Eye Pathology Research Articles

Значение мелатонина для физиологии и патологии глаза

Значение мелатонина для физиологии и патологии глаза

Ocular blood flow assessment in vascular pathology of the eye

The review discusses some of the most common methods of ocular microcirculation assessment in vascular lesions of the eye: color and power Doppler imaging, laser Doppler flowmetry, fluorescent and indocyanine green angiography, digital retinal photographs and measurement of retinal vascular caliber, pulsative ocular blood flow analyzer, OCT-angiography. These methods are used in diagnostic of impairment of blood flow in vessels of optic nerve and retina, which also are full informative in early diagnostic of vascular pathology of eye.

A Retrospective Review of Conjunctival Melanoma Presentation, Treatment, and Outcome and an Investigation of Features Associated With BRAF Mutations.

Large studies investigating clinical presentation and treatment in primary conjunctival melanoma (CM) are rare. Clinicopathological characteristics of BRAF-mutated CM have not been studied thoroughly. To determine the associations of clinicopathological tumor features and treatment with local recurrence, metastasis, and mortality and to determine the association of BRAF mutations with these features. Population-based cohort study at the Eye Pathology Institute, Copenhagen, Denmark. Participants included 139 patients with primary CM in Denmark from January 1, 1960, to December 31, 2012. For BRAF analysis, all patients with available formalin-fixed, paraffin-embedded tumor samples from January 1, 1994, to December 31, 2012, were included. BRAF mutations, local recurrence, regional and distant metastasis, melanoma-related mortality, and all-cause mortality were examined. A poor prognosis of tumors involving the extrabulbar conjunctiva and adjacent tissue structures was confirmed in multivariable Cox proportional hazards regression models. Patients undergoing incisional biopsy more frequently developed metastasis (hazard ratio [HR], 2.46; 95% CI, 1.08-5.58; P = .03). Excision without adjuvant treatment was associated with local recurrence (HR, 1.97; 95% CI, 0.11-3.48; P = .02), metastatic disease (HR, 2.51; 95% CI, 1.07-5.91; P = .03), and all-cause mortality (HR, 1.80; 95% CI, 1.05-3.08; P = .03). BRAF mutations were identified in 19 of 47 primary CMs (40.4%) and were more frequent in younger patients (P = .005), less frequent in the extrabulbar conjunctiva (P = .05), more frequently classified as T1 tumors (P = .03), and rarely manifested with primary acquired melanosis (P = .001) or with a uniformly pigmented lesion (P = .006). Distant metastases developed in 6 of 19 BRAF-mutated CMs (31.6%) as opposed to 1 of 28 BRAF wild-type CMs (3.6%). No definitive association with distant metastasis was seen in multivariable Cox proportional hazards regression models. Incisional biopsy and excision without adjuvant therapy were associated with a poor outcome in patients with CM. Extrabulbar location was also associated with a poor outcome in multivariable analysis. BRAF-mutated CMs were frequent in younger patients and were rare in tumors involving the extrabulbar conjunctiva. Despite a more favorable location, BRAF-mutated tumors may be associated with more frequent distant metastasis.

Real time B-Scan evaluation of Posterior chamber & extraocular pathologies of Eye & Orbit

Objective: Aim of this study is to assess the usefulness and accuracy of high frequency real time ultrasound using non dedicated all purpose scanner to detect and characterise posterior chamber and extraocular pathologies in trauma and non-traumatic eye and to establish etiology of proptosis. Material & Method: A total number of 138 cases (145 eyes) were included in the study. Ultrasound evaluation of eyes with diagnosed or suspected posterior segment pathology, cases of trauma, suspected or diagnosed intraocular tumors / extraocular pathologies and cases presenting with proptosis. Patients lost to follow up and eyes with normal scan were excluded. Supplementary investigation (CT, MRI) done where ever needed. The findings of B-scan then correlated with the ophthalmoscopic/ surgical findings/histology/follow up after treatment. Results: Distinction between intra and extra-ocular pathologies was 100%. The commonest posterior segment pathology in non traumatic eyes was retinal detachment and in traumatic eye was vitreous haemorrhage with diagnostic accuracy of 98.9% and 97.9% respectively. Retinoblastoma and pseudotumor (15%) were the commonest intra and extraocular mass lesions respectively. Accuracy in localization of foreign bodies and dislocated lens, in diagnosing retinoblastoma, in diagnosis and characterization of thyroid orbitopathy, cavernous hemangioma, tumors, cellulitis, dermoids, cysticercosis and intraorbital cysts was excellent. “Triple wall” sign is typical for intraorbital hydatid cyst. Conclusion: B-mode real time ultrasound using non-dedicated all purpose high frequency transducer provides non-ionizing, cost effective, non-invasive technique with excellent image quality and high accuracy for diagnosis and assessment of posterior segment and extraocular pathologies.

A study of role of B scan ultrasound in posterior segment pathology of eye

Introduction: Ophthalmic ultrasonography has become the most important accurate diagnostic imaging modality for directly evaluating lesions of posterior segment having opaque ocular media. Study was conducted to assess the role of B scan ultrasound in posterior segment pathology of eye. Material and Method: This prospective study was conducted in Department of Radiodiagnosis, NSCB Medical College and Hospital, Jabalpur from October 2013 to October 2014.The study included patients referred for high resolution ultrasonography from Department of Ophthalmology. 50 patients were subjected to clinical Ophthalmological examination and B scan USG evaluation. Results: The cases were divided according to age ranging from 0-80 years. Maximum no. of patients studied was in 5th decade (22%). Male predominance was seen with sex ratio 3.1:1 (M:F). Loss of vision and redness of eye were the leading symptoms. Maximum no. of ocular abnormalities studied were of Vitreous (40.2%) followed by Retina (25.77%). Also Among vitreous abnormalities, Vitreous hemorrhage was the most common accounting for 56.41% cases followed by vitreous detachment (33.33%), vitreous band was found in 10.25% cases. Retinal detachment was the common retinal abnormality detected (41.5%), while retinoblastoma was seen in 5.66 % cases. Cataract is the most commonly encountered lens abnormality. 81.81% eyes had cataract among total lens abnormalities followed by dislocation of lens (18.18% among lens abnormalities). Choroidal abnormalities include maximum cases of choroidal detachment (80%), while choroidal hemorrhage was seen in 20%. Conclusion-From, the present study it was noted that B-scan is very efficient tool in diagnosing various ocular abnormalities. B-scan can categorize the lesions in the posterior chamber well, depending on the echotexture and anatomy. Even the exact location of the lesion can be well made out.

Barriers to Receiving Follow-Up Eye Care and Detection of Non-Glaucomatous Ocular Pathology in the Philadelphia Glaucoma Detection and Treatment Project.

This cross-sectional study aimed to evaluate adherence rates and identify barriers to receiving follow-up eye care in participants diagnosed with significant non-glaucomatous eye pathology in the Philadelphia Glaucoma Detection and Treatment Project. This community-based project aimed to improve detection, management, treatment, and follow-up eye care of individuals at high risk for glaucoma in community-based settings. Participants throughout Philadelphia, Pennsylvania, USA were enrolled. After a comprehensive eye examination, follow-up recommendations were given to each participant. A telephone survey was administered to individuals diagnosed with non-glaucomatous ocular pathology 3 months after initial eye examination to assess rates of follow-up and to evaluate potential barriers to follow-up. Of the 1649 participants enrolled in this project, 249 (15 %) were diagnosed with significant non-glaucomatous ocular pathology requiring follow-up care. There were 143 (57 %) who responded to the telephone survey. Respondents had a median age of 72 years, and were predominately female (69 %) and African-American (64 %). Of the respondents, 36 (25 %) attended a follow-up appointment. Participants who did not remember the results of their examinations, did not remember their recommendations, and had not seen an eye doctor within the past year were less likely to make a follow-up appointment (P = 0.04, 0.001 and 0.005, respectively). The Philadelphia Glaucoma Detection and Treatment Program was able to detect a significant amount of non-glaucomatous ocular pathology requiring follow-up care. Actual follow-up rates were sub-optimal. Further research is needed to determine interventions to overcome barriers and increase adherence with follow-up recommendations.

5p13.3p13.2 duplication associated with developmental delay, congenital malformations and chromosome instability manifested as low-level aneuploidy.

Recent developments in molecular cytogenetics allow the detection of genomic rearrangements at an unprecedented level leading to discoveries of previously unknown chromosomal imbalances (zygotic and post-zygotic/mosaic). These can be accompanied by a different kind of pathological genome variations, i.e. chromosome instability (CIN) manifested as structural chromosomal rearrangements and low-level mosaic aneuploidy. Fortunately, combining whole-genome and single-cell molecular cytogenetic techniques with bioinformatics offers an opportunity to link genomic changes to specific molecular or cellular pathology. High-resolution chromosomal SNP microarray analysis was performed to study the genome of a 15-month-aged boy presented with developmental delay, congenital malformations, feeding problems, deafness, epileptiform activity, and eye pathology. In addition, somatic chromosomal mutations (CIN) were analyzed by fluorescence in situ hybridization (FISH). Interstitial 5p13.3p13.2 duplication was revealed in the index patient. Moreover, CIN manifested almost exclusively as chromosome losses and gains (aneuploidy) was detected. Using bioinformatic analysis of SNP array data and FISH results, CIN association with the genomic imbalance resulted from the duplication was proposed. The duplication was demonstrated to encompass genes implicated in cell cycle, programmed cell death, chromosome segregation and genome stability maintenance pathways as shown by an interactomic analysis. Genotype-phenotype correlations were observed, as well. To the best our knowledge, identical duplications have not been reported in the available literature. Apart from genotype-phenotype correlations, it was possible to propose a link between the duplication and CIN (aneuploidy). This case study demonstrates that combining SNP array genomic analysis, bioinformatics and molecular cytogenetic evaluation of somatic genome variations is able to provide a view on cellular and molecular pathology in a personalized manner. Therefore, one can speculate that similar approaches targeting both interindividual and intercellular genomic variations could be useful for a better understanding of disease mechanisms and disease-related biological processes.

The history of the description of retinopathy in onchocerciasis

SummaryUp until 1930 the scientific community considered African onchocerciasis to be a pure skin disease and not the blinding disease encountered in America. Jean Hissette, a belgian general practitioner with a special interest in eye pathology, was the first to document onchocerciasis in Africa as a blinding disease. Between 1931 and 1938, he published a series of articles on the subject, based on the experience he gained from several expeditions in the endemic Babindi country (Belgian Congo). His discussions with J Bryant in 1932 stimulated the latter to publish an article in 1935 on the posible relationship between Onchocerca volvulus and endemic choroiditis in Sudan. As the result of his collaboration with R Strong, an expert from Harvard on the Central American form of the disease, Hissette wrote a paper that appeared in 1938 as a supplement to the American Journal of Tropical Medicine. In this landmark paper he describes with great precision the chorioretinitis of the posterior pole typical of onchocerciasis, later to be known as the Hissette‐Ridley fundus. Although the names of the two men are linked, Hissette's work preceded Harold Ridley's publication in the BJO on ocular onchocerciasis in Ghana by more than a decade.

Retinal pathology in Susac syndrome detected by spectral-domain optical coherence tomography.

The aim of this non-interventional study was to characterize retinal layer pathology in Susac syndrome (SuS), a disease with presumably autoimmune-mediated microvessel occlusions in the retina, brain, and inner ear, in comparison to the most important differential diagnosis multiple sclerosis (MS). Seventeen patients with SuS and 17 age- and sex-matched patients with relapsing-remitting MS (RRMS) and healthy controls (HC) were prospectively investigated by spectral-domain optical coherence tomography (OCT) including intraretinal layer segmentation in a multicenter study. Patients with SuS additionally received retinal fluorescein angiography (FA) and automated perimetry. Patchy thinning of the retinal nerve fiber layer, ganglion cell layer, inner plexiform layer, inner nuclear layer, and outer plexiform layer compared to corresponding sectors in RRMS and HC eyes (p < 0.003 for SuS vs RRMS and HC) was observed in 23/34 (68%) SuS eyes, particularly in temporal quadrants. The outer nuclear layer (ONL) and photoreceptor layers (PRL) were not affected. FA performed in 15/17 patients with SuS was negative for disease-specific branch retinal artery occlusions in all but 1 eye at the time of OCT examination and revealed no additional vascular abnormalities, even in severely damaged OCT areas. In a subset of patients with SuS, associations of visual field data with distinct retinal layers were observed. Distinct OCT patterns of scattered, scar-like intraretinal pathology in SuS eyes, sparing the ONL and PRL, suggest a retinal, but not choroidal, vascular pathomechanism and clearly differentiate SuS from RRMS. Depending on the disease stage, OCT and FA provide specific complementary diagnostic information in SuS.

Incontinentia Pigmenti: A Comprehensive Review and Update.

Incontinentia pigmenti (IP) is a rare syndrome with skin lesions, ocular abnormalities in the retina and elsewhere, central nervous system abnormalities, and teeth defects. The authors present an updated review of the literature, highlighting diagnosis, epidemiology, pathophysiology, clinical features, and management of IP. IP is an X-linked dominant syndrome with an incidence of 0.0025%; most patients are female. IP is caused by a mutation in the IKBKG gene, causing a loss of function of NF-κß, leaving cells susceptible to apoptosis from intrinsic factors. The cardinal feature of IP is four stages of skin distinctive lesions. Of those with IP, 36.5% have detectable eye pathology and 60% to 90% of those have retinal issues. Peripheral avascularity and macular occlusive disease commonly occur. The authors performed a comprehensive review of Medline from 1947 to 2014. All papers mentioning IP in ophthalmologic journals were reviewed as well as applicable publications from other medical specialties.

Squamous cell dysplasia and carcinoma of the conjunctiva. A nationwide, retrospective, epidemiological study of Danish patients.

To investigate the epidemiology of squamous cell dysplasia and carcinoma of the conjunctiva in Denmark. Review of the histopathological case reports at the Eye Pathology Institute (EPI), University of Copenhagen, and the National Danish Pathology Bank from 1980 to 2011. Information regarding distribution of age and sex, localization, earlier pathology, comorbidity and recurrence of the condition was registered. The Cause of Death Registry at Statens Serum Institut was used to obtain information regarding cause of death. A total of 143 cases were identified. Ninety-five (61%) had epithelial dysplasia, 19 (13%) had carcinoma in situ, and 29 (20%) had squamous cell carcinoma. A significantly higher proportion of men were found. The median age at diagnosis was 65 years. The risk of recurrence was 10.0% [95% confidence interval (CI): 5.0-15.0] after 1 year and 17.2% (95% CI: 10.8-23.7) after 5 years. The lesions were most often localized to the corneal limbus. In our records, one patient had a lymph node metastasis and the disease necessitated enucleation in two patients. No patients had died from squamous cell carcinoma of the conjunctiva. Overall, our data are in agreement with the results of previous studies in Northern, high-latitude countries. There is a low incidence rate; the lesions are predominantly seen in men in their seventh decade and localized to the corneal limbus. The risk of recurrence is high, and the benign lesions have potential to progress to frank carcinoma.

Visual impairment and unmet eye care needs among homeless adults in a Canadian city.

The ocular status of homeless populations remains largely unknown. Given that visual acuity has been shown to be heavily correlated with reduced well-being and decreased earning potential, findings of poor vision could have important health implications for people experiencing homelessness. To assess the prevalence of visual impairment and to identify unmet eye care needs in an adult homeless population. For this cross-sectional study, we recruited 100 homeless persons using a stratified random sampling technique from January to March 2014. Recruitment took place at 10 randomly selected adult shelters in Toronto, Ontario, Canada. All English-speaking persons older than 18 years of age were eligible to participate. Information was obtained on sociodemographic characteristics, ocular history, and subjective visual acuity. A comprehensive vision screening and an undilated retinal examination were performed for each participant. Rates of functional visual impairment and prevalence of nonrefractive eye pathology. The median age of participants was 48 years (interquartile range, 36-56 years), and 62% were men. The median lifetime duration of homelessness was 12 months (interquartile range, 5-36 months). Based on the participants' presenting visual acuity, the age-standardized rate of visual impairment was 25.2% (95% CI, 16.7%-33.7%). After pinhole occlusion, this number decreased to 15.2% (95% CI, 7.7%-22.7%). In total, 13.0% (95% CI, 7.8%-20.0%) of participants experienced visual impairment secondary to a correctable refractive error. Although the major problem for this demographic was limited access to refractive correction, a large degree of nonrefractive pathology was also observed. Of all the participants, 34.0% (95% CI, 24.7%-43.3%) had 1 or more abnormal findings during the vision screening, and 8% (95% CI, 2.7%-13.3%) required urgent referral to an ophthalmologist. A large majority of participants (89.0%) indicated interest in accessing free eye examinations. These data suggest that homeless adults have a high prevalence of visual impairment, even when living within a system of universal health insurance. Given the high level of interest in eye care among homeless persons, ongoing vision-screening programs and readily accessible free eye clinics may help address this need.

Automatic Segmentation of the Eye in 3D Magnetic Resonance Imaging: A Novel Statistical Shape Model for Treatment Planning of Retinoblastoma

Proper delineation of ocular anatomy in 3-dimensional (3D) imaging is a big challenge, particularly when developing treatment plans for ocular diseases. Magnetic resonance imaging (MRI) is presently used in clinical practice for diagnosis confirmation and treatment planning for treatment of retinoblastoma in infants, where it serves as a source of information, complementary to the fundus or ultrasonographic imaging. Here we present a framework to fully automatically segment the eye anatomy for MRI based on 3D active shape models (ASM), and we validate the results and present a proof of concept to automatically segment pathological eyes. Manual and automatic segmentation were performed in 24 images of healthy children's eyes (3.29 ± 2.15 years of age). Imaging was performed using a 3-T MRI scanner. The ASM consists of the lens, the vitreous humor, the sclera, and the cornea. The model was fitted by first automatically detecting the position of the eye center, the lens, and the optic nerve, and then aligning the model and fitting it to the patient. We validated our segmentation method by using a leave-one-out cross-validation. The segmentation results were evaluated by measuring the overlap, using the Dice similarity coefficient (DSC) and the mean distance error. We obtained a DSC of 94.90 ± 2.12% for the sclera and the cornea, 94.72 ± 1.89% for the vitreous humor, and 85.16 ± 4.91% for the lens. The mean distance error was 0.26 ± 0.09 mm. The entire process took 14 seconds on average per eye. We provide a reliable and accurate tool that enables clinicians to automatically segment the sclera, the cornea, the vitreous humor, and the lens, using MRI. We additionally present a proof of concept for fully automatically segmenting eye pathology. This tool reduces the time needed for eye shape delineation and thus can help clinicians when planning eye treatment and confirming the extent of the tumor.

Climate Changes and Vision Loss a Possible Problem of Public Health

Weather changes raise a major concern during last decades, in all areas, including their consequences on public health. The impact of changing weather on eye pathology was not widely studied. Ocular diseases have a major impact on the quality of life and on working ability. Thus we considered of interest to investigate the possibility of any correlation between meteorological factors and ocular diseases. Glaucoma is known to be a degenerative multifactorial eye disease, which may lead to blindness. Its pathogeny still remains controversial for ophthalmologists worldwide. This work points out the correlation found between weather factors and acute glaucoma. Our study included 262 cases of patients, presented in Ophthalmology Department from Constanta Emergency Hospital, between 2002 and 2013. As weather element, the phase’s survey offers the opportunity to study glaucoma during stable or changing weather, because it provides the advantage of synthetically vision on the situation of all meteorological factors. Weather changes turned out to have an obvious role in generating acute glaucoma.

Change in the organ of vision in somatic diseases

The functional or morphological changes associated with systemic diseases make up the bulk of eye pathology. Accordingly, systemic drug therapy for these diseases can affect the eye. Changes of the organ of vision and appropriate ophthalmological advice can assist an internist to diagnose and adequately treat the patient. The article considers possible changes in the organ of vision in the presence of somatic diseases, as well as alterations resulting from drug therapy for these diseases.

Desiccating stress-induced chemokine expression in the epithelium is dependent on upregulation of NKG2D/RAE-1 and release of IFN-γ in experimental dry eye.

The Th1-associated chemokines CXCL9, CXCL10, and CXCL11 coordinate migration of CXCR3(+) Th1 cells. The objective of this study was to evaluate the role of the innate immune system in stimulating chemokine expression in an experimental model of dry eye and bridge the gap between innate and adaptive immunity. Desiccating stress (DS) induced very early (6 h) expression and production of Th1-associated chemokines in cornea and conjunctiva of C57BL/6 and RAG1 knockout (KO) mice, demonstrating that chemokine expression does not require innate T cells. We then demonstrated that activating the innate immune system prior to adoptive transfer of T cells to RAG1KO mice increased disease severity. Interestingly, lack of induction of chemokines CXCL9, CXCL10, and CXCL11 in IFN-γKO mice provided evidence that their expression requires IFN-γ for induction. Treatment of RAG1KO mice with anti-NK1.1 prevented the increase of CXCL9, CXCL10, and CXCL11 in response to DS, compared with isotype controls. Additionally, DS increased the expression of NKG2D in the conjunctiva. The expression of the NKG2D ligand, retinoic acid early inducible gene 1, also increased at the ocular surface at both the protein and gene levels. Neutralization of NKG2D at the ocular surface decreased the expression of CXCL9, CXCL10, CXCL11, and IFN-γ. In summary, upregulation of CXCL9, CXCL10, and CXCL11 expression in experimental dry eye is T cell-independent, requiring IFN-γ-producing NKG2D(+) NK cells that are activated in response to DS-induced stress signals. This study provides insight into the events that trigger the initial immune response in dry eye pathology.

Practical issues concerning tear protein assays in dry eye.

Dry eye is a common clinical condition diagnosed by cumulative evidence of symptoms and signs. Many new treatments in dry eye are either expensive, invasive, have potential for side effects, or are not easily accessible. In severe dry eye, the ideal modality of treatment to begin with is often not clear as specific molecular disturbances are not evident from just examination of clinical manifestations. Assessing the effects of ongoing treatment is not straight forward since there is lack of agreement between clinical signs and symptoms. There is a need to have more objective methods of selecting treatment for dry eye and monitoring the effect of treatment.Recently, there are many new technologies applied to the discovery of tear biomarkers, for e.g., mass spectrometry based proteomics techniques and multiplex assays such as the bead-based sandwich indirect immunofluorescent assays. Tear proteins assays have even been made available as point-of-care devices. This review focuses on the evidence for the involvements of tear proteins in dry eye, possible changes in tear concentrations with therapy and the strength of evidence regarding dry eye pathology. Much remains to be done in terms of developing office-based assays and ascertaining their reliability, but current evidence suggests that tear proteins have a role in the clinical practice of dry eye.

Phenotypes and biomarkers of diabetic retinopathy. Personalized medicine for diabetic retinopathy: the Weisenfeld award.

Phenotypes and biomarkers of diabetic retinopathy. Personalized medicine for diabetic retinopathy: the Weisenfeld award.

Eye AIDS patholgy evaluation by using ultrasound examination

AbstractPurpose Ultrasound B scan is an important diagnostic method in eye pathology. We want to demonstrate the usefulness of ultrasound B scan in early diagnosis of AIDS symptoms and structural changes in the eyes. 30 years old female with bilateral uveitis was examined. Patient had suddenly unilateral loss of vision acuity.Methods Patient undergo full ophthalmological examination and ultrasound B scan diagnostic examination.Results During 2 weeks patient noticed sudden loss of vision acuity. Slit lamp examination revealed acute anterior uveitis. Fundus examination revealed hard changes in vitreous body. In right eye we diagnosed vitreitis and in left eye was more intensive changes of endophthalmitis. During systemic treatment of toxoplasmosis and AIDS in right eye we noticed full process stabilisation. Acute retinal necrosis and full loss vision we noticed in left eye. Ultrasound B scan revealed only structural changes of vitreous in right eye and vitreous hemorrhages and total retina detachment in left eye.Conclusion We recommend early referral of cases of AIDS pathology in the eyes for baseline Ultrasound scan and follow up scan in 2 weeks, 4 weeks, 3 months and for later time to detect underlying pathology.

Accurate and reliable segmentation of the optic disc in digital fundus images

We describe a complete pipeline for the detection and accurate automatic segmentation of the optic disc in digital fundus images. This procedure provides separation of vascular information and accurate inpainting of vessel-removed images, symmetry-based optic disc localization, and fitting of incrementally complex contour models at increasing resolutions using information related to inpainted images and vessel masks. Validation experiments, performed on a large dataset of images of healthy and pathological eyes, annotated by experts and partially graded with a quality label, demonstrate the good performances of the proposed approach. The method is able to detect the optic disc and trace its contours better than the other systems presented in the literature and tested on the same data. The average error in the obtained contour masks is reasonably close to the interoperator errors and suitable for practical applications. The optic disc segmentation pipeline is currently integrated in a complete software suite for the semiautomatic quantification of retinal vessel properties from fundus camera images (VAMPIRE).