion of AS, as well as in 12 control subjects. Aqueductal patency was visually scored (grade 0, normal; grade 1, partial obstruction; grade 2, complete stenosis) by 2 experienced radiologists on PC-MRI (plus routine T1-weighted and T2-weighted images) and 3D-SPACE images. Two separate scores were statistically compared with each other as well as with the consensus scores obtained from general agreement of both radiologists. There was an excellent correlation between 3D-SPACE and PC-MRI scores (κ = 0.828). The correlation between 3D-SPACE scorings and consensus-based scorings was higher compared with the correlation between PC-MRI and consensus-based scorings (r = 1, P < .001 and r = 0.966, P < .001, respectively). 3D-SPACE sequence with VFAM alone can be used for adequate and successful evaluation of the aqueductal patency without the need for additional sequences and examinations. Noninvasive evaluation of the whole cranium is possible in a short time with high resolution by using 3D-SPACE.

可変フリップ角を用いた３Ｄ−Ｔ２強調像（３Ｄ−ＳＰＡＣＥ）におけるコントラスト特性の検討

Sampling perfection with application optimized contrasts using different flip angle evolution (3D-SPACE) sequence enables one to decrease specific absorption rate (SAR) by using variable flip angle refocusing pulse. Therefore, it is expected that the contrast obtained with 3D-SPACE sequences is different from that of spin echo (SE) images and turbo spin echo (TSE) images. The purpose of this study was to evaluate the characteristics of the signal intensity and central nervous system (CNS) image contrast in T(2) weighted 3D-SPACE. Using 3 different sequences (SE, 3D-TSE and 3D-SPACE) with TR/TE=3500/70, 90 and 115 ms, we obtained T(2) weighted magnetic resonance (MR) images of inhouse phantom and five healthy volunteers' brain. Signal intensity of the phantom which contains various T(1) and T(2) value was evaluated. Tissue contrasts of white/gray matter, cerebrospinal fluid (CSF)/subcutaneous fat and gray matter/subcutaneous fat were evaluated for a clinical image study. The phantom study showed that signal intensity in 3D-SPACE significantly decreased under a T(1) value of 250 ms. It was markedly decreased in comparison to other sequences, as effective echo time (TE) was extended. White/gray matter contrast of 3D-SPACE was the highest in all sequences. On the other hand, CSF/fat and gray matter/fat contrast of 3D-SPACE was higher than TSE but lower than SE. CNS image contrasts of 3D-SPACE were comparable to that of SE. Signal intensity had decreased in the range where T(1) and T(2) values were extremely short.

3D MR Cisternography to Identify Distal Dural Rings: Comparison of 3D-CISS and 3D-SPACE Sequences

The distal dural ring (DDR) is an anatomical landmark used to distinguish intra- and extradural aneurysms. We investigated identification of the DDR using 2 three-dimensional (3D) magnetic resonance (MR) cisternography sequences--3D constructive interference in steady state (CISS) and 3D sampling perfection with application optimized contrasts using different flip angle evolutions (SPACE)--at 3.0 tesla. Ten healthy adult volunteers underwent imaging with 3D-CISS, 3D-SPACE, and time-of-flight (TOF) MR angiography (TOF-MRA) sequences at 3.0T. We analyzed DDR identification and internal carotid artery (ICA) signal intensity and classified the shape of the carotid cave. We identified the DDR using both 3D-SPACE and 3D-CISS, with no significant difference between the sequences. Visualization of the outline of the ICA in the cavernous sinus (CS) was significantly clearer with 3D-SPACE than 3D-CISS. In the CS and petrous portions, signal intensity was lower with 3D-SPACE, and the flow void was poor with 3D-CISS in some subjects. We identified the DDR with both 3D-SPACE and 3D-CISS, but the superior contrast of the ICA in the CS using 3D-SPACE suggests the superiority of this sequence for evaluating the DDR.

New approaches in imaging of the brachial plexus

Imaging plays an essential role for the detection and analysis of pathologic conditions of the brachial plexus. Currently, several new techniques are used in addition to conventional 2D MR sequences to study the brachial plexus: the 3D STIR SPACE sequence, 3D heavily T2w MR myelography sequences (balanced SSFP = CISS 3D, True FISP 3D, bFFE and FIESTA), and the diffusion-weighted (DW) neurography sequence with fiber tracking reconstruction (tractography). The 3D STIR sequence offers complete anatomical coverage of the brachial plexus and the ability to slice through the volume helps to analyze fiber course modification and structure alteration. It allows precise assessment of distortion, compression and interruption of postganglionic nerve fibers thanks to the capability of performing maximum intensity projections (MIP) and multiplanar reconstructions (MPRs). The CISS 3D, b-SSFP sequences allow good visualization of nerve roots within the spinal canal and may be used for MR myelography in traumatic plexus injuries. The DW neurography sequence with tractography is still a work in progress, able to demonstrate nerves tracts, their structure alteration or deformation due to pathologic processes surrounding or located along the postganglionic brachial plexus. It may become a precious tool for the understanding of the underlying molecular pathophysiologic mechanisms in diseases affecting the brachial plexus and may play a role for surgical planning procedures in the near future.

Morphologic and Dynamic Renal Imaging With Assessment of Glomerular Filtration Rate in a pcy-Mouse Model Using a Clinical 3.0 Tesla Scanner

OBJECTIVE Morphologic and dynamic renal imaging is necessary for characterization of kidney function in renal insufficiency. Assessment of renal perfusion and the glomerular filtration rate (GFR) are essential, as the serum creatinine level and urea are not sensitive at an early stage of kidney damage. Currently available GFR estimation methods are time consuming, expensive, and lead to radiation exposure for the patient. Therefore, the aim was to determine the feasibility of morphologic and contrast-enhanced dynamic magnetic resonance imaging for GFR assessment in pcy (polycystic kidneys and fibrosis) mice, using a clinical 3.0 Tesla scanner. Fourteen pcy-mice were anesthetized and an internal jugular vein catheter was implanted to which a dedicated extension tube with a 0.28 mm inner diameter was connected, filled with 1:100 microL diluted gadobutrol (Gadovist Bayer Schering Pharma, Berlin, Germany). Imaging of the mice was performed with a dedicated 8-element mouse coil (Rapid Biomedical, Rimpar, Germany) plugged into a clinical 32-channel 3.0 Tesla magnetic resonance-scanner (Magnetom Verio, Siemens Medical Solution, Erlangen, Germany). In this study, different morphologic sequences comprising a T1-w 3D volume-interpolated breathhold examination, T2-w 2D half-Fourier acquired turbo spin echo (HASTE), T2-w 2D BLADE-TSE with fat saturation, and a T2-w 3D SPACE were acquired. The dynamic sequence performed for assessment of GFR, was a 2D SR-Turbo FLASH sequence. Image analysis and data assessment was performed by 2 radiologists who were experienced in assessment of human kidney disease. A 3-point scale for visual assessment of renal cystic changes in the pcy-mice was applied. The appearance of cysts, considering a detailed demarcation of the cyst with an enhancing rim and a hypointense core, were assessed as detailed: (1) faint (2) and not to be differentiated, (3) findings in the morphologic sequences. Quantitative parameters of renal function (cortex plasma flow mL/100 mL/min, cortex plasma volume mL/100 mL, and PT sec) were fitted to a 2-compartment model and compared with blood samples of creatinine and urea. Histologic progression of cysts and fibrosis in the pcy-mice was analyzed. The T2-w 3D SPACE and T1-w 3D volume-interpolated breathhold examination sequence post contrast with thinnest slice thickness of 1 to 1.2 mm were well suited for delineation of the kidneys with detailed demarcation of the cysts (image quality score: 1.14 +/- 0.37 and 1.2 +/- 0.70, respectively). The T2-w 2D BLADE-TSE proved feasible, too (image quality score: 1.28 +/- 0.59). The T2-w 2D HASTE sequence with minimally achievable slice thickness of 2 mm was not suitable for morphologic assessment (image quality score: 2.9 +/- 0.37). The HASTE sequence suffered from blurring artifacts which further decreased the conspicuity of small cystic changes. The 2D SR-Turbo FLASH sequence showed the renal first pass of the contrast agent and enabled assessment of GFR. The data after time resolved 2D SR-Turbo FLASH perfusion analysis was used for GFR evaluation and demonstrated better GFR values in the young pcy-mice (0.558 mL/min) compared with the older pcy-mice (0.066 mL/min). Application of dedicated coils with a clinical 3.0 Tesla magnetic resonance-scanner have proved feasible for morphologic and dynamic renal imaging with assessment of GFR in pcy-mice.

Controlled comparison of cimetidine and carbenoxolone sodium in gastric ulcer.

Fifty-four outpatients with endoscopically diagnosed benign gastric ulcer were allocated at random to treatment with either cimetidine 800 mg daily for six weeks or carbenoxolone sodium 300 mg daily for one week then 150 mg daily for five weeks. Ulcers were reassessed by endoscopy at the end of the trial. The endoscopist was unaware of the treatment and did not take part in the clinical care of the patients. Twenty-one of the 27 patients (78%) given cimetidine and 14 of the 27 (52%) given carbenoxolone had healed ulcers. Symptomatic response occurred earlier with cimetidine but was not significantly better. Unwanted effects were more common in the carbenoxolone group: 12 patients developed hypokalaemia, four of whom needed oral potassium supplements. The results suggest that histamine H2-receptor blockade is at least as effective as carbenoxolone sodium for benign gastric ulcer and produces fewer side effects.