Researcher engagement in policy deemed societally beneficial yet unrewarded.

Maintaining the continued flow of benefits from science, as well as societal support for science, requires sustained engagement between the research community and the general public. On the basis of data from an international survey of 1092 participants (634 established researchers and 458 students) in 55 countries and 315 research institutions, we found that institutional recognition of engagement activities is perceived to be undervalued relative to the societal benefit of those activities. Many researchers report that their institutions do not reward engagement activities despite institutions' mission statements promoting such engagement. Furthermore, institutions that actually measure engagement activities do so only to a limited extent. Most researchers are strongly motivated to engage with the public for selfless reasons, which suggests that incentives focused on monetary benefits or career progress may not align with researchers' values. If institutions encourage researchers' engagement activities in a more appropriate way - by moving beyond incentives - they might better achieve their institutional missions and bolster the crucial contributions of researchers to society.

Segregation indices for disease clustering.

Spatial clustering has important implications in various fields. In particular, disease clustering is of major public concern in epidemiology. In this article, we propose the use of two distance-based segregation indices to test the significance of disease clustering among subjects whose locations are from a homogeneous or an inhomogeneous population. We derive the asymptotic distributions of the segregation indices and compare them with other distance-based disease clustering tests in terms of empirical size and power by extensive Monte Carlo simulations. The null pattern we consider is the random labeling (RL) of cases and controls to the given locations. Along this line, we investigate the sensitivity of the size of these tests to the underlying background pattern (e.g., clustered or homogenous) on which the RL is applied, the level of clustering and number of clusters, or to differences in relative abundances of the classes. We demonstrate that differences in relative abundances have the highest influence on the empirical sizes of the tests. We also propose various non-RL patterns as alternatives to the RL pattern and assess the empirical power performances of the tests under these alternatives. We observe that the empirical size of one of the indices is more robust to the differences in relative abundances, and this index performs comparable with the best performers in literature in terms of power. We illustrate the methods on two real-life examples from epidemiology.

Testing spatial symmetry using contingency tables based on nearest neighbor relations.

We consider two types of spatial symmetry, namely, symmetry in the mixed or shared nearest neighbor (NN) structures. We use Pielou's and Dixon's symmetry tests which are defined using contingency tables based on the NN relationships between the data points. We generalize these tests to multiple classes and demonstrate that both the asymptotic and exact versions of Pielou's first type of symmetry test are extremely conservative in rejecting symmetry in the mixed NN structure and hence should be avoided or only the Monte Carlo randomized version should be used. Under RL, we derive the asymptotic distribution for Dixon's symmetry test and also observe that the usual independence test seems to be appropriate for Pielou's second type of test. Moreover, we apply variants of Fisher's exact test on the shared NN contingency table for Pielou's second test and determine the most appropriate version for our setting. We also consider pairwise and one-versus-rest type tests in post hoc analysis after a significant overall symmetry test. We investigate the asymptotic properties of the tests, prove their consistency under appropriate null hypotheses, and investigate finite sample performance of them by extensive Monte Carlo simulations. The methods are illustrated on a real-life ecological data set.

Deep cerebral venous abnormalities in premature babies with GMH-IVH: a single-centre retrospective study.

PURPOSE: Germinal matrix haemorrhage/intraventricular haemorrhage (GMH-IVH) is a multifactorial injury with both anatomic and haemodynamic involvement. Normal variants in preterm deep cerebral venous anatomy associated with GMH-IVH have been previously described using MRI susceptibility weighted imaging (SWI). The aims of this study were to use SWI to compare the deep venous systems of a cohort of preterm neonates with various grades of GMH-IVH to a group of age-matched controls without GMH-IVH and to present novel retrospective SWI imaging findings. METHODS: A neuroradiologist retrospectively evaluated 3T MRI SWI and phase imaging of 56 preterm neonates with GMH-IVH (14 of each grade) and 27 controls without GMH-IVH, scoring the venous irregularities according to three variables: decreased venous patency, increased lumen susceptibility and the presence of collaterals. Eight different venous locations, including indicated bilateral components, were evaluated: straight sinus, vein of galen, internal cerebral, direct lateral, thalamostriate, atrial and the anterior septal veins. Variables were analysed for statistical significance. Inter-rater reliability was determined via subset evaluation by a second paediatric radiologist. RESULTS: Deep venous abnormalities were significantly more common in patients with GMH-IVH, with Wilcoxon Rank Sum Test demonstrating significant increase with GMH-IVH for total decreased venous patency (W=0, p<0.0001), increased lumen susceptibility and collateral formation. Venous abnormalities were also positively correlated with an increase in GMH-IVH grade from I to IV (patency, ρ=0.782, p<0.01) (increased lumen susceptibility, ρ=0.739, p<0.01) (collaterals, ρ=0.649, p<0.01), not just GMH-IVH alone. CONCLUSION: Deep venous abnormalities are significantly correlated with GMH-IVH alone and an increase in GMH-IVH grade. Further study is needed to determine cause and effect.

Anastomoses of the vestibular, cochlear, and facial nerves.

The internal auditory canal (IAC) is 10 to 17 mm in length, and the facial nerve and vestibulocochlear nerve, which consist of the cochlear nerve, the superior vestibular nerve, and the inferior vestibular nerve, run together in the IAC packaged in dura mater. Oort first described the vestibulocochlear anastomoses in 1918, which is important for the understanding of the pathogenesis and pathophysiology of otologic disorders. The current study documents the existence of vestibulofacial and vestibulocochlear neural connections and topographical relationship of the nerves as part of a radiologic evaluation of 73 human temporal bones from brainstem to the lateral portion of IAC.

Hypotonic swelling of salicylate-treated cochlear outer hair cells.

The outer hair cell (OHC) is a hydrostat with a low hydraulic conductivity of Pf=3x10(-4) cm/s across the plasma membrane (PM) and subsurface cisterna that make up the OHC's lateral wall. The SSC is structurally and functionally a transport barrier in normal cells that is known to be disrupted by salicylate. The effect of sodium salicylate on Pf is determined from osmotic experiments in which isolated, control and salicylate-treated OHCs were exposed to hypotonic solutions in a constant flow chamber. The value of Pf=3.5+/-0.5x10(-4) cm/s (mean+/-s.e.m., n=34) for salicylate-treated OHCs was not significantly different from Pf=2.4+/-0.3x10(-4) cm/s (mean+/-s.e.m., n=31) for untreated OHCs (p=.3302). Thus Pf is determined by the PM and is unaffected by salicylate treatment. The ratio of longitudinal strain to radial strain epsilonz/epsilonc=-0.76 for salicylate-treated OHCs was significantly smaller (p=.0143) from -0.72 for untreated OHCs, and is also independent of the magnitude of the applied osmotic challenge. Salicylate-treated OHCs took longer to attain a steady-state volume which is larger than that for untreated OHCs and increased in volume by 8-15% prior to hypotonic perfusion unlike sodium alpha-ketoglutarate-treated OHCs. It is suggested that depolymerization of cytoskeletal proteins and/or glycogen may be responsible for the large volume increase in salicylate-treated OHCs as well as the different responses to different modes of application of the hypotonic solution.

Is early bladder activity in radionuclide cisternography an indirect sign of spontaneous intracranial hypotension or sequence of lumbar puncture?

Spontaneous intracranial hypotension (SIH) is characterized by severe postural headache and low cerebrospinal fluid (CSF) pressure. Radionuclide cisternography (RC) is of some value in diagnosing CSF leakage causing SIH. However, the sensitivity of RC is too low to demonstrate the site of leakage. In these cases, the early appearance of the radioactivity in the urinary bladder has also been used as an indirect finding in the diagnosis of SIH. The aim of this study was to evaluate the diagnostic reliability of early urinary bladder activity as an indirect sign of SIH. We investigated early bladder activity in 21 patients with suspicion of normal pressure hydrocephalus. Of the 21 subjects, 13 (62%) showed early bladder activity. We demonstrated that early bladder activity is observed in patients without CSF leakage such as normal pressure hydrocephalus. Therefore, this indirect finding of RC is not a reliable finding in diagnosing SIH.

Demonstration of vascular abnormalities compressing esophagus by MDCT: special focus on dysphagia lusoria.

PURPOSE: Dysphagia lusoria (DL) is described in the literature as difficulty in swallowing caused by vascular abnormalities. The most common cause is an aberrant right subclavian artery (SCA) which passes behind the esophagus and is also called arteria lusoria (AL). Our aim was to demonstrate the use of multidetector computed tomography (MDCT) in the diagnosis of AL, as there is no comprehensive study investigating the role of MDCT in such cases. MATERIAL AND METHODS: A total of 38 consecutive patients, comprising of 23 females (61%) and 15 males (39%), who had extrinsic compression were included in the study. These patients are selected from the cases who were admitted due to their gastrointestinal symptoms, such as dysphagia, epigastric pain, chronic nausea, vomiting, etc. The mean age of patients was 40 +/- 25 years (range 15-65). Following barium esophagogram and then endoscopy performed, MDCT angiography was carried out on the same or the following few days. MDCT sections were examined to determine the following: presence of vascular abnormality; the diameter and angle of that vascular structure; and the compressed area of esophagus. Radiological findings and dysphagia scores were also compared. RESULTS: In each of 15 cases, there was a compression due to vascular abnormality which were all located between the esophagus and the spine. There was an esophageal compression in each of 12 cases, due to right aberrant SCA, in one case due to right superior aortic arch and in two cases due to both right aortic arch and left SCA with Kommerell's diverticulum. The mean diameter and the angle of AL were 16.4 mm and 48.8 degrees , respectively, and the mean area of pressured esophagus was 194.7 mm2. Dysphagia scores of the cases was 1 in thirteen cases and 2 in two cases. However, dysphagia scores were not correlated with these parameters. CONCLUSIONS: MDCT angiography is a useful diagnostic tool for evaluation of patients with dysphagia, especially caused by a vascular abnormality.

Frequency of Nerve Root Sleeve Cysts in Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: There is sporadic data about the occurrence of spinal meningeal cysts in patients with autosomal dominant polycystic kidney disease (ADPKD). We suggest that there is a relationship with the frequency and size of spinal meningeal cysts and headache, intracranial aneurysms, and cerebrospinal fluid leakage in patients with ADPKD. AIM: To investigate the relationship with spinal meningeal cyst, cerebrospinal fluid leakage, and headache in patients with ADPKD. STUDY DESIGN: Cross-sectional study. METHODS: We enrolled 50 patients with ADPKD and 37 healthy volunteers. This cross-sectional study included patients with ADPKD and matched healthy volunteers. Magnetic resonance imaging myelography was performed using the 3D-T2 HASTE technique in an MRI scanner. We questioned our subjects regarding presence of headache and evaluated headache severity using a visual analog scale. The relationship between the number and size of spinal meningeal cysts with headache, intracranial aneurysms, and liver cysts was also investigated. RESULTS: Spinal meningeal cysts were more numerous and larger in patients than in controls (14.8±11.6 vs. 6.4±4.6 cysts respectively, p<0.001, 68.3±49.3 vs. 25.4±20.1 mm, p<0.001, respectively). Spinal cyst number and size were similar in APDKD patients with or without intracranial aneurysms. Headache score was correlated with the size and number of spinal meningeal cysts. This was valid only in patients with ADPKD. CONCLUSION: Abnormality involving the vessel wall in ADPKD may explain the increased number of spinal meningeal cysts in ADPKD. Moreover, leakage of cerebrospinal fluid secondary to spinal meningeal cyst may be responsible for recurrent severe headache by causing spontaneous intracranial hypotension in these patients.

Morphometric differences in planum temporale in schizophrenia and bipolar disorder revealed by statistical analysis of labeled cortical depth maps.

Differences in cortical thickness in the lateral temporal lobe, including the planum temporale (PT), have been reported in MRI studies of schizophrenia (SCZ) and bipolar disorder (BPD) patients. Most of these studies have used a single-valued global or local measure for thickness. However, additional and complementary information can be obtained by generating labeled cortical distance maps (LCDMs), which are distances of labeled gray matter (GM) voxels from the nearest point on the GM/white matter (WM) (inner) cortical surface. Statistical analyses of pooled and censored LCDM distances reveal subtle differences in PT between SCZ and BPD groups from data generated by Ratnanather et al. (Schizophrenia Research, http://dx.doi.org/10.1016/j.schres.2013.08.014). These results confirm that the left planum temporale (LPT) is more sensitive than the right PT in distinguishing between SCZ, BPD, and healthy controls. Also confirmed is a strong gender effect, with a thicker PT seen in males than in females. The differences between groups at smaller distances in the LPT revealed by pooled and censored LCDM analysis suggest that SCZ and BPD have different effects on the cortical mantle close to the GM/WM surface. This is consistent with reported subtle changes in the cortical mantle observed in post-mortem studies.

Censoring distances based on labeled cortical distance maps in cortical morphometry.

It has been demonstrated that shape differences in cortical structures may be manifested in neuropsychiatric disorders. Such morphometric differences can be measured by labeled cortical distance mapping (LCDM) which characterizes the morphometry of the laminar cortical mantle of cortical structures. LCDM data consist of signed/labeled distances of gray matter (GM) voxels with respect to GM/white matter (WM) surface. Volumes and other summary measures for each subject and the pooled distances can help determine the morphometric differences between diagnostic groups, however they do not reveal all the morphometric information contained in LCDM distances. To extract more information from LCDM data, censoring of the pooled distances is introduced for each diagnostic group where the range of LCDM distances is partitioned at a fixed increment size; and at each censoring step, the distances not exceeding the censoring distance are kept. Censored LCDM distances inherit the advantages of the pooled distances but also provide information about the location of morphometric differences which cannot be obtained from the pooled distances. However, at each step, the censored distances aggregate, which might confound the results. The influence of data aggregation is investigated with an extensive Monte Carlo simulation analysis and it is demonstrated that this influence is negligible. As an illustrative example, GM of ventral medial prefrontal cortices (VMPFCs) of subjects with major depressive disorder (MDD), subjects at high risk (HR) of MDD, and healthy control (Ctrl) subjects are used. A significant reduction in laminar thickness of the VMPFC in MDD and HR subjects is observed compared to Ctrl subjects. Moreover, the GM LCDM distances (i.e., locations with respect to the GM/WM surface) for which these differences start to occur are determined. The methodology is also applicable to LCDM-based morphometric measures of other cortical structures affected by disease.

Reduced anterior cingulate gray matter volume and thickness in subjects with deficit schizophrenia.

BACKGROUND: Patients with deficit schizophrenia (D-SZ) differ from patients with the non-deficit form of schizophrenia (ND-SZ) in several aspects such as risk factors, neurobiological correlates, treatment response and clinical outcome. It has been debated if brain morphology could differentiate D-SZ from ND-SZ. Anterior cingulate gyrus (ACG) region regulates cognitive and emotional processing and past studies reported structural changes in this region in patients with SZ. METHODS: 1.5-T 3D MRI scans were obtained from 18 D-SZ patients, 30 ND-SZ patients and 82 healthy controls (HCs). We used FreeSurfer-initalized labeled cortical distance mapping (FSLCDM) to measure ACG gray matter volume, cortical thickness, and area of the gray/white interface. Furthermore, cortical thickness was compared among the 3 groups using the pooled labeled cortical distance mapping (LCDM) method. RESULTS: The ACG cortex of the D-SZ group was thinner than the ND-SZ group. Pooled LCDM demonstrated that the ACG cortex was bilaterally thinner in both the ND-SZ group and the D-SZ group compared with the control group. The right ACG gray matter volume was significantly reduced in D-SZ patients as compared with healthy controls (p=0.005 CONCLUSION: Our data suggest that qualitative, categorical differences in neuroanatomy may distinguish between deficit and non-deficit subtypes of schizophrenia.

Morphometry of superior temporal gyrus and planum temporale in schizophrenia and psychotic bipolar disorder.

Structural abnormalities in temporal lobe, including the superior temporal gyrus (STG) and planum temporale (PT), have been reported in schizophrenia (SCZ) and bipolar disorder (BPD) patients. While most MRI studies have suggested gray matter volume and surface area reduction in temporal lobe regions, few have explored changes in laminar thickness in PT and STG in SCZ and BPD. ROI subvolumes of the STG from 94 subjects were used to yield gray matter volume, gray/white surface area and laminar thickness for STG and PT cortical regions. Morphometric analysis suggests that there may be gender and laterality effects on the size and shape of the PT in BPD (n=36) and SCZ (n=31) with reduced laterality in PT in subjects with SCZ but not in BPD. In addition, PT surface area was seen to be larger in males, and asymmetry in PT surface area was larger in BPD. Subjects with SCZ had reduced thickness and smaller asymmetry in PT volume. Thus, the PT probably plays a more sensitive role than the STG in structural abnormalities seen in SCZ.

Metric distances between hippocampal shapes indicate different rates of change over time in nondemented and demented subjects.

In this article, we use longitudinal morphometry (shape and size) measures of hippocampus in subjects with mild dementia of Alzheimer type (DAT) and nondemented controls in logistic discrimination. The morphometric measures we use are volume and metric distance measures at baseline and follow-up (two years apart from baseline). Morphometric differences with respect to a template hippocampus were measured by the metric distance obtained from the large deformation diffeomorphic metric mapping (LDDMM) algorithm. LDDMM assigns metric distances on the space of anatomical images, thereby allowing for the direct comparison and quantization of morphometric changes. We also apply principal component analysis (PCA) on volume and metric distance measures to obtain principal components that capture some salient aspect of morphometry. We construct classifiers based on logistic regression to distinguish diseased and healthy hippocampi (hence potentially diagnose the mild form of DAT). We consider logistic classifiers based on volume and metric distance change over time (from baseline to follow-up), on the raw volumes and metric distances, and on principal components from various types of PCA analysis. We provide a detailed comparison of the performance of these classifiers and guidelines for their practical use. Moreover, combining the information conveyed by volume and metric distance measures by PCA can provide a better biomarker for detection of dementia compared to volume, metric distance, or both.

A Radiological Study on the Topographical Relationships between the Vestibular, Cochlear and Facial Nerves.

OBJECTIVE: The purpose of our study was to investigate the topographical relationship between these nerves along their course from the brainstem through the internal acoustic canal IAC in the living human brain using MR imaging. MATERIALS AND METHODS: We performed three-dimensional gradient echo balanced Fast Field Echo (3D bFFE) sequence oblique parasagittal MR imaging in 73 healthy subjects. The IACs were analyzed from the brainstem end of the IAC to the fundus in contiguous sections. At five levels, the topographical relationships between the facial and vestibulocochlear nerves (VCN) were recorded. In the lateral portions of the IACs where they separated from each other, the relative sizes of the individual nerves were examined. RESULTS: In general, the facial nerve (FN), which is a round structure, is located anteriorly and superiorly to the vestibulocochlear nerve throughout its course. The vestibulocochlear nerve is usually rectangular; however, it was found to be round and at times triangular in shape near the brainstem, before it became crescent-shaped at the porus in 89% of the cases. The superior vestibular nerve kept its posterosuperior position in the canal, and the inferior vestibular nerve (IVN) and the cochlear nerve (CN) travelled inferior to it. The superior and inferior vestibular nerves were divided by the falciform crest in 53% of the cases. The inferior vestibular nerve was the smallest nerve in 52% of the cases, and the cochlear nerve was the largest in 36% of the cases. CONCLUSION: To the best of our knowledge, this study is the largest in vivo MR study, and most of our findings differ from previous cadaver studies. Determination of these topographical relationships may facilitate our understanding of the complicated physiological relationships between the 7(th) and 8(th) nerve complexes during surgery in this region.

Prediction and control of number of cells in microdroplets by stochastic modeling.

Manipulation and encapsulation of cells in microdroplets has found many applications in various fields such as clinical diagnostics, pharmaceutical research, and regenerative medicine. The control over the number of cells in individual droplets is important especially for microfluidic and bioprinting applications. There is a growing need for modeling approaches that enable control over a number of cells within individual droplets. In this study, we developed statistical models based on negative binomial regression to determine the dependence of number of cells per droplet on three main factors: cell concentration in the ejection fluid, droplet size, and cell size. These models were based on experimental data obtained by using a microdroplet generator, where the presented statistical models estimated the number of cells encapsulated in droplets. We also propose a stochastic model for the total volume of cells per droplet. The statistical and stochastic models introduced in this study are adaptable to various cell types and cell encapsulation technologies such as microfluidic and acoustic methods that require reliable control over number of cells per droplet provided that settings and interaction of the variables is similar.

Statistical modeling of single target cell encapsulation.

High throughput drop-on-demand systems for separation and encapsulation of individual target cells from heterogeneous mixtures of multiple cell types is an emerging method in biotechnology that has broad applications in tissue engineering and regenerative medicine, genomics, and cryobiology. However, cell encapsulation in droplets is a random process that is hard to control. Statistical models can provide an understanding of the underlying processes and estimation of the relevant parameters, and enable reliable and repeatable control over the encapsulation of cells in droplets during the isolation process with high confidence level. We have modeled and experimentally verified a microdroplet-based cell encapsulation process for various combinations of cell loading and target cell concentrations. Here, we explain theoretically and validate experimentally a model to isolate and pattern single target cells from heterogeneous mixtures without using complex peripheral systems.

Quantization and analysis of hippocampal morphometric changes due to dementia of Alzheimer type using metric distances based on large deformation diffeomorphic metric mapping.

The metric distance obtained from the large deformation diffeomorphic metric mapping (LDDMM) algorithm is used to quantize changes in morphometry of brain structures due to neuropsychiatric diseases. For illustrative purposes we consider changes in hippocampal morphometry (shape and size) due to very mild dementia of the Alzheimer type (DAT). LDDMM, which was previously used to calculate dense one-to-one correspondence vector fields between hippocampal shapes, measures the morphometric differences with respect to a template hippocampus by assigning metric distances on the space of anatomical images thereby allowing for direct comparison of morphometric differences. We characterize what information the metric distances provide in terms of size and shape given the hippocampal, brain and intracranial volumes. We demonstrate that metric distance is a measure of morphometry (i.e., shape and size) but mostly a measure of shape, while volume is mostly a measure of size. Moreover, we show how metric distances can be used in cross-sectional, longitudinal analysis, as well as left-right asymmetry comparisons, and provide how the metric distances can serve as a discriminative tool using logistic regression. Thus, we show that metric distances with respect to a template computed via LDDMM can be a powerful tool in detecting differences in shape.

Diagnostic performance of multidetector computed tomography for detecting aorto-ostial lesions compared with catheter coronary angiography: multidetector computed tomography coronary angiography is superior to catheter angiography in detection of aorto-ostial lesions.

PURPOSE: In this study, our goal is to determine the use of multidetector computed tomography (MDCT) in detection of aorto-ostial lesions. MATERIALS AND METHODS: Thirty-three patients suspected to have aorto-ostial lesion by either catheter angiography (CA) or MDCT coronary angiography comprised our study population. In 19 patients (group 1), aorto-ostial lesion was suspected based on CA, then MDCT coronary angiography was performed. In the remaining 14 patients (group 2), aorto-ostial lesion diagnosis was made by MDCT coronary angiography, and then afterward, CA was performed. A cardiologist and a radiologist reevaluated both the CA and MDCT coronary angiography recordings of all patients and their consensus formed the diagnosis. We accepted this consensus diagnosis as our criterion standard because a universal criterion standard to compare CA and MDCT findings with is not available. Then, the previous diagnoses by CA and MDCT coronary angiography were compared with the consensus diagnoses. RESULTS: Finally, 26 patients were diagnosed with aorto-ostial lesion, whereas 5 patients were found not to have aorto-ostial lesions. Two patients were diagnosed with abnormal origination of a coronary artery. When the results were evaluated in terms of the presence of aorto-ostial lesion, MDCT coronary angiography correctly diagnosed all 26 patients, and in the 5 patients with normal ostium, MDCT coronary angiography finding was also normal. However, 7 of 26 patients with aorto-ostial lesion were reported to be normal by CA, and also 5 patients with normal ostia were reported to have aorto-ostial lesion by CA. That is, 12 of 33 patients were misdiagnosed by CA. Moreover, CA missed the abnormal origination of the coronary arteries in 2 patients. When the results were evaluated in terms of the degree of stenosis in 26 patients with aorto-ostial lesion; MDCT coronary angiography predicted the final diagnosis in all 26 patients correctly. However, CA predicted the final degree of stenosis only in 12 patients. Catheter angiography underestimated the degree of the stenosis in 2 patients, overestimated in 5 patients and missed the lesion in 7 patients. CONCLUSIONS: Our findings suggest that MDCT is a reliable tool for diagnosing the presence and severity of aorto-ostial lesions. In addition, MDCT might be useful in preventing the false diagnosis due to the catheter-induced spasms in patients who were diagnosed with aorto-ostial lesion by CA. Moreover, if MDCT coronary angiography detects a lesion in aorto-ostial region, there is no need to perform CA to merely verify this pathology.