The ocular surface in medically controlled glaucoma : An in vivo confocal study

PURPOSE. To study clinical and in vivo laser scanning confocal microscopy (LSCM) ocular surface findings in stable, medically controlled primary open-angle glaucoma (MCPOAG) patients. METHODS. We recruited 100 consecutive patients with MCPOAG and 50 healthy controls. Patients had to have been treated with the same medical regimen without variation for the 18 months before enrollment and were excluded if there was a history of dry eye prior to glaucoma diagnosis. Each participant underwent ocular surface clinical and LSCM examination. RESULTS. In MCPOAG patients, subbasal nerve length and tortuosity and dendritic cell density were increased compared to controls (P < 0.01), but there were no clinical abnormalities. Patients treated with preserved drugs (n = 80) had reduced tear film breakup time (P < 0.05, ANOVA), and those preserved with benzalkonium chloride (n = 72) had reduced Schirmer test values (P < 0.001). Patients (n = 50) treated with two or more drugs had increased lissamine green conjunctival staining (P < 0.001, LSD post hoc test). Patients (n = 29) treated with three or more eye drops daily had decreased Schirmer test values. Laser scanning confocal microscopy showed subbasal changes related to preservatives, type and number of drugs, and number of eye drops. CONCLUSIONS. In stable MCPOAG patients without dry eye history, the ocular surface changes due to antiglaucoma medications are mostly subclinical. Active ingredients, preservatives, number of concomitant drugs, and number of eye drops instilled per day are all elements that can induce ocular surface changes. The clinical relevance of these changes remains to be determined

The Ocular Surface in Medically Controlled Glaucoma: An In Vivo Confocal Study

METHODS. We recruited 100 consecutive patients with MCPOAG and 50 healthy controls. Patients had to have been treated with the same medical regimen without variation for the 18 months before enrollment and were excluded if there was a history of dry eye prior to glaucoma diagnosis. Each participant underwent ocular surface clinical and LSCM examination. RESULTS. In MCPOAG patients, subbasal nerve length and tortuosity and dendritic cell density were increased compared to controls (P &lt; 0.01), but there were no clinical abnormalities. Patients treated with preserved drugs (n ¼ 80) had reduced tear film breakup time (P &lt; 0.05, ANOVA), and those preserved with benzalkonium chloride (n ¼ 72) had reduced Schirmer test values (P &lt; 0.001). Patients (n ¼ 50) treated with two or more drugs had increased lissamine green conjunctival staining (P &lt; 0.001, LSD post hoc test). Patients (n ¼ 29) treated with three or more eye drops daily had decreased Schirmer test values. Laser scanning confocal microscopy showed subbasal changes related to preservatives, type and number of drugs, and number of eye drops. CONCLUSIONS. In stable MCPOAG patients without dry eye history, the ocular surface changes due to antiglaucoma medications are mostly subclinical. Active ingredients, preservatives, number of concomitant drugs, and number of eye drops instilled per day are all elements that can induce ocular surface changes. The clinical relevance of these changes remains to be determined

C3aR-initiated signaling is a critical mechanism of podocyte injury in membranous nephropathy

: The deposition of anti-podocyte auto-antibodies in the glomerular subepithelial space induces primary membranous nephropathy (MN), the leading cause of nephrotic syndrome worldwide. Taking advantage of the glomerulus-on-a-chip system, we modeled human primary MN induced by anti-PLA2R antibodies. Here we show that exposure of primary human podocytes expressing PLA2R to MN serum results in IgG deposition and complement activation on their surface, leading to loss of the chip permselectivity to albumin. C3a receptor (C3aR) antagonists as well as C3AR gene silencing in podocytes reduced oxidative stress induced by MN serum and prevented albumin leakage. In contrast, inhibition of the formation of the membrane-attack-complex (MAC), previously thought to play a major role in MN pathogenesis, did not affect permselectivity to albumin. In addition, treatment with a C3aR antagonist effectively prevented proteinuria in a mouse model of MN, substantiating the chip findings. In conclusion, using a combination of pathophysiologically relevant in vitro and in vivo models, we established that C3a/C3aR signaling plays a critical role in complement-mediated MN pathogenesis, indicating an alternative therapeutic target for MN

Heat release by controlled continuous-time Markov jump processes

We derive the equations governing the protocols minimizing the heat released by a continuous-time Markov jump process on a one-dimensional countable state space during a transition between assigned initial and final probability distributions in a finite time horizon. In particular, we identify the hypotheses on the transition rates under which the optimal control strategy and the probability distribution of the Markov jump problem obey a system of differential equations of Hamilton-Bellman-Jacobi-type. As the state-space mesh tends to zero, these equations converge to those satisfied by the diffusion process minimizing the heat released in the Langevin formulation of the same problem. We also show that in full analogy with the continuum case, heat minimization is equivalent to entropy production minimization. Thus, our results may be interpreted as a refined version of the second law of thermodynamics.Comment: final version, section 2.1 revised, 26 pages, 3 figure

Thermal design of structures and the changing climate

The report presents the work of the Joint Research Centre’s scientific network on adaptation of structural design to climate change focusing on the thermal design of buildings and infrastructure considering the changing climate. It presents scientific and technical background intended to stimulate debate and serve as a basis for further work to study the implications of climate change on the thermal design of structures. The report first outlines recent EU policies in support of sustainability and climate resilience of infrastructure and buildings. It highlights how the construction sector is encouraged to adopt more sustainable and circular economy practices, extend the lifetime of buildings and strive for better performance of buildings and infrastructure throughout their life cycle. It further emphasises the ongoing action plan to adapt the European standards to a changing climate. Following, the report explains the concept of the definition of thermal actions for the design of buildings and infrastructure using the European standards for structural design, i.e. the Eurocodes. It is showed that the adaptation of structural design to the implications of climate change is strongly linked with the assessment of changing characteristics of climatic actions (including thermal ones) in terms of the Eurocodes concept for the variable climatic actions. Variations in temperature that would directly affect the design values for thermal actions in the European standards are studied in depth for the case study of Italy. It is concluded that an increase in the maximum and minimum temperature used for structural design is expected all over Italy. It is discussed that structures, as bridges for example, are expected to be influenced by stresses from extreme temperatures and thus, should be designed for temperature amplitudes justified from climate projections for the actual region. However, the current European maps for thermal design are based on climatic data which, with some exceptions, are mostly 10 to 15 years old and ignore the potential effects of climate change. Thus, new European maps for the thermal design of structures should be developed using data that project more realistically the future climate. To this end, the authors present a methodology for developing thermal maps for structural design taking into account the influence of the changing climate and present an implementation of the methodology using the example of Italy.JRC.E.4-Safety and Security of Building

Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation