Efficacy and Safety of Artificial Tears Containing Lipidure and Hypromellose for the Treatment of Moderate Dry Eye Disease in Contact Lens Wearers.

Background and Objectives: Dry eye disease (DED) affects 5-50% of the global population and deeply influences everyday life activities. This study compared the efficacy, tolerability, and safety of novel Respilac artificial tears containing lipidure and hypromellose (HPMC) with the widely used Nextal artificial tears, which are also HPMC-based, for the treatment of moderate DED in contact lenses (CL) wearers. Materials and Methods: In a prospective, single-center, randomized investigation, 30 patients aged ≥18 years, diagnosed with moderate DED, and wearing CL were randomly assigned to the Respilac (n = 15) or Nextal group (n = 15). Patients self-administrated one drop of Respilac or Nextal in both eyes three times daily for 21 days. Changes in the endpoint (visual analogue scale (VAS) score for ocular tolerability, symptom assessment in dry eye (SANDE) score, non-invasive first break-up time (NIF-BUT) results, tear analysis value, meibography results, and CL tolerability results were assessed, comparing treatment groups and time-point evaluations. Adverse events (AEs) were also recorded and evaluated. Results: VAS scores decreased with time (p < 0.001) in both groups, showing no statistically significant difference among them (p = 0.13). Improvements were also detected from screening to end-of-treatment, which were indicated by the SANDE scores for severity and frequency (p < 0.001) and by tear analysis results (p < 0.001) with no observed difference between the Nextal and Respilac arms. NIF-BUT, meibography, and CL tolerability values were shown to be non-significantly affected by treatment and time. There were no AEs detected in this study cohort. Conclusions: Respilac was confirmed to be effective, safe, and well-tolerated. Lipidure-based ophthalmic solution was shown not to be inferior to the currently used Nextal, however, showing improvements in DED symptoms. Within the existing literature, our study is one of the first to report that MPC plus HPMC-containing eye drops are an effective option for the treatment of moderate dry eye disease and desiccation damage prevention in contact lens wearers.

The dynamics of norm change in the cultural evolution of language.

What happens when a new social convention replaces an old one? While the possible forces favoring norm change-such as institutions or committed activists-have been identified for a long time, little is known about how a population adopts a new convention, due to the difficulties of finding representative data. Here, we address this issue by looking at changes that occurred to 2,541 orthographic and lexical norms in English and Spanish through the analysis of a large corpora of books published between the years 1800 and 2008. We detect three markedly distinct patterns in the data, depending on whether the behavioral change results from the action of a formal institution, an informal authority, or a spontaneous process of unregulated evolution. We propose a simple evolutionary model able to capture all of the observed behaviors, and we show that it reproduces quantitatively the empirical data. This work identifies general mechanisms of norm change, and we anticipate that it will be of interest to researchers investigating the cultural evolution of language and, more broadly, human collective behavior.

Withdrawal Assessment Tool-1 Monitoring in PICU: A Multicenter Study on Iatrogenic Withdrawal Syndrome.

OBJECTIVES: Withdrawal syndrome is an adverse reaction of analgesic and sedative therapy, with a reported occurrence rate between 17% and 57% in critically ill children. Although some factors related to the development of withdrawal syndrome have been identified, there is weak evidence for the effectiveness of preventive and therapeutic strategies. The main aim of this study was to evaluate the frequency of withdrawal syndrome in Italian PICUs, using a validated instrument. We also analyzed differences in patient characteristics, analgesic and sedative treatment, and patients' outcome between patients with and without withdrawal syndrome. DESIGN: Observational multicenter prospective study. SETTING: Eight Italian PICUs belonging to the national PICU network Italian PICU network. PATIENTS: One hundred thirteen patients, less than 18 years old, mechanically ventilated and treated with analgesic and sedative therapy for five or more days. They were admitted in PICU from November 2012 to May 2014. INTERVENTIONS: Symptoms of withdrawal syndrome were monitored with Withdrawal Assessment Tool-1 scale. MEASUREMENTS AND MAIN RESULTS: The occurrence rate of withdrawal syndrome was 64.6%. The following variables were significantly different between the patients who developed withdrawal syndrome and those who did not: type, duration, and cumulative dose of analgesic therapy; duration and cumulative dose of sedative therapy; clinical team judgment about analgesia and sedation's difficulty; and duration of analgesic weaning, mechanical ventilation, and PICU stay. Multivariate logistic regression analysis revealed that patients receiving morphine as their primary analgesic were 83% less likely to develop withdrawal syndrome than those receiving fentanyl or remifentanil. CONCLUSIONS: Withdrawal syndrome was frequent in PICU patients, and patients with withdrawal syndrome had prolonged hospital treatment. We suggest adopting the lowest effective dose of analgesic and sedative drugs and frequent reevaluation of the need for continued use. Further studies are necessary to define common preventive and therapeutic strategies.

The Importance of Mortality Risk Assessment: Validation of the Pediatric Index of Mortality 3 Score.

OBJECTIVE: To evaluate the performance of the newest version of the Pediatric Index of Mortality 3 score and compare it with the Pediatric Index of Mortality 2 in a multicenter national cohort of children admitted to PICU. DESIGN: Retrospective, prospective cohort study. SETTING: Seventeen Italian PICUs. PATIENTS: All children 0 to 15 years old admitted in PICU from January 2010 to October 2014. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Eleven thousand one hundred nine children were enrolled in the study. The mean Pediatric Index of Mortality 2 and 3 values of 4.9 and 3.9, respectively, differed significantly (p < 0.05). Overall mortality rate was 3.9%, and the standardized mortality ratio was 0.80 for Pediatric Index of Mortality 2 and 0.98 for Pediatric Index of Mortality 3 (p < 0.05). The area under the curve of the receiver operating characteristic curves was similar for Pediatric Index of Mortality 2 and Pediatric Index of Mortality 3. The Hosmer-Lemeshow test was not significant for Pediatric Index of Mortality 3 (p = 0.21) but was highly significant for Pediatric Index of Mortality 2 (p < 0.001), which overestimated death mainly in high-risk categories. CONCLUSIONS: Mortality indices require validation in each country where it is used. The new Pediatric Index of Mortality 3 score performed well in an Italian population. Both calibration and discrimination were appropriate, and the score more accurately predicted the mortality risk than Pediatric Index of Mortality 2.

Retinal Vascular Abnormalities and Clinical Parameters in Systemic Sclerosis.

Background: Systemic sclerosis is a complex autoimmune disease characterized by vasculopathy, fibrosis, and immune dysregulation. Ocular manifestations in these patients are increasingly recognized, suggesting potential correlations between systemic vascular abnormalities and ocular microvascular changes. Advancements in molecular immunology and imaging technology using ocular coherence tomography (OCT) have unveiled intricate pathways underlying possible disease pathogenesis. Understanding the interplay between retinal vascular abnormalities and molecular immunology parameters could provide insights into disease mechanisms and potential biomarkers. Purpose: The aim of this study was to investigate vascular abnormalities, detected with optical coherence tomography angiography (OCT-A), in systemic sclerosis patients and to find correlations between the severity of the disease detected with molecular immunology findings and OCT-A parameters. Methods: A group of 32 systemic sclerosis patients were compared with 9 healthy controls. Ganglion cell complex thickness (GCC), retina thickness of the fovea and parafovea, nerve fiber layer thickness (RNFL) and cup/disc area ratio were investigated using OCT. Vessel density (VD) of the superficial (SCP) and deep capillary plexus (DCP) of the whole macular area and ETDRS grid, size of the foveal avascular zone (FAZ) and vessel density of the radial peripapillary capillary plexus (RPCP) were evaluated using OCT-A. Modified Rodnan skin score (mRSS), capillaroscopy and disease duration were used to stage disease severity. Results: There was a statistically significant reduction in retina thickness of the fovea and parafovea, VD of the whole DCP, VD of the SCP and DCP in ETDRS grid in the patient group compared to controls (p < 0.001). The patients presented a significant enlargement of the FAZ (p 0.005). No significant correlation between OCT and OCT-A parameters and disease severity scores was found. Conclusions: OCT-A could represent a non-invasive tool to detect retinal microvascular damage in systemic sclerosis.

Baby Food and Oral Health: Knowledge of the Existing Interaction.

BACKGROUND: The purpose of this study is to verify parents' knowledge of child nutrition and their awareness of the interaction between unhealthy sugars in their child's diet and caries formation. METHODS: a questionnaire was proposed using Instagram to analyze type of breastfeeding; type of weaning and diet; home oral hygiene maneuvers; bad habits (use of pacifiers, bottles, and sugary substances); knowledge on the usefulness of fluoride; and first dental visit. A total of 200 parents from different regions of Italy with children aged 2 months to 6 years were contacted. Results showed that 66% parents preferred breastfeeding, while the remaining 34% chose artificial breastfeeding. Fifty percent (100 babies) started weaning at six months, 20% (40 babies) at the fifth month, 13.5% (27 babies) at the fourth month, and only 11.5% (23 babies) in a range from the seventh to ninth month of life. Oral hygiene practices were performed only by 25% of parents before eruption of the first tooth. After eruption of the first tooth, there is greater attention to home oral hygiene practices: 59% of parents carry out and teach their children daily home oral hygiene maneuvers. CONCLUSIONS: it is possible to raise awareness among parents and caregivers on the importance of food education.

The Multiple Facets of ATRX Protein.

ATRX gene codifies for a protein member of the SWI-SNF family and was cloned for the first time over 25 years ago as the gene responsible for a rare developmental disorder characterized by α-thalassemia and intellectual disability called Alpha Thalassemia/mental Retardation syndrome X-linked (ATRX) syndrome. Since its discovery as a helicase involved in alpha-globin gene transcriptional regulation, our understanding of the multiple roles played by the ATRX protein increased continuously, leading to the recognition of this multifaceted protein as a central "caretaker" of the human genome involved in cancer suppression. In this review, we report recent advances in the comprehension of the ATRX manifold functions that encompass heterochromatin epigenetic regulation and maintenance, telomere function, replicative stress response, genome stability, and the suppression of endogenous transposable elements and exogenous viral genomes.

The influence of refractive errors on IOP measurement by rebound tonometry (ICare) and Goldmann applanation tonometry.

PURPOSE: To evaluate the effect of refractive errors and central corneal thickness (CCT) on the measurement of intraocular pressure (IOP) by ICare rebound tonometer (RT), and its agreement with measurements by Goldmann applanation tonometer (GAT). PATIENTS AND METHODS: Two observers measured the IOP by using RT and GAT in four groups of healthy volunteers with emmetropic (n = 78), hyperopic (n = 83), myopic (n = 87) and astigmatic (n = 79) eyes. Refraction was assessed by an autorefractometer. CCT was assessed by ultrasound pachymetry. RESULTS: In all groups, no significant interobserver difference was seen in IOP values detected by both tonometers (Wilcoxon signed-rank test not significant). In all groups, IOP values were higher as measured by RT than by GAT (paired t-test p = 0.000): mean RT-GAT difference was higher in myopic eyes (+1.6 +/- 1.8 mmHg), and it was less than 1 mmHg in the other groups. RT-GAT difference was correlated to the refraction (p < 0.001), and it was greater when an higher IOP was detected by RT (significant correlation between RT-GAT difference and IOP by RT, p < 0.001). Compared with GAT values, the IOP readings by RT were greater than 2 mmHg in respectively 17.9% (emmetropic), 13.3% (hyperopic), 34.5% (myopic) and 7.6% (astigmatic) of the eyes. With both tonometers, in all groups the IOP values were correlated with CCT (p < 0.05), but the discrepancy between RT and GAT values was not related to CCT. CONCLUSIONS: In all groups of subjects, higher IOP values were detected by RT; the IOP readings exceed the GAT values usually in a range of less than 1 mmHg, except when RT detects IOP >18 mmHg and generally in myopic eyes; RT-GAT discrepancy is related to the refractive error, but not to CCT.

G-quadruplex Stabilization Fuels the ALT Pathway in ALT-positive Osteosarcoma Cells.

Most human tumors maintain telomere lengths by telomerase, whereas a portion of them (10%-15%) uses a mechanism named alternative lengthening of telomeres (ALT). The telomeric G-quadruplex (G4) ligand RHPS4 is known for its potent antiproliferative effect, as shown in telomerase-positive cancer models. Moreover, RHPS4 is also able to reduce cell proliferation in ALT cells, although the influence of G4 stabilization on the ALT mechanism has so far been poorly investigated. Here we show that sensitivity to RHPS4 is comparable in ALT-positive (U2OS; SAOS-2) and telomerase-positive (HOS) osteosarcoma cell lines, unlinking the telomere maintenance mechanism and RHPS4 responsiveness. To investigate the impact of G4 stabilization on ALT, the cardinal ALT hallmarks were analyzed. A significant induction of telomeric doublets, telomeric clusterized DNA damage, ALT-associated Promyelocytic Leukaemia-bodies (APBs), telomere sister chromatid exchanges (T-SCE) and c-circles was found exclusively in RHPS4-treated ALT cells. We surmise that RHPS4 affects ALT mechanisms through the induction of replicative stress that in turn is converted in DNA damage at telomeres, fueling recombination. In conclusion, our work indicates that RHPS4-induced telomeric DNA damage promotes overactivation of telomeric recombination in ALT cells, opening new questions on the therapeutic employment of G4 ligands in the treatment of ALT positive tumors.

Dry Eye in Systemic Sclerosis Patients: Novel Methods to Monitor Disease Activity.

BACKGROUND: In systemic sclerosis (SSc) patients, dry eye syndrome (DES) is the most frequent ocular feature. The aim of this study was to investigate ocular DES-related SSc patients and to establish any correlation with the severity of the disease. METHODS: Retrospectively, data from 60 patients with SSc underwent ophthalmic examination, where non-invasive film tear break-up time (NIF-TBUT), tear film lipid layer thickness (LLT), anesthetic-free Schirmer test I, tear osmolarity measurement (TearLab System), and modified Rodnan skin score (mRSS) data were collected. The visual analog scale (VAS) and Symptom Assessment in Dry Eye (SANDE) methods were utilized. The results were correlated with mRSS and the duration of SSc. RESULTS: Severe DES occurred in 84% of cases, and was more severe in women. The eyelids were involved in 86.6%, secondary to meibomian gland disease (MGD). A direct correlation was found between the tear osmolarity (mean 328.51 ± 23.8 SD) and skin score (mRSS) (r = 0.79; p < 0.01). Significantly reduced NIF-TBUT, LLT, and Schirmer test I values were observed in the case of severe skin involvement. CONCLUSIONS: SSc patients show lipid tear dysfunction related to the severity and duration of the disease due to inflammation and the subsequent atrophy of the meibomian glands.

Measurement of the Retention Time of Different Ophthalmic Formulations with Ultrahigh-Resolution Optical Coherence Tomography.

Purpose/aim of the study: The purpose of this study was to measure the pre-corneal retention time of two marketed formulations (eye drops and eye gel) of a steroid-antibiotic fixed combination (FC) containing 0.1% dexamethasone and 0.3% netilmicin. MATERIALS AND METHODS: Pre-corneal retention time was evaluated in 16 healthy subjects using an ultrahigh-resolution anterior segment spectral domain optical coherence tomography (OCT). All subjects randomly received both formulations of the FC (Netildex, SIFI, Italy). Central tear film thickness (CTFT) was measured before instillation (time 0) and then after 1, 10, 20, 30, 40 50, 60 and 120 min. The pre-corneal retention time was calculated by plotting CTFT as a function of time. Differences between time points and groups were analyzed by Student's t-test. RESULTS: CTFT increased significantly after the instillation of the eye gel formulation (p < 0.001). CTFT reached its maximum value 1 min after instillation and returned to baseline after 60 min. No effect on CTFT was observed after the instillation of eye drops. The difference between the two formulations was statistically significant at time 1 min (p < 0.0001), 10 min (p < 0.001) and 20 min (p < 0.01). CONCLUSIONS: The FC formulated as eye gel was retained on the ocular surface longer than the corresponding eye drop solution. Consequently, the use of the eye gel might extend the interval between instillations and decrease the frequency of administration.

Changes in visual evoked potentials during the menstrual cycle in young women.

PURPOSE: Since, during the menstrual cycle, changes in neuronal activity and in auditory, olfactory, and taste thresholds were found, visual evoked potentials were investigated. MATERIALS & METHODS: In 50 healthy women the latency and the amplitude of P100 wave of pattern reversal visual evoked potentials were measured during the different menstrual phases (follicular, periovular, and luteal), as determined by sonography and serum progesterone level. RESULTS: Compared with the follicular phase, during the luteal phase significant reduction in latency (101.29+/-4.42 vs. 104.76+/-5.02 ms, P<0.01) and increase in amplitude (10.44+/-3.15 vs. 8.62+/-3.09 microV, P<0.05) were recorded. CONCLUSIONS: Fluctuations in ovarian steroid hormones affect the excitability of the visual system.

Interplay between social influence and competitive strategical games in multiplex networks.

We present a model that takes into account the coupling between evolutionary game dynamics and social influence. Importantly, social influence and game dynamics take place in different domains, which we model as different layers of a multiplex network. We show that the coupling between these dynamical processes can lead to cooperation in scenarios where the pure game dynamics predicts defection. In addition, we show that the structure of the network layers and the relation between them can further increase cooperation. Remarkably, if the layers are related in a certain way, the system can reach a polarized metastable state. These findings could explain the prevalence of polarization observed in many social dilemmas.

Risk factors and underlying cardiovascular diseases in incident ESRD patients.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of mortality and morbidity in dialysis patients. The aim of this study was to evaluate the prevalence of cardiovascular risk factors and of CVD on admission to hemodialysis. METHODS: Data were collected in 31 Italian clinics belonging to a clinic network using a prospective database (EuCliD), the main purpose of which is the support of quality assurance. Six hundred and thirty-six patients, mean age 63.9+/-15.4 years, admitted between January 1, 2000 and September 30, 2003, were separated into two groups on the basis of presence of CVD and observed for a median follow-up period of 16 months. RESULTS: In the CVD group, patients were significantly older and the percentage of diabetics and smokers was significantly greater than in the CVD-free group. There were no significant differences between the groups in term of uremia-related risk factors. According to logistic regression analysis evaluating the impact of traditional and nontraditional cardiovascular risk factors, only smoking habit (OR 1.87, 95% CI 1.25-2.79) and diabetes (OR 1.87, 95% CI 1.19-2.95) were associated with a higher relative risk for the presence of CVD at baseline. At the time of admission, CVD was present in 27% of patients. The following de novo development of CVD was observed: hypertensive disease (0.28 new cases/100 pt-years), ischemic heart disease (0.71 new cases/100 pt-years), other forms of heart disease (1.57 new cases/100 pt-years), disease of arteries, arterioles, etc. (1.85 new cases/100 pt-years) and cerebrovascular disease (0.71 new cases/100 pt-years). The rate of developing de novo CVD events was 3.70 per 100 patient-years. CONCLUSIONS: The prevalence of cardiovascular risk factors is already high at admission to dialysis. Despite the care provided to dialysis patients, a significant proportion of patients develop de novo CVD.

Low levels of 17-ß-oestradiol, oestrone and testosterone correlate with severe evaporative dysfunctional tear syndrome in postmenopausal women: a case-control study.

AIMS: To evaluate the role of 17-ß-oestradiol, oestrone and total testosterone (TT) deficiency in the pathogenesis of severe evaporative dry eye syndrome (DES), investigating the relationship between tear osmolarity, tear film break-up time (TF-BUT), Schirmer test and serum sex hormones in postmenopausal women. METHODS: 44 postmenopausal women were recruited for a case-control study: 22 women with severe evaporative DES (Group A) and 22 without DES (Group B). The tests performed included laboratory blood analysis: fasting plasma profile (17-ß-oestradiol, oestrone and TT), glucose level and lipid profile. Detailed eye examinations, including corneal and conjunctival staining, tear osmolarity measurement, tear volume and TF-BUT, were performed. The Ocular Surface Disease Index Questionnaire was also administered. RESULTS: Values of Schirmer test and TF-BUT in Group A were significantly lower in comparison with Group B (p<0.001). Serum levels of 17-ß-oestradiol, oestrone and TT were significantly lower in Group A compared with Group B (p<0.05). In women with severe evaporative DES, the levels of 17-ß-oestradiol, oestrone and TT were inversely correlated with the tear film osmolarity (r=-0.7, -0.88, -0.81, respectively). CONCLUSIONS: In postmenopausal women with severe evaporative DES, sex hormone levels are lower than control and that tear osmolarity is negatively correlated with sex hormone levels.

Ocular hypotensive effect of oral palmitoyl-ethanolamide: a clinical trial.

PURPOSE: To investigate the effect of oral palmitoyl-ethanolamide (PEA) on intraocular pressure (IOP) in primary open angle glaucoma (POAG) and ocular hypertension (OH). METHODS: In a prospective, randomized, double-blind, crossover clinical trial, 42 patients with POAG or OH who were treated with timolol 0.5% and whose IOP was between 19 and 24 mm Hg received oral PEA (300-mg tablets twice a day) or placebo (PEA vehicle tablets twice a day) for 2 months (period 1), and, after a 2-month washout, received the other treatment for 1 month (period 2). IOP, best-corrected visual acuity, and visual field parameters were considered. RESULTS: After PEA treatment (mean baseline IOP, 21.6 ± 1.7 mm Hg), IOP was reduced by 3.2 ± 1.3 mm Hg at 1 month and by 3.5 ± 1.2 mm Hg (15.9% ± 5.1%) at 2 months (ANOVA, P < 0.001; both Tukey-Kramer, P < 0.01 vs. baseline); after placebo (mean baseline IOP, 21.5 ± 1.5 mm Hg), IOP was reduced by 0.4 ± 1.2 mm Hg at 1 month and by 0.3 ± 1.3 mm Hg at 2 months (t-test at both time points, P < 0.001 vs. PEA). No statistically significant vital signs, visual field, visual acuity changes, or adverse events were detected in either group. CONCLUSIONS: Systemic administration of PEA reduces IOP in patients with glaucoma and ocular hypertension. PEA could be a valuable tool for the treatment of glaucoma (http://www.umin.ac.jp/ctr/index/htm number, UMIN000002833).