domain: shs sdv info

text:
Flávio Alves-Damasceno
email: flavio.damasceno@deg.ufla.br

Luciano Barreto-Mendes

Tadayuki Yanagi Junior

Jofran Luiz-De Oliveira

Jairo Alexander Osorio-Saraz

Assessment of evaporative cooling efficiency in greenhouses equiped with wetted porous plates •

Keywords: Greenhouse, mathematical modeling, simulation, heat and mass transfer Invernadero, modelo matemático, simulación, transferencia de calor y masa

The main objective of this study was to experimentally validate a mechanistic model for predicting the cooling efficiency (η) of wetted porous plates built with expanded clay. The expanded clay material was physically characterized by specific mass, surface area, and volume. The model was validated with dry bulb temperature (Tdb, °C) and air relative humidity (RH, %) data, which were continuously monitored in two different points, upstream and downstream the direction of the air passing through the porous plate. Data collection was carried out consecutively for a period of 10 days, between 11:00 a.m. and 4:00 p.m. Average values for η, simulated and observed, were 74.8 ± 7.4% and 68.3 ± 8.3%, respectively. Based on the developed model, it was observed that η was higher than 40% for Tdb > 30 °C and constant RH at 45%. The simulation for predictions indicates that the increase in the air temperature greater than 20 °C may affect negatively the production in greenhouses from states located in tropical and subtropical countries as Minas Gerais, Brazil, if some design criteria in the evaporative cooling system are not revised.

Introduction

Climate change is no longer considered a questionable scientific hypothesis, but an inevitable paradigm [START_REF]Climate Change 2013: The physical science basis, contribution of working group I to the fifth assessment[END_REF]. One of its consequences is that some regions of the globe are being Production efficiency in greenhouse systems are inherently dependent on external factors such as climatic agents (dry bulb temperature -T db , relative humidity -RH, solar radiation, etc.), and design factors such as the roofing and walls materials and the presence of insect protection screens [START_REF] Soni | Effect of screen mesh size on vertical temperature distribution in naturally ventilated greenhouses tropical[END_REF][START_REF] Duarte | Changes in temperature of the air through the screens on the sides planted with tomato greenhouses[END_REF]. Climate control mechanisms, such as the ventilation and evaporative cooling systems [START_REF] Voltan | Spatial variability of relative humidity inside a greenhouse in tropical climate[END_REF], are essential for allowing optimum convective transfer of water vapor, gases and heat, keeping the internal environment at healthy levels.

Typical forms of evaporative cooling systems for protected environments consist of misting systems (low and high pressure), or forced passage of air through wetted porous plates by means of a ventilation system. According to [START_REF] Tinôco | Effect of different environment conditioning systems, and metabolizable energy levels in the diet on performance of broiler headquarters in summer and autumn conditions[END_REF], depending on the climatic conditions of the region where the evaporative cooling system is developed, Tdb may be reduced up to 11°C. In tropical regions such as in Brazil, the average temperature drop is about 6°C.

The operating principle of evaporative cooling systems involves processes induced by heat and mass transfer, where water (either in its liquid or vapor state) and air are the working fluids. This process consists in evaporating water induced by the passage of an airflow, thus decreasing the T db [START_REF] Camargo | Mathematical model for direct evaporative cooling air conditioning system[END_REF][START_REF] Justino | Efeito do resfriamento evaporativo e do balanço eletrolítico sobre a lactação de porcas em condições de verão tropical[END_REF][START_REF] Medeiros | Analysis of a prototype of adsorptive evaporative air conditioner for hot and humid weather[END_REF].

In order to evaluate and compare different evaporative cooling systems, various research studies have been conducted in the field [START_REF] Ahmed | Performance evaluation of three different types of location evaporative cooling pads in greenhouses in Sudan[END_REF][START_REF] Kouchakzadeh | The evaluation of the bulk charcoal greenhouse evaporative cooling pad[END_REF][START_REF] Chen | Analysis and optimization of the fan-pad evaporative cooling system for greenhouse based on CFD[END_REF]. However, limitations such as insufficient number of greenhouses with similar systems at the same location, and the high costs for conducting experimental research, have hampered the conduction of field studies covering a significant number of variables and factors.

A possible solution to this problem can be the use of models and computer simulations, followed by field validations. Subsequently, such validated models may be used to indicate the most relevant factors or variables, which, ultimately, are to be tested experimentally. Currently, a number of modeling techniques have been applied to simulate evaporative cooling systems in greenhouses [START_REF] Franco | Aerodynamic analysis and CFD simulation of evaporative cooling pads several cellulose used in Mediterranean greenhouses[END_REF][START_REF] Montazeria | Evaporative cooling by water spray systems: CFD simulation, experimental validation and sensitivity analysis[END_REF]. These modeling approaches are still labor-intensive and require the acquisition of expensive specific commercial packages.

The development or adaptation of a mechanistic model for evaporative cooling systems that is relatively simpler but still able to accurately represent reality needs to be further evaluated. Evaporative coolers have been widely used for crop production in greenhouses due to their relatively good cost/benefit ratio. In these systems, the quantification of the efficiency (η) is of great importance.

The aim of the present work was: a) to describe and validate a mechanistic model developed to predict the evaporative cooling efficiency (η) of a wetted porous plate (PAD) system applied to a greenhouse, and b) present some experimental results in future scenarios of climate change.

Material and methods

Model description

The evaporative cooling efficiency (η) is calculated from the variables dry bulb temperature (Tdb) and wet bulb temperature (T wb ) of the air, measured both upstream and downstream the pads, according to Eq.1 [START_REF]HVAC Systems and Equipment Handdbook[END_REF].

db,i db,o db,i wb,i η = T -T T -T 100     ⋅     (1)
Where: η -evaporative cooling efficiency (%); T db,i and T db,o -dry bulb temperature of the air upstream and downstream the pad cooling system, respectively ( o C); and T wb,i -wet bulb temperature of the air upstream the pad cooling system, ( o C).

Fig. 1 can be observed the schematic representation of an evaporative cooling system of the wetted porous material type, where: a) Variable of air upstream the PAD cooling system: T db,i -dry bulb temperature ( o C), ω a,i -mixing ratio gradient (kg kg -1 ); P atm -Atmospheric pressure (kPa), a m flow of water passing through the cooling plate (kg s -1 ); b) Variable of water: T water,i -water temperature used to wet the cooling plate (° C) and w m  -water flow through the cooling plate (kg s -1 ); c) Variable of PAD cooling: W -cooling plate width (m); H -cooling plate height (m) and L -thickness of the cooling plate (m); d) Variable of air downstream the PAD cooling system: T db,o -dry bulb temperature of the air upstream (° C) and ω a,o -air mixture ratio after going through the cooling plate (kg kg -1 ).

Hence, a mathematical model for predicting η in pad cooling systems was developed, based on the heat and mass transfer equations proposed by [START_REF] Yanagi | Cooling efficiency of evaporative Modeling in wetted porous plates systems[END_REF]. The transfer of sensible heat between the air and the existing water film of the porous material can be expressed by Eq. 2, which, after integration (Eq. 3), resulted in Eq. 4, that predicts the temperature of the air after crossing the cooler (T bs,o ). Where: dq a,s -sensible heat gradient (W); m a -mass flow of air across the cooling plate (kg s -1 ); c p,a -specific heat of air (kJ kg -1 K -1 ); dT bs -dry bulb air temperature gradient (°C); h -convective heat transfer coefficient (W m -2 K -1 ); T water -Figure 1. Schematic representation of an evaporative cooling system. Source: The authors.

temperature of the water used in the cooling plate wetting (ºC); and dA -area gradient (m2).

( )

db,o db,i T L db water db a p,a T 0 1 h dT = α W H dx T -T m c ⋅ ⋅ ⋅ ⋅ ⋅ ∫ ∫ (3)
Where: α -surface area of wetted porous plate, per unit volume (m 2 m -3 ); W -cooling plate width (m); H -cooling plate height (m); L -thickness of the cooling plate (m); and dx -infinitesimal variation of the cooling plate thickness (m).

(

)

a p,a h α W H L m c db,o water db,i water T = T + T -T e   -  ⋅ ⋅ ⋅ ⋅   ⋅   ⋅ (4)
Where: T db,o -air temperature before crossing the plate (ºC).

Similar to the heat balance performed in equations 1 through 4, a mass balance was performed for water vapor (Eq. 5), which, after substitutions and subsequent incorporation into (Eq. 6) resulted in Eq. 7, used for the prediction of air mixing ratio after crossing the plate (ω a,o ).

a d A,s water A m dω = k ω T -ω dA   ⋅ ⋅ ⋅ ⋅    (5)
Where: dω a -mixing ratio gradient (kg kg -1 ); k d -mass transfer coefficient based on the use of the mixing ratio (kg m -2 s -1 ); ω A,s . (T w ) -mixing ratio to saturation conditions, depending on water temperature (kg kg -1 ); and ω A -mixing ratio in saturation conditions, depending on the water temperature (kg kg -1 ).

a,o a,i ω L m a A a,s water a a ω 0 h ρ 1 dω = α W H dx ω T -ω m ⋅ ⋅ ⋅ ⋅ ⋅ ⋅ ∫ ∫  (6)
Where: ω a,i -air mixture ratio that passes through the cooling plate (kg kg -1 ); ω a,o -air mixture ratio after going through the cooling plate (kg kg -1 ); h m -mass transfer coefficient (m s -1 ); and ρ a -air density (kg m -3 ).

( )

m a a h ρ - α W H L m a,o a,s water a,s water a,i ω = ω T -ω T -ω e   ⋅ ⋅ ⋅ ⋅ ⋅     ⋅ ⋅ ⋅ (7)
For the calculation of the mass transfer coefficient (h m ), Eq. 8 was used, and the Colburn factor j h was calculated by Eq. 9, as proposed by [START_REF] Wilhelm | Numerical calculation of psychrometric properties in SI units[END_REF]. Eq. 9 is valid for the Prandtl number of about 0.7 and a Reynolds number between 90 and 4000.

m h h = 0.929 j υ ⋅ ⋅ (8)
Where: j h -J factor of Colburn (dimensionless); and υmass flow of air across the cooling plate (kg s -1 ).

-0.575 D h

Re

j = ε ⋅ (9)
Where: Re D -Reynolds number defined according to the diameter of the spheres (dimensionless); and ε -porosity of the cooling plate filling material (decimal).

Based on temperature and relative humidity inputs before crossing the wet porous plate (T db,i and RH, i respectively), wet bulb temperature was calculated (T wb,i ). With the values of T db,i and T wb,i associated with T db,o , obtained by Eq. 4, the η simulated was obtained with Eq. 10. For the calculation of these and other psychometric properties, the methodology proposed by [START_REF] Moreira | Net efficiency of comparison in the determination of the bulk density of agricultural grains[END_REF] was used.

( )

a p,a h α W H L m c db,i water db,i water simulated db,i wb,i T -T + T -T e η 100 T -T   -  ⋅ ⋅ ⋅ ⋅   ⋅       ⋅     = ⋅     (10)
The equations demonstrated above were implemented into MS Excel®, where all calculations and simulations of this study were performed.

Characterization of the porous material

It was used expanded clay pebbles as the porous material in this experiment. It was physically characterized by determining the bulk density, porosity, average diameter, average volume and surface area. Each sample consisted of 50 expanded clay pebbles collected randomly from the porous plate. The density of the porous material, Eq. 11, was determined using the methodology of volume complementation, similar to that adopted for determining the bulk density of grain [START_REF] Araujo | Estimation and classification of soil compaction due to agricultural machine traffic through the nebula modeling[END_REF].

m ρ = V ( 11
)
Where: ρ -density of the porous material (g cm -3 ); mmass of porous material (g); and V -volume of the porous material (cm 3 ).

The porosity, Eq. 12, was determined indirectly, by filling the pores of the expanded clay sample with a fluid until saturation, and from the measured volume of the liquid and the sample, determining the total porosity [START_REF]Ministério da Agricultura e Reforma Agrária[END_REF].

total V P = 100 V ⋅ (12)
Where: P -total porosity of clays (%); V -porous volume (cm 3 ); and V total -total volume of the container (cm 3 ).

The average diameter, volume and the surface area of the samples were obtained by taking photographs of 50 expanded clay with a digital camera (4.0 Mega-pixels) at different angles. These images were processed via Autocad program ® 2012 (Autodesk). The results were used to calibrate the equations in order to characterize the modeled porous material as expanded clay.

Experimental setup and data collection for model validation

In order to check whether or not the model was able to realistically represent the cooling process of porous plates Portable recorders were installed and pre-programmed to collect Tbs and relative humidity (RH) (Hobo®, mod. U12-012, resolution: temperature of 0.03°C and RH of 0.03%) next to the two sides of the wetted porous plate at two-second intervals. In order to assure accuracy of measurements, the sensors were calibrated using a weather station following the manufacturer's instructions.

The variable T water was monitored at the water reservoir with a digital thermometer (Instrutherm®, mod. TH-060, resolution of ± 0.1ºC and precision of 0.1%), at intervals of 30 minutes.

In order to determine the airflow rate through the wetted porous plate, one of the plates (dimensions 1.6 m Height × 1.5 m Length) was randomly selected and divided into nine equidistant sampling points according to the scheme of Fig. 3. Air velocity measurements were made via a digital propeller anemometer (Kestrel®, mod. 4000, precision of ± 3%), at 12 locations. The airflow values used in the simulations was obtained by the product of measured air velocity and area of the plate.

Prediction of evaporative cooling efficiency for future scenarios

The composition of the future scenarios was developed in accordance to the forecast reported from [START_REF]Climate Change 2013: The physical science basis, contribution of working group I to the fifth assessment[END_REF], adding to the air 16.4 ± 0.5 Mean flow rate per linear meter (L s -1 m -1 ) 0.050 ± 0.03 Source: The authors. temperature 2.0°C and 2.5ºC to the scenario B2 (more optimistic) in 2050 and 2100, respectively. For the composition of the scenario A2 (less optimistic) it was added 3.0°C e 8.0ºC for the years of 2050 and 2100 respectively.

The simulations were performed considering the dimensions of the cooling pad used for validation. The relative humidity, average temperature, maximum temperature and maximum atmospheric pressure were obtained from official climatologic maps for Minas Gerais state, in the period of 1961-1990 [START_REF] Silva | Comparison of evaporative panels of expanded clay and cellulose for adiabatic cooling systems of air in poultry houses with negative pressure in tunnel model[END_REF]. The simulations via mathematical model were performed using the empirical equations adjusted in this experiment in order to estimate the efficiency of the pad cooling.

Results and discussion

Summary of experimental data

Table 1 shows the average values of the main physical properties of the porous materials (volume, surface area, mean diameter, density and porosity), and variables form the cooling pads.

The diameter of the porous material was found to be (1.43 ± 0.23) cm, a result inferior to that described by [START_REF] Rosa | Dimensionamento de painéis porosos para condicionamento do ar em ambientes climatizados[END_REF], who found an average diameter of 2.7 cm for expanded clay. When evaluating different materials in wetted porous plates [START_REF] Peixoto | Performance of different types of applied materials to coverings of facilities for animal production -Simulation[END_REF] found the best cooling efficiency with expanded clay The density of expanded clay characterized in this study showed the average calculated value of 0.36 ± 0.03 g cm -3 , which was lower than that found by [START_REF] Wiersma | Evaporative cooling[END_REF], of 0.45 g cm -3 . In addition, the found value for porosity of (68 ± 0.7) %, did not coincide with the value of 50% found by [START_REF] Wiersma | Evaporative cooling[END_REF].

To the extent that the thickness of the porous material increases, resistance to airflow usually increases and therefore the air contact time with the moist porous material increases. If, for a given thickness, porosity and capillary action of the porous material is increased, the water distribution will be more uniform; however, a larger volume of water is necessary, thereby increasing the resistance to the ventilation of the air [START_REF][END_REF].

The measured water flow rates of (0.05 ± 0.03) L s -1 m -1 was much lower value than that described by [START_REF] Rosa | Dimensionamento de painéis porosos para condicionamento do ar em ambientes climatizados[END_REF], 0.14 L s -1 m -1 adopted for cellulose plates 10 and 15 cm thick. According to [START_REF] Rosa | Dimensionamento de painéis porosos para condicionamento do ar em ambientes climatizados[END_REF], the flow of water passing through the plate should be high enough to clean the dirt and mineral salts, without allowing their accumulation. Relatively lower flow value could cause clogging of pipes and holes due to algae growth as observed in their system. These algae can also grow within the porous material, thereby increasing resistance to airflow and decreasing the cooling efficiency.

The average air speed of (0.9 ± 0.31) ms -1 was similar to that found by [START_REF] Peixoto | Performance of different types of applied materials to coverings of facilities for animal production -Simulation[END_REF], which varied between 0.74 to 1.09 ms -1 for expanded clay plates with 120 mm thick. According to [START_REF] Peixoto | Performance of different types of applied materials to coverings of facilities for animal production -Simulation[END_REF], the evaporative cooling efficiency is greater for any air velocity between 0.44 and 1.28 ms -1 .

The mean airflow rate calculated by the product of average speed and area of the porous plate was 2.04 m 3 s -1 , which was higher than that found by [START_REF] Wiersma | Evaporative cooling[END_REF] which ranged between 0.85 and 1.25 m3 s-1.

Heat transfer coefficient and evaporative cooling efficiency

The heat transfer coefficient by convection (h) is corrected (h') in Eq. 13 as a function of a set factor (F1) which is the difference between the simulated and observed values of h as a function of the air temperature as shown in Eq. ( 14), r² = 0.8005.

This correction was required because the original equation used to calculate the convective heat transfer coefficient was

To determine the independent variable that most influenced the F1 values, we proceeded to the regression analysis based on the maximum coefficient of determination (r2) using the PROC REG of SAS® [START_REF][END_REF].

After applying the correction factor in heat and mass transfer coefficient, cooling efficiency results improved, whose mean values, observed and simulated, were 74.8 ± 7.4% and 68.3 ± 8.3%, respectively. Fig. 5 shows the behavior of the observed efficiency as a function of time, and it is further observed that in general the simulated values underestimated the real efficiency.

In Fig. 5a, it is observed graphically the behavior of the average of air temperature before crossing the plate and cooling efficiency observed and simulated throughout the day. Little variation was observed in the efficiencies values, more variation occurring at the start of data collection, during which the evaporative cooling system is on and off frequently, staying on for approximately 1-3 minutes, not therefore reaching state balance (Fig. 5b). In turn, the next 16 hours, the system was kept engaged for longer periods, 30 to 120 minutes, providing better equilibrium conditions. As it can be seen in Fig. 6, as the D increases it reduces the cooling capacity of the air RH, o and η (Fig. 6c and6d). The calculated evaporative cooling efficiency was 54%. This value is in accordance to [START_REF] Borges | Climate changes influence on inside thermal environment of broiler houses[END_REF], who found η values of from 43% to 55% for plates with 5 cm thick and velocity ranging from 1.0 to 1.3 m s -1 .

Prediction of evaporative cooling efficiency for future scenarios

It can be observed in Fig. 7, the behavior of the average air temperature (Tdb,i) and (Tdb,o), and the evaporative cooling system efficiency (η) according to average temperature of the period 1961-1990 and the scenarios B2 and A2 for the years of 2050 and 2100. Evaluating predictions of climate changes, it could be observed negative impacts in the agriculture production (Fig. 7b) [START_REF] Nääs | Impact of global warming on beef cattle production cost in Brazil[END_REF][START_REF] Silva | Cenários de mudanças climáticas e seus impactos na produção leiteira em estados nordestinos[END_REF][START_REF] Gomes | Predição do índice de temperatura do globo negro e umidade e do impacto das variações climáticas em galpões avícolas climatizados[END_REF]. If no precaution is taken, there might occur the migration of plant production to regions in order to achieve better thermal environment [29]. It can be harmful to the Brazilian economy, once Brazil is one of the countries most susceptible to the impacts of climate changes [START_REF] Fearnside | Tropical forests of amazonia in schneider. Climate Changes Science and Politicy[END_REF].

Conclusions

1. The mathematical model developed is suitable to simulate the PAD cooling systems, allowing the simulation of different system configurations, and may thus be used as a tool in the decision making process during the phase of design and dimensioning of evaporative cooling systems of the wetted porous plate type built with expanded clay; 2. With the variation of the diameter of the expanded clay filler used in the evaporative cooling plate, it was detected reduction of the capacity and efficiency of air cooling; and 3. The increase in the air temperature predicted in future scenarios can affect negatively the plant production in greenhouses from Minas Gerais state, especially during the warmest period in the year.

Figure 2 .

 2 Figure 2. Schematic representation of the greenhouse performed in this study. Unit: meters (m). Source: The authors.

Figure 3 .

 3 Figure 3. Schematic representation of equidistant points used to collect air velocity in wetted porous plate. Unit: meters (m). Source: The authors.

Figure 4 .

 4 Figure 4. Values of relative frequencies for the diameters (Ø, cm) of the samples. Source: The authors.

Figure 5 .

 5 Figure 5. Simulated and observed cooling efficiencies (η, %) over time (a) and (b) plotted against one another as compared to a 45 o slope line. Source: The authors.

Figure 6 .

 6 Sensitivity of cooling efficiency (η, o C) to inlet dry bulb temperature (T db,i , o C, A), inlet water temperature (T w,i , o C, B), inlet air relative humidity (RH i , %, C) and expanded clay average diameter (D, mm). Source: The authors.

3. 3 .

 3 Model sensitivitySimulations were performed for prediction of the behavior of T db,o , RH, o and η in function of air temperature before crossing the pad (T db,i of 25 °C to 45°C), as can been seen in Fig.6. The dimensions of the evaporative cooling plate were considered to be 11.70 m x 2.00 m x 0.075 m, diameter of the material used to fill the evaporative cooling plate (D) of 10 mm, external relative humidity (RH, i ) 45%, atmospheric pressure (Patm) 101.32 kPa, mean air velocity inside the shed (V) 1.2 m s -1 , mass flow of air across the pad (m a ) 41 kg s -1 , water temperature applied to the porous plate (T water ) of 20 °C and the relationship between surface area and volume of the porous material (α) of 170 m 2 m -3 . From Fig. 6 the capacity for reducing temperature and variation of RH, o can be seen as T db,i increases causing the increase in η. Later, adopting T db,i equal to 35 °C, D = 5, 10, 15 and 20 mm, corresponding to values of 157.08 m 2 m -3 , 78.54 m 2 m -3 , 52.36 m 2 m -3 and 23.56 m 2 m -3 respectively, and assuming the values of the other variables described above, the behavior of T db,o , RH, o and η were simulated.

Figure 7 .

 7 Behavior of average air temperature before (T db,i ) and after (T db,o ) crossing the wetted porous plate (a) and evaporative cooling efficiency (η) due to the variation of the air temperature (T db,i ) before crossing the wetted porous plate (b) according to the estimated average air temperature for the period of 1961-1990 and according to the B2 and A2 scenarios (IPCC, 2013), for the years 2050 and 2100. Source: The authors. The simulation results for (T db,i ) and (T db,o ) are shown in Fig. 7a, which indicates the gradual increase of T db,o in time into the greenhouse. The simulations indicate the need of dimensioning the evaporative cooling systems in order to adequate the internal environment of the greenhouse to the plants needs. The simulations results present general tendencies that might be important in the definition of strategies for ventilation projects.

Table 1 .

 1 Physical properties of the cooling pads (mean ± standard error).

	Volume (cm 3 )	1.74 ± 0.88
	Superficial area (cm 2 )	7.14 ± 2.39
	Diameter (cm)	1.43 ± 0.23
	Density (g cm -3 )	0.36 ± 0.03
	Pososity (%)	68 ± 0.7
	Surface area of the wetted porous plate (m 2 )	12,8
	Water temperature at top of plate (

o C) 16.8 ± 0.5 Water temperature at bottom of plate ( o C)

Acknowledgements

The authors thank the CAPES, CNPq and FAPEMIG for their financial support of the project.


MD Antonio M Fea
email: antoniomfea@gmail.com.

MD Alain M Bron

MD Mario A Economou

PhD Gianluca Laffi

MD Enrico Martini

MD Michele Figus

PhD, FEBO Francesco Oddone

Dr Fea

Santen

Sooft

A real-life prospective study on the efficacy of the XEN 45 stent: a European study Running head: Real-life use of the XEN 45 stent

Purpose: This study investigated the efficacy and safety of a cross-linked collagen stent (XEN 45) with or without cataract surgery in the treatment of glaucoma.

Setting: Real-life setting.

Design:

Prospective, open-label, multicenter clinical trial.

Methods: Eligible patients with glaucoma inadequately controlled by treatment, or poor compliance or intolerance to topical therapy were included. Patients were divided into those with implant only (solo group; phakic and pseudophakic patients) and implant combined with cataract surgery (combo group). Differences in average intraocular pressure (IOP) and number of medications between baseline and study end (12 months), and the rate of qualified and complete success were evaluated.

Results: Overall, there were 115 patients in the solo group (43 phakic and 72 pseudophakic) and 56 in the combo group. Compared with baseline, mean IOP (23.9 ± 7.6 to 15.5 ± 3.9) and number of medications (3.0 ± 1.1 to 0.5 ± 1.0) decreased significantly at study end (P < 0.001 for both). A >20% and >30% reduction in IOP from baseline was achieved by 72.3% and 52.6% of patients, respectively. IOP at one week post-op was a predictor of success, and the

A C C E P T E D

Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065 3 needling rate was inversely correlated to early post-op IOP. The number of pre-operative medications and patientage were not significantly associated with failure.

Conclusions: Insertion of the XEN 45 stent alone or combined with phacoemulsification is effective and safe in the treatment of open angle glaucoma, with a substantial reduction in IOP and number of medications. Future randomized, comparative studies on the use of this device are warranted.

A C C E P T E D

INTRODUCTION

Glaucoma is a group of diseases leading to a chronic and progressive optic neuropathy and loss of vision. It affects more than 60 million patients and represents the second cause of blindness worldwide; 1,2 its prevalence is increasing due to aging of the world's population. [START_REF] Lavia | Minimally-invasive glaucoma surgeries (MIGS) for open angle glaucoma: A systematic review and meta-analysis[END_REF][START_REF] Tham | Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis[END_REF] Primary open-angle glaucoma (POAG) is the most common form of the disease. [START_REF] Tham | Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis[END_REF] The aim of all glaucoma treatments is to decrease intraocular pressure (IOP), since IOP is the only modifiable parameter among other well-identified risk factors. The modalities of treatment should be individualized considering the characteristics of the disease (type of glaucoma, stage, rate of progression) and the patient (age, lifestyle, expectations). Increasing attention to quality of life has emerged in recent years and new surgical techniques have been designed to reduce possible morbidity connected with traditional glaucoma surgery.

Target IOP is most often used in clinical practice and is defined as a decrease of at least 20% in early glaucoma and 30% in moderate glaucoma versus baseline IOP.XEN 45 is a new device consisting of a porcine gelatin stent cross-linked with glutaraldehyde and comes preloaded in an injector; it has been designed to create a channel from the anterior chamber (AC) to the subconjunctival space and to allow aqueous humor outflow when inserted through a small corneal incision via a minimally invasive procedure. [START_REF] Gregorio | XEN glaucoma treatment system in the management of refractory glaucomas: a short review on trial data and potential role in clinical practice[END_REF][START_REF] Dupont | Nouvelle approche chirurgicale dans le glaucome à angle ouvert: le XEN Gel Stent, une technique micro-invasive[END_REF][START_REF] Grover | Performance and Safety of a New Ab Interno Gelatin Stent in Refractory Glaucoma at 12 Months[END_REF] Several studies have demonstrated that the device is both effective and safe, either alone [START_REF] Grover | Performance and Safety of a New Ab Interno Gelatin Stent in Refractory Glaucoma at 12 Months[END_REF][START_REF] Heidinger | A Retrospective Study of 199 Xen45 Stent Implantations From 2014 to 2016[END_REF][START_REF] Schlenker | Factors for Failure of Standalone Ab Interno Gelatin Microstent Implantation versus Standalone Trabeculectomy[END_REF][START_REF] Widder | The XEN45 Gel Stent as a minimally invasive procedure in glaucoma surgery: success rates, risk profile, and rates of re-surgery after 261 surgeries[END_REF] or combined with other interventions. [START_REF] Gregorio | Minimally invasive combined glaucoma and cataract surgery: clinical results of the smallest ab interno gel stent[END_REF][START_REF] Galal | XEN Glaucoma Implant with Mitomycin C 1-Year Follow-Up: Result and Complications[END_REF][START_REF] Hohberger | MIGS: therapeutic success of combined Xen Gel Stent implantation with cataract surgery[END_REF][START_REF] Jimenez-Roman | Effect of phacoemulsification on intraocular pressure in patients with primary open angle glaucoma and pseudoexfoliation glaucoma[END_REF][START_REF] Karimi | A multi-centre interventional case series of 259 ab-interno Xen gel implants for glaucoma, with and without combined cataract[END_REF][16][17] XEN 45 has been approved by the FDA on the basis of the favorable results in terms of efficacy and safety in a pivotal study on 65 patients with glaucoma refractory to other therapeutic interventions. [START_REF] Schlenker | Factors for Failure of Standalone Ab Interno Gelatin Microstent Implantation versus Standalone Trabeculectomy[END_REF] The aim of our study was to evaluate the efficacy and safety of XEN 45 in a real-life setting, either alone or combined with standard phacoemulsification, in a group of patients with glaucoma.

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Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065

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PATIENTS AND METHODS

Study design and participants

This was a prospective, open-label, multicenter clinical trial on real-life patients from 7

European centers, with data collected according to a common protocol. In all centers, the study protocol was approved by the local Ethics Committee, and patients gave written informed consent prior to enrollment. The study was conducted in accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice and principles of the Declaration of Helsinki.

Eligible patients had glaucoma inadequately controlled by treatment, or a poor compliance or intolerance to topical therapy. Patients with narrow-angle glaucoma, ocular pemphigoid, phacodonesis, or patients with a conjunctival scar, which in the opinion of the surgeon could compromise the outcome of the procedure, were excluded. Contrary to recommendations in the instruction manual of the XEN 45, and considering the real-life setting of the present study, patients who had previously undergone surgery for glaucoma or who had pseudoexfoliation were not excluded.

Patients with a significant cataract (decrease of visual acuity ≥7/10 or with significant cataract-related visual symptoms) were treated with standard phacoemulsification combined with implantation of the XEN 45 device. Patients were divided into two groups: implant only (solo group) and implant combined with cataract surgery (combo group); within the solo group, phakic and pseudophakic patients were also analyzed separately.

XEN 45 stent and surgical technique

The XEN 45 gel stent (Allergan, Dublin, Ireland) is made of porcine collagen cross-linked with glutaraldehyde. The cross-linked collagen stent is 6 mm long, has a 45 µm inner lumen diameter, and is preloaded into a single-use injector. Standard ophthalmic surgical techniques

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Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065 6 were used to prepare patients and eyes. In the combo group, all subjects underwent standard corneal phacoemulsification with intraocular lens implantation. If the surgeon considered it necessary, acetylcholine was injected into the AC to constrict the pupil before implant of a cross-linked collagen stent. The majority of needlings were performed with 5-fluorouracil (5-FU) at the discretion of the surgeon. Intraoperative 0.1 mL mitomycin C 0.02% (MMC) was injected sub-conjunctivally using a 30 G hypodermic needle under Tenon capsule and spread with a microsponge applied to the conjunctiva in the superior nasal quadrant where the implant was to be inserted before the implant was injected or, in case of cataract extraction, before phacoemulsification (performed in 13 patients at the surgeon's discretion). Using an ab interno approach, the preloaded injector needle was inserted through a 1.8 mm corneal incision in case of the solo procedure (or a 2.2 mm corneal incision in case of combo with cataract) opposite to the site of desired implantation after the AC was filled with the highly cohesive viscoelastic device. The needle was then directed across the AC towards the superonasal quadrant. Intraoperatively, a goniolens could be used at the surgeon's discretion to verify placement through the angle to avoid trauma to the iris, iris root, or the trabecular meshwork. The implant tracked 3.0 mm posterior to the limbus exiting through the sclera into the subconjunctival space. Approximately 1 to 2 mm of the implant was left in the AC to provide a connection from the AC to the subconjunctival space. Viscoelastic material was removed from the AC by irrigation/aspiration in the combo group or by washing with saline in the solo group.

Post-operative management

Topical IOP-lowering medications, as well as systemic IOP-lowering medications, were suspended on the day of surgery. Antibiotic-corticosteroid therapy or corticosteroid monotherapy was administered and progressively withdrawn over one month. In the

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Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065 7 following months, a drop of corticosteroid was administered at the dosage and schedule according to the physicians' preferences.

After surgery, needling was performed if necessary either at slit-lamp or in the operating room according to the surgeon's preference (IOP increase over target, flat bleb or fibrotic bleb, or high risk of bleb failure in the investigator's opinion). In case of repeated failure after needling, IOP-lowering medications were restarted. The number of post-operative needling procedures allowed were left to the investigator's discretion. If the IOP remained higher than the patient's target pressure in two consecutive measurements after needling and/or if, according to the surgeon's opinion, bleb revision was not possible, IOP-lowering medications were restarted with the regimen decided by the physician. IOP-lowering medications were also started while waiting for the needling procedure, if necessary.

Assessments

Patients were evaluated with a baseline pre-operative visit (within 1 month prior to surgery) and follow-up assessments were planned at 1 day, 1 week, and 1, 3, 6, 9, and 12 months after surgery. During the baseline visit, patients' personal and anamnestic data were collected as follows: IOP measurement assessed by two operators, best-corrected visual acuity evaluation, an examination of the anterior segment and the fundus, and a computerized visual field testing. The two-operator IOP measurement was repeated at each post-operative visit at 9 am (± 1 hour); if in the opinion of the surgeon the bleb was cystic or flat, or in the case of IOP increase over target in two consecutive measurements at least one day apart, needling with 5-FU or MMC was performed according to the center protocol.

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Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065 8

Endpoints

The primary endpoints were the reduction in mean IOP and number of medications between baseline and study end. The rates of qualified success (defined as IOP ≤18, 16, and 14 mmHg, and a >20% and >30% IOP reduction from baseline, irrespective of pharmacological treatment) at 12 months and complete success (same IOP reductions as above and without pharmacological treatment) were also evaluated and compared between groups. Failures were considered IOP <4 mmHg for more than two post-operative visits, need for further glaucoma surgery or surgery for complications. We also calculated whether IOP on day 1 (<6, 8 or 10 mmHg) was related to complete success. Moreover, we evaluated whether an increase in IOP of >4 mmHg or >6 mmHg between the first three post-operative visits (at 1 day, 1 week, and 1 month) was related to the success rate or to the number of needling procedures. The preoperative number of eye drops and patient age were evaluated as possible risk factors for failure or to the number of needling procedures.

Statistical analysis

All analyses were performed on the intent-to-treat (ITT) population. Patients with more than 30% missing data were dropped and case-wise deletion was used in the remaining data set.

Variables with a normal distribution were expressed as mean ± standard deviation and compared using a paired or unpaired t-test. Categorical variables were expressed as numbers (percentages) and compared with Fisher's exact test or Mann-Whitney test as appropriate.

Correlations were evaluated using the Pearson coefficient for Gaussian and Spearman for non-Gaussian distributed variables. A P value of <0.05 was considered significant and all tests were two-tailed. Analyse-it 4.8 and Prism 8 software were used for the analysis.

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Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065

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RESULTS

Demographic and baseline characteristics

In total, 298 patients were enrolled; 171 patients had ≥9 months of follow-up and were included in the analysis. As no significant differences were detected at baseline between the enrolled population and the patient population with ≥9 months follow-up (Table 1), the analyzed sample can be considered representative of the entire population. Of the 171 patients, 115 were treated with the XEN-45 gel stent only (solo group; 43 phakic and 72 pseudophakic) and 56 with the XEN-45 gel stent plus phacoemulsification (combo group); two patients with mixed mechanism glaucoma were included, one in each treatment group (Table 2).

Twelve patients (8 in the solo group and 4 in the combo group) underwent other surgical procedures; data from these patients were considered until the last visit before surgery.

Rupture of the stent occurred during the needling procedure in one patient; this data was, however, included in the analysis.

Of the 171 patients with baseline assessment, data were available for 131, 166, 166, 148, 145, 141, and 137 patients at 1 day, 1 week, and 1, 3, 6, 9, and 12 months after surgery, respectively. At the 12-month visit, data were available for 87.1% of patients (149/171), including patients who needed other glaucoma surgery.

Despite not being a randomized study, baseline characteristics of the combo and solo groups were mostly similar, with the exception of IOP and number of medications, which were significantly higher in the solo group than in the combo group; the solo group also had significantly higher visual acuity, which was as expected (Table 2).

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Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065 10

Efficacy

Compared with baseline, mean IOP and number of medications decreased significantly at 12month follow-up (from 23.9 ± 7 to 15.5 ± 3.9 and from 3.0 ± 1.1 to 0.5 ± 1.0, respectively; both P < 0.001) (Figure 1). Figure 2 shows the same set of IOP data presented in a scatterplot format to show the changes in pressure. Although 28 patients were receiving acetazolamide combined with topical therapy at baseline (Table 2), no patients received acetazolamide during the post-operative period.

One week and 1 month post-operative IOP were correlated with final IOP (P = 0.04 and P = 0.01 respectively), whereas there was no correlation between 1 day post-operative IOP and final IOP (Table 3). Patients with a 1 week post-operative IOP <6, 8 or 10 mmHg had a significantly higher probability of success defined as an IOP ≤14, 16 or 18 mmHg at the final follow-up visit, as did patients with a 1 month post-operative IOP <10 mmHg (Table 3). In addition, patients with a change in IOP between 1 week and 1 month of <4 or 6 mmHg had a significantly higher chance of achieving an IOP ≤16 or 18 mmHg at the final follow-up visit (Table 3).

Neither patient age nor the number of medications at baseline were related with treatment outcome.

The number of needling procedures was significantly correlated with 1 day (r=0.24, P = 0.006), 1 week (r=0.27, P < 0.001), and 1 month (r=0.32, P < 0.0001) post-operative IOP, but not with the pre-operative number of medications or pre-operative IOP, nor to patient age.

Patients subjected to needling had a similar pre-operative IOP (no needling, 23.3±7.5; needling, 24.4±7.7; P=0.96), although post-operative IOP was significantly less in the group that did not undergo needling (no needling, 14.8±3.1; needling, 16.5±4.5; P = 0.01) with no differences in the number of medications pre-and post-operative (no needling: pre-, 2.9±1.2; post-, 0.3±0.9; needling: pre-, 3±0.9 and 0.8±1.2). All three patients with uveitic glaucoma

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Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065 11 were subjected to needling (one patient once and two patients twice each).Patients who did not undergo needling had a significantly higher rate of complete success at the end of followup period compared with patients treated with needling, with an IOP ≤14 mmHg in 68.8% vs. 46.7%, (P = 0.02), ≤16 mmHg in 66.7% vs. 41.9%, (P = 0.002), and ≤18 mmHg in 66.7% vs. 39.3% of patients (P = 0.001).

Compared with baseline, IOP decreased in both the combo and solo groups at the final visit (from 21.42 mmHg to 15.81 mmHg, and from 25.03 mmHg to 15.36 mmHg, respectively) (Figure 3). At 1 week, IOP was significantly lower in the solo group compared with the combo group (P = 0.04), but no significant differences were detected at the following visits.

Throughout the follow-up period, the mean number of medications was not significantly different between the two groups.

No significant differences in IOP or the number of medications were detected between phakic and pseudophakic patients in the solo group at the end of the follow-up period (Figure 4).

The mean difference between baseline and the end of the follow-up period in IOP and the number of medications was significantly higher in the solo group compared with the combo group (P = 0.0032 and P < 0.0001, respectively) (Table 4). Compared with baseline, IOP and the number of medications were reduced at the final visit by 38.6% and 83.7% in the solo group and by 26.2% and 80.1% in the combo group, respectively. Phakic patients achieved the highest percentage reduction for both parameters.

Table 5 shows the final results at the 12-month follow-up visit. Overall, a >20% and >30% IOP reduction from baseline was achieved by 72.3% and 52.6% of patients, respectively, and 71.5% of patients were without medications (70.8% and 71.9% in the combo and solo groups, respectively). There were no significant differences between phakic and pseudophakic patients in terms of the percentage of patients with a >20% and >30% IOP

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Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065 12 reduction from baseline. Similarly, no significant differences were found for either qualified or complete success, with IOP ≤18 and ≤16 mmHg with or without medications, respectively, although more patients in the solo group achieved complete success with IOP ≤14 mmHg and no medications compared with the combo group (41.6% vs. 22.9%, respectively; P = 0.03) (Table 5). For qualified success in the solo group, a higher percentage of phakic patients obtained IOP ≤16 and ≤14 mmHg compared with the pseudophakic group (72.4% and 62.1% vs. 70.0% and 40.0%, respectively), but these differences were not statistically significant (Table 5).

In the subpopulation of patients who had undergone previous surgery for glaucoma or other ocular procedures no differences were observed in the number of needlings, although it is worthwhile mentioning that conjunctival perforation occurred in one case and hypoathalamia was seen in another case that resolved with medical therapy. In addition, one patient who had undergone previous iridectomy was subjected to successive trabeculectomy and one with prior trabeculectomy needed an Ahmed valve. The number of re-interventions in the group with prior ocular interventions was numerically higher compared to those without, although statistical analysis was not possible due to the small number of patients. In consideration of the different diagnoses, the only subgroup with a sufficient number of patients was those with pseudoexfoliation. There were no significant differences between these patients and the remaining group in terms of number of drugs administered (0.2±0.5 vs 0.6±1.0) or needlings (1.0±1.3 vs 0.8±1.2) at last follow-up. In addition, IOP at last follow-up was also similar (14.9±3.4 vs 15.6±3.9), even if those with psuedoexfoliation has a slighter higher preoperative IPO (25.0±6.5 vs 23.6±7.7). Of the three patients with uveitis, one had been previously subjected to trabulectomy and needed a Baerveldt valve. The other two patients had an IOP at follow-up that was slightly higher than the entire group (21.1 vs 19.3,

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Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065 13 respectively) and a mean of 2 vs 3 drugs administered. Bleeding in the anterior chamber was also observed in one of these patients.

Safety

Post-operative complications are reported in Table6. Additional surgery was performed in 12 (7%) patients (8 in the solo group and 4 in the combo group) including: trabeculectomy (n=8), Ahmed valve implant (n=1), Baerveldt valve implant (n=1), vitrectomy for malignant glaucoma (n=1), and bleb revision for exposure to the cross-linked collagen stent (n=1). Four of the additional procedures were done on patients who had undergone previous glaucoma surgery.

Overall, 147 needlings were performed in 79 patients (46.2%), corresponding to 1 (n=41), 2 (n=21), 3 (n=10), 4 (n=3), 5 (n=2), and 6 procedures (n=2). The needling rate was significantly higher in patients in the combo group compared with the solo group (48.21% vs. 45.22%, P < 0.01), and in pseudophakic vs. phakic patients (45.83% vs. 44.19%, P = 0.002) (Table 7).

Cases of hyphema, hypoathalamia, choroidal detachment, and fibrin reaction were all treated with medical therapy and had a post-operative course that was broadly similar to entire population. The case of perforation was treated with suture of the conjunctiva and topical antibiotic therapy, and resolved after 4 weeks. The case of stent rupture did not require intervention. The cases of stent repositioning and stent in the anterior chamber underwent removal and reimplantation of the stent. All these cases had outcomes that were similar to the entire group. The case of malignant glaucoma manifested on the fourth day; following 48 hours of medical therapy with atropine and acetazolamide the patient was subjected to vitrectomy 23 G (VPP) associated with irido-zonular-hyaloidectomy of the anterior chamber.

The outcome was satisfying with good control of ocular pressure (19.0 mmHg at 6 months;

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Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065 14 timolol 0.1% every morning), but visual acuity was reduced to 1/10. The reduced visual was partially attributable to pre-existing age-related dry maculopathy. There were no cases of endophthalmitis.

DISCUSSION

This prospective, open-label, multicenter clinical trial aimed to demonstrate the effectiveness and safety of the XEN 45 stent in patients with uncontrolled glaucoma or with poor compliance or intolerance to medical therapy in a real-life setting. In our study, the 35.2% reduction seen in IOP is consistent with previous prospective studies, which showed reductions of 35.6%, 7 31%, 16 and 30.4% 18 . Although our inclusion criteria differed, the final (one year) IOP of 15.5 mmHg is in line with that reported by other studies: 15.9 mmHg, [START_REF] Grover | Performance and Safety of a New Ab Interno Gelatin Stent in Refractory Glaucoma at 12 Months[END_REF] 13.9 mmHg, 16 and 14.9 mmHg 18 , suggesting that the results obtained with the use of XEN 45 stent are consistent, at least in a Caucasian population. It is of note that both mean IOP and the percentage of patients with IOP ≤18 and 16 mmHg (83.7% and 60.7% of patients with IOP ≤18 mmHg and ≤15 mmHg, respectively, in the Apex study 18 compared with 81% and 70% of patients with IOP ≤18 mmHg and ≤16 mmHg, respectively, in our study) are very similar to those reported in the multicenter Apex group study. This is despite the fact that, in the Apex study, only POAG patients with moderate severity and without previous glaucoma surgery were included.

Previous studies have speculated that a low IOP in the early post-trabeculectomy period may be predictive of a more favorable outcome. Some have suggested that lower IOPs on first post-operative day are predictive of longer-term success, 19 while others found that IOPs at the first month 20 were a predictive factor for success; 21 Karimi et al. found that low IOP on day 1 after XEN gel implantation may be a positive predictive factor for final outcomes (Table 8). 22 In our study, 1 week and 1 month post-operative IOP were correlated with the final IOP, whereas day 1 post-operative IOP was not. By grouping patients according to IOP at day 1, 1 week and 1 month, those with a lower IOP at 1 week had a higher chance of success.

Patients with an IOP difference of <4 or <6 mmHg between the 1 week and 1 month postoperative visits had a higher probability of having a final IOP ≤16 or 18 mmHg. Early IOP post-surgical procedures for glaucoma may be influenced by a variety of different factors and this might explain why we did not observe any relationship with the success rate and day 1 post-operative IOP. Week 1 post-operative IOP seems to hold a greater predictive value towards the final IOP. Similar results were obtained when comparing the IOP difference between week 1 and month 1.

Previous authors used anterior segment-optical coherence tomography to find predictors of surgical success. 23,24 Although the bleb resulting after implantation of a cross-linked collagen stent is smaller and easier to study compared to the one after trabeculectomy, bleb analysis is time consuming and there are no widely accepted definitions of bleb morphology. The possibility of summarizing a variety of factors in a single variable (early post-operative IOP) that can be a reasonable predictor of the longer IOP target is promising, although it should be confirmed by further studies. Midha and colleagues demonstrated that eyes with lower IOP on day 1 were less likely to require needling. 25 Similarly, we found a significant correlation with IOP at day 1, week 1 and month 1, but not with pre-operative IOP patient age, number of pre-operative medications, or number of needling procedures. Taken together, these observations strongly support the hypothesis that early post-operative IOP can predict the final surgical outcome and suggest that closer follow-up is warranted in patients with a relatively higher post-operative IOP.

The percentage IOP reduction in this sample is not a meaningful way of measuring success due to the fact that starting IOP pressures were significantly different between the solo and combo groups, and a floor effect may not be excluded. As far as final pressures are

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Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065 16 concerned, which are an important marker of success, there was no significant difference between the solo and combo groups.

The solo group demonstrated a significantly higher percentage of patients with IOP ≤14mmHg at the 12-month follow-up visit, a significantly higher mean decrease of medications, and significantly fewer patients who underwent needling. Taken together, these data suggest that the combination of phacoemulsification with the XEN 45 gel stent may be slightly less effective compared with implantation of the same stent alone. If we do not concentrate only on mean pressure, but analyze our data in more detail, it is apparent that there are differences between the two groups and that these differences are clinically meaningful. This can also explain some of the different results described in the literature. Our results are in line with the those reported by Mansouri and colleagues. 16 Widder et al. [START_REF] Widder | The XEN45 Gel Stent as a minimally invasive procedure in glaucoma surgery: success rates, risk profile, and rates of re-surgery after 261 surgeries[END_REF] similarly reported a better success rate in solo surgery, while other authors could not show any difference between solo and combo surgery. [START_REF] Hohberger | MIGS: therapeutic success of combined Xen Gel Stent implantation with cataract surgery[END_REF][START_REF] Karimi | A multi-centre interventional case series of 259 ab-interno Xen gel implants for glaucoma, with and without combined cataract[END_REF]18 It should be noted, nevertheless, that both Karimi et al. [START_REF] Karimi | A multi-centre interventional case series of 259 ab-interno Xen gel implants for glaucoma, with and without combined cataract[END_REF] and the Apex study 18 only compared mean IOPs between the two groups, which was also not significantly different in our sample.

The needling rate in our sample was higher (46.1%) compared with previous studies (range 2.4%-43% 26 ) and probably reflects a proactive approach to needling. It should also be noted that no strict guidance was prospectively defined and that different centers used different approaches. In the literature, nevertheless, there is no clear and objective criteria for needling other than increased IOP or appearance of bleb, which is a somewhat subjective criterion. Furthermore, in our group, some surgeons prefer to establish a limit for the number of needling procedures (i.e., no more than 2 or 3), because they fear the cumulative effect of antimetabolite injections or feel that if two needling procedures are ineffective the probability of success with a third needling would be very low; others, however, may proceed with needling whenever they deemed it necessary and eventually decided to use steroids instead of

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Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065 17 antimetabolites to limit potential adverse events. Further research is definitely warranted in this area to better define the number, type, and indications for needling. Additional surgery was required by 7% of our patients and one-third of those requiring additional surgery had glaucoma surgery prior to implantation of the XEN 45 stent. Little is known about the results of implantation of a cross-linked collagen stent on patients with previous surgery, although Karimi et al. 15 suggested that the XEN implant was equally effective in patients with or without previous glaucoma surgery (18 patients of 226). Most complications reported in our study were self-limited with medical therapy (hyphema, choroidal detachment, fibrinoid reaction in the AC), but a case of malignant glaucoma, which required vitrectomy, also occurred as well erosion through the conjunctiva. Although rare, these complications may lead to a severe impairment of visual function. 27 The strengths of this study are represented by its prospective, multicenter (with a common protocol), and comparative design, its real-life setting, the relatively large number of cases, and the subanalysis between phakic and pseudophakic patients. This study is limited by its non-randomized design, and by the differences, albeit slight, at baseline between the combo and solo groups in terms of IOP and number of medications. Finally, baseline unmedicated IOP was not recorded, due to the lack of a wash out period.

In conclusion, our study showed that insertion of the XEN 45 stent alone or combined with phacoemulsification is effective and safe in the treatment of open angle glaucoma, with a substantial reduction of IOP and number of medications, a good success rate, and a low number of adverse effects. Future randomized, comparative studies with a long-term followup on the use of this device are warranted.

A C C E P T E D

Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065

18

WHAT WAS KNOWN

• In patients with glaucoma, the association with cataract is common and combined surgical therapy is often needed.

• The XEN 45 stent was effective and safe in the surgical treatment of glaucoma.

WHAT THIS PAPER ADDS

• The use of the XEN 45 stent, either alone or in combination with phacoemulsification, is effective and safe in the treatment of open angle glaucoma in a "real-life setting".

• The combination of the XEN 45 stent plus phacoemulsification may be slightly less effective than implantation of the same stent alone.

• Early post-operative IOP may predict the final surgical outcome suggesting closer follow-up in patients with a relatively higher post-operative IOP is warranted. Fibrin reaction in the anterior chamber

SYNOPSIS

  Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065 15

FIGURE LEGENDS Figure 1 .

 LEGENDS1 FIGURE LEGENDS

Figure 2 .

 2 Figure 2. Scatterplot of intraocular pressure (IOP) reduction as a function of post-operative

Figure 3 .

 3 Figure 3. Mean intraocular pressure (IOP) and number of medications during the study, solo

Figure 4 .

 4 Figure 4. Mean intraocular pressure (IOP) and number of medications in the standalone

  Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065 13

  Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065 Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065 Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065 Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065 Published by Wolters Kluwer on behalf of ASCRS and ESCRS. Unauthorized reproduction of this article is prohibited.

Table 1 .

 1 TABLESBaseline characteristics of the patient population with ≥9 months of follow-up compared with the overall enrolled population. Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065 Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065 Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065 4

	All	Follow up ≥9 months	p-value
	(n=298)	(n=171)

Table 2 .

 2 Baseline characteristics of solo group (cross-linked collagen stent only) and combo group (cross-linked collagen stent implant combined with cataract surgery) treatment groups. Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065 Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065 Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065 7

		Combo group	Solo group	p-value	Phakic	Pseudophakic	p-value
	Age (years), mean ± sd Female, %	(n=56) 71.4 ± 7.9 31	(n=115) 70 ± 13.3 58 E P T E D (Solo vs. Combo) (n=43) (n=72) 0.47 62.2 ± 15 74.7 ± 9.4 0.66 15 43	(Phakic vs. Pseudophakic) <0.001 0.02
	Glaucoma type, n POAG PXG	45 8 A C C 89 19	0.66 0.71	31 8	58 11	0.41 0.84
	Juvenile		2	0.33	2		0.27

Table 3 .

 3 Association between final intraocular pressure (IOP) and early post-operative IOP, and between final IOP and ∆ in early post-operative IOP.

	Final IOP
	≤14 mmHg ≤16 mmHg ≤18 mmHg

Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065 Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065 9

Table 4 .

 4 Mean difference between baseline and the end of the follow-up period in intraocular pressure (IOP) and number of medications according to the treatment groups.

	IOP mmHg,	Number of medications,
	mean ± sd	mean ± sd
	Overall Combo Solo Phakic Pseudophakic Abbreviations: sd, standard deviation -7.4 ± 7.9 -4.54 ± 8.35 -8.8 ± 7.5* -10.88 ± 9.79 -7.78 ± 5.88 *P = 0.0032 vs combo group **P < 0.0001 vs combo group C E P T E D -2.32 ± 1.31 -1.94 ± 1.16 -2.6 ± 1.35** -2.7 ± 1.42 -2.6 ± 1.33
	A C

Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065 10

Table 5 .

 5 Final results at the 12-month follow-up visit.

			Overall	Combo group	Solo group	P value	Phakic	Pseudophakic	P value
			(n=137)	(n=48)	(n=89)	(Solo vs.	(n=29)	(n=60)	(Phakic vs.
	No medications IOP reduction from baseline >20% >30%	98 (71.5) 95 (69.3) 69 (50.4)	Combo) 0.53 0.06 0.19 E P T E D 34 (70.8) 64 (71.9) 22 (75.3) 28 (58.3) 67 (75.3) 23 (79.3) 20 (41.7) 49 (55.1) 19 (65.5)	42 (70) 44 (73.3) 30 (50)	Pseudophakic) 0.44 0.73 0.25
	IOP medications (mmHg),	with	A C C
	≤18		111 (81.0)	39 (81.3)	72 (80.9)	0.96	22 (75.9)	50 (83.3)	0.41

Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065

Abbreviations: IOP, intraocular pressure; ns, not significant. Data is shown as number of patients (%).

Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065 12

Table 6 .

 6 Post-operative complications.

	All	Solo group	Combo group

Table 7 .

 7 Needling procedures performed during the post-operative period. Κ 2 =6.32, P < 0.01 vs. solo group **Κ 2 =9.45, P < 0.002 vs. pseudophakic group Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065 14

		Patients who	Overall	Needling
		underwent	needling, n	procedures,
		needling, n (%)		mean ± sd
	Combo (n=56)	27 (48.21)*	54	0.98 ± 1.4
	Solo (n=115)	52 (45.22)	93	0.98 ± 1.15
	Phakic (n=43)	19 (44.19)**	28	0.65 ± 0.9
	Pseudophakic (n=72)	33 (45.83)	65	0.90 ± 1.3

Abbreviations: n, number, sd, standard deviation. *

Table 8 .

 8 Comparison of outcomes between studies.Comment citer ce document : Fea, A. M., Bron, A. M., Economou, M. A., Laffi, G., Martini, E., Figus, M., Oddone, F. (2020). A real-life prospective study on the efficacy of the XEN 45 stent: a European study. Journal of Cataract and Refractive Surgery, Epub ahead of print, 1-42. , DOI : 10.1097/j.jcrs.0000000000000065

	Author	Design	Mean pre-op	Mean post-op	% IOP	Mean pre-op	Mean post-op	% medication
			IOP (mmHg)*	IOP (mmHg)*		medication*	medication*	reduction
	Present study Galal et al. 2017 12 Grover et al. 2017 7 Fea et al. 2017 23 De Gregorio et al. 2018 11	Pro mc Pro sc Pro mc Pro sc Pro sc	23.9 (7.6) 16 (4) 25.1 (3.7) 21.8 (2.8) 22.5 (3.7) A C 15.5 (3.9) 12 (3) 15.9 (5.2) 14.9 (2.1) 13.1 (2.4) C E P T E D 35.2 3 (1.1) 23 1.9 (1) 35.6 3.5 (1.0) 31.6 2.92 (1.16) 0.5 (0.53) 0.5 (1) 0.3 (0.4) 1.7 (1.5) 41.8 2.5 (0.9) 0.4 (0.8)	83.3 95 38.5 84 83
	Mansouri et al. Pro sc	20 (7.1)	13.9 (4.3)	31	1.9 (1.3)	0.5 (0.8)	73.7

Abbreviations: IOP, intraocular pressure; mc, multicenter; Pro, Prospective; Retro, Retrospective; sc, single center; sd, standard deviation. *Data is presented as mean (sd).

Copyright © 20 Published by Wolters Kluwer on behalf of ASCRS and ESCRS. Unauthorized reproduction of this article is prohibited.

ACKNOWLEDGEMENTS

Writing and editorial assistance was provided to the authors by Maria Carla Brunenghi and Melanie Gatt (PhD), an independent medical writer, on behalf of Health Publishing & Services Srl and funded by Allergan plc, Dublin, Ireland, at the request of the investigator.

All authors met the ICMJE authorship criteria. Neither honoraria nor payments were made for authorship.

The contribution of IRCCS Fondazione Bietti to this paper was supported by the Italian Ministry of Health and by Fondazione Roma.