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The aim of our research was to obtain expert consensus for updated definition and classification of dry eye disease using formal methodology. The nominal group technique (NGT) involved a steering committee of four ophthalmologists began with collection of ideas followed by group discussion. The ideas were collated, refined, and voted upon. The main characteristics considered, each with different degrees of severity in types I, II, and III, were the ability or not of the ocular surface to re-equilibrate itself, frequency of symptoms, presence of inflammation, epithelial alterations, and possible alterations in the quality of vision. This was followed by three rounds of a “mini-Delphi” involving an expert panel of 13 ophthalmologists, with the last round including all 17 ophthalmologists. Consensus in the final round of voting (⩾75% of votes) was reached on the definition of dry eye disease and on criteria for its classification in three forms. Type I is a transient and reversible form with subclinical inflammation, possible epithelial alterations, and occasional alterations in vision. Type II is a recurrent form characterized by a reduced ability to re-equilibrate the ocular surface, frequent symptoms and alterations in vision with clinically-evident inflammation, and clear evidence of epithelial alterations. Type III is a chronic form with inability to re-equilibrate the ocular surface and accompanied by clinically-evident and chronic inflammation, persistent epithelial alterations, and frequent alterations in quality of vision. The vast majority of patients with dry eye disease can be easily classified into one of these three forms. Dry eye disease definition was updated accordingly.

Postpartum haemorrhage (PPH) is one of the main causes of mortality and severe maternal morbidity and its incidence is increasing also in Western countries. Aim of this study is to estimate the incidence and the trend of PPH in the Umbrian population using the validated Umbrian health database and to identify possible determinants for the development of PPH.The source of the data was the regional Healthcare Database of the Umbria Region. The population of interest was represented by women who gave birth in Umbria between 2006 and 2017. The PPH was identified from the hospital data using the ICD-9-CM 666.x codes. Demographic data, principal and secondary diagnoses and data on maternal morbidity and blood component transfusion were collected. The incidence of PPH was calculated taking into account cases of PPH over the total number of births. The determinants of PPH, the associated morbidity and the variation in the severity of the PPH over time have been identified by logistic regression models.In Umbria, between 2006 and 2017, 93,403 births were registered (69% by vaginal delivery and 31% by caesarean section) and the rate of caesarean sections decreased by about 4%. The incidence of PPH increased three-fold during this period with an increase (p0.001) of women with PPH who received transfusions. Regarding the caesarean sections, the PPH trend increased by 53% (p=0.3), while in the vaginal deliveries the PPHs increased by 233% (p0.001). Logistic regression analysis showed that possible risk factors for the occurrence of PPH are maternal morbidity (OR 22.8, 95% CI 18.5-30.0), twin birth (OR 2.0, 95% CI 1.3-3.2) and antepartum haemorrhage (OR 5.7, 95% CI 3.1-10.4).The incidence of PPH has increased in recent years, while the morbidity associated with PPH has remained substantially unchanged. The study identified several risk factors responsible for PPH that can be used in the monitoring of pregnant women and for planning prevention strategies such as Patient Blood Management.

Purpose To evaluate clinical features, systemic associations, treatment and visual outcomes in Italian patients with episcleritis and scleritis. Methods Retrospective analysis of 110 consecutive patients with episcleritis and scleritis seen at the Uveitis Service of San Raffaele Scientific Institute, Milan, between 2006 and 2010. Each patient underwent complete clinical ophthalmological evaluation and slit-lamp high-resolution digital pictures were obtained. Results Of the 110 patients, 25 (23%) had episcleritis and 85 (77%) had scleritis. There was a predominance of women (64%) and unilateral disease (80%) in episcleritis and of women (74%) and unilateral disease (75%) in scleritis. Mean age at presentation was 42 in the episcleritis group and 52 in the scleritis group. Among those with episcleritis, 10 (40%) had focal episcleritis and 15 (60%) had diffuse episcleritis. Investigation revealed systemic disease association in 7 patients (28%) with episcleritis. Among those with scleritis, 28 (33%) had nodular anterior scleritis, 49 (58%) had diffuse anterior scleritis, 6 (7%) had necrotizing anterior scleritis and 2 (2%) had posterior scleritis. Thirteen patients (15%) had an associated infective disease: Herpes simplex (5%), Herpes zoster ophthalmicus (6%), Tuberculosis (2%), Syphilis (2%). Thirty patients (36%) had an associated autoimmune disease: Rheumatoid arthritis (10%), vasculitis (20%), HLA-B27 related diseases (2%), relapsing polychondritis (4%). Two (8%) patients with episcleritis lost visual acuity while 48 (56%) of the scleritis patients had a decrease in visual acuity. Only 16% of patients with episcleritis required more than topical corticosteroid treatment, while among the scleritis patients 33 (39%) required systemic NSAIDs, 21 (25%) oral corticosteroids, 18 (21%) immunosuppressive drugs and 13 (15%) antibiotics or antivirals. Conclusions An associated systemic disorder was found in 28% of Italian patients with episcleritis and in 51% of those with scleritis with a prevalence of autoimmune diseases over infectious diseases. Our study suggests that episcleritis is a mild ocular disorder which generally responds to topical medication. Conversely, scleritis is often associated with a decrease in visual function and requires oral medication.

Purpose to identify the predictors for poor visual outcome in patients with uveitis and biopsy proven sarcoidosis. Methods charts of 44 patients with uveitis and biopsy proven sarcoidosis seen between 1997 and 2009 were reviewed. Ocular parameters evaluated at presentation were: location and type of uveitis, visual acuity, presence of posterior synechia, iris nodules, vitritis, snowballs, chorio-retinal lesions, retinal vasculitis, papillitis, macular edema , cataract, glaucoma. Laboratory abnormalities and presence of pulmonary involvement of sarcoidosis were recorded.visual acuity at the end of follow-up of the worst-seeing eye was the outcome considered in the univariable and multivariable analyses. Visual acuity of the worst-seeing eye was stratified into two categories according to the threshold 20/50 ( 20/50 and > 20/50). Results 44 Caucasian patients with bilateral uveitis, with a median age at diagnosis of 59 years (IQR 45-67) were studied. The majority of patients presented with panuveitis (52%), granulomatous type (61%), posterior synechia (62%). The most frequent vision-threatening complications were cystoid macular edema (56%) and cataract (56%). The median best corrected visual acuity in the worst seeing eye at presentation and at end of follow-up was respectively 0.4 (IQR 0.26-0.80) and 0.63 (IQR 0.36-1.00. At univariable analysis, the presence of iris nodules (p=0.049), cystoid macular edema (p=0.007) and cataract (p=0.007) were clinical significant conditions for a visual outcome of 20/50 or worse in the worst-seeing eye; higher ages at diagnosis of uveitis (p=0.045) and ages at diagnosis of sarcoidosis (p=0.041) were also significantly associated with a poor visual acuity at follow-up. However, at multivariable analysis, the presence of cystoid macular edema (p=0.034) was the only statistically significant predictor associated with an unfavourable visual outcome. Conclusions in our study we have attempted to find risk factors for poor visual outcome in patients with uveitis associated to sarcoidosis. Our results suggest that only the presence of cystoid macular edema was significantly associated with a worst visual outcome; further investigations are needed to confirm the role of age, cataract and iris nodules.

Purpose in this pilot study we evaluated the efficacy of intralesional anti-CD20 monoclonal antibody (Rituximab) injection in five patients affected by histologically proven ocular adnexal lymphoma (OAL). Methods five consecutive patients with OAL diagnosed at the Ocular Oncology Service of Scientific Institute San Raffaele,Milan were treated with intralesional Rituximab injection as a single therapeutic agent. Two patients had monolateral conjunctival MALT lymphoma, two had monolateral conjunctival follicular lymphoma and one had follicular lymphoma of the eyelid. The treatment protocol consisted of one intralesional Rituximab injection every week for four consecutive weeks, followed by one injection every month for six consecutive months. After topical anesthesia, we slowly injected 1.5ml of undiluted Rituximab (10mg/mL) into the conjunctival lesion. We followed the patients for six months after the treatment course to evaluate its efficacy. During the treatment protocol steps and every three months during the follow-up each patient underwent complete clinical ophthalmological evaluation and slit-lamp high-resolution digital pictures of the lesion were obtained. Outcome assessments were based on the macroscopic reduction of the lesion and on the presence or absence of recurrence. Results we achieved a complete clinical remission in two patients with conjunctival MALT lymphoma and in one patient with follicular lymphoma of the eyelid. Two patients with follicular lymphoma of the conjunctiva only achieved partial clinical remission. All patients completed the planned treatment without local or systemic side effects. Conclusions our pilot study demonstrates that intralesional Rituximab injection is an effective single-agent therapy for OALs, with a better response for those with conjunctival MALT lymphoma and with follicular lymphoma of the eyelid than for those with conjunctival follicular lymphoma. We recognize that our short disease-free follow-up period (6 months) is a limiting factor of this study. Duration of response and potential late effects remain to be defined, and a large prospective trial to address this promising approach is warranted.

Previous research has considered extensively the causes and effects of market entry order and timing. It has neglected, however, the timeliness of such entry — the degree to which a firm delivered a new product on the date it had set for its release. In this article, we begin to fill the need for such research by evaluating some strategic explanations for why a firm might miss a scheduled entry date. We then test whether such “tardy entry” influences sales performance in the new market.

Previous research has considered how exploratory market learning processes moderate market and technological uncertainty in radical product development. Scholars argue that new product development (NPD) teams may increase the chances of success of radically new projects by acquiring, assimilating and implementing new information from market feedback. However, research has not tackled how information is assimilated by the NPD team and to what extent the process of information implementation occurs. In this article, we begin to fill the need for such research by investigating the interaction between internal team values (beliefs and possibly ideology) and external market feedback / information in radical projects. Via the lens of a 2-year longitudinal participant-observation study, we suggest that information assimilation is not automatic, but rather influenced in interesting ways by internal team values. The findings imply that shared team values act as a selective assimilation mechanism determining whether a development team will act on user feedback. Furthermore, the type of information (e.g., functional vs. conceptual feedback) processed by the development team acts as a moderating factor on the relationship between the team values and information processing.

Environmental issues, while of growing interest, have been outside the main focus of business scholarship. This position on the periphery may have been a good thing. It allowed scholars of business and the environment to consider unusual theories and evaluate overlooked phenomenon. In doing so, they created a body of research that provides new insights on two topics of mainstream interest -- the sources of competitive advantage and the origin and function of self-regulatory institutions.

Studies dealing with environmental issues in New Product Development have made significant progress explaining how firms can develop greener new products that succeed in the market and Environmental New Product Development (ENPD) has become a wide-spread practice within an increasing number of firms. Nevertheless, green entrepreneurs and product developers who have tried to develop more sustainable products have had mixed experiences. Through an empirical study in the human powered vehicle sector, this research study examines the challenges product developers teams and green entrepreneurs face in their attempts to incorporate environmental issues into NPD. The purpose of this exploratory research study is a better understanding of the implications of environmental issues in new product development. In particular, this thesis examines the relationship between environmental ambition and the innovation process. From the descriptions and analyses of two cases study this research study suggests that a high level of environmental ambition increases the complexity of the product innovation process. Moreover, a high level of environmental ambition may hamper a product innovation process because it may lead the developers away from the market that their product is to serve. Accordingly, this research study attempts to explain and predict how environmental ambition influences new product development processes. This claim provides a theoretical contribution to existing NPD and ENPD research.

Purpose: To identify main qualitative and quantitative changes by spectral-domain optical coherence tomography (SD-OCT) in eyes with vitreoretinal lymphoma (VRL) shifting form active to remission phase, after intravitreal rituximab (IVR). Methods: SD-OCT scans retrospectively assessed for: hyperreflective retinal dots (HRD), intraretinal infiltration, subretinal infiltration, outer retina (OR) fuzzy borders, and pigment epithelium detachments (PED).Central macular thickness (CMT) and choroidal thickness (CT) were measured. These features were examined in active and in remission phase. Results: Eighteen eyes of nine patients enrolled. Patients received 5.3±2.1 IVR according to a 2-weekly or monthly schedule. In remission phase, presence of HRD (p =0.02), intraretinal infiltration (p =0.02), OR fuzzy borders (p =0.01) significantly reduced. Treatment frequency did not influence rate of disappearance of these features. CMT (p =0.04) and CT (P =0.004) became thinner. Conclusions: Signs referable to lymphoma-induced inflammation (CMT, CT, HRD) and infiltration (intraretinal infiltrates, OR fuzzy borders) decreased in remission phase. Further comparative studies needed to identify the specific role of IVR in inducing these changes.

Purpose To report the clinical features and outcomes of corneal toxicity following mirvetuximab soravtansine therapy. Methods Five patients who were treated with mirvetuximab soravtansine were evaluated in our hospital for ocular symptoms during a period of 5 months between December 2017 and April 2018. A complete ophthalmologic examination, including anterior segment infrared reflectance (AS-IR) and anterior segment optical coherence tomography (AS-OCT), was performed. Results All 5 patients were female (average age, 62.4 ± 5.5 years) and being treated for advanced epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. Both eyes were involved in each case. Patients complained of blurred vision (n = 5), ocular pain (n = 2), tearing (n = 5), foreign-body sensation (n = 4), and photophobia (n = 4). Slit-lamp examination demonstrated fine corneal subepithelial opacities, mainly involving the corneal periphery migrating toward the center. AS-IR revealed the presence of hyporeflective dots on the cornea, suggesting that they were cystic. AS-OCT confirmed the subepithelial location of lesions. In all patients, the cornea cleared, and visual acuity recovered fully with a short course of topical steroids and lubricants. Conclusions Mirvetuximab soravtansine therapy can cause transient corneal toxicity. A short course of topical steroids can reduce the patient symptoms.

Purpose This study aimed to assess the prevalence and clinical manifestations of ocular graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods 269 patients who received allo-HSCT for hematologic malignancies were evaluated between December 2013 and April 2017 in this prospective observational study. Subjects underwent ophthalmologic examination at 6, 12 and 24 months after allo-HSCT. We evaluated the ophthalmologic and hematological data using the NIH consensus criteria definition and the International Chronic Ocular GVHD Consensus Group scoring systems. Results According to NIH consensus criteria definition, ocular GVHD developed in 46.1%, 51.9% and 54.7% of patients at the follow-up visits. According to the International Chronic Ocular GVHD Consensus Group, ocular GVHD developed in 41.3%, 47.7% and 51.9% of patients at the follow-up visits. We found a strong association between the presence of systemic GVHD and the development of chronic ocular GVHD throughout the entire follow-up period. Weaker associations were found between the presence of a female donor, matched related donor, conjunctival hyperemia and conjunctival fibrosis. Conclusions More than 50% of subjects develop chronic ocular GVHD after allo-HSCT. The presence of active systemic GVHD, female donor and matched related donor are associated with ocular GVHD development.

Purpose: To evaluate demographic characteristics, clinical features, systemic disease associations, visual outcomes, and treatment modalities of patients with episcleritis and scleritis in an Italian tertiary care referral center. Methods: Data from 25 patients with episcleritis and from 85 patients with scleritis followed from 2003 to 2012 were retrospectively evaluated. The main outcome measures were demographics, ocular disease characteristics, presence of systemic associated disease, treatment regimen, and follow-up period. Results: Episcleritis and scleritis were found bilaterally in 24% and 31% of patients, respectively (p

Background/aims To evaluate retrospectively the long-term efficacy of rituximab in patients with severe juvenile idiopathic arthritis (JIA)-associated uveitis. Methods Eight patients (15 eyes) with severe and longstanding JIA uveitis, who had an inadequate response in controlling uveitis to one or more biologic agents including tumour necrosis factor blockers and abatacept, received rituximab therapy. Rituximab was given at a dose of 1000 mg per infusion on days 1 and 15 and then every 6 months. Clinical responses to treatment, including decrease in uveitis activity, visual acuity changes, reduction of concomitant local and systemic corticosteroid and/or immunosuppressants, and occurrence of adverse events, were assessed. Results Eight patients with a mean +/- SD age of 22.8 +/- 5.5 years were treated. The mean ocular disease duration was 17.7 years; the mean +/- SD follow-up time on rituximab was 44.75 +/- 4.9 months; and the mean number of rituximab infusions received was 8.75 (range 6-12). All patients achieved complete control of uveitis, but in two patients rituximab was discontinued due to inefficacy in treating arthritis. The decrease in uveitis activity was evident 4-5 months after the first infusion. Systemic corticosteroids and immunosuppressants used in association with rituximab were discontinued in five patients at the end of follow-up. None of the patients experienced visual worsening during the follow-up. No drug-related complications were encountered. Conclusions Rituximab may be a promising effective treatment option for refractory uveitis associated with JIA leading to long-term quiescence of uveitis, particularly for patients who have not previously responded to other biologic therapies.

PURPOSE: To evaluate the effects of intravitreal bevacizumab injections in the treatment of nonsubfoveal choroidal neovascularization (CNV) associated with angioid streaks. DESIGN: Nonrandomized, interventional, prospective case series. METHODS: Fifteen patients (15 eyes) affected by juxtafoveal or extrafoveal CNV secondary to angioid streaks were enrolled in the study. All patients underwent a complete ophthalmologic examination, including best-corrected visual acuity (BCVA) measurement on Early Treatment Diabetic Retinopathy Study (ETDRS) chart, optical coherence tomography (OCT), and fluorescein angiography (FA). The protocol treatment included a first injection, followed by repeated injections over a 12-month follow-up period on the basis of the detection of new hemorrhage on biomicroscopic examination, any type of fluid on OCT, or presence of leakage on FA. Primary outcome measures: Mean changes in BCVA and proportion of eyes gaining at least 10. letters (2 ETDRS lines) at the end of the follow-up. Secondary outcomes: Mean changes of central macular thickness (CMT) and extension to the fovea. RESULTS: Mean BCVA did not change throughout the follow-up period, being 0.2 +/- 0.2 logMAR at baseline and 0.2 +/- 0.3 logMAR at the 12-month examination. A functional improvement of at least 2 ETDRS lines was achieved by 5 eyes (33%), with 3 eyes (20%) gaining 3 lines. Mean CMT at baseline was 215 +/- 13 mu m and 225 +/- 85 mu m at the 12-month examination. Two eyes (13.3%) showed CNV extension to the fovea. CONCLUSIONS: Intravitreal bevacizumab injection can be a beneficial approach for the management of nonsubfoveal CNV secondary to angioid streaks over a 1-year follow-up. (C) 2014 by Elsevier Inc. All rights reserved.

Purpose:The aim of this study was to evaluate tear film osmolarity in patients with ocular mucous membrane pemphigoid (MMP).Methods:This observational cross-sectional study included 40 patients with biopsy-proven ocular MMP at Foster stage III referred to the tertiary-care Ocular Immunology and Uveitis Service at the San Raffaele Scientific Institute in Milan from June 2010 to August 2013. We evaluated the following clinical parameters: tear film osmolarity, ocular surface disease symptoms (OSDI) questionnaire, Schirmer test, tear film break-up time (TFBUT), and corneal and conjunctival staining.Results:Forty patients (27 women and 13 men) were enrolled. All patients were undergoing systemic immunosuppressive therapy: 19 patients (47.5%) were on methotrexate, 9 (22.5%) were on mycophenolate mofetil, 9 (22.5%) were on low-dose corticosteroids, and 3 (7.5%) were on azathioprine. The mean osmolarity was 322.90 33.39 mOsm/L, the mean OSDI score was 73.2 +/- 17.9, the mean TFBUT was 6.60 +/- 3.13 seconds, and the mean Schirmer test value was 4.07 +/- 3.58 seconds. Tear film osmolarity significantly correlated with the TFBUT (r(2) = 0.80; P < 0.0001), whereas no clinical correlation was found with the Schirmer test value (r(2) = 0.01; P = 0.40) or with the OSDI score (r(2) = 0.02; P = 0.29). Osmolarity did not turn out to be statistically different in the subgroups according to the Oxford corneal staining scale (P = 0.71) and to the Van Bijsterveld conjunctival staining score (P = 0.31).Conclusions:Tear osmolarity increased in patients with ocular MMP and correlated with the TFBUT. This result emphasizes the role of evaporative dry-eye condition in patients with ocular MMP. Tear osmolarity may be considered as a useful test in the diagnostic assessment of dry eye associated with MMP and for targeting therapeutic decisions.

PURPOSE. The purpose of this study is to evaluate the rate of Mycobacterium tuberculosis infection in uveitis patients using an ELISPOT-IFN-gamma (ELISPOT-MTP) assay and a tuberculin skin test (TST). METHODS. Fifty-three patients with suspicious tuberculous uveitis, seen at the Ocular Immunology and Uveitis Service, Scientific Institute San Raffaele, Milan, Italy, were compared with 233 healthy control subjects. All uveitis patients, together with healthy control subjects, underwent in-house ELISPOT-MTP assay and then the TST. RESULTS. None of the patients had signs of active tuberculosis. A total of 75.5% of uveitis patients showed positive TST reaction while 58.5% responded positively to ELISPOT-MTP. In healthy individuals, these responses were 30.5% and 25.3%, respectively (p

We investigated TET2 deletion in 418 patients with hematological malignancies. Overall interphase FISH detected complete or partial TET2 monoallelic deletion (TET2del) in 20/418 cases (4.7%). TET2del was very rare in lymphoid malignancies (1/242 cases; 0.4%). Among 19 positive myeloid malignancies TET2del was associated with a 4q24 karyotypic abnormality in 18 cases. In AML, TET2del occurred in CD34-positive hematopoietic precursors and preceded established genomic abnormalities, such as 5q− and −7/7q−, which were the most frequent associated changes (Fisher's exact test P = 0.000).

Purpose: The aim of this study was to evaluate tear osmolarity in patients with chronic graft-versus-host disease (cGVHD) with ocular involvement. Methods: In this observational cross-sectional study of 56 patients with ocular cGVHD referred to the tertiary-care Ocular Immunology and Uveitis Service at the San Raffaele Scientific Institute, Milan, from May 2010 to November 2013, we evaluated the following clinical parameters: Ocular Surface Disease Index (OSDI) symptoms questionnaire, tear osmolarity, Schirmer test, tear film break-up time (TBUT), corneal and conjunctival staining. Results: All patients developed systemic GVHD after undergoing allogeneic hematologic stem cell transplantation. Mean osmolarity was 314.0 +/- 22.1 mOsm/L, mean OSDI score was 26.4 +/- 21.2, mean TBUT was 6.50 +/- 4.75 seconds, and mean Schirmer test value was 3.8 +/- 3.3 mm. Tear osmolarity significantly inversely correlated with TBUT (r(2) = 0.681; P < 0.001). Statistically significant inverse correlation was present with the Schirmer test (r(2) = 0.203; P < 0.001), and positive correlation with the OSDI score (r(2) = 0.188; P < 0.001), but both with low correlation strength. Osmolarity was statistically different in the subgroups according to the Oxford corneal staining scale (P = 0.0006) and to the van Bijsterveld conjunctival staining score (P = 0.006). Conclusions: Tear osmolarity increased in patients with ocular cGVHD, significantly correlated with TBUT and, to a lesser extent, with the Schirmer test value and OSDI. These results emphasize the role of aqueous-deficient and evaporative dry eye disease in patients with cGVHD after undergoing allogeneic hematologic stem cell transplantation. Tear osmolarity may be considered a useful test in diagnostic assessment of dry eye disease associated with cGVHD.