The concentration of CS, Alg and CaCl2 were taken as independent variables, while drug loading, particle size and zeta potential were taken as dependent variables. The study showed that the loading efficiency and particle size depend on the CS, Alg and CaCl2 concentrations, whereas zeta potential depends only on the Alg and CaCl2 concentrations. The MET-CS-AlgNPs nanocomposites were characterized by X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), thermal gravimetric analysis (TGA), scanning electron microscopy (SEM) and in vitro drug release studies. XRD datashowed that the crystalline properties of MET changed to an amorphous-like pattern when the nanocomposites were formed.The XRD pattern of MET-CS-AlgNPs showed reflections at 2θ = 14.2° and 22.1°, indicating that the formation of the nanocompositesprepared at the optimum conditions havea mean diameter of (165±20) nm, with a MET loading of (46.0 ± 2.1)% and a zeta potential of (−9.2 ± 0.5) mV.The FTIR data of MET-CS-AlgNPs showed some bands of MET, such as 3283, 1585 and 1413 cm−1, confirming the presence of the drug in the MET-CS-AlgNPs nanocomposites. The TGA for the optimized sample of MET-CS-AlgNPs showed a 70.2% weight loss compared to 55.3% for CS-AlgNPs, and the difference is due to the incorporation of MET in the CS-AlgNPs for the formation of MET-CS-AlgNPs nanocomposites. The release of MET from the nanocomposite showed sustained-release properties, indicating the presence of an interaction between MET and the polymer. The nanocomposite shows a smooth surface and spherical shape. The release profile of MET from its MET-CS-AlgNPs nanocomposites was found to be governed by the second kinetic model (R2 between 0.956–0.990) with more than 90% release during the first 50 h, which suggests that the release of the MET drug can be extended or prolonged via the nanocomposite formulation.The goal of this study was to develop and statistically optimize the metronidazole (MET), chitosan (CS) and alginate (Alg) nanoparticles (NP) nanocomposites (MET-CS-AlgNPs) using a (2 Design of experiment (DE) is a systematic method in research used to determine the relationship between independent variables and response variables ,2. ThereIn pharmacy, the term optimization can be defined as the process of discovering the best way of using the existing resources while taking into account all the parameters that influence the decisions of any experiment . Modern x) and the dependent variable (y) as an nth degree polynomial in x. Different ways can be used in the fitting of the regression analysis for establishing approximate mathematical models. One of these fitting methods is called the stepwise method [Polynomial is one form of regression analysis. It is a non-linear analysis that correlates between the independent variable , is an antibiotic drug usually used to treat bacterial infections of the vagina, stomach or intestines, liver, skin, joints, brain, heart and respiratory tract. However, it is ineffective for viral infections (such as the common cold and flu). There have been many attempts by researchers to load MET using nano-formulations such as nanostructure lipid carriers (NLCs) , nano-em2) on three dependent variables  for the synthesis of CS-Alg nanoparticles.In the present study, the incorporation of MET into polymer nanoparticles was achieved. To the best of our knowledge, this work is reported for the first time, where MET as a guest drug was encapsulated into CS for the formation of CS-Algnanoparticleswith optimized preparation parameters.Traditionally, optimization is done by evaluating each factor independently. However, in a single-factor experiment, the interactions between important parameters are ignored. Response surface methodology (RSM) can be used to analyze the interactions between the different variables. The experimental data is input as a quadratic equation and the response is predicted. Stepwise regression analysis is one of the methodsthat can derive the best equation that can describe the data via surface or contour plots. Thus, in this work, Minitab softwareversion 18.1 and full factorial design were used to examine the effect of three independent variables , Sigma-Aldrich, Taufkirchen, Germany), low molecular weight chitosan , and low viscosity sodium alginate . All HPLCsolutions were used from VWR . All other chemicals, including acetic acid and calcium chloride, were purchased from Chem CO .The chemicals used in this study are metronidazole  was presented. Secondly, the FFD was built to perform the experiments. This was followed by the use of multiple regressions to develop the loading efficiency, particle size and zeta potential model responses. Finally, the analysis of concentration variance was used to analyze the experimental data to predict the effects and contribution of parameters on responses.The loading efficiency percentis the first response, which was taken as a parameter and was defined as the amount of total entrapped drug divided by the total weight of the nanoparticles. The second and third responses measured were particle size and zeta potential. 1 × 31 × 21) × 3 = 36 combinations were used, corresponding to n = 3 parameters or factors   is a method used by researchersto design experiments that consist of several factors with separate possible levels. With FFD, the experiment takes all possible combinations of the levels across all such factors. FFD allows researchers to study the effect of each factor, as well as their interactions, on the response variable . In thisd CaCl2) .v/v). The flow rate was 1.0 mL/min. The LE was calculated as follows: p is the total mass of MET used to prepare the nanocomposites, and Tf is the free mass of MET in the supernatant.High-speed centrifugation was used to determine the loading efficiency (LE) of MET in the prepared nanocomposites, in which 2.0 mL of suspension were centrifuged  at 10,000 rpm for 10 min, and the drug loading was measured by high-performance liquid chromatography , using a Venusil C18 column  at 25°C. The UV detection wavelength was 323 nm, and the mobile phase was prepared by mixing acetonitrile/0.1% with phosphoric acid  method using a Zetasizer Nano S  at the Arab Pharmaceutical Manufacturing. The analysis was performed in triplicates at a temperature of 25 °C.For the particle size analysis, the samples were dispersed in distilled water, the cells were filled and capped and checked for the absence of any bubbles. The samples were prepared for zeta potential analysis by dispersing themin the distilled water and measuring the zeta values at 25 °C. max of 323 nm. A suitable amount of each nanocomposite was added to 2 mL of the media. The cumulative amount of drug released into the solution was measured at preset time intervals at corresponding λmax.The in vitro release of MET from the nanocomposites wasdetermined in a solution at pH 1.2, using a Perkin Elmer UV–Vis spectrophotometer with λThe percentage release of MET into the release media was calculated according to the formula: The concentration corresponding to 100% release was obtained by adding a known amount of the nanocomposites into 2 mL HCl followed by sonicating and heating the nanocomposites at 37 °C.α radiation (λ=1.5406 Å) at 30 kV and 30 mA at Universiti Putra Malaysia. Fourier transform infrared spectroscopy (FTIR) spectra of the materials were recorded over the range of 400–4000 cm−1 on a Perkin Elmer (model Smart UAIR-two). The thermogravimetric analysis was carried out using a Metter-Toledo 851e instrument (Switzerland) with a heating rate of 10 °C min−1, in 150 μL alumina crucibles and in the range of 30–900 °C. The zeta potential was measured at 25 °C by the dynamic light scattering (DLS) method using a Malvern Zetasizer Nano ZS . UV–Vis spectra were measured to determine the release profiles using a Shimadzu UV-1601 spectrophotometer. Powder X-ray diffraction (XRD) patterns were used to determine the crystal structure of the samples in the range of 2–70 degrees on an XRD-6000 diffractometer  using CuKR²) indicates how well the data fit the multiple regression models. It provides a measure of how well-observed outcomes are replicated by the model, as the proportion of total variation of outcomes explained by the model. An R² close to 1 indicates that the regression model perfectly fits the data; the higher the R², the more the dependent variations are explained by input variables and therefore the better the model. Multiple regression analysis is a statistical method that is used to estimate the correlation between dependent and independent variables. The term correlation coefficient , linear-square  and linear-interaction equations  have been fitted using a Minitab software for LE, particle size and zeta potential variables. The data was analyzed using stepwise regression which is a way to build a model by adding or removing independent variables, usually via a series of F-tests or T-tests. The variables to be added or removed are chosen based on the test statistics of the estimated coefficients.The linear  indicating that the fitted model is accurate enough to predict the response. The mathematical models were developed to determine the optimal values of the MET-CS-AlgNPs formulation conditions leading to maximum values of LE, minimumvalues of particle size and a negative value (~20 mV) of zeta potential.The equations can be given in terms of the coded values of the independent variables as shown in the following P-value 0.05) indicates the minimum magnitude of statistically significant effects, considering the statistical significance of 95%.A Pareto chart  is a gra2) has the highest standardized effect on the LE followed by A, B, C, AB and BC. Hence, the term BB should not be considered for the empirical relation. The insignificance of BB can also be reasserted from the normal plot  has the highest standardized effect on the zeta potential followed by AC, A, BB, and BC. Hence, the terms AB and B should not be considered for the empirical relation.2 concentration while decreasing the Alg concentrationled to an increase in the LE response. 2 concentration led to an increase of the LE by more than 52%.The effect of the formulation and process variables on LE responsecan be evaluated by studying thecontour and response surface plots. 2. In the case of CS and CaCl2 variables in 2 concentrations ranging between 30 and 60 mg.2on the zeta potential charge. The plots show that all the variables affect the zeta potential with rising ridge patterns. 2 on the zeta potential. The zeta potential was between −8 and −18 mV; it was around −18 mV at low concentrations of both Alg and CaCl2, and around −8 mV at Alg concentrations between 200–350 mg with concentrations of CaCl2 between 55–60 mg.2 of 55–60 mg and CS concentrations below 50 mg and higher than 200 mg. The zeta potential response at −4 mV can be achieved at a low concentration of CaCl2 of below 30 mg and a CS concentration between 75–175 mg.2) used to examine differences between level means for LE, particle size and zeta potential factors. All factors seem to affect the LE, particle size and zeta potential because the line is not horizontal. 2 concentration of 30 mg had a higher LE mean (50%) than the one at 60 mg (45%). The CS also affected the LE, with 200 mg of CS having had a higher LE mean (51%) than at 60 mg (43%). It is evident from 2 (60 mg). In addition, the minimal particle size of approximately 100 nm can be obtained with the lowest level of CS (60 mg).2 parameters tested. Both the parameters of Alg and CaCl2 concentrations show a linear potential pattern with an increase in their levels. However, CS concentration shows otherwise; although the highest level of CS concentration tested resulted in −7 mV potential, its mid-point shows a downward curvature in its response. The −11, −10 and −14 mV values of the mean zeta potential are observed at 200 mg of Alg, 120 mg of CS and 30 mg of CaCl2. From our studies, based on their potential data, the prepared nanocomposites were stable.Based on the main effect plots in The interaction plots in 2. For example, if 300 mg of Alg is used, then 30, 45 and 60 mg of CaCl2 are associated with the 50 % LE means, similar to that in In this interaction plot, the lines in 2 , 3100 cm−1 (C–C stretching), 1534 and 1366 cm−1)nitroso N–O stretch), and 1075, 875 cm−1 (C–N stretch) [FTIR spectra of MET, CS-AlgNPs and MET-CS-AlgNPs are presented in stretch) .−1 was observed due to O–H and N–H stretching. Absorptions due to vibration asymmetry CH2 and symmetry CH2 were located at 2930 and 2850 cm−1, respectively. A strong band near 1589 cm−1 corresponds to the C=O, C–N and N–H bending of amide I. Asymmetric stretching band of the COO− group was centered near to 1420 cm−1 [For CS-AlgNPs B, a band420 cm−1 .−1, from 1589 to 1585 cm−1 and from 1408 to 1413 cm−1. This can be explained due to the interaction between MET and CS-AlgNPs.For MET-CS-AlgNPs C, some bThe thermal decomposition process of MET-CS-AlgNPs nanocomposites and its pure counterpart CS-AlgNPs was evaluated by TGA/DTG analyses. These analysis curves give thepercentage weight loss due to the thermal decomposition . The res2O molecules can be bounded by the hydroxyl group [The CS-AlgNPs show three main thermal stages; the first stage of the decomposition process occurred between 60–200 °C, which was due to the vaporization of volatile components, such as water molecules immobilized between chitosan chains during the coating process . Based oyl group . The second stage of weight loss, which occurred between 200–520 °C, is due to the release of water bound to the functional groups of CS and Alg polymers, which was not completely removed in the first step of the dehydration, and to the degradation of both polymers. A third inflection point occurred between 520–800 °C, which may be associated with the decomposition of functional groups of both polymers which were not completely removed by the previous stages. The TGA of MET-CS-AlgNPs  also shoThe CS-AlgNPs and MET-CS-AlgNPs were morphologically characterized using the SEM . The micThe MET-CS-AlgNPs nanocomposites were also examined using the transmission electron microscope (TEM), and the structure is as shown in 2–) groups, which led to the formation of different hydrogen bonds with CS and Alg polymers . As shown in 2, the best fitted model for all MAC 8, MAC 21, MAC 19, and MAC 5 nanocomposites was the second kinetic model with R2 values of 0.988, 0.956, 0.990 and 0.977, respectively. The release kinetics of MET from MAC 8, MAC 21, MAC 19, and MAC 5 nanocomposites in 0.1M HCl were evaluated by fitting the data to various kinetic models . Based o2 concentrations. Selected mathematical models showed that the developed response surface methodology models werestatistically significant and suitable for all conditions to have higher R² and adjusted R² values. High correlation values were determined between the experimental data and predicted ones.The concentrations of Alg, CS and CaCl2 with values of 350, 150 and 40 mg, respectively, were determined as the optimum conditions, resulting in the maximum LE (46.04%), the minimum particle size (164 nm) and the optimum zeta potential (−9.25 mV). The verification experiment was carried out to check the validity of the developed mathematical model that predicted LE, particle size and zeta potential within the range of 10% error limit and the prepared nanocomposites were generally stable.For the multiple linear regression analysis, the mathematical models for LE, particle size and zeta potential were developed using the responsesurface methodology to formulate the input parameters, which were Alg, CS and CaClIn vitro MET release study of selected formulations; MAC 8, MAC 21, MAC 19, and MAC 5 showed 97%, 90%, 90% and 99% release in 60, 40, 20 and 10h, respectively. These results indicate that the nanocomposites could be effective in sustaining the MET release for a prolonged period.


Graphene oxide (GO) has been widely used as an additive due to its numerous unique properties. In this study, the compressive strength, flexural strength and elasticity modulus of concrete containing 0.02 wt%, 0.05 wt % and 0.08 wt % GO, and its dry shrinkage performance have been experimentally investigated. After the sample preparation, apparatus for compression test and flexural test were used to test the relevant properties of concrete containing GO. The dial indicators were used to measure the shrinkage of samples. The results indicate that GO can considerably improve the compressive strength, flexural strength, and elasticity modulus of concrete at the concrete age of 28 days by 4.04–12.65%, 3.8–7.38%, and 3.92–10.97%, respectively, which are substantially smaller than the increment at the age of 3 d by 5.02–21.51%, 4.25–13.06%, and 6.07–27.45% under a water-cement ratio of 0.35. It was also found that GO can increase the shrinkage strain of concrete. For example, at the age of 60 days, 0.02 wt%, 0.05 wt% and 0.08 wt% GO can increase the shrinkage strain of ordinary concrete by 1.99%, 5.79% and 7.45% respectively under a water-cement ratio of 0.49. The study has advanced our understanding on mechanical and shrinkage behavior of concrete containing GO. Since the emerging of concrete, researchers have been devoted to obtaining concrete with higher strength and better performance ,2,3. GraIn addition, it is discovered that graphene oxide (GO) and its derivatives, as an additive, can be used for repairing cracks and pores in concrete ,8. CompaMany studies have focused on the effect of GO on mechanical properties of concrete . Wang etFrom a three-dimensional perspective, Long et al.  have dem3S). It was widely believed that GO can promote the hydration reaction of cement-based materials [Kang et al.  exploredaterials ,26,27,28aterials ,29. It waterials  discoveraterials  have perAlthough above studies have investigated mechanical and physical properties of cement-based materials with GO, there is no consistent conclusion for mechanical properties and shrinkage effect of GO concrete. Specially, the influence level of GO on compressive strength and flexural strength remains controversial. Therefore, in addition to the exploration about drying shrinkage effect of GO concrete, this study also aims to study compressive strength and flexural strength of concrete containing GO nanosheets.The cement used to make concrete was ordinary Portland cement P.O 42.5. Details of the material components and parameters can be found in . A scannThe YAW-2000 compression-testing machine provided by Center of Engineering Materials at Chongqing University was used as the concrete compression strength instrument, as shown in In the experiment, four groups of C50 concrete samples were prepared, and they were numbered as PC50, GOC50-1, GOC50-2 and GOC50-3, where PC50 was the ordinary concrete and GOC50-1, GOC50-2, GOC50-3 were concrete added with 0.02 wt%, 0.05 wt%, 0.08 wt% GO, respectively. 36 samples were included in each group. The water-cement ratio (w/c) was 0.35. The specific mixture ratio is shown in Standard for Test Method of Mechanical Properties of on Ordinary Concrete (GB/T 50081-2002). The dimension of the samples for compressive strength tests was 100 mm × 100 mm × 100 mm, and the dimension of the samples for flexural strength tests was 100 mm × 100 mm × 400 mm, and the dimension of the samples for elasticity modulus tests under static pressure was 150 mm × 150 mm × 300 mm.The preparation method for samples is stated in the Before preparation for the samples, the GO powder was dissolved in water, and a polycarboxylate superplasticizer was added into the water solution of GO to make the GO powder dissolve in water better. Subsequently, the solution was mixed with other binding materials and aggregates. The concrete mixture was put into the test mold and the slice was used to smash the internal wall of the test mold. The mixture should be higher than the test mold orifice. After loading, the test mold was placed on the shaking table for vibration until paste appeared on the surface. When the samples were shaped up, a water-proof thin film was attached to the surface to prevent water desorption. During the preparation of the mixture, abnormal phenomenon didn’t been observed. The samples were numbered and the mold was removed after 24 h. Then, the samples were immediately moved into a standard curing room with the temperature of 20 ± 2 ℃ and relative humidity of above 95%.Standard for Test Method of Mechanical Properties of on Ordinary Concrete (GB/T 50081-2002). When the sample began to deform rapidly and approached destruction, adjustment of the tester accelerator was stopped until the sample was destroyed. Then the data were recorded.During the compressive strength test, the sample was taken out from the curing room, and the surface was dried. Then the sample was placed in the center of lower platen for loading with the loading speed of 0.07 MPa/s according to the During the flexural test, the sample was taken out, and the surface was dried. Then the sample was installed according to Before the static pressure test, the sample was taken out from the curing room, and the surface of the sample and the upper and lower bearing plates of the apparatus were wiped up. Static pressure test was conducted for 3 samples and axial compression test was conducted for 3 samples at the same time. The data of axial compression test were used to verify the validity of the data of static pressure test. Then the apparatus was started to load till the benchmark stress was 0.5 MPa. The loading duration was kept for 60 s, and the deformation at various measurement points was recorded. Then the load was increased to 1/3 of axial compressive strength uniformly. The loading duration was kept for 60 s, and the deformation at various measurement points was recorded. Subsequently, the load was reduced to the benchmark stress of 0.5 MPa at the same loading speed, and repeated the above process for two times after the loading duration was kept for 60 s. Then the benchmark stress was kept for 60 s, and the deformation at various measurement points was recorded. Subsequently, the load was increased to 1/3 of axial compressive strength at the same speed, the loading duration was kept for 60 s, and the deformation at various measurement points was recorded. Finally, the deformation measuring instrument was removed, and the load was increased at the same speed until the sample was destroyed. The failure load was recorded, and the schematic diagram for loading is shown in The C40 ordinary concrete was used for the drying shrinkage experiment. The raw materials were the same as the materials for mechanical performance test in the previous section. The mixture ratio of concrete is presented in Standard for Test Methods of Long-term Performance and Durability of Ordinary Concrete (GB/T 50082-2009), and the contact method was adopted as the test method. The size of the samples was 100 mm × 100 mm × 515 mm, and the preparation and curing for samples were the same as the conditions for mechanical properties test. The measuring head was affixed to the samples after the mold was removed, and then it was placed in the standard curing room for 3 days. After being taken out, it was immediately put into the drying room under the temperature of (20 ± 2) ℃ and relative humidity of above (60 ± 5) %. The dial indicator was fixed on the standing support, and the support should not be influenced by external vibration. After the dial indicator was installed, the sample was put on the support for reading of the first time, as shown in The drying shrinkage experiment followed the According to the increasing rate of compressive strength presented in With the increase of age, the influence of GO on the compressive strength of concrete decreases gradually. GOC50-1, GOC50-2 and GOC50-3 samples can increase the compressive strength at the age of 3 days by 5.02%, 14.7% and 21.5% based on PC50, and increase the compressive strength at the age of 28 days by 4.04%, 8.08% and 12.65%, respectively.GOC50-1, GOC50-2 and GOC50-3 can increase the flexural strength at the age of 3 days by 4.25%, 7.24% and 13.06%, and increase the flexural strength at the age of 28 days by 3.80%, 4.78% and 7.38%. Comparatively speaking, the influence of GO on flexural strength is smaller than the influence on compressive strength. For example, at the age of 28 days, GOC50-3 can increase the compressive strength by 12.65% with respect to PC50, but can only increase the flexural strength by 7.38%.According to the figure, the influence of 0.02 wt% GO on the elasticity modulus of concrete decreases first and then increases, and the influence of 0.05 wt% and 0.08 wt% GO on the elasticity modulus of concrete drops with the rise of age.According to the figure, the GO mainly has a big influence on the early-stage shrinkage strain of concrete. On the first day, the shrinkage strain of GO concrete changes within the scope of −22.22–22.22% when compared with that of ordinary concrete. On the third day, the shrinkage strain of concrete with the GO dosage of 0.08 wt% shows the highest increasing rate, which is 32.43%. Later, the shrinkage strain increasing rate of GO concrete in different groups decreases. On the 60th day, the increasing rate of various groups drops to 7.45%. The concrete with the GO dosage of 0.02 wt% has the smallest influence, and the increasing rate of its shrinkage strain with respect to ordinary concrete is only 1.99%.2, which would accelerate hydration by reacting with GO(-COOH) in GO nanosheets [It is found that the influence of GO nanosheets on the mechanical properties and drying shrinkage of concrete is closely related to the influence of GO on hydration degree, internal microcrack development of concrete and porosity. In the hydration process of concrete, CaO in the cement paste will be hydrated to generate Ca(OH)nosheets ,27. Whennosheets . By measnosheets  have proIn the hydration process, more compact crystal structures will be generated in concrete , so the From the micro perspective, the concrete is divided into aggregate, mortar and interfacial transition zone (ITZ). Some studies have proved that ITZ is the weak phase of mechanical properties of concrete . TherefoThe reasons influencing early-stage drying shrinkage of concrete containing GO nanosheets might include the following ones. First, GO nanosheets can increase the hydration degree, reduce the total volume of cement paste, and as a result increase the shrinkage strain. Secondly, Van der Waals force of GO nanosheets under nanoscale will reduce the shrinkage strain . ThirdlyExisting experiments prove that GO nanosheets could reduce the volume of pores with a diameter of no more than 10 nm, 10-100 nm and above 100 nm in mortar, but increase the number of pores with a diameter of below 10 nm and 10-100 nm . Hence, In addition, the SEM figure in  verifies(1)GO nanosheets can considerably improve the compressive strength at the age of 3, 7 and 28 days. The higher the GO dosage is, the more obvious the strength increase will be. GO nanosheets of different contents can increase the compressive strength of concrete at the age of 28 days by 4.04–12.65%. GO nanosheets can considerably improve the compressive strength of concrete at the age of 3 d the most obviously by 5.02–21.51%.(2)GO nanosheets can increase the flexural strength of concrete, but the increasing degree is lower than that of compressive strength. Its effect on early-stage strength is comparatively significant, and the most obvious effect happens on the 3rd day (4.25–13.06%). The enhancement effect of flexural strength on the 28th day reaches 3.8–7.38%. Moreover, the flexural strength of concrete will be further improved with the increase of GO nanosheets content.(3)The enhancement effect of GO nanosheets on early-stage elasticity modulus of concrete is relatively big. The higher the GO content is, the higher the increasing rate of elasticity modulus will be. GO nanosheets can increase the elasticity modulus of concrete at the age of 3 days by 6.05–27.46%, and increase the elasticity modulus at the age of 28 days by 3.92–10.97%.(4)GO nanosheets will increase the shrinkage strain of ordinary concrete. The higher the content is, the more obvious the enhancement effect will be. GO nanosheets have a comparatively big influence on the increase of early-stage shrinkage strain of ordinary concrete. At the age of 60 days, the GO dosages of 0.02 wt%, 0.05 wt % and 0.08 wt % can increase the shrinkage strain of ordinary concrete by 1.99%, 5.79% and 7.45%, respectively.In this study, the compressive strength, flexural strength and elasticity modulus of concrete containing GO nanosheets, and its dry shrinkage performance have been experimentally investigated. Main findings are summarized as follows:


This paper presents influence of treatment and mixing methods on recycled aggregate concretes (RAC) designed regarding various techniques. Absolute Volume Method (AVM) according to TS 802, Equivalent Mortar Volume Method (EMV), silica fume (SF) as a mineral addition were considered in the design of concretes. In total, four groups of concretes were produced in the laboratory: (1) natural aggregate concrete (NAC) designed with AVM as control concrete, (2) RAC designed with AVM as control RAC, (3) RAC with SF as a mineral addition designed with AVM as treated RAC and (4) RAC designed with EMV as treated RAC. The tests were performed at 28th days and the statistical analysis were made on the test results. According to the results, EMV and SF increased the compressive strength of concretes and this resulted an increase in the strength class of concrete. A significant statistical difference between the concretes were determined. According to multiple comparison analysis, it was found that especially there was a significant relationship among NAC, RAC and RAC-EMV. In addition, it was recommended that EMV and AVM with 5% SF could be used in the design of RAC rather than AVM only to achieve the target strength class C30/37. Demolition of concrete structures and waste concrete products have been mainly discussed in the countries. Authorities were worked on identifying a struggle process with the huge mass of waste concrete and offered environmental solutions for the use of waste concrete in newly manufactured concrete as recycled aggregate (RA) taking measures such as regulation and standards for RA . EnvironTo solve the complexity of the use of RA in new concrete safely, some researchers proposed new mixture prescriptions including mineral additions  ,4, grounIn this experimental research, the properties of concretes  were compared to observe the effect of treatment methods . Here, NGeneral purpose CEM I cement suitable with TS EN 197-1  was usedIn the concrete mixes, natural coarse aggregate and recycled coarse aggregate were used as the coarse ones and the granulometry of the mixes are the same. Natural gravel was crushed, calcareous aggregate and also sand was utilized as fine aggregate in the mixes . Super p3) of concrete is filled with the components of concrete (Equation (1)) [Four concrete mixes were produced in the laboratory with the target strength class C30/37 . Absolution (1)) :(1)V1m3=aggV is volume of aggregate, cemV is volume of cement, wV is volume of water, chV is volume of chemicals and airV is volume of air in concrete.Here, EMV requires that recycled aggregate concrete has same amount of total mortar volume with control concrete so to constant aggregate volume. Hence the residual content should be determined for RA . HCl solEMV requires the constant volume of aggregate as (Equation (3)) :(2)VRCARRMC is the residual mortar content of RA and R is the volume fraction of fresh natural aggregate content of RAC to fresh natural aggregate content of control mix.Here, The cement quantity and water-to-cement ratio was kept constant for all concrete mixes. Concrete was cast incompatible with ASTM C192/C192M–13a  and vibr95% confidence interval was considered, and strength class of concrete groups were determined using Equations (3) and (4) :fc,avg ≥ckf characteristic compressive strength of group (MPa), c, avgf is the average compressive strength of group (MPa), σ standard deviation, and c, minf is the minimum compressive strength of group (MPa).Here, In this study, Shapiro-Wilk normality test was performed on NAC, RAC, RAC-SF, RAC-EMV . The Pea2 in the cement paste, 2) Filler effect (closing concrete pores) [According to the results given in e pores) . In addie pores) . This sue pores) ,41,42,43As given in In the Shapiro-Wilk normality, skewness, kurtosis ratio to standard error results are given in The Pearson Correlation coefficient was a measure of the variation of two or more variables. The conducted correlation analysis showed how a change in interrelated variables affected the other variables and the relationship among them. For the correlation coefficient , ”0” is the non-correlation, ”−1” represents the perfect negative relationship and,”1” represents the perfect positive relationship. The interpretation of the correlation coefficient is given in the A scatterplot gives the relations between two variables measured for the dataset. Each individual in the data appears as a point on the graph. It is convenient to use scatter plots with correlation test results. As shown in p-value = 0.00 < 0.05). It is known that TS-500 [Variance analysis (ANOVA) measures the significance of compressive strengths on concrete types and the results of ANOVA is given in t TS-500  considert TS-500 . Also, aMineral Addition Treatment Method with SF and EMV gives convincing results eliminating the negative effect of attached old mortar (AOM) in RA.The target strength class C30/37 is achieved for NAC, RAC-SF and RAC-EMV, and however, RAC cannot achieve C30/37. SF addition and EMV facilitate to obtain the target strength class.The compressive strength of all concretes distributes normally according to the Shapiro-Wilk normality test and Skewness and Kurtosis to standard error ratios.It is found that the correlation analysis and the scatter plots give compatible results. The correlation analysis and the scatter plots indicate that the relation between concretes behavior pattern is observed at low level. Especially, for instance, the relation between behaviors of NAC and RAC is equal −0.20 and it means that there is very weak relation due to RA.According to the results of ANOVA, the relationship between the concretes are significant at 95% reliability level, although generally concrete standards consider 90% reliability level.Games-Howell Multiple Comparison Test demonstrates that the most significant bilateral relationships between (RAC-EMV)-(RAC) and (RAC)-(NAC) are found. In this paper, a statistical study was conducted, and the compressive strength test results of concretes designed with Absolute Volume Method (AVM) and Equivalent Mortar Volume Method (EMV) and included natural aggregate (NA), recycled aggregate (RA) and silica fume (SF) were investigated. Based on the results, the following conclusions were made:In summary, according to the statistical evolutions, there is a major difference between the concretes and this phenomenon depends on the utilized components and considered mixing methods generally. However, Mineral Addition Treatment Method (here it is SF) and EMV are useful to improve the performance of RAC, and especially, EMV is strongly recommended for RAC mix design by the authors instead of AVM. If AVM is considered, SF addition use in mixes is recommended by the authors.The data used in the statistical approaches were collected from experiments and at first strength class of concrete series were determined. In this point it was thought whether the concretes were in the required strength class (C30/37), and the results were checked in consideration of the helpful evaluation equations given in the related codes. However, it is well-known that the concrete, commonly used in the engineering area, includes the natural aggregate and, also the compressive strength results of natural aggregate concrete are distributed compatible with the normal distribution function. Here, it is expected that the concretes included recycled aggregate and designed with different mixing methods would show a similar behavior with natural aggregate concrete. However, the truth of recycled aggregate concrete was different. For instance, as a result of the normality test evaluations , when recycled aggregate was considered, the distribution of the test results of recycled aggregate concrete presented a non-similarity with natural ones although the use of silica fume changed a bit the behavior of recycled aggregate concrete from recycled aggregate concrete to natural aggregate concrete. According to this, it could be concluded that despite the consideration of silica fume in recycled aggregate concrete, natural aggregate concrete and recycled aggregate concrete had different characteristics and it was thought that the observed difference depended on the components such as recycled aggregate. To present the difference/similarity of concretes behavior, in addition, the comparison techniques were employed and hence the difference between the concrete types was obviously seen. The first comparison technique was made in consideration of Person Correlation Coefficient and the most suitable similarity between recycled aggregate concrete and natural aggregate concrete was found as 0.20 (the higher is good up to 1.0 and down to −1.0). The second comparison technique was made in consideration of ANOVA with Games-Howell Multiple Comparison Test and Games-Howell Comparison Test had an interrelation assessment approach. As expected, the first and the second approaches demonstrated the similar results: There was a specific difference between the concretes included natural and recycled aggregates in dependent of mixing methods such as AVM and EMV and, also mineral addition such as silica fume.The critics and discussions on the results canalized the authors to think that the evaluation of test results of different types of concretes  could mislead decision makers and the evaluation of test results of different concrete types may be separated in the standards and the evaluation equations for each concrete type could be proposed in the codes after several trial-and-error tests.Considering the various studies in the literature, Tukey’s Test (it is a comparison test) was mostly used together with ANOVA analysis . In In addition, the following discussions were made after the evaluation of the results and conclusions:Also, there is a lack of knowledge in RAC application included many mineral additions  and fibers  and also those under the different curing conditions. In this paper only SF as a mineral addition, AVM and EMV as a design method is considered and compared evaluating statistical data obtained various stochastic approaches. In addition, it is though that aggregate types , water-to-binder ratio, chemical admixtures, etc. are the other components effecting the statistical results and the approaches considered in this paper can be applied to those. Besides, in the future studies, clustering methods, the analysis of discriminant and regression and multivariate statistical methods etc. are able to be utilized to evaluate the effect of materials, methods etc. on concretes’ relations and behaviors.


To identify spatial and space-time clusters with high incidence rates of AIDS in men living in the city of São Paulo since the first case of the disease in 1980.HIV/AIDS notifications were obtained from the Notifiable Diseases Information System  between January 1980 and June 2012. The cases were geocoded by residence address; then analyses of purely spatial, space-time and spatial variation in temporal trends were performed for three sets of data: total cases of AIDS in men aged 13 years or older, men aged 50 years or older, and deaths from AIDS.It was possible to geocode a significant proportion of AIDS cases (93.7%). In the purely spatial scanning analysis, considering the entire period evaluated, the AIDS epidemic in men presented an important spatial concentration in the Center and in contiguous areas of the North, Southeast and West regions of the municipality, regardless of age group and evolution to death (relative risks between 1.22 and 5.90). Considering space and time simultaneously, several clusters were found, spread throughout all regions of the municipality (relative risks between 1.44 and 8.61). In the analysis of spatial variation in temporal trends, the clusters in the most peripheral regions presented a higher annual percentage increase in disease rates (up to 7.58%), denoting the tendency of “peripherization” of the epidemic in men in the city of São Paulo.This study allowed the detection of geographic clusters of high risk for AIDS in men, pointing to priority areas in the municipality, both for programmatic actions and to guide other studies. However, investigating the spatial structure of this epidemic is still a challenge, because large geographical areas with low population density can mask spatial variation and lead to a misinterpretation of the true underlying geographic patterns,–,,, China,,,–Some statistical methods help detect relevant disease clusters due to actual effects and not chance, helping in the allocation of resourcesHIV/AIDS has already completed almost 40 years of history in the city of São Paulo; however, little was studied about space as a determinant of disease trends in this location. The objective of this study was to identify spatial and space-time clusters with high incidence rates of AIDS in men , living in the city of São Paulo, since the first case of the disease, identified in 1980.This study has a descriptive ecological design and was developed in the city of São Paulo, with an estimated population of 11.8 million inhabitants in 2019, 47.6% of them men. The city's area is 1,521.11 km² and the population density is 7,765.06 inhabitants/km², according to the State Data Analysis System FoundationCoordenadorias Regionais de Saúde : North, Center, West, Southeast, East and South. The study includes 310 specifically chosen key study areas , from the Health Surveillance Coordination of the city of São Paulo. The cartographic base was obtained from the Center for Metropolitan Studies (CMS)The data for this study come from the HIV/AIDS notification database of the We chose to describe the trajectory of AIDS exclusively in males, since, in the city of São Paulo, among the 88,424 cases reported between 1980 and 2013, 72.2% were menThe geocoding of AIDS cases was performed according to the home address , for the comparison with the CMS-produced digital map of the city of São PauloIt was necessary to standardize the addresses, due to many inaccuracies and lack of uniformity, as well as to make them compatible with the digital street database, before obtaining the geographical locations. Quality of geocoding was verified by checking 10% of the geocoded addresses, randomly drawn, and overlapping the layer of the geocoded points to the layer of addresses of the city, obtaining 96% accuracy.TM program (version 9.4.2),,,TM standard),,This study aimed to detect significantly high geographic clusters of AIDS in men in space and space-time. The statistical scanning analyses were performed in the SaTScanThe trajectory of AIDS cases was analyzed by three modalities of scanning statistics: (1) purely spatial; (2) space-time; (3) spatial variation in temporal trends. Scanning statistics are used to detect and evaluate clusters of cases in a purely temporal, purely spatial, or space-time configuration. This is done through the gradual scanning of a window over time and/or space, indicating the expected and actual number of observations inside the window in each locationMaps with significant clusters (p < 0.05) and respective relative risks  as well as internal and external temporal trends  were elaborated in the ArcGIS application (version 10.1).,TM26:For each modality, three sets of data were evaluated: (a) all cases of AIDS in men aged 13 years or older – the age group considered by surveillance as “AIDS in adults”Case file: Contains the number of cases in each area. For the space-time analyses, the time reference was the date of AIDS diagnosis, in the year/month format. Age was included as a covariate, stratified in the following age groups: 10–19; 20–29, 30–39, 40–49, 50–59, 60–69, and 70 or more.TM performed linear interpolation based on the populations of the censuses immediately before and afterPopulation archive: comprises a population size at risk for each combination of locality, time (in years) and covariate. Populations according to age groups were specified for each area in census years . For the years between each census, the SaTScan,Spatial coordinate archive: pairs of latitude and longitude coordinates of the centroids of the study areas, used as a proxy for the location of the study participantsThe use of the data for the purposes of this study was approved by the Research Ethics Committee of the School of Public Health of the University of São Paulo . For any circumstances, the norms and guidelines regulating research involving human beings were considered .Among the 57,440 cases of AIDS in men, 53,825 were geolocated in several stages, reaching a final geocoding rate of 93.7%. Fifty-three cases with ignored age were excluded. Thus, for each data set, the following were analyzed: (a) 53,772 cases of men aged 13 years or older; (b) 5,272 cases of men aged 50 years or older; (c) 28,981 deaths caused by AIDS.Regarding the purely spatial analysis of the total cases, 12 statistically significant high-risk spatial clusters (p < 0.05) were identified. Throughout the analyzed period, the epidemic was concentrated in the central area, with the main cluster with relative risk (RR) of 4.90 . The twoIn the analysis of cases aged 50 years or older, three significant clusters were identified. The main one, with RR of 5.90  occupiedIn the spatial scanning analysis of deaths, eight significant clusters were found. The main one, with RR of 4.44  remainedThrough the space-time scanning statistics of the total cases, 16 significant clusters were identified. The main one, with RR of 7.20  occurredIn the age group aged 50 years or more, seven significant clusters were detected. The main one, with RR of 8.61 , was locIn the space-time analysis of deaths, 15 significant clusters were found. The main one, with RR of 8.36  remainedIn the analysis of spatial variation in temporal trends, nine significant clusters were found in the total set of cases. The values of internal temporal trends (INT) and external (EXT) of the clusters are presented. With an internal annual increase of 4.52%, the most significant cluster occurred in the Southern region of the city .In the age group aged 50 years or more, three significant clusters were detected. The main one, with an internal annual increase of 7.58%, was also located in the South CRS, near the border with the West region .In the subset of deaths, seven significant clusters were detected. The main one, with an internal annual increase of 1.23% , involveRegardless of the age group and the evolution of AIDS cases in men, there are spatial clusters, especially in the most peripheral regions of the city, which showed a higher annual percentage increase in the rates of the disease within the clusters, compared to the areas outside them, which denotes a tendency to “peripherize” the epidemic in men in this municipality.The –,–This study sought to identify spatial and space-time clusters of AIDS in men aged 13 years or older in the city of São Paulo, from the first case in 1980 to June 2012. Several methods analyze global and local clusters, with differences in performance in terms of power and precision,The progression of HIV in populations does not occur randomly and uniformly, but rather due to intimate and complex social behaviors among two or more peopleThe use of spatial analysis tools allows identifying differentials in HIV/AIDS behavior in populations and in the spaces they occupy. Such techniques also contribute to the identification of locations where there is a higher risk of falling ill or dying due to the disease, which can help select areas for specific policies and interventions by the competent agenciesThe purely spatial scanning analysis showed that AIDS was concentrated in the Central region of the city of São Paulo, regardless of age group and evolution to death. The 2014 São Paulo City Epidemiological Bulletin on AIDS, HIV and STD,The relative risk of the cluster of men aged 50 years or older was the highest among all those observed in purely spatial analyses. Between 1996 and 2005, the incidence rate of AIDS among men aged 50 to 59 years increased from 18.2 to 29.8 cases/100,000 men. In those over 60 years, in the same period, there was also an increase in the rate, from 5.9 to 8.8. Until 2010, this increase remained in the age groups above 50 years,,,The “aging” of the AIDS-infected population has been highlighted as a trend of the epidemic in Brazil, and the older population are rarely the target of interventions to reduce contagionAccording to recent data from the Ministry of Health, in the last decade there has been an increase in the rate of AIDS detection in men aged 15 to 29 years and aged 55 years or more, especially for young people aged 15 to 24 yearsIn the scan analysis of space-time, an expressive number of clusters were observed, denoting that all regions of the municipality were affected at some point, except the South. The main cluster remained between October 1987 and March 2004, in the city center, including 1992, which had the highest incidence rate of AIDS in adult men The similarity of the subset of deaths with the one that included all cases can be explained by the high lethality of the disease in men (54.7%), especially between 1990 and 1996,The peak of AIDS mortality in men in the city of São Paulo occurred in 1994 An analysis conducted with the death certificates of the Mortality Information System (MIS) with mention of HIV/AIDS in any field of completion of causes of death showed that in Brazil, between 2000 and 2007, there was an important increase in the percentage of deaths of people infected with the virus due to basic causes not related to HIV/AIDS, from 2.5% to 7.0%. This fact indicates that other diseases  have increasingly impacted the survival of people with HIV/AIDS,Factors such as late diagnosis, co-infections, lack of access to health resources, among others, affect people living with HIV/AIDS more intensely in some locations than in othersIn this study of the trajectory of AIDS in the city of São Paulo, a tendency of “peripherization” of the disease was evidenced in men, since more peripheral areas presented, over time, a greater percentage increase in rates within the clusters than the areas outside them. It is noteworthy that a statistically significant cluster in this type of analysis does not necessarily imply that the overall rate of disease is higher or lower in it, since the scan statistic of spatial variation in temporal trends is not looking for clusters of high or low risk, but rather seeking clusters with a higher or lower internal trend than the trend outside themThe poorest population is the most affected by AIDS, due to several aspects related to vulnerability, such as lack of resources for HIV prevention; difficulty in accessing health services; embarrassment, pressure and threats; precariousness of housing, food and employment; low schooling and difficult access to information,,,In 1994, the “pauperization” of AIDS was already indicated, which mainly affected the poorest social class and residents of the peripheral regionsThis study presents some limitations, among which it is noteworthy that only cases of AIDS were studied, not including those of asymptomatic HIV, because only AIDS was a mandatory notification condition during the study period. The prolonged latency period of AIDS makes it difficult to characterize the place where individuals acquired HIV, because when they are reported with AIDS-defining infections, a long time has passed since the moment of infection. Other limitations relate to the address of patients informed in the AIDS notification and investigation forms, which may not represent the actual place of residence, because inaccurate addresses are provided in order to gain access to the care network outside the region of residence.It is also considered the possibility of underreporting of the disease in surveillance and mortality systems, especially in the first decades of the epidemic, due to changes in the versions of the International Classification of Diseases , besides the stigma related to the disease, which may have contributed to the non-mention of this cause in death certificates. In addition, the scanning techniques do not allow to verify associations between exposure and outcome, revealing only the localities with higher risk or protection in the rates of the disease.The study strength is the highlighting of the significant proportion of geocoded AIDS cases (93.7%). The ecological design allowed to evidence effects not detected at the individual level, and the choice of strictly spatial, space-time and spatial variation in temporal trends techniques allowed the detection of geographic clusters of high risk of AIDS in men.In conclusion, the AIDS epidemic in men was concentrated in the central region of the city of São Paulo and in contiguous areas of the North, Southeast and West regions, regardless of the age group analyzed and the evolution to death. Over time, the disease reached men in all regions of the municipality, with a tendency to “peripherization.” The study helped to reveal priority areas in the city of São Paulo, both for programmatic actions in the scope of HIV/AIDS and to guide other studies. –,No início da década de 1980, a epidemia do vírus da imunodeficiência humana/síndrome da imunodeficiência adquirida (HIV/aids) no Brasil atingia principalmente as regiões metropolitanas de São Paulo e Rio de JaneiroA análise da heterogeneidade geográfica da morbimortalidade do HIV/aids é fundamental para a vigilância e o acompanhamento das tendências desse agravo. Contudo, investigar a estrutura espacial dessa epidemia ainda é um desafio, pois grandes áreas geográficas com baixa densidade populacional podem mascarar a variação espacial e levar a uma má interpretação dos verdadeiros padrões geográficos subjacentes,–,,,,–Alguns métodos estatísticos auxiliam a detectar aglomerados de casos de doenças não devidos ao acaso, ajudando na alocação de recursosO HIV/aids já completa quase 40 anos de história no município de São Paulo (MSP); contudo, pouco se estudou a respeito do espaço como determinante das tendências da doença nesse local. O objetivo deste trabalho foi identificar aglomerados espaciais e espaço-temporais de altas taxas de incidência de aids em homens (considerados aqui em função do sexo biológico), residentes no município de São Paulo, desde o primeiro caso da doença, identificado em 1980.Estudo descritivo ecológico na cidade de São Paulo, capital do estado de mesmo nome, com população estimada, em 2019, de 11,8 milhões de habitantes, sendo 47,6% homens. Sua área é de 1.521,11 km² e a densidade demográfica de 7.765,06 habitantes/km², de acordo com a Fundação Sistema Estadual de Análise de DadosPara o planejamento de ações de saúde, o município está dividido em seis Coordenadorias Regionais de Saúde (CRS): Norte, Centro, Oeste, Sudeste, Leste e Sul. Possui 310 áreas de ponderação (AP), unidades de análise escolhidas para este estudo , formadaOs dados para este trabalho provêm do banco de notificações de HIV/aids do Sistema de Informação de Agravos de Notificação (Sinan), da Coordenadoria de Vigilância em Saúde do município de São Paulo. A base cartográfica de logradouros do MSP foi obtida no Centro de Estudos da Metrópole (CEM)Optou-se por descrever a trajetória da aids exclusivamente no sexo masculino, visto que, no município de São Paulo, dos 88.424 casos notificados entre 1980 e 2013, 72,2% eram homenssoftware MapInfo Professional (versão 11.0), além de sistemas complementares baseados no Google Earth.A geocodificação dos casos de aids foi realizada conforme o endereço de moradia , para o relacionamento com o mapa digital de logradouros do MSP do CEMFoi necessário padronizar os endereços dos casos, por falta de uniformidade e incorreções, como também para compatibilizá-los à base digital de logradouros, antes de se obter as localizações geográficas. A qualidade da geocodificação foi verificada pela checagem de 10% dos endereços geocodificados, sorteados aleatoriamente, sobrepondo-se a camada dos pontos geocodificados à camada de logradouros do MSP, obtendo-se 96% de acurácia.TM (versão 9.4.2),,,TM),,O presente trabalho buscou detectar aglomerados geográficos significativamente altos de aids em homens no espaço e no espaço-tempo. As análises estatísticas de varredura foram realizadas no programa SaTScanA trajetória dos casos de aids foi analisada por três modalidades de estatísticas de varredura: (1) puramente espacial; (2) espaço-temporal; (3) de variação espacial nas tendências temporais. Estatísticas de varredura são usadas para detectar e avaliar aglomerados de casos em uma configuração puramente temporal, puramente espacial ou espaço-temporal. Isso é feito pela varredura gradual de uma janela ao longo do tempo e/ou do espaço, assinalando o número de observações observadas e esperadas no interior da janela em cada localidadeOs mapas com os aglomerados significativos  e respectivos riscos relativos , e tendências temporais internas e externas  foram elaborados no aplicativo ArcGIS (versão 10.1).,TM, de três arquivosPara cada modalidade, foram avaliados três conjuntos de dados: (a) todos os casos de aids em homens com 13 anos de idade ou mais – faixa etária considerada pela vigilância como “aids em adultos”Arquivo de casos: contém o número de casos em cada AP. Para as análises espaço-temporais, o referencial de tempo foi a data de diagnóstico de aids, no formato ano/mês. A idade foi incluída como uma covariável, estratificada nas seguintes faixas etárias: 10–19; 20–29, 30–39, 40–49, 50–59, 60–69 e 70 ou mais.TM realizou uma interpolação linear baseada nas populações dos censos imediatamente anterior e posteriorArquivo de população: compreende um tamanho de população sob risco para cada combinação de localidade (AP), tempo (em anos) e covariável. As populações segundo as faixas etárias foram especificadas para cada AP nos anos censitários . Para os anos intercensitários, o SaTScanproxy para a localização dos participantes do estudo,Arquivo de coordenadas espaciais: pares de coordenadas de latitude e longitude dos centroides das AP, utilizadas como um A utilização dos dados para fins deste trabalho foi aprovada pelo Comitê de Ética em Pesquisa da Faculdade de Saúde Pública da Universidade de São Paulo . Para quaisquer circunstâncias, foram consideradas as normas e diretrizes que regulamentam as pesquisas envolvendo seres humanos .Do total de 57.440 casos de aids em homens, 53.825 foram geolocalizados em várias etapas, atingindo uma taxa final de geocodificação de 93,7%. Foram excluídos 53 casos com idade ignorada. Assim, para cada conjunto de dados, foram analisados: (a) 53.772 casos com 13 anos de idade ou mais; (b) 5.272 casos com 50 anos ou mais; (c) 28.981 óbitos por aids.No que se refere à análise puramente espacial do total de casos, foram identificados 12 aglomerados espaciais de alto risco estatisticamente significativos . Em todo o período analisado, a epidemia se concentrou no Centro do MSP, com o aglomerado principal com risco relativo (RR) de 4,90 . Os doisNa análise dos casos com 50 anos ou mais, identificaram-se três aglomerados significativos. O principal, com RR de 5,90  ocupou eNa análise de varredura espacial dos óbitos, foram encontrados oito aglomerados significativos. O principal, com RR de 4,44  permanecPor meio da estatística de varredura espaço-temporal do total de casos, foram identificados 16 aglomerados significativos. O principal, com RR de 7,20  ocorreu Na faixa etária com 50 anos ou mais, foram detectados sete aglomerados significativos. O principal, com RR de 8,61 , situou-Na análise espaço-temporal dos óbitos, foram encontrados 15 aglomerados significativos. O principal, com RR de 8,36  permanecNa análise de variação espacial nas tendências temporais, foram encontrados nove aglomerados significativos no conjunto do total de casos. Apresentam-se os valores das tendências temporais internas (INT) e externas (EXT) dos aglomerados. Com incremento anual interno de 4,52%, o aglomerado mais significativo ocorreu na região Sul do MSP .Na faixa etária de 50 anos ou mais, foram detectados apenas três aglomerados significativos. O principal, com incremento anual interno de 7,58%, também foi localizado na CRS Sul, próximo à fronteira com a região Oeste .No subconjunto dos óbitos, foram detectados sete aglomerados significativos. O principal, com incremento anual interno de 1,23% , envolveIndependentemente da faixa etária e da evolução dos casos de aids em homens, existem aglomerados espaciais, sobretudo nas regiões mais periféricas do MSP, que apresentaram maior incremento percentual anual das taxas da doença dentro dos aglomerados, em comparação às áreas externas a eles, o que denota uma tendência de “periferização” da epidemia nos homens neste município.Na –,–Este estudo procurou identificar aglomerados espaciais e espaço-temporais de aids em homens com 13 anos de idade ou mais no município de São Paulo, desde o aparecimento do primeiro caso, em 1980, até junho de 2012. Diversos métodos analisam a aglomeração global e local, com diferenças de desempenho em termos de poder e precisão,A progressão do HIV nas populações não ocorre de modo aleatório e uniforme, mas sim em função de comportamentos sociais íntimos e complexos entre duas ou mais pessoasO uso de ferramentas de análise espacial permite identificar diferenciais no comportamento do HIV/aids nas populações e nos espaços que ocupam. Tais técnicas contribuem também para a identificação de localidades onde há maior risco de adoecer ou morrer em função da doença, o que pode auxiliar a selecionar áreas para políticas e intervenções específicas por parte dos órgãos competentesA análise de varredura puramente espacial evidenciou que a aids se concentrou no Centro do município de São Paulo, independentemente da faixa etária e da evolução para o óbito. O Boletim Epidemiológico de Aids, HIV e DST do MSP de 2014,O risco relativo do aglomerado de homens com 50 anos ou mais de idade foi o maior dentre todos aqueles observados nas análises puramente espaciais. Entre 1996 e 2005, a taxa de incidência de aids entre homens de 50 a 59 anos passou de 18,2 para 29,8 casos/100.000 homens. Nos maiores de 60 anos, no mesmo período, também houve aumento da taxa, de 5,9 para 8,8. Até 2010, tal aumento se manteve nas faixas etárias acima dos 50 anos,,,O “envelhecimento” da população com aids tem sido destacado como uma tendência da epidemia no Brasil, e os idosos raramente são alvo de intervenções para a redução do contágioSegundo dados recentes do Ministério da Saúde, na última década observou-se um incremento da taxa de detecção de aids nos homens de 15 a 29 anos e com 55 anos ou mais, com destaque para os jovens de 15 a 24 anosNa análise de varredura espaço-temporal, foi observado um número expressivo de aglomerados, denotando que todas as regiões do município foram acometidas em algum momento, exceto a Sul. O aglomerado principal se manteve entre outubro de 1987 e março de 2004, no Centro da cidade, incluindo o ano de 1992, que apresentou a maior taxa de incidência de aids em homens adultos A semelhança do subconjunto de óbitos com aquele que incluiu todos os casos pode ser explicada pela alta letalidade da doença nos homens , sobretudo entre 1990 e 1996,O pico da mortalidade por aids em homens no município de São Paulo ocorreu em 1994 Uma análise realizada com as declarações de óbito (DO) do Sistema de Informações sobre Mortalidade (SIM) com menção de HIV/aids em qualquer campo de preenchimento das causas de óbito mostrou que no Brasil, entre 2000 e 2007, ocorreu um importante aumento no percentual de óbitos de pessoas infectadas pelo vírus por causas básicas não relacionadas ao HIV/aids, passando de 2,5% para 7,0%. Esse fato indica que outros agravos  têm impactado de forma crescente na sobrevida das pessoas com HIV/aids,Fatores como o diagnóstico tardio, coinfecções, a falta de acesso aos recursos de saúde, entre outros, atingem as pessoas vivendo com HIV/aids de forma mais intensa em algumas localidades do que em outrasNesse estudo da trajetória da aids no município de São Paulo, evidenciou-se uma tendência de “periferização” da doença nos homens, visto que áreas mais periféricas apresentaram, ao longo do tempo, maior incremento percentual das taxas dentro dos aglomerados do que as áreas externas a eles. Destaca-se que um aglomerado estatisticamente significativo nessa modalidade de análise não implica, necessariamente, que a taxa global da doença seja maior ou menor nele, visto que a estatística de varredura da variação espacial nas tendências temporais não está à procura de aglomerados de alto ou baixo risco, mas sim busca aglomerados com uma tendência interna maior ou menor do que a tendência fora delesOs estratos mais pobres são os mais afetados pela aids, em função de diversos aspectos relacionados à vulnerabilidade, como falta de recursos para a prevenção do HIV; dificuldade de acesso a serviços de saúde; situações de constrangimento, pressão e ameaças; precariedade de moradia, alimentação e emprego; baixa escolaridade e difícil acesso à informação,,,Em 1994, já se sinalizava a “pauperização” da aids, que acometia principalmente os estratos sociais mais pobres e moradores da periferiaEste trabalho apresenta algumas limitações, dentre as quais destaca-se terem sido estudados somente os casos de aids, não incluindo os de HIV assintomáticos, pois apenas a aids era agravo de notificação obrigatória no período do estudo. O período de latência prolongado da aids dificulta a caracterização do local onde os indivíduos adquiriram o HIV, pois quando são notificados com infecções definidoras de aids, um longo tempo já se passou desde o momento da infecção. Outra limitação diz respeito ao endereço de moradia dos pacientes informado nas fichas de notificação e investigação de aids, que pode não representar o verdadeiro local de residência, pois endereços imprecisos são fornecidos com o objetivo de se conseguir acesso à rede de assistência fora da região de moradia.Considera-se, ainda, a possibilidade de sub-registros da doença nos sistemas de vigilância e de mortalidade, principalmente nas primeiras décadas da epidemia, em função de mudanças nas versões da Classificação Internacional de Doenças , além do estigma relacionado à doença, que pode ter colaborado para a não menção dessa causa nas declarações de óbito. Além disso, as técnicas de varredura não possibilitam verificar associações entre exposição e desfecho, revelando apenas as localidades com maior risco ou proteção nas taxas da doença.Como ponto forte do estudo, destaca-se a expressiva proporção de casos de aids geocodificados . Além disso, o delineamento ecológico permitiu evidenciar efeitos não detectados no plano individual, e a opção por técnicas de varredura espacial, espaço-temporal e de variação espacial nas tendências temporais possibilitou a detecção de aglomerados geográficos de alto risco de aids em homens.Em conclusão, a epidemia de aids nos homens se concentrou na região central do município de São Paulo e em áreas contíguas das regiões Norte, Sudeste e Oeste, independentemente da faixa etária analisada e da evolução para o óbito. Ao longo do tempo, a doença alcançou homens em todas as regiões do município, com tendência de “periferização”. O estudo auxiliou a revelar áreas prioritárias no município de São Paulo, tanto para ações programáticas no âmbito do HIV/aids como para nortear outros estudos.


The number of patients and clinical conditions treated in home healthcare (HHC) is increasing. Care in home settings presents many challenges, including healthcare-associated infections (HAI). Currently, in Belgium, data and guidelines on the topic are lacking.To develop a definition of HAI in HHC and investigate associated risk factors and recommendations for infection prevention and control (IPC).The study included three components: a scoping literature review, in-depth interviews with individuals involved in HHC and a two-round Delphi survey to reach consensus among key informants on the previous steps’ results.The literature review included 47 publications. We conducted 21 in-depth interviews. The Delphi survey’s two rounds had 21 and 23 participants, respectively. No standard definition was broadly accepted or known. Evidence on associated risk factors was impacted by methodological limitations and recommendations were inconsistent. Agreement was reached on defining HAI in HHC as any infection specifically linked with providing care that develops in a patient receiving HHC from a professional healthcare worker and occurs ≥ 48 hours after starting HHC. Risk factors were hand hygiene, untrained patients and caregivers, patients’ hygiene and presence and management of invasive devices. Agreed recommendations were to adapt and standardise existing IPC guidelines to HHC and to perform a national point prevalence study to measure the burden of HAI in HHC.This study offers an overview of available evidence and field knowledge of HAI in HHC. It provides a framework for a prevalence study, future monitoring policies and guidelines on IPC in Belgium. In an ageing society, where the prevalence of chronic diseases is increasing and leading to new, advanced and often complex medical treatments, demand for healthcare is constantly rising. Considered the most frequent adverse event (AE) in healthcare delivery worldwide , healthcIn Belgium, as in other European and western countries, a considerable shift from inpatient care, provided in hospitals, to outpatient care, including home healthcare (HHC), has been observed in recent years ,7. HHC iIn recent decades, awareness of HAI has led to extensive research worldwide, which has identified risk factors and proposed measures and interventions to prevent or mitigate the consequences of HAI in inpatient care -14; howeThis study aimed to conduct a conceptual analysis of HAI in HHC, with the following objectives: (i) develop a definition for HAI in HHC, (ii) identify specific risk factors for HAI acquisition in HHC settings and (iii) develop a standardised framework for prevention and control of HAI in HHC in Belgium.To address the study objectives, we performed a scoping literature review, in-depth interviews and a two-round Delphi survey.Supplement I.The scoping literature review included peer-reviewed papers and grey literature written in English, Dutch, French, German, Italian and Spanish, conducted on patients receiving HHC, published in high-income countries after 1999 and relevant to at least one of the three aspects defined in the study objectives. We used PubMed, Embase, Science Direct, the Cumulative Index to Nursing and Allied Health Literature and Cochrane Library to search for peer-reviewed papers, and Google Scholar, Open Grey, the Networked Digital Library of theses and Dissertations, and Grey Literature Report to find grey literature. We screened the websites of WHO, the United States (US) Centres for Disease Control and Prevention, the European Centre for Disease Prevention and Control (ECDC), the Belgian Healthcare Knowledge Centre and the Belgian Superior Health Council and conducted hand searching of references to identify relevant cross citations. The search strategy and exact strings used are presented in Supplement II). We qualified these profiles based on their function or job title and their work experience. It was important to include individuals who were familiar with organisational, management and/or policy concepts regarding HHC and HAI so that they would be able to address the study objectives. Key informants were selected from all three Belgian regions: Brussels-capital, Flanders and Wallonia. We aimed to conduct a total of 30 interviews; however, this number could be lowered during the study if the information being collected was no longer adding new insights. Two of the study researchers (ED and LM) conducted recruitment and interviewed key informants, starting with individuals they already knew through their networks. Additional participants were recommended by this first group  or by colleagues, and others were identified though web-based searches performed using keywords such as ‘HHC in Belgium’, ‘hospitalisation at home projects’ and names of Belgian organisations providing HHC. An interview guide was developed and used during the interviews (Supplement III).We conducted in-depth interviews with key informants in Belgium, including healthcare professionals who were carrying out home visits or were involved in healthcare policy, HHC management or projects on hospitalisation at home. Key informants were selected using the purposive sampling method . To guidSupplement IV). The Delphi survey was conducted online, using LimeSurvey, and targeted the same key informants as the in-depth interviews.The Delphi survey consisted of two rounds. The first questionnaire was developed based on the results of the scoping review and the in-depth interviews, while the second was based on the results of the first round , in the participants’ native languages, in January and February 2019. They were audio recorded and interview notes were taken. For the data analysis we used the deductive framework approach, in which the research objectives are used to group the data and then look for similarities and differences ,19. ImmeStrongly disagree/very low importance”) to 4 (“Strongly agree/very high importance”), as well as the option “I don’t know”. Consensus was defined as a minimum of 80% of the respondents agreeing or strongly agreeing  with the statement. The “I don’t know” answers were excluded from the calculation and did not contribute to the denominator of the consensus percentage. Among the statements that achieved consensus, the mean was calculated and used to determine the level of importance. Statements for which consensus was reached in the first round of the survey were excluded from the second round. If contradictory statements achieved consensus in the first round, or if no consensus was reached, the statement was assessed again in the second round. For risk factors only, even statements for which consensus was reached in the first round were further assessed in the second round in order to identify the five most necessary and five most feasible to act on.The Delphi survey was conducted in March and April 2019. Level of agreement was measured and calculated using a four-point Likert scale ranging from 1 . Thirteen publications were articles written by experts that presented the state of the art or discussed best practices or guidelines, four were official guidelines and one was a draft of definitions for a surveillance system. The remaining 29 publications were research articles: 13 retrospective observational investigations, seven surveys, three literature reviews, three cohort studies, two point prevalence studies (PPS) and one randomised clinical trial.Supplement V.Among the 47 publications included in the study, 22 were from the US, 16 were from Europe, six were from Canada, one was from Hong Kong, one was from Saudi Arabia and one was not country specific and was published by WHO. Twenty-five publications focused on general unspecified HAI, or on multiple types of infection together, while 20 dealt specifically with catheter-related infections and two with ventilator-associated pneumonia. An overview of the results of the literature review is shown in Supplement VI.A total of 20 healthcare professionals  and one family caregiver participated in the in-depth interviews. Eleven interviews were conducted in Dutch and 10 in French, with each lasting 19–46 min. About half of the invited candidates agreed to be interviewed and we stopped enrolling participants when saturation of information was reached. A detailed description of the participants is provided in The response rate in the first and second round of the Delphi survey was 21/43 and 23/42, respectively. The two groups had an average of 14 years and 17 years of work experience in healthcare, respectively, of which more than half was specifically in HHC. The professional activities that were most represented were IPC, HHC practice and management of an organisation offering HHC services and policymaking.The definitions we encountered in the literature were heterogeneous. The Association for Professionals in Infection Control and Epidemiology (APIC) definition  was the During the in-depth interviews, most of the interviewees said they had never encountered or used a specific definition of HAI in HHC. A few referred to the APIC definition.Various risk factors emerged from the literature review; some were specific to a certain type of infection , while others were more general. The methodology through which risk factors were identified varied, and included multivariable analyses on datasets of patients in HHC who developed HAI , literatDuring the in-depth interviews, the vast majority of interviewees stated that risk factors for HAI at home were different than in hospital and classified them in three main categories: (i) patient’s lifestyle, living environment and socioeconomic status; (ii) patient’s characteristics and pathology; and (iii) the care provided.Several risk factors were selected based on the literature review and in-depth interview findings and were presented in the Delphi survey. Respondents agreed that an action to control risk factors is needed and feasible for the following: hand hygiene, patients’ personal hygiene, training of patients and caregivers about measures to prevent HAI in HHC and presence and management of invasive devices .The vast majority of the studies included in the literature review (43/47) provided some kind of recommendations, focusing either on prevention and control of HAI in HHC or more broadly on the improvement of the standardisation, reporting and benchmarking of HAI in HHC across different countries. Several studies highlighted the need to raise awareness of HAI in HHC among patients and their caregivers, as well as to empower and train patients and caregivers on the measures and practices that can contribute to safe and HAI-free HHC ,23,34-36Interviewees mentioned that the basic principles of IPC for HAI in hospitals and HHC were the same; nevertheless, their implementation in the home setting appears to be more challenging. The management of HAI in HHC is generally neglected compared with HAI prevention and control in hospitals and nursing homes, and the people working in the field of HHC feel the lack of general standardised guidelines.In the first round of the Delphi survey, respondents reached consensus for all of the suggested measures to prevent and control HAI in HHC. In particular, all respondents agreed on the need for standardised IPC guidelines for HHC, available and accessible to all staff involved in HHC, with room for adaptation to the local context. As shown in Based on the findings of this study, the definition of HAI in HHC should contain three main components: the specific link to care, the presence of a professional healthcare provider and occurrence at least 48 hours after HHC began . The DelThe lack of a broadly accepted definition of HAI in HHC is currently the main barrier to compiling and standardising the available evidence, and our work highlights that this lack, which has been previously reported in the US , is alsoMost of the information regarding risk factors for developing HAI comes from studies conducted in hospital settings, and the few studies done in homes are not consistent enough to establish robust and reproducible evidence. Previous efforts  and our Due to limitations in definition and risk factors, international recommendations for best practices are missing. Most published recommendations focus on ideas to initiate surveillance systems measuring infection and AE occurring in HHC, as well as to standardise indicators so that benchmarking is possible and best practices can be highlighted and implemented -43. ReceA few limitations might have impacted the results of our study. First, we did not perform a systematic review of the literature, as the scoping approach allowed more flexibility in the selection process and in the evaluation of the quality of the selected publications. Second, we excluded publications before the year 2000, which we found to be outdated in regards to our research topic, and were more often discursive rather than observational or experimental studies (data not shown). Third, selection bias might have been introduced in the in-depth interviews and the Delphi survey, as participation was on a voluntary basis and might not be representative of all healthcare professionals working with HAI in HHC. Further, some participants were known and selected by two of the study researchers (ED and LM) who work in HAI surveillance in Belgian; however, we considered their network to be quite representative of the HHC professionals working in the area. More specifically, we lacked participation of academics. Finally, the number of participants in the interviews and the Delphi survey was relatively limited. However, the interviews were conducted until we reached saturation of information, and the voluntary participation in the first round of the Delphi survey was around 50% and stayed almost stable in the second round.To our knowledge, this is the first study that attempts to disentangle various aspects of HAI in HHC in Belgium. We tackled the issue from different perspectives  in order to compile a wide range of information and we strongly believe that it serves as valid ground for harmonised work and further research in order to guarantee quality across the continuum of healthcare.To better understand the dynamics of HAI in HHC in Belgium, and to address the knowledge gaps identified, it appears necessary to conduct a national PPS that covers the whole country and uses the proposed definition. We suggest that it be conducted as an independent investigation, coordinated by a study group who could refer to the ECDC protocols of HAI in acute care hospitals  and HAI Additionally, we suggest the development of specific recommendations and guidelines regarding the prevention and control of HAI in HHC at the national level. The drafting of these guidelines could be coordinated and written by the Belgian Superior Health Council, who could use existing national and international guidelines (e.g. WHO guidelines on hand hygiene) and empirically adapt these to the HHC context.Our study refers mainly to Belgium, but we are aware that several HHC realities across Europe are similar to what we observed. The study recommendations—for a standardised definition of HAI in HHC and adaptation of ICP guidelines—can therefore be applicable to other countries as well. In order to harmonise definitions and practices surrounding HAI in HHC and support individual countries in dealing with the complexity of this topic, institutions such as ECDC could contribute by promoting collaboration towards a standardised definition and agreement on common ICP guidelines to use across Europe.