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Objectives: To identify differences between two cohorts of adult and pediatric patients affected by Crohn's disease (CD), with regard to lesion location in the small intestine and colon-rectum, lesion activity, and prevalence of perianal disease (PD), using MRI as the main diagnostic tool., Methods: We retrospectively reviewed 350 consecutive MRI examinations performed between 2013 and 2016 in outpatients or inpatients with histologically proven CD, monitored by the Gastroenterology and Pediatric Units of our Hospital. The magnetic resonance enterography (MRE) protocol for adult and pediatric CD patients routinely includes evaluation of nine different intestinal segments (from jejunum to rectum) and of the anal canal. Intestinal activity was also calculated using a validated score. Perianal disease (PD) was staged. Fisher's exact test was used and the odds ratio (OR) was calculated., Results: Two hundred and nineteen out of 350 MRI studies (118 adults and 101 children) were included. The prevalence of PD was 34.6% in children and 16.1% in adults (OR = 2.8; p = 0.0017). Pediatric patients showed more frequent rectal involvement (29.7% vs 13.5%, OR = 2.7; p = 0.0045) and higher risk of PD in the presence of rectal disease (p = 0.043; OR = 4.5). In pediatric patients with severe colorectal disease, the prevalence of PD was twofold (86.7% vs 40%; p = 0.072). Using the clinical Montreal classification for lesion location, no significant differences emerged between the two patient populations., Conclusions: MRI showed a significantly higher prevalence of rectal involvement and perianal disease in the pediatric population. These results may have a relevant clinical impact and deserve further investigation., Key Points: • To our knowledge, this is the largest morphological comparative study available in the literature using MRI as the main diagnostic tool to compare adult patients and children with Crohn's disease. • Our study showed significant differences between adults and children: a higher prevalence of rectal and perianal fistulous disease (PD) in pediatric patients and an increased prevalence of PD in the presence of severe colon-rectum involvement. • The association of rectal and perianal disease implies a poorer clinical prognosis and a higher risk of disabling complications in pediatric patients.

Background & Aims: Pan-enteric capsule endoscopy (PCE) is effective for assessment of small intestinal and colonic Crohn's disease (CD) in pediatric patients. We aimed to determine whether PCE can be used to monitor mucosal healing and deep remission, in a treat to target strategy for pediatric patients with CD., Methods: We performed a prospective study of 48 children with a diagnosis of CD at a tertiary care pediatric gastroenterology unit; 46 patients were included in the final analysis. Biomarker, imaging, and PCE analyses were performed at baseline and after 24 and 52 weeks. Small bowel and colonic mucosal healing were defined by Lewis scores <135 and simple endoscopic score for CD ≤1, respectively. Clinical remission was defined as defined as a pediatric CD activity index score <10 and biomarker-based remission based on normal levels of biomarkers; deep remission was defined as a combination of clinical remission, biomarker-based remission, and mucosal healing. Treatments were adjusted based on findings from PCE (imaging was considered only for patients with negative findings from PCE). Therapies were introduced, optimized, switched, or combined at the discretion of treating clinicians. The primary outcome was the ability of PCE to assess mucosal healing and deep remission at 3 timepoints and to guide a treat to target strategy., Results: PCE detected inflammation in 34 patients (71%) at baseline, 22 patients (46%) at week 24, and 18 patients (39%) at week 52 (P for comparison among timepoints <.05). Findings from PCE led to a change in therapy for 34 patients (71%) at baseline and 11 patients (23%) at 24 weeks, whereas only 2 patients with negative results from PCE (4%) changed therapies based on findings from imaging. When the treat to target strategy was applied, proportions of patients with mucosal healing and deep remission increased from 21% at baseline, to 54% at week 24, to 58% at week 52 (P for comparison among timepoints <.05); 2 patients (4%) did not respond to treatment., Conclusion: In a prospective study of 48 children with CD, we found a treat to target strategy, based on findings from PCE, to significantly increase the proportions of patients with mucosal healing and deep remission., Clinical Trial: gov no: NCT03161886., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Left ventricle assist devices (VADs) aid the heart pumping blood into the systemic circulation and grant the required cardiac output (CO) when the heart itself cannot provide it. However, it is unclear how effective these devices are at restoring not only physiological CO values but also normal intraventricular hemodynamics. In this work, the modified hemodynamics due to a VAD implantation is studied in vitro using an elastic ventricle made of silicone, which is incorporated into a pulse-duplicator setup prescribing a realistic pulsatile flow. Thereafter, a continuous axial pump is connected at the ventricle apex to mimic a VAD and its effect on the ventricular hemodynamics is investigated as a function of the pump flow suction. Using particle image velocimetry (PIV), we observe that the continuous pump flow effectively provides unloading on the ventricle and yields an increased CO. Conversely, the continuous blood suction from the ventricle apex deeply alters the hemodynamics and, in addition, the VAD obstruction in the ventricle behaves as a bluff body that affects the vorticity distribution in the LV thus creating a stagnant region at the ventricle apex. This phenomenon is rationalized by measuring in a modified set-up the benefits on the hemodynamics of a flush-mounted device. Additionally, the suction operated by the VAD reduces the ventricular pressure and yields an increase in the swirling motion around the ventricle axis, in a similar fashion as the bath-tub vortex effect, thus further modifying the intraventricular hemodynamics with respect to healthy conditions.

Objectives: We aimed to identify early noninvasive predictors of clinical and endoscopic remission in children with Crohn disease (CD) under infliximab (IFX)., Methods: Prospective observational study conducted in children with moderate-to-severe CD starting IFX. All patients underwent weighted pediatric CD activity index (wPCDAI) assessment, C-reactive protein and fecal calprotectin (FC) at week 0, 14, and 48. Endoscopy was performed at 0 and 48 weeks. The primary outcome was to determine the ability of 14-week wPCDAI, C-reactive protein, and FC to predict 1-year steroid-free clinical remission and mucosal healing. As a secondary outcome we evaluated their concordance with Simple Endoscopic Score for CD (SES-CD) at week 48., Results: Forty-one children were enrolled. At 1 year, 21 (51%) and 16 (39%) were in clinical and endoscopic remission. Only combined postinduction FC and wPCDAI were able to predict 1-year clinical and endoscopic remission (hazard ratio 4.81 [95% confidence interval 1.76-20.45], P = 0.05 and hazard ratio 5.51 [95% confidence interval 1.83-26.9], P = 0.03). One-year SES-CD moderately correlated with FC (r = 0.52; P = 0.001). The FC cut-off value for mucosal healing was 120.5 μg/g (area under the curve 0.863, 83% sensitivity, 75.5% specificity; P = 0.005). The concordance between wPCDAI and SES-CD was excellent and good for severe disease and remission (k 0.87 and 0.76)., Conclusions: Post induction FC combined with wPCDAI can predict 1-year clinical and endoscopic response to IFX in pediatric CD. FC shows a moderate correlation with SES-CD, whereas wPCDAI has a good concordance with endoscopic remission or severe disease, but not with mild and moderate disease.

Objective: Perioperative coagulation testing often is performed with arterial samples even though device reference ranges typically are established in venous samples. Although limited studies exist comparing coagulation parameters across sampling sites, viscoelastic testing devices have demonstrated some differences. The objective of this study was to compare coagulation parameters determined using the Quantra System for venous and arterial samples., Design: Prospective, observational study., Setting: Tertiary care university hospital., Participants: The study comprised 30 adult patients undergoing cardiac surgery., Interventions: Paired arterial and venous samples were obtained at 2 of the following time points: baseline, during bypass, or after protamine reversal of heparin. Quantra measurements included Clot Time (CT), Heparinase Clot Time (CTH), Clot Time Ratio (CTR), Clot Stiffness (CS), and Fibrinogen (FCS) and Platelet (PCS) Contributions to clot stiffness., Measurements and Main Results: The relationship and agreement between matched data pairs were established and statistical analysis was performed via paired t tests. CTR, CS, FCS, and PCS were unaffected by the sampling site, whereas CT and CTH demonstrated statistically significant differences between arterial and venous samples (p < 0.001). Arterial clot times were prolonged relative to the venous ones with a mean percent error of 14.2 % and 11.9 %, respectively. These results are in general agreement with those reported for other viscoelastic testing devices., Conclusions: This study demonstrates that Quantra clot stiffness-based parameters (CS, FCS, PCS) are unaffected by sampling site, whereas the clot time parameters (CT and CTH) show good correlation in the presence of a bias. CTR, a ratio of CT and CTH, also is unaffected., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: To evaluate the functional long-term outcome in patients with macular oedema (MO) secondary to central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO) treated with dexamethasone implant (DEX implant) and to identify its clinical predictors., Methods: A 24-month, retrospective, multinational, real-world study. Chart review of patients with either naïve or recurrent MO secondary to CRVO/BRVO treated with DEX implant, including best-corrected visual acuity (BCVA), central subfield thickness (CST), demographic baseline characteristics and details of any additional treatment during follow-up., Results: A total of 155 eyes (65 CRVO, 90 BRVO) from 155 patients were included. At 24 months, mean BCVA did not change significantly in CRVO (-2.1±24.5 letters, p=0.96) and BRVO patients (1.3±27.0 letters, p=0.07). A worse baseline BCVA (p<0.001), visual acuity (VA) gain ≥5 letters at 2 months (p=0.006) and no need for adjunctive intravitreal therapy after first DEX implant (p=0.001) were associated with a better final BCVA gain. Treatment-naïve patients (p=0.006, OR: 0.25, 95% CI 0.11 to 0.57) and those with a baseline CST≤400 µm (p=0.02, OR: 0.25, 95% CI 0.10 to 0.63) were identified as being less likely to need additional intravitreal therapy., Conclusion: Clinical baseline characteristics and the early treatment response were identified as possible predictors for long-term outcome and the need of adjunctive intravitreal therapy in MO secondary to BRVO/CRVO treated by DEX implant., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

New computational techniques providing more accurate representation of human heart pathologies could help uncovering relevant physical phenomena and improve the outcome of medical therapies. In this framework, the present work describes an efficient computational model for the evaluation of the ventricular flow alteration in presence of mitral valve stenosis. The model is based on the direct numerical simulation of the Navier-Stokes equations two-way coupled with a structural solver for the left ventricle and mitral valve dynamics. The presence of mitral valve stenosis is mimicked by a single-parameter constraint acting on the kinematics of the mitral leaflets. Four different degrees of mitral valve stenosis are considered focusing on the hemodynamic alterations occurring in pathologic conditions. The mitral jet, generated during diastole, is seen to shrink and strengthen when the stenosis gets more severe. As a consequence, the kinetic energy of the flow, the tissues shear stresses, the transvalvular pressure drop and mitral regurgitation increase. It results that, as the stenosis severity level increases, the geometric and effective orifice areas decrease up to 50% with respect the normal case due to the reduced leaflets mobility and stronger blood acceleration during the diastolic phase. The modified intraventricular hemodynamics is also related to a stronger pressure gradient that, for severe stenosis, can be more than ten times larger than the healthy valve case. These computational results are fully consistent with the available clinical literature and open the way to the virtual assessment of surgical procedures and to the evaluation of prosthetic devices., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The importance of neurodegeneration in multiple sclerosis (MS) is increasingly well recognized., Objectives: To evaluate retinal pathology using optical coherence tomography (OCT) and to investigate possible associations between retinal layers' thickness and specific patterns of gray matter volume in patients with a new diagnosis of MS., Methods: A total of 31 patients underwent OCT scans and brain magnetic resonance imaging. In total, 30 controls underwent the same OCT procedure. The association between focal cortical volume and OCT measurements was investigated with voxel-based morphometry (VBM)., Results: Compared to controls, patients' macular retinal nerve fiber layer (mRNFL), macular ganglion cell layer (mGCL), macular inner plexiform layer (mIPL), and macular ganglion cell-inner plexiform layer (mGCIPL) thickness were significantly reduced ( p = 0.0009, p = 0.0003, p = 0.0049, and p = 0.0007, respectively). Peripapillary RNFL (pRNFL) and temporal sector pRNFL (T-pRNFL) did not show any significant changes, although there was a trend toward T-pRNFL thinning ( p = 0.0254). VBM analysis showed that mGCIPL and pRNFL were significantly correlated with the volume reduction of occipital-parietal cortex ( p < 0.005)., Conclusion: mRNFL, mGCL, and mIPL are significantly reduced in MS patients without concomitant pRNFL thinning. These retinal changes show a significant association with cortical regions that are known to be important for visuospatial performance.

Background: The possibility of non-invasively assessing load-independent parameters characterizing cardiac function is of high clinical value. Typically, these parameters are assessed during resting conditions. However, for diagnostic purposes, the parameter behavior across a physiologically relevant range of heart rate and loads is more relevant than the isolated measurements performed at rest. This study sought to evaluate changes in non-invasive estimations of load-independent parameters of left-ventricular contraction and relaxation patterns at rest and during dobutamine stress. Methods: We applied a previously developed approach that combines non-invasive measurements with a physiologically-based, reduced-order model of the cardiovascular system to provide subject-specific estimates of parameters characterizing left ventricular function. In this model, the contractile state of the heart at each time point along the cardiac cycle is modeled using a time-varying elastance curve. Non-invasive data, including four-dimensional magnetic resonance imaging (4D Flow MRI) measurements, were acquired in nine subjects without a known heart disease at rest and during dobutamine stress. For each of the study subjects, we constructed two personalized models corresponding to the resting and the stress state. Results: Applying the modeling framework, we identified significant increases in the left ventricular contraction rate constant [from 1.5 ± 0.3 to 2 ± 0.5 ( p = 0.038)] and relaxation constant [from 37.2 ± 6.9 to 46.1 ± 12 ( p = 0.028)]. In addition, we found a significant decrease in the elastance diastolic time constant from 0.4 ± 0.04 s to 0.3 ± 0.03 s ( p = 0.008). Conclusions: The integrated image-modeling approach allows the assessment of cardiovascular function given as model-based parameters. The agreement between the estimated parameter values and previously reported effects of dobutamine demonstrates the potential of the approach to assess advanced metrics of pathophysiology that are otherwise difficult to obtain non-invasively in clinical practice.

Background and Aims: Empirical dose intensification and therapeutic drug monitoring [TDM] of infliximab [IFX] trough levels [ITLs] and antibody to infliximab [ATI] assays are recognized approaches for managing loss of response [LoR] in patients with inflammatory bowel disease [IBD]. The aim of the study was to compare these two interventions in a clinical setting, in terms of effectiveness and cost savings., Methods: Consecutive IBD patients experiencing LoR were clinically managed according to a TDM algorithm. A historical group of empirically treated patients, for whom sera for ITLs and ATI assays had been collected, served as the control group. Clinical outcomes 12 weeks after the therapeutic interventions were compared between the two groups. A cost-minimization analysis was performed to compare the economic impact of these two approaches., Results: Ninety-six patients were enrolled prospectively and compared with 52 controls. The two cohorts were similar in characteristics and in the distribution of TDM results. In the prospective cohort, however, we observed less IFX dose escalations compared with in the controls [45% versus 71%, p = 0.003]. Also, more patients were switched to a different anti-TNFα in the prospective cohort than in the control cohort [25% versus 4%, p = 0.001]. The percentages of patients achieving a clinical response at 12 weeks were 52% and 54% for the prospective and control groups, respectively. By cost analysis, we estimated a savings of 15% if the TDM algorithm was applied., Conclusions: In our population, applying a TDM algorithm for LoR to IFX resulted in less dose escalations, without loss of efficacy, compared with empirical adjustment. In addition, the TDM approach was cost-effective., (Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: To correlate changes in choroidal thickness and vascularity index with disease activity in patients with neovascular age-related macular degeneration (nAMD)., Methods: Eyes diagnosed with AMD that had two sequential visits within 12 months and that had no choroidal neovascularization (CNV) or had inactive CNV at the first visit were included. Those that had active CNV at follow-up were enrolled as cases. Eyes that did not developed a CNV or that were still inactive at the second visit were enrolled as controls. Disease activity was based on optical coherence tomography (OCT) and fluorescein angiography findings. Subfoveal choroidal thickness (SCT), mean choroidal thickness (MCT), and choroidal vascularity index (CVI) were assessed on enhanced depth imaging OCT and compared between the baseline and follow-up visit. Subgroup analysis accounting for lesion type and previous treatment, if any, were performed., Results: Sixty-five eyes from 60 patients (35 females) and 50 age- and sex-matched controls were included. At the active visit, cases had an increase from 164 ± 67 μm to 175 ± 70 μm in mean ± SD SCT and from 144 ± 45 μm to 152 ± 45 μm in MCT (both P < 0.0001). The mean CVI also increased at from 54.5% ± 3.3% to 55.4% ± 3.8% (P = 0.04). Controls did not show significant changes in choroidal measurements between the two visits. Mean SCT, MCT, and CVI values were similar for previously treated and treatment-naive eyes., Conclusions: Choroidal thickness and CVI significantly increased with active disease in nAMD eyes. Changes in choroidal thickness may predict CNV development or recurrence before they are otherwise evident clinically.

Purpose: (1) To collect a dataset of normative Early Treatment Diabetic Retinopathy Study (ETDRS) thickness map values for single retinal layers automatically segmented by Spectralis (Heidelberg Engineering, Heidelberg, Germany) spectral-domain OCT (SD-OCT) in a healthy white population. (2) To test the effect of age, sex, and axial length (AXL) on such values., Design: Cross-sectional study., Subjects: Healthy adult emmetropic white subjects with no history of ongoing or past conditions known to affect retinal anatomy., Methods: SD-OCT scans (30 × 25-degree volume) centered on the fovea were collected. Retinal-layer automatic segmentation was performed. Mean thickness values of 9 ETDRS sectors were calculated for each layer in 1 eye from each subject. The effect of age, sex, and AXL on the thickness of the central subfield, inner ring (IR), and outer ring (OR) of the ETDRS grid was tested. Scans were performed twice on a subset of patients to assess the repeatability of measurements., Main Outcome Measures: Retinal-layer thickness., Results: Two hundred eyes from 200 subjects (110 females, mean age 39.9±13.9 years [range 20-74 years]) were used for this study. The mean AXL was 24.30±1.07 mm (range 22.23-27.14 mm). Full retinal thickness was higher in males regardless of the subfield (all P < 0.05). Ganglion cell layer thickness correlated positively with AXL in the C (P = 0.02) but negatively in the OR (P = 0.0001). The inner plexiform layer was thicker in males in the IR (P = 0.01) and thinner in longer eyes in the OR (P = 0.002). The inner nuclear layer was thicker in males in the C and the IR (P = 0.002 and P = 0.0009, respectively). The outer plexiform layer thickness did not change with age and gender but correlated positively with AXL in the C (P = 0.009). Males had thicker outer nuclear layers in all subfields (all P < 0.05). The thickness of the nerve fiber layer and retinal pigment epithelium was not affected by the studied variables in any subfield. The intraclass correlation coefficient ranged from 0.872 for the outer plexiform layer to 0.990 for the retinal nerve fiber layer and the ganglion cell layer., Conclusions: The thickness values of each retinal layer in a large white population are provided. The thickness of retinal layers is influenced by gender, sex, and AXL, with a variable extent depending on the analyzed ETDRS map ring., (Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Scene representation-the process of converting visual sensory data into concise descriptions-is a requirement for intelligent behavior. Recent work has shown that neural networks excel at this task when provided with large, labeled datasets. However, removing the reliance on human labeling remains an important open problem. To this end, we introduce the Generative Query Network (GQN), a framework within which machines learn to represent scenes using only their own sensors. The GQN takes as input images of a scene taken from different viewpoints, constructs an internal representation, and uses this representation to predict the appearance of that scene from previously unobserved viewpoints. The GQN demonstrates representation learning without human labels or domain knowledge, paving the way toward machines that autonomously learn to understand the world around them., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Aim: Sclerosing cholangitis (SC) is a chronic cholestatic liver disease that is being increasingly diagnosed in childhood. The long-term course and prognosis of pediatric SC are poorly described., Methods: We reviewed data of pediatric SC patients, followed in two referral centers, during a period of up to 20 years. We aimed to evaluate long-term outcomes according to SC phenotype., Results: Among 45 patients (median age, 10.4 years; male patients, 73.4%) 29 (64.4%) were asymptomatic at presentation. Twenty patients (44%) had a concomitant inflammatory bowel disease (SC/IBD). Autoimmune features were found in 20 patients (44%). Liver biopsy showed severe fibrosis or cirrhosis in 32% of cases. Patients with SC alone had a higher rate of interface hepatitis at liver biopsy than SC/IBD patients. All children received ursodeoxycholic acid at diagnosis, and 17 received steroids and/or azathioprine. After a mean follow-up of 8.7 ± 5.6 years, all patients were alive and seven developed at least one liver-related complication. At the end of follow-up, 10 patients stopped immunosuppressants and two had no therapy. Only two patients underwent liver transplantation. Complication-free survival did not differ between SC/IBD and SC patients, but survival was longer in patients without autoimmune features., Conclusions: In our early diagnosed cohort, the 9-year survival with native liver was better than that reported in other studies. Approximately 15% of patients developed liver-related disease complications, less than previously reported. The long-term course of SC was negatively influenced by the presence of autoimmune features, but not by concomitant IBD., (© 2018 The Japan Society of Hepatology.)

The aims of this study were to identify the presence of endothelial dysfunction as a marker of early atherosclerosis by measuring aortic and carotid intimal-medial thickness (aIMT and cIMT) and flow-mediated dilation (FMD) and their correlation with traditional and no traditional risk factors for atherosclerosis in children with rheumatic diseases. Thirty-nine patients (mean age 15.3 ± 5.7 years), 23 juvenile idiopathic arthritis, 9 juvenile spondyloarthropathies, 7 connective tissue diseases (mean disease duration and onset respectively 5 ± 3.6 and 10 ± 5 years), and 52 healthy children matched for sex and age were enrolled. Demographic data (age, sex, familiarity for cardiovascular disease), traditional risk factors for atherosclerosis (BMI, active and passive smoking, dyslipidemia), activity disease indexes (reactive count protein, erythrocyte sedimentation rate) autoantibodies, and complement tests were collected. aIMT, cIMT, and FMD were assessed following a standardized protocol by high-resolution ultrasonography. Patients resulted significantly more exposed to passive smoking and had a lower BMI and higher homocysteine level than controls. cIMT and aIMT were significantly higher in patients than controls (p < 0.001) and correlated with age at diagnosis (p < 0.001 r 0.516 and 0.706, respectively) but not with mean disease duration. FMD % was significantly reduced in patients compared to controls (p < 0.001). Subclinical atherosclerosis occurs in pediatric rheumatic diseases, mainly in early onset forms, and aIMT is an earlier marker of preclinical atherosclerosis. Premature endothelial dysfunction could be included in the follow-up of children with rheumatic disorders to plan prevention strategies of cardiovascular disease already in pediatrics.

Deep neural networks have achieved impressive successes in fields ranging from object recognition to complex games such as Go 1,2 . Navigation, however, remains a substantial challenge for artificial agents, with deep neural networks trained by reinforcement learning 3-5 failing to rival the proficiency of mammalian spatial behaviour, which is underpinned by grid cells in the entorhinal cortex 6 . Grid cells are thought to provide a multi-scale periodic representation that functions as a metric for coding space 7,8 and is critical for integrating self-motion (path integration) 6,7,9 and planning direct trajectories to goals (vector-based navigation) 7,10,11 . Here we set out to leverage the computational functions of grid cells to develop a deep reinforcement learning agent with mammal-like navigational abilities. We first trained a recurrent network to perform path integration, leading to the emergence of representations resembling grid cells, as well as other entorhinal cell types 12 . We then showed that this representation provided an effective basis for an agent to locate goals in challenging, unfamiliar, and changeable environments-optimizing the primary objective of navigation through deep reinforcement learning. The performance of agents endowed with grid-like representations surpassed that of an expert human and comparison agents, with the metric quantities necessary for vector-based navigation derived from grid-like units within the network. Furthermore, grid-like representations enabled agents to conduct shortcut behaviours reminiscent of those performed by mammals. Our findings show that emergent grid-like representations furnish agents with a Euclidean spatial metric and associated vector operations, providing a foundation for proficient navigation. As such, our results support neuroscientific theories that see grid cells as critical for vector-based navigation 7,10,11 , demonstrating that the latter can be combined with path-based strategies to support navigation in challenging environments.

Purpose: To investigate retinal sensitivity (Se) in dome-shaped macula (DSM) using microperimetry and to correlate functional findings to specific spectral domain optical coherence tomography features., Methods: Patients affected by DSM in at least 1 eye were consecutively enrolled in a prospective, cross-sectional study. All studied eyes performed best-corrected visual acuity measurement, microperimetry to assess Se and optical coherence tomography to investigate DSM pattern and to measure bulge height and retinal and choroidal thicknesses., Results: Fifty-three eyes of 29 patients were studied. Dome-shaped macula was vertically oriented (V-DSM) in 23 (43.4%), symmetric (S-DSM) in 17 (32.1%), and horizontally oriented (H-DSM) in 13 eyes (24.5%). Foveal subretinal fluid was present in 29/53 (54.7%) cases; it correlated to the bulge height (P < 0.0001) and determined a reduction of Se (P < 0.0001) not of best-corrected visual acuity (P = 0.7105). Mean Se was 13.9 ± 3.2 dB. Microperimetry parameters did not differ among the different DSM patterns. However, Se was significantly impaired if foveal subretinal fluid was present in V-DSM and in S-DSM, but not in H-DSM (V-DSM: P < 0.0001; S-DSM: P = 0.0252; H-DSM: P = 0.5723). In H-DSM, inferior choroidal thickness was thicker in cases with foveal subretinal fluid compared with those without it (P = 0.0363)., Conclusion: In DSM, Se evaluation better reflects the central functional impairment than best-corrected visual acuity, particularly when some optical coherence tomography features, such as foveal subretinal fluid and higher bulge height, are present.

Aims: To compare optical coherence tomography (OCT) features of active necrotising infectious retinitis (NIR) due to toxoplasmosis or herpesviruses and to determine distinctive OCT signs for these two causes of infectious retinitis., Methods: OCT scans from eyes with active NIR due to varicella zoster virus (VZV), herpes simplex virus (HSV), cytomegalovirus (CMV), and toxoplasmosis (TOXO) were reviewed. All images were evaluated for the presence of previously described OCT findings in TOXO-NIR and compared with the viral group. New OCT findings were recorded and compared. Retinal and choroidal thickness were measured at the site of NIR and compared., Results: 10 eyes diagnosed with TOXO-NIR and 13 eyes affected by viral-NIR (9 CMV and 4 VZV) were analysed. All eyes showed full thickness hyper-reflectivity, disruption of the retina and a variable degree of vitritis. Among previously described OCT signs, hyper-reflective oval deposits and hypo-reflectivity of the choroid had a higher prevalence in TOXO (p=0.018 and p<0.0001, respectively). Among the new signs, hyper-reflective round deposits along the posterior hyaloid, retrohyaloid hyper-reflective spots and a disruption of the choroidal architecture were more frequent in TOXO eyes (all p<0.01). Intra-retinal oedema and hyper-reflective vertical strips within the outer nuclear layer were suggestive of a viral aetiology (p=0.045). Retinal thickness at the site of NIR did not differ between the two groups. Choroidal thickness was significantly higher in TOXO eyes (p=0.01)., Conclusions: The diagnosis of NIR is largely based on clinical and laboratory findings. OCT changes may be useful in differentiating different causes of NIR., Competing Interests: Competing interests: GS has financial relations with OCT manufacturers including: Heidelberg Engineering, Zeiss, Nidek, Canon, Optovue., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Correction to: Journal of Human Genetics advance online publication 27 July 2017; https://doi.org/10.1038/jhg.2017.78.

Purpose: Intraocular tuberculosis (IOTB) can be complicated by choroidal neovascularization (CNV). However, when the CNV development is not accompanied by clear signs of inflammation, the etiology can be missed, especially in countries nonendemic for tuberculosis. We describe the clinical and imaging features of CNVs presenting as the first sign of IOTB initially misdiagnosed as exudative age-related macular degeneration (AMD)., Methods: A retrospective review of clinical and imaging data of patients initially misdiagnosed with neovascular AMD later diagnosed with inflammatory CNV secondary to IOTB at tertiary referral centers was conducted. Features of fundus photography, fluorescein angiography, indocyanine green angiography, and enhanced depth imaging optical coherence tomography were analyzed. Distinguishing features between neovascular AMD and IOTB-associated CNV were evaluated., Results: Five patients over 55 years of age, erroneously diagnosed with exudative AMD, were included in the study. Multimodal imaging analysis allowed identification of peculiar choroidal alterations such as choroidal granulomas or choroiditis suggestive for posterior uveitis. Systemic workup for granulomatous uveitis including immunologic investigations such as tuberculin skin test or QuantiFERON TB Gold® and radiologic investigations revealed tubercular etiology in all the cases, allowing correct diagnosis and management of the uveitis and related CNV., Conclusions: Choroidal neovascularization represents a rare and unusual presenting sign of IOTB that can be misleading especially when it occurs in the elderly living in countries with low prevalence of the disease. Multimodal imaging can be helpful and should be employed, especially in atypical cases of CNV, in order to avoid misdiagnosis and/or diagnostic delays.

Purpose: To identify systemic risk factors for sickle cell maculopathy, and to analyze the microstructure of the macula of Sickle Cell Disease (SCD) patients by using automated segmentation of individual retinal layers., Methods: Thirty consecutive patients with SCD and 30 matched controls underwent spectral-domain optical coherence tomography (SD-OCT) and automated thickness measurement for each retinal layer; thicknesses for SCD patients were then compared to normal controls. Demographic data, systemic data, and lab results were collected for each SCD patient; multivariate logistic regression analysis was used to identify potential risk factors for sickle cell maculopathy., Results: Ongoing chelation treatment (p = 0.0187) was the most predictive factor for the presence of sickle cell maculopathy; the odds were 94.2% lower when chelation was present. HbF level tended to influence sickle cell maculopathy (p = 0.0775); the odds decreased by 12.9% when HbF increased by 1%. Sickle cell maculopathy was detected in 43% of SCD patients as patchy areas of retinal thinning on SD-OCT thickness map, mostly located temporally to the macula, especially in eyes with more advanced forms of sickle cell retinopathy (p = 0.003). In comparison to controls, SCD patients had a subtle thinning of the overall macula and temporal retina compared to controls (most p<0.0001), involving inner and outer retinal layers. Thickening of the retinal pigment epithelium was also detected in SCD eyes (p<0.0001)., Conclusions: Chronic chelation therapy and, potentially, high levels of HbF are possible protective factors for the presence of sickle cell maculopathy, especially for patients with more advanced forms of sickle cell retinopathy. A subtle thinning of the overall macula occurs in SCD patients and involves multiple retinal layers, suggesting that ischemic vasculopathy may happen in both superficial and deep capillary plexi. Thinning of the outer retinal layers suggests that an ischemic insult of the choriocapillaris may also occur in SCD patients.

Purpose: To evaluate the vitreal, retinal, and choroidal features using spectral domain optical coherence tomography (SD-OCT) in eyes affected by cytomegalovirus (CMV) retinitis., Methods: Patients diagnosed with either active or inactive CMV retinitis were included in the study. Complete ophthalmic examination, serial color fundus photography, and SD-OCT (with and without enhanced depth imaging function) were performed for all the subjects at baseline and follow-up visits. The SD-OCT images were analyzed by two independent graders to evaluate the structural changes in areas of CMV retinitis. Prevalence data for vitreal, retinal, and choroidal SD-OCT features were collected., Results: Twelve eyes from 9 patients (6 males, mean age: 52.7 ± 10.3 years) were enrolled. Nine eyes were diagnosed with active CMV retinitis at baseline. Active disease SD-OCT characteristic findings included nebulous vitritis (100%), posterior hyaloid thickening (83.3%), epiretinal membrane (100%), and retinal swelling (100%). Two distinct patterns of chorioretinal involvement were observed in active retinitis: 1) full-thickness retinitis (Full thickness retinitis) (n = 7 eyes) with choriocapillaris alterations and retinal pigment epithelial thickening and 2) cavernous retinitis (n = 3 eyes) characterized by inner retinal hyperreflectivity, large empty spaces in outer nuclear layer, and bridges of retinal tissue but retinal pigment epithelium and choriocapillaris sparing. Patients with cavernous retinitis develop retinal detachment during follow-up. Eyes with Full thickness retinitis developed choriocapillaris atrophy and choroidal thinning and retinal scars as the lesions healed., Conclusion: There are two distinct patterns of chorioretinal involvement in CMV retinitis. SD-OCT is a useful tool in the diagnosis, management, and prediction of the outcome of CMV retinitis.

Age-related Macular Degeneration (AMD) represents one of the most sight-threatening diseases in developed countries that substantially impacts the patients' lifestyle by compromising everyday activities, such as reading and driving. In this context, understanding the prevalence, burden, and population-specific risk/protective factors of AMD is essential for adequate health care planning and provision. Our work aimed to characterize exudative AMD in Italian population and to identify the susceptibility/protective factors (genetic variants, age, sex, smoking and dietary habits) which are specific for the onset of disease. Our study involved a cohort of 1976 subjects, including 976 patients affected with exudative AMD and 1000 control subjects. In particular, the sample cohort has been subjected to a large genotyping analysis of 20 genetic variants which are known to be associated with AMD among European and Asiatic populations. This analysis revealed that 8 genetic variants ( CFH, ARMS2, IL-8, TIMP3, SLC16A8, RAD51B, VEGFA and COL8A1 ) were significantly associated with AMD susceptibility. Successively, we performed a multivariate analysis, considering both genetic and non-genetic data available for our sample cohort. The multivariate analysis showed that age, smoking, dietary habits and sex, together with the genetic variants, were significantly associated with AMD in our population. Altogether, these data represent a starting point for the set-up of adequate preventive and personalized strategies aimed to decrease the burden of disease and improve the patients' quality of life., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no competing interests.

Neurofibromatosis type 1 (NF1) is an hereditary disorder characterized by abnormal proliferation of multiple tissues of neural crest origin, and presents mainly with multiple café-au-lait macules, axillary freckling and neurofibromas. Choroidal involvement in NF1 patients has been studied, thanks to the development of non-invasive tools such as infrared monochromatic light during fundus examination, which showed bright patchy lesions consistent with choroidal nodules. Choroidal abnormalities identified with near-infrared reflectance have reported with a frequency of up to 100% in NF1, and have been recently been proposed as a novel diagnostic criterion for NF1. Legius syndrome can be clinically indistinguishable from NF1 and results in a small percentage of individuals being misdiagnosed. We investigated the presence of choroidal abnormalities in Legius syndrome to determine their specificity to NF1 and their potential usefulness as a novel diagnostic criterion for NF1. We examined the fundus of 16 eyes by confocal scanning laser ophthalmoscopy with infrared monochromatic light in eight patients with molecularly confirmed Legius syndrome. No abnormalities were observed, confirming the diagnostic value of choroidal abnormalities for the diagnosis of NF1.

Purpose: To assess the ability of swept-source (SS) optical coherence tomography (OCT) of the anterior segment (AS) to measure anterior chamber (AC) inflammation (both flare and cells) objectively. To compare OCT-derived inflammatory indices with standard techniques., Design: Prospective evaluation of a diagnostic test., Participants: Patients diagnosed with anterior uveitis (active or inactive) and controls., Methods: Participants underwent an AC inflammation evaluation including: clinical cell and flare grading and laser flare photometry (LFP). Uveitis patients were divided into active or inactive uveitis status according to clinical grading. Anterior segment SS-OCT scans were obtained for each participant. Tomographic images were analyzed to count the AC cells, and to calculate to absolute measurements of aqueous signal intensity. The absolute values were compared with the signal measured by the scan outside the eye, generating an optical density ratio (aqueous-to-air relative intensity [ARI] index). Correlations between OCT-derived AC inflammatory indexes and LFP, clinical grading, participant category (active or inactive uveitis, control), age, gender, and central corneal thickness (CCT) were assessed., Main Outcome Measures: Correlation between OCT-derived AC inflammatory indexes (ARI index and AC cells on OCT) and standard clinical techniques (LFP, clinical cell grading)., Results: Two hundred thirty-seven eyes (70 active uveitis, 97 inactive uveitis, and 70 controls) were included. Anterior chamber cells count on OCT did not differ between inactive uveitis and controls, but was significantly higher in active uveitis compared to the other categories (both P < 0.0001). All groups had different LFP (all P < 0.0001). Active uveitis had significantly higher ARI index compared with inactive uveitis and controls (both P < 0.0001). Interobserver agreement (intraclass correlation coefficient) for ARI index was 0.78. The ARI index correlated positively with age (P = 0.043) and negatively with CCT (P = 0.006). The ARI index correlated with LFP in the active uveitis group (P < 0.0001), but not in the others. Anterior chamber cells on OCT increased among all cell clinical grades (P < 0.0001). The ARI index increased among all flare clinical grades (P < 0.005)., Conclusions: Anterior segment SS-OCT could be used for a comprehensive assessment of AC inflammation, providing objective measurements of inflammatory cells and aqueous flare., (Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Lumped parameter models of the cardiovascular system have the potential to assist researchers and clinicians to better understand cardiovascular function. The value of such models increases when they are subject specific. However, most approaches to personalize lumped parameter models have thus far required invasive measurements or fall short of being subject specific due to a lack of the necessary clinical data. Here, we propose an approach to personalize parameters in a model of the heart and the systemic circulation using exclusively non-invasive measurements. The personalized model is created using flow data from four-dimensional magnetic resonance imaging and cuff pressure measurements in the brachial artery. We term this personalized model the cardiovascular avatar. In our proof-of-concept study, we evaluated the capability of the avatar to reproduce pressures and flows in a group of eight healthy subjects. Both quantitatively and qualitatively, the model-based results agreed well with the pressure and flow measurements obtained in vivo for each subject. This non-invasive and personalized approach can synthesize medical data into clinically relevant indicators of cardiovascular function, and estimate hemodynamic variables that cannot be assessed directly from clinical measurements.

Context: In animal models, disruption of thyroid hormone (TH) receptor-β (TRβ) reduces the long/medium wavelength (L/M) and increases the short-wavelength (S) cones. Retinal photoreceptor (RP) functions are unknown in patients with resistance to TH syndrome (RTHβ) with dominant-negative TRβ mutations., Objective: To investigate RP functions in RTHβ., Design, Setting, and Participants: Case-control study involving 27 RTHβ patients and 31 age/sex-matched controls, conducted in two tertiary referral centers in Italy., Main Outcome Measures: Color vision sensitivity assessed by Farnsworth; central macular thickness (CMT) of the outer retinal layer measured by spectral-domain optical coherence tomography; and retinal function tested by full-field electroretinogram (ERG) and S-cone ERG., Results: Color sensitivity was worse in RTHβ patients than controls (P = 0.002). CMT was overlapping between the study groups but directly correlated with sex hormone-binding globuline levels in RTHβ. We found a significant reduction in amplitude of the cone (P = 0.024) and of the rod response (P = 0.006) in the ERG of RTHβ patients compared with controls. The response of the L/M cones measured by a specialized ERG test was lower in RTHβ than controls (P = 0.027), whereas no differences were found in the S-cone response. No correlations were found between TH levels, total error score, or electrophysiological results. Furthermore, no differences were found between patients with maternal or de novo/paternal inheritance., Conclusions: We report, to our knowledge, the first in vivo evidence of functional defects of RP in RTHβ. These changes occur independently of endogenous TH levels or the prenatal exposure to high or normal maternal TH., (Copyright © 2017 Endocrine Society)

Purpose: To determine the prevalence of drusen-like deposits (DLDs) and choroidal changes in patients with systemic lupus erythematosus (SLE), with or without glomerulonephritis; and to correlate ocular findings with systemic features., Design: Case-control study., Methods: Sixty patients with SLE (age, 18-55 years; 30 with and 30 without SLE-related glomerulonephritis) and 60 age- and sex-matched healthy controls were enrolled. All patients underwent noninvasive multimodal imaging that included fundus photography, near-infrared reflectance, blue autofluorescence, blue reflectance, and spectral-domain optical coherence tomography (SDOCT). Images were analyzed for the prevalence of DLDs. Distribution, size, and number of DLDs were measured. Correlations between ocular findings and systemic features were analyzed. Subfoveal choroidal thickness (SCT) was measured using the SDOCT., Results: Drusen-like deposits were detected in 40% of SLE subjects and 3.33% of controls (P < .0001). Compared with other techniques, SDOCT detected the largest number of affected subjects. In eyes with DLDs, small, medium, and large lesions were found in 75%, 50%, and 42% of cases, respectively. Drusen-like deposits were located in the nasal, temporal, inferior, superior, and central regions of the posterior pole in 83%, 75%, 67%, 54%, and 25% of eyes, respectively. The prevalence of DLDs in patients with SLE was similar regardless of renal involvement, but patients with glomerulonephritis had more DLDs per eye, larger deposits, and DLDs in >3 quadrants (P < .001, P = .03, P = .009, respectively). Subfoveal choroidal thickness was greater in patients with SLE (P = .002)., Conclusions: Drusen-like deposits in patients with SLE were independent of renal disease and were best detected with SDOCT. Lupus-related glomerulonephritis was associated with more fundus abnormalities and a screening SDOCT should be considered in all patients with SLE. Drusen-like deposits in the absence of glomerulonephritis may support the recent proposal that complement alteration is the primary cause of these lesions., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To describe the outcomes of intravitreal anti-vascular endothelial growth factor (VEGF) in the treatment of retinal angiomatous proliferation (RAP) in real-life practice in 7 Italian centers under the Progetto Luce initiative., Methods: Clinical data of 95 eyes of 95 patients affected by RAP, regularly followed up and treated with either intravitreal ranibizumab or bevacizumab over 12 months, were examined. After a loading phase of 3 consecutive injections, retreatments were administered following a pro-re-nata regimen on the basis of the persistence or the recurrence of subretinal/intraretinal fluid on optical coherence tomography, or leakage on fluorescein angiography., Results: Overall, the mean best corrected visual acuity changed from 0.66 to 0.53 LogMAR (P: 0.0003); 36.8% of eyes gained at least 3 ETDRS lines, whereas 13.7% lost >3 lines at the end of the follow-up. Mean central retinal thickness improved from 384 μm at baseline to 262 μm at the 12-month examination (P < 0.001). A serous pigment epithelium detachment (PED) was identified in 68.4% of eyes at baseline, and it was still detectable in 30.5% at the end of follow-up. The mean number of injections was 4.4 over the follow-up. A significantly greater proportion of eyes showed PED resolution in the subgroup treated with ranibizumab (P < 0.001)., Conclusions: Intravitreal anti-VEGF treatment in routine clinical practice allows a significant improvement in visual function in patients affected by RAP. A limited number of anti-VEGF injections are generally required in most cases.

Purpose: To assess the ability of enhanced depth imaging optical coherence tomography (EDI-OCT) in detecting variations in the structure and size of choroidal granulomas in response to treatment and to compare these findings with indocyanine green angiography (ICGA)., Methods: EDI-OCT and ICGA images of choroidal granulomas in eyes of patients diagnosed with tubercular or sarcoid uveitis were obtained at baseline and follow-up visits. Two independent masked observers analyzed the lesions to compare changes in their structural features such as shape, reflectivity, and margins, among others, through time. The size of each lesion was manually measured on EDI-OCT and ICGA images at all the visits. In addition, longitudinal assessment of choroidal area was performed on the EDI-OCT images during the course of follow-up., Results: Twenty-eight granulomas (16 tubercular and 12 sarcoid; 7 patients) were included in the study. Using EDI-OCT, significant decrease in the mean size of lesions could be appreciated after 1 month of treatment (0.29 mm at baseline vs. 0.18 mm at 1 month; P < 0.001). However, ICGA did not reveal significant decrease in lesion size at 1 month compared with baseline (0.94 vs. 0.76 mm; P = 0.07). The granulomas followed a characteristic healing pattern in which the antero-posterior extent (depth) decreased first, followed by decrease in their lateral extent. Apart from size, the choroidal granulomas did not show significant changes in their morphological features on EDI-OCT with treatment., Conclusion: EDI-OCT may be more sensitive than ICGA in detecting early variations in the size of choroidal granulomas. Morphometric analyses of choroidal granulomas on EDI-OCT may be very useful in monitoring the response to treatment in patients with choroidal granulomas.

Major surgical procedures often result in significant intra- and postoperative bleeding. The ability to identify the cause of the bleeding has the potential to reduce the transfusion of blood products and improve patient care. We present a novel device, the Quantra Hemostasis Analyzer, which has been designed for automated, rapid, near-patient monitoring of hemostasis. The Quantra is based on Sonic Estimation of Elasticity via Resonance Sonorheometry, a proprietary technology that uses ultrasound to measure clot time and clot stiffness from changes in viscoelastic properties of whole blood during coagulation. We present results of internal validation and analytical performance testing of the technology and demonstrate the ability to characterize the key functional components of hemostasis.

The space charge accumulation phenomenon has garnered great interest over the last two decades because of the increased use of direct current in high voltage electrical systems. In this context, a significant relevance has been achieved by the thermal methods, used for solid dielectrics. This paper presents a review of this non-destructive measurement system used for the measurement of space charge. The thermal pulse method, the thermal step method, and the laser intensity modulation method are described. For each configuration, the principle of operation, the thicknesses analyzed, and the spatial resolution are described, reporting also the main related applications.

Background: Crohn's disease is a chronic inflammatory disease characterized by a progressive transmural bowel damage leading to complications. Anti-TNFα therapy is effective in achieving mucosal healing (MH), but its efficacy on transmural inflammation has been poorly investigated. The aim of this study is to evaluate, in pediatric Crohn's disease, the efficacy of anti-tumor necrosis factor α agents in inducing transmural healing (TH) as assessed by ultrasonography (US)., Methods: Children with Crohn's disease requiring anti-tumor necrosis factor α therapy were prospectively enrolled. Clinical activity, laboratory tests, endoscopic activity, and transmural disease assessed by small intestine contrast US (SICUS) were evaluated at baseline (T0) and then after 9 to 12 months of therapy (T1). We evaluated US quantitative and qualitative parameters: disease extension (centimeters), bowel wall (BW) thickness >3 mm, BW vascularity and stratification strictures, and prestenotic dilatation. TH was defined as a BW thickness <3 mm and normalization of all US parameters at T1., Results: Thirty-two patients were included. Patients with mucosal healing (MH) showed a significant decrease of BW thickness and disease extension at T1 (4.3 ± 1.4 mm and 8 ± 6.3 cm versus 6.1 ± 2.3 mm and 13 ± 5 cm at baseline, respectively) (P < 0.001). Increased vascularity of the BW was found in 80% of patients at T0 and in 18% at T1 (P < 0.001). These parameters did not change in patients without MH, despite clinical and laboratory remission. The presence of stenosis and prestenotic dilatation did not modify in any group. A complete TH was achieved in 14% of patients, all of them showing complete MH., Conclusions: Biologics induce clinical and laboratory remission and MH in pediatric CD. Although caution is needed due to the small sample size, our data suggest that transmural inflammation also improves during therapy, but a complete TH is achieved only in a small percentage of patients.

Purpose: To detect choriocapillaris changes by enhanced depth imaging optical coherence tomography (EDI-OCT) in areas of choriocapillaris hypoperfusion visualized on indocyanine green angiography., Methods: Combined indocyanine green angiography and EDI-OCT from patients diagnosed with inflammatory choriocapillaris hypoperfusion were retrospectively analyzed. The EDI-OCTs were compared with indocyanine green angiography to detect choriocapillaris changes suggestive of choriocapillaris hypoperfusion in both active stage (AS) and inactive stage of the disease. The EDI-OCT was graded by two independent observers for choriocapillaris pattern (normal/altered) and reflectivity (hyper/hypo/isoreflective) changes. Manual measurements of choriocapillaris thickness were obtained. Interobserver agreement was assessed using Cohen's kappa, and differences in groups were assessed using McNemar's test., Results: Forty-two lesions from 11 eyes (8 patients, 3 males) were analyzed. Three patients (4 eyes, 17 lesions) were diagnosed with serpiginous choroiditis, and 5 patients (7 eyes, 25 lesions) were diagnosed with acute posterior multifocal placoid pigmented epitheliopathy. All the lesions demonstrated choriocapillaris hyporeflectivity on EDI-OCT during AS and isoreflectivity during inactive stage. The characteristic choriocapillaris dotted pattern was absent during AS. Choriocapillaris thickness at the sites of hypoperfusion was significantly higher during AS (63.07 ± 16.47 μm) than in inactive stage (22.92 ± 7.65 μm) (P < 0.001). Disruption of retinal pigment epithelium during AS was strongly associated with choriocapillaris atrophy during follow-up (P < 0.001)., Conclusion: The EDI-OCT shows characteristic choriocapillaris changes suggestive of choriocapillaris hypoperfusion that correlate with ischemia on indocyanine green angiography during both AS and inactive stage of the disease.

The Mediterranean area is historically characterized by high human pressure on water resources. Today, while climate is projected to be modified in the future, through precipitation decrease and temperature increase, that jointly and non-linearly may affect runoff, concerns about water availability are increasing. For these reasons, quantitative assessment of future modifications in the mean annual water availability are important; likewise, the description of the future interannual variability of some hydrological components such as runoff and evapotranspiration are highly wished for water management and ecosystems dynamics analyses. This study investigates at basin spatial scale future runoff and evapotranspiration, exploring their probability density functions and their interdependence as functions of climatic changes. In order to do that, a parsimonious conceptual lumped model is here used. The model is forced by different future climate scenarios, generated through a weather generator based on a stochastic downscaling of an ensemble of General Circulation Models (GCMs) realizations. The use of the adopted hydrological model, under reliable stochastic future climate scenarios, allows to project future values of evapotranspiration and runoff in a probabilistic framework and, at the same time, the evaluation of their bivariate frequency distributions for changes through the Multivariate Kernel Density Estimation method. As a case study, a benchmark Mediterranean watershed has been proposed (Imera Meridionale, Italy). Results suggest a radical shift and shape modification of the annual runoff and evapotranspiration probability density functions. Possible implications and impacts on water resources management are here addressed and discussed., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Impaired platelet function may underlie bleeding associated with cardiopulmonary bypass (CPB) and at present is incompletely evaluated with existing diagnostic technologies. Sonorheometry (SR) is a recently developed ultrasound-based technology that quantifies hemostasis and platelet activity from a blood sample by measuring ex vivo clot stiffness (S). We hypothesized that impaired platelet-fibrin interactions as assessed by SR would correlate with transfusion during CPB and history of prior aspirin therapy., Methods: Thirty-nine patients undergoing elective cardiopulmonary bypass (CPB) were enrolled following informed consent (University of Virginia IRB#14050) in a prospective observational pilot study to assess pre-operative platelet function and transfusion frequency. To assess platelet activity, abciximab was added to blood prior to SR and native S versus abciximab treated S created a differential test for platelet activity. Patient blood samples were activated with kaolin and SR was then used to measure clot stiffness. Patients were transfused with blood products as directed by clinical practice, with the surgical team blinded to SR results., Results: Blood clot stiffness with and without abciximab, was compared in a ratio test (S/Sabciximab) named the Platelet Function Index (PFI). PFI was hypothesized to be positively correlated with platelet contributions through integrin αIIbβ3 to clot stiffness. PFI for CPB subjects was lower for those receiving transfusions than those not receiving transfusions (p<0.006). A receiver-operator characteristics (ROC) analysis correlating the PFI with the blinded surgical team's decision on transfusions that included platelet concentrates generated an area under the curve (AUC) of 0.79 (p<0.001). Additionally, the mean value of PFI for subjects on aspirin therapy was lower than for those not on aspirin therapy (p<0.02) and correlated with a 1.73-fold enhanced risk of receiving a peri-operative transfusion., Conclusion: Evaluation of platelet function with SR may help in the specification of blood transfusion needs in cardiac surgery and in the assessment of aspirin effects on risk of surgical bleeding., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Recent years have been witnessing an increasing interest on global climate change and, although we are only at the first stage of the projected trends, some signals of climate alteration are already visible. Climate change encompasses modifications in the characteristics of several interrelated climate variables, and unavoidably produces relevant effects on almost all the natural processes related to the hydrological cycle. This study focuses on potential impacts of climate variations on the streamflow regime of small river basins in Mediterranean, seasonally dry, regions. The paper provides a quantitative evaluation of potential modifications in the flow duration curves (FDCs) and in the partitioning between surface and subsurface contributions to streamflow, induced by climate changes projected over the next century in different basins, also exploring the role exerted by different soil–vegetation compositions. To this aim, it is used a recent hydrological model, which is calibrated at five Sicilian (Italy) basins using a past period with available streamflow observations. The model is then forced by daily precipitation and reference evapotranspiration series representative of the current climatic conditions and two future temporal horizons, referring to the time windows 2045–2065 and 2081–2100. Future climatic series are generated by a weather generator, based on a stochastic downscaling of an ensemble of General Circulation Models. The results show how the projected climatic modifications are differently reflected in the hydrological response of the selected basins, implying, in general, a sensible downshift of the FDCs, with a significant reduction in the mean annual streamflow, and substantial alterations in streamflow seasonality and in the relative importance of the surface and subsurface components. The projected climate change impact on the hydrological regime of ephemeral rivers could have important implications for the water resource management and for the sustainability of many riparian Mediterranean ecosystems.

Background and Aims: There is growing evidence that in Crohn's disease the achievement and maintenance of mucosal healing (MH) through anti-TNFα antibodies may change the natural history of the disease. Few studies evaluating such outcome as a therapeutic goal are available in paediatrics. The primary aim of the study was to assess the efficacy of biologics in obtaining MH in a paediatric Crohn's disease cohort. The secondary aims were: (1) to assess response based on early or late treatment introduction and on combination therapy with immunomodulators versus biologics alone; and (2) to evaluate clinical outcome 2 years after the second endoscopy., Methods: Biologic-naive paediatric Crohn's disease patients starting anti-tumour necrosis factor α (TNFα) treatment were enrolled. Patients' demographic and treatment data were recorded. Clinical [Pediatric Crohn's Disease Activity Index (PCDAI)] and endoscopic [Simple Endoscopic Score for Crohn's Disease (SES-CD)] evaluations were performed at time 0 (T0) and after 9-12 months (follow-up). Appropriate induction and maintenance therapeutic schemes were applied., Results: Thirty-seven patients were enrolled. At enrolment, mean age was 12.3 ± 3.4 years and mean disease duration was 13.0 ± 16 months. At follow-up there was a significant decrease in PCDAI and SES-CD compared with T0 (p < 0.01). No statistical difference in frequency of MH between the early and late treatment introduction groups was found. Combination therapy was superior in obtaining complete plus partial MH (p < 0.01). One and 2 years after the second endoscopy, all and 79% of patients with complete MH and 75 and 67% of those with partial MH were still in clinical remission, respectively., Conclusions: Biologics improve mucosal lesions, apparently more effectively if given in combination with immunomodulators. MH appears to sustain a better disease course., (Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

A comparative study on post-squalene sterol synthesis in intact yeast cells and spheroplasts was carried out with strains from three genera (Saccharomyces cerevisiae, Schizosaccharomyces pombe, Pichia pastoris) as well as with engineered S. cerevisiae cells altered in regard to the late ergosterol synthesis pathway. A common outcome of incubation experiments with radioactive acetate was that in intact cells the metabolic pathway flows till its specific end product (ergosterol and its precursor, depending on the enzyme deficiency), whereas in spheroplasts the pathway was stalled some step upstream. For example, in spheroplasts from wt strains, non-cyclic triterpenes squalene and oxidosqualene accumulated as though the metabolic path was kept from producing steroid-shaped molecules different from the end product. Accumulation of non-cyclic triterpenes was observed also in spheroplasts from S. cerevisiae cells lacking 3-ketosteroid reductase activity, an enzyme belonging to the C4-demethylase complex. When production of cyclic triterpenes was compromised by loss or poor functionality of oxidosqualene cyclase (EC 5.4.99.7), the difference between intact cells and spheroplasts was still remarkable, yet limited to the different oxido/dioxidosqualene ratio. The characteristics of spheroplasts as non-proliferating cells may partially explain the observed differences in post-squalene pathway from intact cells. We cannot say if the difference in metabolic pathways in spheroplasts and intact cells is a rule. We think, however, that it is worthwhile to search for an answer, as a wider picture of the points where the metabolic pathways are stalled in spheroplasts could provide original ideas about the metabolic network in yeast.

Purpose: To assess the characteristics and prevalence of fundus abnormalities in vitreoretinal lymphoma (VRL) using multimodal imaging., Methods: We retrospectively reviewed chart and imaging studies of patients diagnosed with VRL., Results: All 10 VRL patients (14 eyes) included in the study showed vitreitis, hyperreflective lesions on near-infrared reflectance imaging, and hypoautofluorescent lesions on fundus autofluorescence. Other findings included hypofluorescent lesions on fluorescein angiography (79%), hypocyanescent lesions on indocyanine green angiography (77%), small retinal pigment epithelium detachments (PEDs) (71%) and large PEDs (36%) on optical coherence tomography (OCT). Outer retinal layer nodularity was identified on OCT in 93% of cases. Small PEDs corresponded to hyperreflective, hyperautofluorescent, hypofluorescent, hypocyanescent lesions., Conclusion: Multiple signs were present on multimodal imaging in VRL eyes. Lymphomatous infiltration created focal PEDs showing abnormal imaging signals. Outer retinal layer nodularity could represent an additional sign of infiltration. Multimodal imaging may guide physicians in the early diagnosis of VRL., (© 2016 S. Karger AG, Basel.)

Purpose: To document the occurrence of Roth spots and retinal hemorrhages by spectral-domain optical coherence tomography (SD-OCT) following endoscopic adhesiolysis for failed back surgery syndrome., Methods: Case report., Results: A 47-year-old patient noted progressive and bilateral visual loss immediately after epidural endoscopy and endoscopic adhesiolysis. Funduscopic examination showed multiple Roth spots and retinal hemorrhages at the posterior pole and the retinal midperiphery in both eyes. Spectral-domain optical coherence tomography demonstrated that Roth spots involved the inner retina, while dot hemorrhages involved the outer retina. Most retinal hemorrhages and Roth spots resolved over 6 weeks, with complete functional recovery in both eyes. However, SD-OCT revealed multiple areas of disruption of the outer retinal layers in the left eye., Conclusions: Roth spots and retinal hemorrhages can occur after endoscopic spinal surgery. Although hemorrhages resolve quickly over few weeks, SD-OCT can demonstrate that retinal damage might persist, especially in the outer retina. This finding may explain cases of incomplete recovery of visual function after complicated endoscopic adhesiolysis.

Objectives: The aims of this study were to determine the presence of endothelial dysfunction by measuring aortic intima-media thickness (aIMT) and carotid intima-media thickness (cIMT) and to evaluate the role of traditional risk factors for premature atherosclerosis in children with inflammatory bowel disease (IBD)., Methods: Thirty-four children with IBD (25 Crohn disease [CD] and 9 ulcerative colitis [UC]; mean age 11.1 years) and 27 healthy subjects matched for sex and age were enrolled. In all of the patients, demographic characteristics and risk factors for atherosclerosis (age, sex, body mass index, blood pressure, dyslipidemia, active and passive smoking, and family history for cardiovascular diseases), CD and UC clinical activity scores, and inflammatory markers were evaluated. aIMT and cIMT were measured by high-resolution B-mode ultrasound., Results: aIMT was significantly higher in patients than in controls (P < 0.0005). No significant differences were found for cIMT, although the carotid thickness was higher in patients with IBD than in healthy subjects. At a univariate analysis, inflammatory markers levels and tobacco smoking exposure were significantly related to higher aIMT values, whereas in a multivariate regression model, the inflammatory status was the only independent variable correlated with high aIMT., Conclusions: aIMT is an earlier marker of preclinical atherosclerosis than cIMT in young children with active IBD. The inflammatory status and the smoking exposure are significantly correlated with the premature endothelial dysfunction. These data emphasize the importance of controlling the chronic intestinal inflammation and endorsing smoke-free environments for children and adolescents with IBD.

Purpose: We analyzed by swept-source anterior segment optical coherence tomography (SS-ASOCT) the three-dimensional iris morphology in a Caucasian population, and correlated the findings with iris color, iris sectors, subject age, and sex., Methods: One eye each from consecutive healthy emmetropic (refractive spherical equivalent ± 3 diopters) volunteers were selected for the study. The enrolled eye underwent standardized anterior segment photography to assess iris color. Iris images were assessed by SS-ASOCT for volume, thickness, width, and pupil size. Sectoral variations of morphometric data among the superior, nasal, inferior, and temporal sectors were recorded., Results: A total of 135 eyes from 57 males and 78 females, age 49 ± 17 years, fulfilled the inclusion criteria. All iris morphometric parameters varied significantly among the different sectors (all P < 0.0001). Iris total volume and thickness were significantly correlated with increasingly darker pigmentation (P < 0.0001, P = 0.0384, respectively). Neither width nor pupil diameter was influenced by iris color. Age did not affect iris volume or thickness; iris width increased and pupil diameter decreased with age (rs = 0.52, rs = -0.58, respectively). There was no effect of sex on iris volume, thickness, or pupil diameter; iris width was significantly greater in males (P = 0.007)., Conclusions: Morphology of the iris varied by iris sector, and iris color was associated with differences in iris volume and thickness. Morphological parameter variations associated with iris color, sector, age, and sex can be used to identify pathological changes in suspect eyes. To be effective in clinical settings, construction of iris morphological databases for different ethnic and racial populations is essential.

Despite the life-preserving function blood clotting serves in the body, inadequate or excessive blood clot stiffness has been associated with life-threatening diseases such as stroke, hemorrhage, and heart attack. The relationship between blood clot stiffness and vascular diseases underscores the importance of quantifying the magnitude and kinetics of blood's transformation from a fluid to a viscoelastic solid. To measure blood plasma clot stiffness, we have developed a method that uses ultrasound acoustic radiation force (ARF) to induce micron-scaled displacements (1-500 μm) on microbeads suspended in blood plasma. The displacements were detected by optical microscopy and took place within a micro-liter sized clot region formed within a larger volume (2 mL sample) to minimize container surface effects. Modulation of the ultrasound generated acoustic radiation force allowed stiffness measurements to be made in blood plasma from before its gel point to the stage where it was a fully developed viscoelastic solid. A 0.5 wt % agarose hydrogel was 9.8-fold stiffer than the plasma (platelet-rich) clot at 1 h post-kaolin stimulus. The acoustic radiation force microbead method was sensitive to the presence of platelets and strength of coagulation stimulus. Platelet depletion reduced clot stiffness 6.9 fold relative to platelet rich plasma. The sensitivity of acoustic radiation force based stiffness assessment may allow for studying platelet regulation of both incipient and mature clot mechanical properties.

Purpose: To describe a case of optic nerve head tubercular granuloma, unresponsive to conventional therapy (antitubercular drugs and systemic steroids), successfully treated with anti-vascular endothelial growth factor (VEGF) intravitreal injections in addition to systemic drugs., Methods: Case report., Results: A 44-year-old patient was referred to our clinic for progressive vision decrease in his left eye during the preceding 4 months. A large granuloma infiltrating optic nerve head was visible at funduscopic examination along with diffuse intraocular inflammation. Workup for granulomatous uveitis supported the diagnosis of presumed intraocular tuberculosis. However, the large granulomatous lesion did not show a good response to conventional therapy for tubercular uveitis (antitubercular drugs and systemic steroids). Anti-VEGF (bevacizumab) intravitreal injections were performed as an adjunct to the ongoing therapy. After 2 injections, the patient showed an almost complete regression of the lesion (demonstrated by optical coherence tomography) and a restoration of vision., Conclusions: Anti-VEGF intravitreal injections should be considered in the treatment of large tubercular granulomatous lesions in addition to conventional systemic therapy. Optical coherence tomography could be a suitable tool for studying and following optic nerve head granulomas.

Purpose: To describe in vivo longitudinal modifications of the Ozurdex intravitreal implant using spectral-domain optical coherence tomography (SD-OCT) over a 6-month period in an eye treated for retinal vein occlusion (RVO)., Methods: Case report., Results: An 82-year-old woman with severe macular edema secondary to branch RVO received an Ozurdex intravitreal implant in the left eye. At day 1, SD-OCT showed that the implant was completely filled with highly reflective dexamethasone. At day 30, complete resolution of macular edema on SD-OCT was noted. At day 60, macular edema started to relapse; SD-OCT scans over the implant showed highly reflective borders that appeared irregular and focally retracted, while the majority of the internal drug had been washed out. At day 180, macular edema returned to baseline levels; SD-OCT scans over the implant showed that the device was contracted with almost complete absence of the internal lumen and drug., Conclusions: Using SD-OCT, we demonstrated that 60 days postinjection most dexamethasone had been released from the Ozurdex implant, which showed multiple irregularities. This was associated with recurrence of macular edema that became worse after 180 days, when there was no residual dexamethasone remaining in the shrunken implant. Low steady levels of the drug in the vitreous and lower biological activity in the retina after the 2-month high-dose release phase may explain why a large number of patients lose clinical improvement 60 days postinjection, as shown by pivotal clinical trials.

Aberrant cholesterol homeostasis and biosynthesis has been observed in different tumour types. This paper investigates the role of the post-squalenic enzyme of cholesterol biosynthesis, oxidosqualene cyclase (OSC), in regulating tumour angiogenesis and metastasis dissemination in mouse models of cancer. We showed that Ro 48-8071, a selective inhibitor of OSC, reduced vascular density and increased pericyte coverage, with a consequent inhibition of tumour growth in a spontaneous mouse model of pancreatic tumour (RIP-Tag2) and two metastatic mouse models of human colon carcinoma (HCT116) and pancreatic adenocarcinoma (HPAF-II). Remarkably, the inhibition of OSC hampered metastasis formation in HCT116 and HPAF-II models. Ro 48-8071 induced tumour vessel normalization and enhanced the anti-tumoral and anti-metastatic effects of 5-fluorouracil (5-FU) in HCT116 mice. Ro 48-8071 exerted a strong anti-angiogenic activity by impairing endothelial cell adhesion and migration, and by blocking vessel formation in angiogenesis assays. OSC inhibition specifically interfered with the PI3K pathway. According to in vitro results, Ro 48-8071 specifically inhibited Akt phosphorylation in both cancer cells and tumour vasculature in all treated models. Thus, our results unveil a crucial role of OSC in the regulation of cancer progression and tumour angiogenesis, and indicate Ro 48-8071 as a potential novel anti-angiogenic and anti-metastatic drug.