Heterozygous factor V Leiden mutation manifesting with combined central retinal vein occlusion, cilioretinal artery occlusion, branch retinal artery occlusion, and anterior ischaemic optic neuropathy: a case report.

BACKGROUND: Our purpose was to describe a patient who developed combined central retinal vein occlusion (CRVO), cilioretinal artery occlusion, branch retinal artery occlusion (BRAO), and anterior ischaemic optic neuropathy (AION) followed by CRVO in the second eye because of the heterozygous factor V Leiden (FVL) mutation. CASE PRESENTATION: A 39-year-old female with a history of recurrent pregnancy losses presented with acute blurred vision in the right eye (RE), with visual acuity limited to counting fingers. She was diagnosed with combined impending CRVO, cilioretinal artery occlusion, BRAO, and AION. The results of thrombophilia testing, not including the FVL mutation, were negative. Retinal atrophy with vascular attenuation and optic disc pallor developed after resolution of acute retinal findings. Nine months after initial presentation, the patient developed an impending CRVO in the left eye (LE), with a secondary progression to a complete CRVO causing a decrease in best corrected visual acuity (BCVA) to 20/40. The patient was determined to be heterozygous for the FVL mutation. She subsequently was treated with acenocoumarol. At the last follow-up visit, the BCVA was 20/400 in the RE and 20/20 in the LE, and there was a complete resolution of the acute CRVO findings in the LE. CONCLUSION: Our case shows that the heterozygous FVL mutation may manifest with combined retinal vascular occlusion involving multiple sites in both eyes. Early recognition of such an inherited thrombophilic disorder is important because it implies the need for long-term anticoagulative therapy to reduce the patient's risk of recurrent, sight-threatening and life-threatening thrombotic events.

Retinal dysfunction parallels morphologic alterations and precede clinically detectable vascular alterations in Meriones shawi, a model of type 2 diabetes.

Diabetic retinopathy is a major cause of reduced visual acuity and acquired blindness. The aim of this work was to analyze functional and vascular changes in diabetic Meriones shawi (M.sh) an animal model of metabolic syndrome and type 2 diabetes. The animals were divided into four groups. Two groups were fed a high fat diet (HFD) for 3 and 7 months, two other groups served as age-matched controls. Retinal function was assessed using full field electroretinogram (Ff-ERG). Retinal thickness and vasculature were examined by optical coherence tomography, eye fundus and fluorescein angiography. Immunohistochemistry was used to examine key proteins of glutamate metabolism and synaptic transmission. Diabetic animals exhibited significantly delayed scotopic and photopic ERG responses and decreases in scotopic and photopic a- and b-wave amplitudes at both time points. Furthermore, a decrease of the amplitude of the flicker response and variable changes in the scotopic and photopic oscillatory potentials was reported. A significant decrease in retinal thickness was observed. No evident change in the visual streak area and no sign of vascular abnormality was present; however, some exudates in the periphery were visible in 7 months diabetic animals. Imunohistochemistry detected a decrease in the expression of glutamate synthetase, vesicular glutamate transporter 1 and synaptophysin proteins. Results indicate that a significant retinal dysfunction was present in the HFD induced diabetes involving both rod and cone pathways and this dysfunction correlate well with the morphological abnormalities reported previously. Furthermore, neurodegeneration and abnormalities in retinal function occur before vascular alterations would be detectable in diabetic M.sh.

Bilateral acute angle-closure glaucoma following tramadol subcutaneous administration.

BACKGROUND: To report a case of bilateral acute angle closure-glaucoma following the use of subcutaneous Tramadol. CASE PRESENTATION: A 42-year-old healthy man with unremarkable past medical and ocular history, was admitted to the Orthopedic Department for surgical treatment of a bilateral open fracture of the femur following a road accident. Three hoursafterTramadolsubcutaneous injection, the patient complained of a bilateral acute painful visual loss with persistent vomiting. An ocular examination showed bilateral acute angle-closure-glaucoma. The patient was treated with topical anti-glaucoma therapy and intravenous Mannitol 20%.After resolution of ocular hypertension attack, NdYag laser peripheral iridotomy was performed on both eyes. After a follow-up period of 7 days visual acuity improved to 20/20 in both eyes and intraocular pressure returned to normal levels. CONCLUSIONS: This case highlights the risk of developing bilateral acute angle-closure glaucoma after Tramadol administration.

Orbital myositis revealing a vegetal intraorbital foreign body: a case report.

INTRODUCTION: Foreign intraorbital bodies are rare. Their clinical manifestation is usually late. CLINICAL CASE:     We report a case of 32 years-old man presenting an old vegetal foreign intraorbital body. The orbitotomy allowed its extraction with favorable result. DISCUSSION: Vegetal foreign intraorbital bodies have clinical aspects. The latency between the trauma and the onset of symptoms is variable. Radiological examination can identify exactly the size and location. Surgical removal is often necessary but can expose to major risks. CONCLUSION: The diagnosis of ignored intraorbital foreign body remains difficult. The management should be early in order to avoid severe functional consequences.

Dry Eye Disease in the Middle East and Northern Africa: A Position Paper on the Current State and Unmet Needs.

In the Middle East and Northern Africa (MENA), dry eye disease (DED) is often misdiagnosed or overlooked. This review summarizes a series of conversations with ophthalmologists in the region around a variety of climatic, lifestyle, and iatrogenic factors that contribute to specific features of DED in the MENA region. These considerations are further classified by patient lifestyle and surgical choices. All statements are based on discussions and formal voting to achieve consensus over three meetings. Overall, a deeper understanding of the disease characteristics of DED specific to MENA can better guide local eyecare practitioners on appropriate management and follow-up care. Additionally, population-based studies and patient and physician education on ocular surface diseases, together with the use of culturally appropriate and language-specific questionnaires can help ease the public health burden of DED in this region.

New infectious etiologies for posterior uveitis.

Emergent and resurgent arthropod vector-borne diseases are major causes of systemic morbidity and death and expanding worldwide. Among them, viral and bacterial agents including West Nile virus, Dengue fever, Chikungunya, Rift Valley fever, and rickettsioses have been recently associated with an array of ocular manifestations. These include anterior uveitis, retinitis, chorioretinitis, retinal vasculitis and optic nerve involvement. Proper clinical diagnosis of any of these infectious diseases is based on epidemiological data, history, systemic symptoms and signs, and the pattern of ocular involvement. The diagnosis is usually confirmed by the detection of a specific antibody in serum. Ocular involvement associated with emergent infections usually has a self-limited course, but it can result in persistent visual impairment. There is currently no proven specific treatment for arboviral diseases, and therapy is mostly supportive. Vaccination for humans against these viruses is still in the research phase. Doxycycline is the treatment of choice for rickettsial diseases. Prevention, including public measures to reduce the number of mosquitoes and personal protection, remains the mainstay for arthropod vector disease control. Influenza A (H1N1) virus was responsible for a pandemic human influenza in 2009, and was recently associated with various posterior segment changes.

Case Report: an unusual orbital tumor.

Introduction Orbital lipoma is an extremely rare tumor, representing less than 1% of all orbital tumors. We review the literature and describe the presentation, the differential diagnosis and the management of this tumor. Case report We report the case of a 63-year-old patient who was referred for a diplopia with recent hemi-cranial headache. Physical examination showed no exophthalmos nor decrease in visual acuity. The patient complained of diplopia on elevation and oculomotricity examination showed limited elevation of the right eye. The Hess Lancaster test was in favor of a limited course of the right inferior rectus muscle. Magnetic resonance imaging revealed a fusiform tissue process in the right inferior rectus muscle with a fatty signal. A complete excision of the tumor was performed by a trasncunjonctival approach. Cytopathological examination was consistent with a pleomorphic lipoma. The postoperative period was uneventful. The definitive histopathologic diagnosis was a lipoma. The postoperative Magnetic resonance imaging showed the complete disappearance of the lesion. With 3 years of follow up, there is no sign of recurrence or ocular motility trouble. Conclusion: Lipomas are rare tumors in the orbit. The clinic is variable depending on the size and the site. The clinical diagnosis is difficult to make. Only histology allows the final diagnosis.

A Case of Painful Diplopia after COVID-19 Vaccination: Could It Be Tolosa-Hunt Syndrome?

Herein, we report a rare case of Tolosa-Hunt syndrome (THS) following coronavirus disease 2019 (COVID-19) vaccine administration. A 64-year-old patient presented with recurrent horizontal diplopia and ipsilateral orbital pain, 2 weeks after being administered the COVID-19 vaccination. A diagnosis of THS was based on the relevant criteria after ruling out the differential diagnoses. The clinical presentation improved with corticosteroid administration. THS must be recognized as a complication of COVID-19 vaccination. This association can be explained by an autoimmune response.

The contribution of simulation in training for pterygium surgery.

INTRODUCTION: Pterygium surgery is a closed globe surface surgery. Although it is perfectly standard and followed by excellent results, it is not exempt from the general rule that there is no surgery without risk. It therefore seems important to integrate simulation as a pedagogical tool for training ophthalmology residents in pterygium surgery. AIM: To evaluate the effectiveness of procedural simulation as a training tool for pterygium surgery. RESULTS: During the study period, eight residents participated in the three workshops. The global assessment of residents' knowledge showed a mean score of 3/5 [1.5/5-4/5] and 4.1/5 [3.25/5-5/5] before and after the training respectively. There was a significant negative correlation between the initial score on the pre-test and the improvement of this score on the post-test, with an r'=-0.87 and a p=0.005. We noted a significant improvement in the global performance score (p<0.001) and even a significant improvement in the specific performance score (p=0.02) between the 3 workshops. The average training satisfaction score was 13.87/16 [10/16-16/16]. We noted a significant positive correlation with r=0.838 and p=0.009 between knowledge improvement and learner satisfaction. CONCLUSION: The training of fundus examination using an ophthalmoscopic simulator can improve the skills and knowledge of ophthalmic learners. This type of training can be an innovative addition to traditional learning methods.

Supratarsal injection of triamcinolone acetonide and childhood allergic keratoconjunctivitis.

To evaluate the efficacy and safety of supratarsal injection of triamcinolone acetonide in the treatment of refractory allergic keratoconjunctivitis in childhood. Thirty-five patients (70 eyes) with severe allergic keratoconjunctivitis were included in this study. Fifteen patients (42.8%) had atopic keratoconjunctivitis (AKC) and 20 (57.2%) had vernal keratoconjuncivitis (VKC). All patients underwent a bilateral supratarsal injection of 20 mg triamcinolone acetonide. Mean follow-up was 28 months (range 14-38). All patients showed a significant symptomatic improvement and partial resolution of clinical features of keratoconjunctivitis within the first 2 weeks. Corneal complications related to keratoconjunctivitis disappeared in all patients. One patient with VKC experienced ocular hypertension. No patient with AKC showed side-effects. Severe relapse of the disease was noted in 10% of eyes with VKC and in 6.7% of eyes with AKC after a mean follow-up of 9 and 11 months, respectively. Supratarsal injection of triamcinolone acetonide is effective and safe in patients with severe chronic allergic keratoconjunctivits to relieve severe inflammation associated with this disease.

Case Report: Optical coherence tomography angiography findings in radiation retinopathy.

We reported the observation of a 31-year-old female followed for a nasopharyngeal carcinoma since 2009, treated by locoregional radiotherapy, with a cumulative dose of 75 Gray. The patient presented with a progressive decline in bilateral vision. Ophthalmologic examination revealed bilateral dry eye, posterior subcapsular cataract, radiation retinopathy, and optic neuropathy. The patient presented all ocular complications of radiotherapy. The most severe was radiation retinopathy. Performing optic coherence tomography angiography (OCT-A) earlier could have speeded up the diagnosis and led to a better prognosis. The OCT-A showed more pronounced macular edema in the right eye, and revealed enlargement of the central avascular zone and loss of the deep and superficial retinal vascular network. The patient received three consecutive monthly intravitreal injections of anti-vascular endothelial growth factor. Yet, we noted a non-improved visual acuity. The aim of this case report was to present the contribution of OCT-A in the diagnosis of radiation maculopathy and attribute these changes to ischemia at the level of the retinal vascular network.

Case Report: Purtscher-like retinopathy in a patient with lung adenocarcinoma.

This case report describes an unreported case of  Purtscher-like retinopathy in a patient with pulmonary adenocarcinoma. A 39-year-old man was hospitalized for exploration of a hemoptysis and bilateral blurry vision. Fundoscopic examination showed multiple areas of retinal whitening in the peripapillary area. A chest computed tomography scan then showed a ground glass opacity in the right upper lobe associated to a hilar lymphadenopathy. A thoracotomy and lung biopsy were performed concluding with the diagnosis of lung adenocarcinoma. The patient was treated with high-dose corticosteroids and received Taxol-Carboplatin chemotherapy with good visual outcomes. The article discusses furthermore the importance of including pulmonary adenocarcinoma to the list of systemic conditions for Purtscher-like retinopathy.

Case Report: Central retinal artery occlusion following sildenafil intake.

Purpose: To report a case of central retinal artery occlusion associated with sildenafil intake and briefly discuss its causative pathogenesis. Methods: A 50-year-old man with no premorbidities presented with symptoms of sudden severe visual field constriction in the left eye (LE). Best-corrected visual acuity in the LE was 20/25. Fundus examination and fluorescein angiography of the LE were suggestive of central retinal artery occlusion (CRAO) with cilioretinal artery sparing. Further investigation revealed that 100 mg of sildenafil had been taken for the first time three hours before the onset of symptoms. Results: The patient was treated promptly with intravenous acetazolamide, sublingual isosorbide dinitrate and ocular massage, but without visual recovery. No other associated systemic or local risk factors were found, and the case was classified as a potential complication of sildenafil. Conclusion: Although no direct link could be established, the aim of this report is to highlight the incidence and to consider this issue when evaluating any case of central retinal artery occlusion.

The contribution of simulation in training for funduscopic examination.

INTRODUCTION: Simulation is emerging as an essential part of health sciences training programs as it provides safer patient care by reducing the risk of error. In the healthcare environment, simulation continues to spread in emergency specialties, but it is still underdeveloped in ophthalmology and there is a shortage of publications on this subject in Tunisia. OBJECTIVE: To evaluate the effectiveness of procedural simulation as a teaching tool for funduscopic examination training. Methods and population studied: This was a prospective study including students who underwent procedural simulation training sessions during their ophthalmology internship. The included students were assessed at the initiation and end of each session by a pre-test and post-test. The procedure for performing the funduscopic examination was evaluated by a specific performance score.  Student satisfaction was assessed at the end of each session. RESULTS: During the study period, four groups of 12 students were included, for a total of 48 participants spread over 4 simulation sessions. Simulation training improved post-test.  assessment scores with an overall median delta of +4.00. It also provided specific skills for performing the funduscopic examination, with an overall median specific performance score of 5.5/8 (5/8 to 7/8). The majority of students were satisfied upon completion of the simulation session. CONCLUSION: The training of fundus examination using an ophthalmoscopic simulator can improve the skills and knowledge of ophthalmic learners. This type of training can be an innovative addition to traditional learning.

Graves' Orbitopathy: Report of 82 cases.

INTRODUCTION: Graves' disease (GD) is a common autoimmune disorder. Graves'orbitopathy (GO) is its most common extrathyroidal manifestation. It is rare but may reveal the disease. AIM: To describe the demographic, clinical and therapeutic features of GO. METHODS: We carried out a retrospective and descriptive analysis of 82 patients with GO. This study was conducted in Ophthalmology and Endocrinology departments of Taher Sfar University Hospital in Mahdia, between January 2010 and December 2017. GD patients diagnosed with GO were included. RESULTS: The mean age was 36.17 years ± 12.81. Patients aged 19-40 years had the highest rate of GO. The male-to-female ratio was 0.49. Family history of autoimmune thyroid disease was present in 15% and associated autoimmune disease in 4% of cases. Smoking was seen in 71% of patients. The onset of GO was simultaneous with onset of GD in 45%, before in 21% and after the onset of GD in 34% of cases. GO was bilateral in 76% of patients. The most common ocular symptoms were prominent eyes (55% of patients), ocular pain (11%) and diplopia (41%). Proptosis and upper eyelid retraction were the most common clinical signs (93% and 90% respectively). Dysthyroid optic neuropathy was present in one eye, keratitis in one eye and glaucoma in five eyes. Severe disease was noted in 11% and active disease was present in 7% of patients. CT-scan and magnetic resonance imaging scan (MRI) were performed in 48% and 42% of cases respectively. Proptosis was the most common radiological sign. Thyroid dysfunction was managed with anti-thyroid medication only (59%), thyroxine replacement (37%), radioactive iodine (35%) and thyroidectomy (6%). 20% of patients received corticosteroids. One patient required immunosuppressive therapy. CONCLUSION: GO is a complex disease, which is associated with impaired quality of life and can potentially result in sight-threatening complications. Appropriate diagnosis, convenient therapy and a regular follow-up are necessary to improve results and avoid the aesthetic and functional sequelae.

Clinical characteristics of intermediate uveitis in Tunisian patients.

To analyze the pattern of intermediate uveitis (IU) in a referral center in Tunisia, North Africa. A retrospective, descriptive study of 87 consecutive patients (145 eyes) examined at the Department of Ophthalmology of Monastir (Tunisia) from January 1996 to August 2008. All patients underwent an extensive ocular and systemic history, a complete ophthalmic examination, and fluorescein angiography. Standard diagnostic criteria of IU were employed. The mean follow-up period was 43.2 months (range, 4-65 months). The mean age at diagnosis of IU was 29.1 years (range, 5-54 years). The male-to-female ratio was 1:1.6. Both eyes were affected in 58 patients (66.7%). The best-corrected visual acuity at onset of uveitis ranged from light perception to 20/20 (mean, 20/32). The most frequent ocular findings were vitritis (100%), snowballs (53.8%), and retinal vasculitis (28.3%). Concurrent anterior uveitis was noted in 38.6% of affected eyes. Intermediate uveitis was most commonly idiopathic (86.2%). Systemic associations were found in 13.8%; sarcoidosis (9.2%) and multiple sclerosis (2.3%) were the most common systemic diseases. The ocular complications that developed during the follow-up period included cystoid macular edema (39.3%), cataract (31.7%), inflammatory optic disc involvement (26.2%), and glaucoma or ocular hypertension (9%). One hundred-twelve affected eyes (77.2%) had a final visual acuity more than or equal to 20/40. Factors of poor visual outcome were initial VA less than 20/40 (P = 0.00011), CME (P = 0.0016), and vitritis more than 3+ cells (P = 0.023). In a hospital population in Tunisia, intermediate uveitis started frequently at the 3rd decade. This type of uveitis was most commonly idiopathic. Cystoid macular edema and cataract were the most frequent complications. Visual prognosis appeared to be fairly good.

A genome-wide linkage scan in Tunisian families identifies a novel locus for non-syndromic posterior microphthalmia to chromosome 2q37.1.

Posterior microphthalmia (PM) is a relatively rare autosomal recessive condition with normal anterior segment and small posterior segment resulting in high hyperopia and retinal folding. It is an uncommon subtype of microphthalmia that has been mostly reported to coexist with several other ophthalmic conditions and to occur in sporadic cases. The membrane-type frizzled-related protein (MFRP) is the only gene so far reported implicated in autosomal recessive, non-syndromic and syndromic forms of PM. Here, we performed a clinical and genetic analysis using six consanguineous families ascertained from different regions of Tunisia and affected with non-syndromic PM that segregates as an autosomal recessive trait. To identify the disease-causing defect in these families, we first analysed MFRP gene, then some candidate genes (CHX10, OPA1, MITF, SOX2, CRYBB1-3 and CRYBA4) and loci (MCOP1, NNO1 and NNO2) previously implicated in different forms of microphthalmia. After exclusion of these genes and loci, we performed a genome-wide scan using a high density single nucleotide polymorphism (SNP) array 50 K in a large consanguineous pedigree. SNP genotyping revealed eight homozygous candidate regions on chromosomes 1, 2, 3, 6, 15, 17 and 21. Linkage analysis with additional microsatellite markers only retained the 2q37.1 region with a maximum LOD score of 8.85 obtained for D2S2344 at theta = 0.00. Further investigations are compatible for linkage of four more families to this region with a refined critical interval of 2.35 Mb. The screening of five candidate genes SAG, PDE6D, CHRND, CHRNG and IRK13 did not reveal any disease-causing mutation.

External ophthalmomyiasis manifesting with keratouveitis.

PURPOSE: To report a case of external ophthalmomyiasis manifesting with keratouveitis. CASE REPORT: A 77-year-old man, presented with keratouveitis secondary to external ophthalmomyiasis. Slit-lamp examination of the affected eye disclosed subepithelial linear opacities, stromal keratitis, and anterior uveitis. There were also some moving maggots identified as Oestrus ovis larvae. Following removal of the maggots and instillation of tobramycin, the symptoms completely resolved within 2 days and visual acuity improved. CONCLUSIONS: Although external ophthalmomyiasis usually manifests with ocular surface involvement, this uncommon condition must be considered in the differential diagnosis of keratouveitis, especially in rural areas.

Pattern of uveitis in Behçet's disease in a referral center in Tunisia, North Africa.

The purpose of this study was to analyze the pattern of uveitis in Behçet's disease in Tunisia, North Africa. We retrospectively reviewed the clinical records of 62 patients (111 eyes) diagnosed with Behçet's uveitis (BU) at the Department of Ophthalmology, Fattouma Bourguiba University Hospital, Monastir, Tunisia, between January 1995 and December 2006. Forty-seven of 62 patients (75.8%) were men and 15 (24.2%) were women. Mean age at onset was 29.3 years. The average follow-up was 75.6 months. The most common extraocular clinical manifestations were recurrent oral ulcer in all patients and pseudofolliculitis in 52 patients (83.9%). Uveitis was bilateral in 79%. Initial best-corrected visual acuity was > or =20/40 in 41 affected eyes (36.9%) and <20/200 in 49 affected eyes (44.2%). Panuveitis (68 eyes, 61.3%) and posterior uveitis (38 eyes, 34.2%) were the most common forms, followed by anterior uveitis (five eyes, 4.5%). Retinal vasculitis was found in 89 eyes (80.2%). Most common complications included posterior synechiae (32.4%), cataract (31.5%), and cystoid macular edema (19.8%). Systemic corticosteroids were administered in 58 patients (93.5%). Immunosuppressive drugs were used in 22 patients (35.5%). Fifty-six affected eyes (50.5%) had final visual acuity > or =20/40 and 34 affected eyes (30.6%) had final visual acuity <20/200. In Tunisia, BU affects predominantly young men. Bilateral panuveitis associated with retinal vasculitis was the most common ocular manifestation. More than 50% of patients maintained a visual acuity of 20/40 or better, and immunosuppressive therapy probably contributed to the improvement of visual prognosis of these patients.

Improvement in ocular symptoms and signs in patients with Demodex anterior blepharitis using a novel terpinen-4-ol (2.5%) and hyaluronic acid (0.2%) cleansing wipe.

Purpose: To evaluate the clinical improvement in ocular symptoms and signs in patients suffering from Demodex anterior blepharitis after using a novel cleansing wipe impregnated with 2.5% terpinen-4-ol and 0.2% hyaluronic acid. Study design: This was an exploratory, multicenter, open, randomized, two-parallel group comparative study. Methods: Forty-eight patients with Demodex anterior blepharitis were randomly assigned to apply the sterile wipe T1172 (Blephademodex®), either once daily (n=24, Group 1) or twice daily (n=24, Group 2) for 29 days. Overall ocular discomfort and other individual symptoms were measured using a 0-10 numeric rating scale at Day 8 and Day 29. Ocular signs, including eyelid margin hyperemia and number of cylindrical dandruff, were examined at slit lamp. Overall treatment performance by investigator, patient satisfaction and tolerance were evaluated with questionnaires. Results: Overall ocular discomfort was significantly reduced from baseline (p<0.0001) in both groups at Day 8 (-3.6±0.3 in Group 1 and -4.0±0.4 in Group 2) and Day 29 (-5.7±0.4 and -6.8±0.7, respectively), with no difference between groups (D8: p=0.718; D29: p=0.505). Each ocular symptom associated with Demodex blepharitis was improved in both groups. Eyelid margin hyperemia was significantly reduced at Day 8 (-0.7±0.7; p<0.001) and Day 29 (-1.1±0.7; p<0.0001) in Group 1. Similar results were observed in Group 2 (Day 8: p<0.001; Day 29: p<0.0001). Total disappearance of cylindrical dandruff was reported in 30.4% of patients in Group 1 and 43.5% in Group 2. Improvements in other ocular signs were observed in both groups. The product was well tolerated. All patients were satisfied or very satisfied and would continue using it. Conclusion: Daily eyelid hygiene using this cleansing wipe impregnated with 2.5% terpinen-4-ol and 0.2% hyaluronic acid during a 4-week period led to a rapid and marked reduction in ocular symptoms and signs associated with Demodex anterior blepharitis and was well tolerated.