Durability improvement is always important for steel–concrete structures exposed to chloride salt environment. The present research investigated the influence of a novel nano-precursor inhibiting material (NPI), organic carboxylic acid ammonium salt, on the mechanical and transport properties of concrete. The NPI caused a slight reduction in the strength of concrete at later ages. NPI significantly decreased water absorption and slowed down the speed of water absorption of concrete. In addition, the NPI decreased the charge passed and the chloride migration coefficient, and the results of the natural chloride diffusion showed that the NPI decreased the chloride concentration and the chloride diffusion coefficient. The NPI effectively improved the resistance of chloride penetration into testing concrete. The improvement in the impermeability of concrete was ascribed to the incorporation with the NPI, which resulted in increasing the contact angle of cement pastes. The contact angle went up from 17.8° to 85.8° for 0% and 1.2% NPI, respectively, and cement pastes became less hydrophilic. Some small pore throats were unconnected. Besides, the NPI also optimized the pore size distribution of hardened cement paste. Chloride salt-induced corrosion of reinforcement steel, in concrete structures exposed to chloride environments, has caused huge losses and casualties. The durability of reinforced concrete remains a challenge for developing green and sustainable infrastructures .Chloride diffusion coefficient is a key parameter of concrete that closely relates with rebar depassivation. Traditionally, many approaches have been applied to decrease the chloride diffusivity of cement-based materials or increase the time of rebar depassivation, including lowering the water–cement ratio of the concrete, replacing cement with mineral admixtures , expandi2 were used to modulate the transport properties: TEOS decreased the porosity of the pores smaller than 0.1 μm, while nano-SiO2 blocked the pores of around 0.1 μm, and thus reduction in water absorption was achieved in the case of both. Kong [Some new chemical admixtures were reported to decrease the water absorption and chloride diffusivity of concrete. Atzeni  reportedth. Kong  observedth. Kong  investigth. Kong  found thth. Kong ,24,25,26th. Kong ,29,30,31As one of the promising chemical admixtures, nanomaterials can be used to improve the durability performance of cementitious materials by refining the pore size distribution and accelerating hydration, while they may cause agglomeration and loss of workability because of their high specific surface. However, there is a strong demand for water-soluble and easy-to-use agents to enhance concrete resistance to chloride ion penetration. Based on preliminary research , the NPIThe chemical compositions of commercially available ordinary Portland cement , and ground granulated blast furnace slag (GGBS) are shown in 2/g, 4827 cm2/g, and 3036 cm2/g respectively. Their particle sizes distributions are illustrated in 50 and volume mean diameter are 18.68 µm and 23.97 µm for cement, 9.12 µm and 14.61 µm for fly ash, and 20.35 µm and 29.03 µm for slag, respectively. The range of particle size distribution of cement is narrower than that of fly ash and slag. Natural river sand and mechanically crushed stone were used in this experiment. The fineness modulus of river sand was 2.6. OPC was manufactured for testing concrete admixtures without mineral admixtures based on the Chinese standard Concrete admixtures (GB/T 8076-2008) . The spe−1 indicated the presence of small amounts of organic acids, and a clear absorption peak between 3300–3500 cm−1 indicated the existence of -NH2 or -NH groups. An absorption peak at 1380 cm−1 was further evidence of the presence of the above groups. An absorption peak at 3100 cm−1 indicated the subsistence of C-H, and an absorption peak at 2850–2960 cm−1 indicated the presence of -CH2. An absorption peak at 1000–1300 cm−1 indicated the existence of a large number of -C-O bonds.The product of organic alcohol amine salt was a light yellow liquid product produced by Jiangsu Sobute New materials Co., Ltd., Nanjing, China. Its solid content was 18%. The preparation process was described as follows: aliphatic organic carboxylic acid with a carbon atom number of 8 to 22, alkylol amine, ethanol, and an appropriate catalyst were put into a three-necked flask and stirred evenly and heated to 140 °C for 12 h. Water and other functional additives were slowly added to the flask after heating treatment and cooling down. Finally, the required concentration of the nano-precursor inhibiting material (NPI) was prepared. The infrared spectrum of the NPI is shown in 3. Concrete specimens with 0%, 0.6%, 0.9%, and 1.2% NPI were cast in this study. The workability of concrete was adjusted by adding a polycarboxylic superplasticizer. The slump was 160 ± 20 mm. The samples were placed in a curing room  after demoulding.The concrete mix is shown in The compressive strength of the concrete was tested at 3, 7, 28, and 112 days according to the China standard for test method of mechanical properties on ordinary concrete (GB/T 50081-2002) , which wIsothermal calorimetry is widely used to measure the thermal power and the heat of hydration of cement-based materials. TAM Air  was employed to investigate the effect of NPI on cement hydration. The apparatus was checked and kept at 20 °C. Then, to test the initial baseline, cement pastes were stirred with an electric machine for 2 min, and 14 g of cement paste was transferred into a vial for the test.The samples were cured for 28 days in water. Then, cement hydration was stopped by ethanol. The samples were vacuum oven-dried for 3 days and were broken into pieces of about 2 g. The MIP technique is extensively applied to characterize the pore structure in porous materials. The testing apparatus used for pore structure measurement is Poremaster GT-60. The MIP test is based on the assumption that the nonwetting liquid mercury (the contact angle between mercury and solid is greater than 90°) will only intrude in the pores of cement-based materials under pressure. The Washburn equation was used to calculate the experimental data.P is the pressure of mercury intrusion (N/m2),d is the test pore diameter (m),γ is the surface tension of mercury (N/m2), andθ is the contact angle between the mercury and the cement paste.The morphologies of cement hydrates were observed with a Quanta 250 field emission scanning electron microscope . An FEI 3D microscope was used. The samples were treated following the same approach applied for MIP and were broken into pieces. Their fresh fracture sections was coated with 15 nm gold before conducting the observation.The concrete samples were dried for 72 ± 2 h at 105 ± 5 °C, then sealed to cool down for 24 h. The mass of the samples was recorded. Next, the samples were immersed in water, so that 25 ± 5 mm of water was above the tops of the specimens. The water on the sample surfaces was removed with a wet cloth, and the mass of the samples was recorded again. The previous procedure was repeated according to the time schedule. The procedures were consistent with BS 1881-122:2011 Testing concrete. Method for determination of water absorption , but theCylindrical concrete was coated with epoxy resin, cut to slices 50 mm thick, and then was vacuum-saturated with a hydroxide solution. Three samples were tested for rapid chloride permeability as per ASTM C1202 . The spenssmD is non-steady-state migration coefficient (×10−12 m2/s);T is the mean value of the initial and final temperatures in the test anolyte solution (°C);L is the thickness of the test concrete specimen (mm);U is the absolute value of the applied voltage (V);t is the test duration time (h); anddx is the average value of the chloride penetration depths (mm).Two samples were coated with epoxy except the cutting surface, saturated with water, and then immersed in 165 g/L sodium chloride solution. After 57 days, the specimens were carefully ground layer by layer, perpendicular to the exposed surface. The total chloride concentration was obtained through titration, based on the standard NT Build 443 .Three cement pastes were sliced to smooth tablets, then dried at 40 °C for 2 days. The contact angle test of cement paste with water was conducted using Drop Shape Analyzer—DSA25. DSA25 is a reliable instrument for measuring the contact angle and surface energy. The testing range of the contact angle is 1–180°. Cement paste was placed on the stage, and the syringe was adjusted to prepare the maximum water droplet adhering to just the needle tip. The stage was slowly lifted up, and the contact process of the water droplet with the surface of the cement paste was recorded with a high-speed camera. Then, the snapshot was used to analyze the contact angle.3A. The induction period of cement hydration was also slightly extended. The exothermal peak of cement hydration was delayed due to the addition of the NPI. However, The exothermal rates of cement pastes with different dosages of the NPI were obtained by isothermal calorimetry, as shown in On the whole, incorporation of the NPI caused a reduction in the compressive strength of concrete. The strength reduction is not significant at the later ages. The compressive strength reduction of the concrete sample incorporated with 0.6% of the NPI was due to a high content of entrained air voids, whereas the hydration was not affected by the NPI, as indicated by the results of isothermal calorimetry.−12 m2/s to 5.9 × 10−12 m2/s with the exception of concrete with 0.6% dosage of the NPI. The chloride migration coefficient of the concrete sample incorporated with the NPI decreased by 28% to 43% at the curing age of 112 days. It is worth noting that the dosage of 0.6% NPI exhibited the biggest drop compared to other samples. The chloride migration coefficient of the concrete sample decreased from 6.1 × 10−12 m2/s to 5.2 × 10−12 m2/s when the dosage of the NPI was increased from 0.6% to 1.2% at the age of 112 days. The concrete samples with 0.6% NPI had higher values of charge passed and the chloride migration coefficient than other groups because of their higher porosity and coarser pore size.The chloride diffusion coefficient and surface chloride concentration were computed by fitting the relevant data points into Equation (3) by means of a non-linear least-squares regression analysis. The fitting results are listed in xC is the chloride content measured at a certain average depth x and exposure time t (% by mass of immersed concrete);sC is the calculated chloride concentration at the exposed surface (% by mass of concrete);iC is the initial chloride content of plain concrete (% by mass of concrete);x is the depth below the top exposed surface to the mid-point of the grounding layer (m);nssD is the non-steady state chloride diffusion coefficient (m2/s); andt is the exposure time (s).The fitting results of the chloride diffusion coefficient were complex. The chloride diffusion coefficient of concrete decreased when the NPI increased from 0% to 0.9%. The chloride diffusion coefficient of concrete with 1.2% NPI increased, but the actual chloride content of the concrete with 1.2% NPI was still the lowest compared with other groups at the same depth. The NPI decreased the chloride diffusivity of concrete. The chloride content was the main factor that resulted in steel corrosion in the concrete structures, so the recommended dosage of the NPI is 1.2% of binder materials.The NPI contributed to improving the concrete resistance to water and chloride penetration. The role of the NPI on transport properties was ascribed to the optimization of pore structure and increment of hydrophobicity.The results of the pore size distribution and the total porosity of cement paste incorporated with the NPI are shown in The results of According to 2/polymethylhydrosiloxane was 116.5° according to Li et al. [As mentioned at the beginning of the present research, the NPI can increase the hydrophobicity of concrete to resist water absorption. The results of the contact angles of cement pastes modified with the NPI are listed in i et al. . The moli et al.  showed tThe NPI not only optimized the pore structures of cement pastes but also increased hydrophobicity. Therefore, incorporation of the NPI was helpful to increase the capacity of concrete to resist the transport of aggressive ions and water, which was proved through the results of water absorption, chloride migration, and diffusivity described in the present research.It was reported ,44 that A novel nano-precursor inhibiting material (NPI), organic carboxylic acid ammonium salt, was used to modify the properties of concrete. It was a promising material for increasing the hydrophobicity of cement paste to improve the resistance of water and chloride ion penetration into concrete, meanwhile minimizing the negative effect of the hydrophobic hydrocarbon chain on the compressive strength of concrete.(1)The NPI caused a reduction in the strength of concrete, but the strength reduction was minor at a later age. The NPI increased the total porosity and entrained big capillary pores in cement pastes, and the alkane chain resulted in a weaker ITZ in concrete. These reasons led to a decline in the compressive strength of the concrete samples.(2)The incorporation of the NPI significantly decreased water absorption and slowed down the speed of water sorptivity in concrete. The NPI also decreased the charge passed and the chloride migration coefficient of concrete. It is worth noting that the NPI effectively decreased the chloride diffusion coefficient and the chloride content at a depth lower than 5 mm and the surface chloride concentration of concrete.(3)The improvement in the transport properties of concrete was due to the incorporation with the NPI, which resulted in a gradual ascent of the contact angle from 17.8° to 85.8° when the dosage of the NPI was increased from 0% to 1.2%, and the surfaces of cement paste became less hydrophilic. Moreover, the NPI also changed the pore size distribution of hardened cement paste.


IgG4-related disease is an immune-mediated chronic, systemic, and autoinflammatory disease that can affect various organs throughout the body. The most commonly affected areas are the pancreas and biliary system. Due to the diverse clinical manifestations of the disease, it affects widely distributed organs. Thus, it is often easy to misdiagnose or miss. The digestive tract is a rarely affected system, and most IgG4-related gastric diseases manifest as tumors detected by endoscopy. This article reports two special cases with IgG4-related disease involving atrophic gastritis and intestinal polyps to provide a more empirical and theoretical basis for clinical diagnosis and treatment. IgG4-related disease (IgG4-RD) is a chronic, systemic, and autoinflammatory disease mediated by the immune system. Although this disease may be classed as ‘autoinflammatory’, in fact this disease has many autoimmune manifestations, such as jaundice, fatigue, joint pain, enlarged glands, etc. The main clinical features of the disease are swelling, fibrosis, and sclerosis of the affected organs. The concentration of serum IgG4 is significantly increased. The affected tissues and organs are infiltrated by a large number of lymphocytes that form germinal centers, in particular, IgG4-positive plasma cells. The disease may involve various organs, such as the pancreas, biliary gland, lymph node, eye, thyroid, lung, kidney, prostate and skin . The bilA 52-year-old male presented with yellow urine and abdominal distension for more than one month and yellowish skin and sclera for 20 days. There was no obvious cause for the darkening of the urine, visible abdominal distension or aversion to oily foods. However, the patient was not concerned about these symptoms. After ten days, he developed yellowish skin and sclera. However, there was no fever, fatigue, skin itching, nausea, vomiting, abdominal pain, or significant change in body weight. Therefore, the patient went to a local hospital for a test for abnormal liver function indicators. Image indicated obstruction at the hilar biliary and hilar occupation at the bile duct. Accordingly, hilar cholangiocarcinoma was likely. After admission, relevant laboratory examinations were performed. Liver function test including AST, ALT, ƴGT, ALP, total bilirubin were all elevated. The autoimmune antigen spectra were all negative. The IgG4 subtype test revealed an IgG4 level of 5.22 g/L , which was significantly higher than the upper limit of normal. Infection-related indicators  and tumor markers had no abnormalities. Other tests  were all normal. Doppler ultrasound of the liver, gallbladder and spleen showed that the inner diameters of the left hepatic duct, right hepatic duct, and common bile duct were approximately 0.72 cm, 0.86 cm, and 1.06 cm, respectively. This result indicated that the bile ducts inside and outside of the liver were dilated. The common bile duct was not clearly displayed, and hypoechoicity could be seen in partial areas. Space-occupying lesions could not be excluded. The patient also completed computed tomography (CT), magnetic resonance cholangiopancreatography (MRCP) and magnetic resonance imaging (MRI) of the abdomen  cells in IgG4-RD lesions produce IL-10 and TGF-β. IL-10 is associated with antibody switching of B cells, and TGF-β is associated with tissue fibrosis . In addiAfter the diagnosis, we identified the patient’s affected organs. One of the most commonly involved organs in IgG4-RD is the pancreas, and the resulting disease is referred to as IgG4-related pancreatitis. The diagnosis is mainly based on typical imaging findings and laboratory examinations. Imaging examination of the patient revealed fullness and swelling of the pancreas, and this finding combined with the IgG4 indicators resulted in the diagnosis of IgG4-related pancreatitis . Bile duTo our surprise, we found that the patients had gastrointestinal involvement, which is less common in IgG4 disease and is easily missed. At present, there are few reported cases of IgG4-RDs involving the digestive tract. A meta-analysis suggests that the relative risk for IgG4-RD and gastric cancer can reach 1.69 . Skorus in vitro and in vivo techniques. Very few patients could be diagnosed with other gastric diseases by gastroscopy. Similar to the previous report, the two cases were diagnosed IgG4-RD involving the gastrointestinal tract with elevated IgG4, which were confirmed by endoscopic biopsy and IgG4 immunohistochemical staining. But it is different that our patients have been diagnosed with IgG4-RD through symptoms, tests, examinations, and pathology. During the process of exploring the related organs, routine endoscopic screening was used to confirm the involvement of the gastrointestinal tract. And the patients in our cases were diagnosed with atrophic gastritis and multiple colon polyps by endoscopy, which is a special and amazing discovery among IgG4-RD patients. Furthermore, IgG4-RD can not only affect the stomach but can also be limited to the stomach. Patients with multiple organ IgG4-RD are mainly elderly men and often have elevated serum IgG4 levels. In contrast, isolated gastric IgG4-RD mainly affects female patients with normal serum IgG4. However, the difference between the two disease presentations needs to be further studied and determined. It is important to note that the concentration of serum IgG4 is only measured in a small number of patients before surgery. Therefore, the stomach is often ignored in IgG4-RD.The incidence of IgG4-related diseases is gradually increasing. Its clinical manifestations are diverse, and the involved organs are widely distributed. Therefore, it is necessary to pay attention to the screening of multiple organs in clinical examinations. The possibility of IgG4-related diseases must be considered in addition to malignant tumors, especially in the presence of biliary space-occupying lesions.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by the First Affiliated Hospital of China Medical University. The patients provided written informed consent to participate in this study. Written informed consent was obtained from the individuals for the publication of any potentially identifiable images or data included in this article.YL designed the study. XZ and XJ wrote the original draft. LG collected the case. XLin and XLi provided the photo. XZ and YL reviewed and edited. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


More emerging evidence showed that homologous recombination (HR) defect (HRD) may predict sensitivity to platinum agents in metastatic prostate cancer (PCa). Platinum-based neoadjuvant chemotherapy for PCa with HRD has not been reported. Here, we reported a man diagnosed as locally advanced PCa with high Gleason Score (5 + 5) and low PSA level (5.2 ng/ml). Next-generation sequencing (NGS) demonstrated HRD. He received six cycles of platinum-based neoadjuvant chemotherapy before radical prostatectomy (RP). Fifteen months after RP, his PSA level was still undetectable, and no imaging progression was found, indicating a potential role for platinum-based neoadjuvant chemotherapy in locally advanced PCa with HRD. The incidence of prostate cancer (PCa) has been increasing and shows younger trend over the years in China, especially in the urban areas, possibly because of more active prostate-specific antigen (PSA) screening, improved biopsy techniques, or popular Westernized lifestyle . Most ChPrevious studies have identified that about 20%–30% of patients with primary PCa harbor alterations in genes involved in homologous recombination (HR) pathway, including BRCA2 . Deleter). Results of prostate-specific membrane antigen (PSMA)-PET/CT scan showed a high level of asymmetrical PSMA uptake in the prostate, confirming invasion of the seminal vesicle and rectum  showed that the prostate was in irregular shape with an estimated volume of 84.6 ml. The boundary of the left lobe of the prostate with the rectum and the bilateral seminal vesicles was not clear. Pathological examination and immunohistochemistry of the tumor tissue from transurethral resection demonstrated that it was PCa adenocarcinoma with a Gleason score 10 (5 + 5) (2 plus cisplatin 130 mg/m2) on October 11, 2019  on his blood sample. The results revealed several pathogenic mutations in the HR pathway including BRCA2 p.F2234fs with a mutant allele frequency (MAF) of 1.2%, RAD51C c.905-2A>G . As the patient refused radiotherapy, neoadjuvant therapy combined with RP was considered. Due to NGS detection of several somatic pathogenic mutations in the HR pathway, he participated in a clinical trial (NCT04869371) and commenced on androgen deprivation therapy (ADT) plus platinum-based neoadjuvant chemotherapy   for localized or locally advanced PCa during 1966–2007. The results showed that NHT prior to RP significantly reduced positive margin rates, grade of tumor, and lymph node invasion but failed to improve overall disease-free survival . NowadayPCa is a highly heterogeneous tumor even at its local stage. Neoadjuvant treatment of PCa is still focusing on intensive hormone therapy and thus lack of individualization, which may result in the limitation of complete pathological response . PrecisiIn our case, the patient was with low PSA level and high Gleason Score at diagnosis. PSMA-PET/CT scan confirmed invasion of his seminal vesicle and rectum. Results of NGS analysis revealed pathogenic somatic mutations in the HR pathway. All of the above features suggested that the patient seemed to be more prone to micro-metastases and produce rapid clinical progression. Thus, a more aggressive treatment, ADT plus platinum-based neoadjuvant chemotherapy combined with RP, was finally chosen for him. After six cycles of treatment, the patient got better with decreased PSA level (0.615 ng/ml), reduced prostate size (from 84.6 to 34.3 ml), and diminished clinical symptoms. In addition, his second NGS results on blood sample collected after neoadjuvant therapy demonstrated that pathogenic mutations in the HR pathway disappeared, indicating tumor cell destroyed by platinum-based chemotherapy. Furthermore, 15 months after RP, the patient remains in clinical benefit and stable disease without increase in PSA and imaging progression. To our knowledge, this is the first case to report locally advanced PCa with HRD exhibiting outstanding response to platinum-based chemotherapy in neoadjuvant setting.We reported a patient with locally advanced PCa with HRD presenting pathological response and long duration of stable disease with no biochemical recurrence or imaging appearance of metastasis to platinum-based neoadjuvant chemotherapy. This work indicates a potential role for platinum-based neoadjuvant chemotherapy in the treatment of locally advanced PCa with HRD and advocate that treatment decisions can be individually tailored, possibly improving patient outcomes.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.Conception and design of the work: JZ, SZ, XQ, YF, SA, TZ, YY, and HG. Supervision and writing of the paper: JZ. All authors contributed to the article and approved the submitted version.TZ and YY are employed by GloriousMed Clinical Laboratory (Shanghai) Co., Ltd.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The importance of closely observing patients receiving antibiotic therapy, performing therapeutic drug monitoring (TDM), and regularly adjusting dosing regimens has been extensively demonstrated. Additionally, antibiotic resistance is a contemporary concerningly dangerous issue. Optimizing the use of antibiotics is crucial to ensure treatment efficacy and prevent toxicity caused by overdosing, as well as to combat the prevalence and wide spread of resistant strains. Some antibiotics have been selected and reserved for the treatment of severe infections, including amikacin, gentamicin, tobramycin, and vancomycin. Critically ill patients often require long treatments, hospitalization, and require particular attention regarding TDM and dosing adjustments. As these antibiotics are eliminated by the kidneys, critical deterioration of renal function and toxic effects must be prevented. In this work, clinical data from a Portuguese cohort of 82 inpatients was analyzed and physiologically based pharmacokinetic (PBPK) modeling and simulation was used to study the influence of different therapeutic regimens and parameters as biological sex, body weight, and renal function on the biodistribution and pharmacokinetic (PK) profile of these four antibiotics. Renal function demonstrated the greatest impact on plasma concentration of these antibiotics, and vancomycin had the most considerable accumulation in plasma over time, particularly in patients with impaired renal function. Thus, through a PBPK study, it is possible to understand which pharmacokinetic parameters will have the greatest variation in a given population receiving antibiotic administrations in hospital context. Therapeutic drug monitoring (TDM) was implemented in the 1960s to improve patient care and clinical outcome, and specializes in the measurement of circulating drug concentrations to adjust dosing regimens, so as to reach a defined target exposure associated with optimal efficacy and minimal toxicity . Since tImportantly for this work, therapeutic drug monitoring and dosage adjustments are crucial for antibiotics, and have confirmed beneficial results ,13,14,15Furthermore, the increasing resistance rates to antimicrobial agents are a pressing problem that has been indefectibly associated with the inappropriate administration and overuse of these drugs, which has accelerated this process over the past 80 years. About half of the antimicrobial agents prescribed to hospital inpatients are considered inappropriate . DiffereThese four antimicrobial agents are an example of antibiotics that have been reserved for the treatment of severe infections, in an attempt to save these valuable drugs from the threat of selection of resistant bacteria. Healing these infections often requires long periods of time of antibiotic therapy and hospitalization. This poses serious concerns, namely regarding plasma accumulation of these drugs, toxicity, and impairment of renal function. Kidneys’ deterioration can be an effect of the disease or a consequence of long-term treatment. Since these antibiotics are mainly renally eliminated and their clearance is an important factor to consider when determining treatment regimens, therapeutic drug monitoring and dose adjustment are imperative to ensure a good clinical outcome of these patients.In this work, clinical data from a cohort of Portuguese inpatients with severe infections were collected and analyzed, and the influence of therapeutic regimens, biological sex, total body weight, and renal function on the pharmacokinetic (PK) profile was studied for four antibiotics: aminoglycosides amikacin, gentamicin, and tobramycin, and glycopeptide vancomycin. PK studies including physiologically based pharmacokinetic (PBPK) modeling and simulations were performed using GastroPlus™, based on our experience and previous works that have highlighted the value of in silico tools ,35,36.Centro Hospitalar Universitário do Porto  with severe systemic infections of different etiologies. These patients received intravenous (IV) treatment with one of four antibiotics: aminoglycoside amikacin, gentamicin, or tobramycin, or glycopeptide vancomycin. Drugs were administered via 30-min infusions in the case of aminoglycosides and 1-h infusions for vancomycin. Throughout the hospitalization and treatment period, trough and peak antibiotic concentrations as well as serum creatinine levels were determined to adjust posology and evaluate renal function  and clinical information were collected from 82 inpatients hospitalized in  formula ). RecommPBPK modeling and simulation software GastroPlus™ version 9.5  was used for the prediction of PK parameters and generation of simulated human plasma concentration profiles. Some physicochemical properties of the four antibiotics and input parameters used in the simulations are presented in GastroPlus™, a powerful mechanistically based simulation and modeling software, has been specifically developed for pharmaceutical research. Physiological parameters of several species, including human, are preinstalled, allowing for the amount of drug that is released, dissolved, and absorbed to be modeled for nine compartments, corresponding to different segments of the digestive tract, based on a set of differential equations. The Advanced Compartmental Absorption and Transit (ACAT) and Physiologically Based Pharmacokinetic (PBPK) models support model-based drug development throughout multiple stages of drug discovery, translational research, and clinical development, making it a powerful tool. As such, this software has been used in numerous research studies, but also by distinguished pharmaceutical companies and by the U.S. Food and Drug Administration, the U.S. Centers for Disease Control and Prevention, the U.S. National Institutes of Health, the U.S. National Cancer Institute, and the China Food and Drug Administration ,46. A PBEvery simulation was performed to study the PK for 72 h after IV administrations of each antibiotic, over 30-min infusions for aminoglycosides amikacin, gentamicin and tobramycin, and 1-h infusions for vancomycin.For each antibiotic, a customized PBPK model was built to represent the average of that subpopulation (receiving treatment with a particular antibiotic). The input parameters were age, total body weight, and renal clearance . DiffereThe available data only included measured concentrations from 2 time points: right before a dose and 1 h (aminoglycosides) or 3 h (vancomycin) after the beginning of an infusion. Since in GastroPlus™ the observed data can only be used as input referring to a single administration, this prevented a further refined parameterization and validation of the developed models. Nevertheless, the predicted pharmacokinetic parameters were reasonably consistent with the observed values after administration of all analyzed doses for these 4 antibiotics.max and AUC: doubling the dose increased these PK parameters by 2-fold. Additionally, with shorter time intervals between doses, antibiotic accumulation in plasma was more evident. Regarding biological sex, slight differences were observed between the profiles simulated for male and female subjects; a higher Cmax, but lower concentrations until following administration is predicted for male individuals, except for vancomycin, where only differences in Cmax were noted.Different therapeutic regimens  were studied for each antibiotic, based on the most common schemes administered to the patients in the study population. The influence of biological sex was also assessed. The simulation-calculated PK parameters are presented in max and higher drug concentrations maintained throughout time. The plasma concentration–time profiles showing the influence of this parameter are shown for each antibiotic in Concerning body composition, the influence of total body weight was assessed, and the resulting PK parameters are presented in Cr was the most significantly impacting factor on antibiotics plasma concentrations. PK parameters are presented in Finally, the influence of renal function was evaluated. This is a particularly relevant consideration, since during treatment , kidneys can be affected as a side effect of medication, and renal function is often impaired. The PBPK simulations confirmed this, and CLCr, antibiotic concentrations are much higher in comparison to individuals with normal functioning kidneys. This is exceptionally important in the case of vancomycin, where the differences between the lower and upper limits of observed CLCr were exceedingly significant.When considering the lowest CLSince the influence of renal function on the PK profile of the antibiotics was so significant, the observed differences were further analyzed.peak of the last and Cpeak of the first administrations were also determined (The differences in the predicted antibiotics concentrations at 72 h between the simulation for the lowest and average CL, and lowest and highest CL were calculated . For thetermined . As aforIn this work, clinical data from inpatients with severe systemic infections were analyzed and PBPK simulations were performed to study the pharmacokinetic profile of four clinically used antibiotics: amikacin, gentamicin, tobramycin, and vancomycin. The importance of therapeutic drug monitoring and regimen adjustment was further demonstrated, by highlighting the influence of parameters such as a patient’s total body weight and the significant impact of renal function on antibiotic plasma concentrations. It was made evident that patients with low body weight and especially those with impaired renal function, whether preexisting or due to kidney deterioration throughout treatment, must be closely monitored and their therapeutic regimens frequently revised to adjust to their plasma antibiotic concentrations and PK profile. We also found that renal function is the parameter that has the greatest impact on the Cp-time profile of these antibiotics, especially vancomycin, but that there are certainly other factors affecting PK and more optimizations to be made to these PBPK models, since the values obtained in the simulations may come even closer to those observed clinically. In particular, it is known that hospitalized and critically ill patients have altered PK and the fact that in this project it was not possible, due to software limitation, to insert the observed concentrations into the models, refining, optimizing, and then validating them, also contributed to the slight differences between the simulated and clinical results.The results presented here deepen the knowledge on the impact and influence of these parameters on the biodistribution of these antibiotics. This is crucial not only to ensure a successful clinical outcome, but also to prevent serious side effects, and, as such, can assist clinicians in the process of adjusting therapeutic regimens. In this context, the helpfulness of in silico tools, such as PBPK modeling and software such as GastroPlus™, was also verified.


Probabilistic procedures considering the durability with respect to corrosion of reinforcement caused by aggressive substances are widely applied; however, they are based on narrow assumptions. The aspects need to be evaluated both in terms of the search for suitable application of the various experimental results and in terms of their impact on the result of the stochastic assessment itself. In this article, sensitivity analysis was used as an ideal tool to prove how input parameters affect the results of the evaluation, with consideration of different types of concrete (ordinary or self-compacting with and without fibres). These concretes may be used in aggressive environments, as an industrial floor or as a part of the load-bearing bridge structure. An example of a reinforced concrete bridge deck was selected as the solved structure. The results show that in the case of a classic evaluation, a larger amount of fibre reports a lower resistance of concrete, which contradicts the assumptions. The sensitivity analysis then shows that self-compacting concrete is more sensitive to the values of the diffusion coefficient, and with the consideration of fibres, the effect is even greater. The driving force behind the research on new concrete-based composite materials is the reduction of greenhouse gases and the increasing of sustainability of load-bearing and other structures . The impOne of the many possibilities is self-compacting concrete (SCC), which is often used in buildings as a cover for industrial floors thanks to its very good workability . The basThere are analytical and numerical approaches to calculate the durability and service life of the structure. Many of them use the finite element method (FEM) in combination with probabilistic methods. Probabilistic calculations of the durability of concrete structures influenced by the aggressive substances play an important role ,23,24. TThis paper aims to provide an analysis of the durability of the concrete in an aggressive environment and subsequent sensitivity analysis of the individual input parameters. The material parameters are based on a published study of SCC with different amounts of fibres . Other pThe compositions of the mixtures are presented in The concretes were prepared with the cooperation of the laboratories of the Silesian University in Gliwice and the VSB Technical University of Ostrava. Concrete mixtures from a comprehensive project dealing with the durability of concrete structures were selected for the study. The reference concrete was made of ordinary Portland cement (OPC). Self-compacting concrete (SCC) was prepared without fibres and also with fibres in amounts of 1% and 2% by weight of mass in the mixtures. The fibres are made of steel, KE20/1.7 type.The same specific production procedures were followed. A concrete collapse test was performed on all concretes, and it was proven that all mixtures belong to the same consistency class. All investigated concretes have a cylinder strength in 28 days of about 40 to 50 MPa and, therefore, could be used in a bridge structure.A previous study  showed tThe numerical model for the calculation of corrosion initiation based on the finite element method was introduced earlier in ,45. It aThe numerical example was performed using a probabilistic approach with a number of 100,000 simulations. The Monte Carlo probabilistic solution was applied in each step of the simulation. The durability analysis was based on a comparison of the actual chloride concentration at the reinforcement level and the chloride threshold value. When the chloride threshold is exceeded, a situation arises where corrosion of the reinforcement can be initiated. The stochastic approach evaluates this at each simulation step and uses the quantity function to evaluate an estimate of the probability of failure. Probability levels of 5%, 10% and 25% were selected.The objective of the sensitivity analysis of the model is to quantify the relative importance of the individual input parameters. This type of analysis is important mainly to reduce the space of random variables for stochastic calculation. An overview of available methods is provided in many review articles, e.g., ,47,48,49As the monitored results, the probability quantile function, the correlation coefficients between the random variables and the resulting values of the reliability function and the significance analysis of the input variables on each other were selected.The problem studied is the probability of corrosion initiation. The quantile function of corrosion initiation for all four investigated concretes is shown in Corrosion initiation represents a period when chloride penetrates the cover layer of concrete, but corrosion has not yet started in any place in the reinforcement ,52. As aBased on the probability results, one should notice that the possibility of corrosion occurs earlier for self-compacting concrete with fibres, for both the 1% and 2% mixes. On the contrary, the probability of failure is observed to be the latest for self-compacting concrete without fibres. Standard concrete (OPC) is then worse than SCC without fibres but better than SCC with steel fibres. SCC, in general, may exhibit better diffusion properties, but conversely, fibres may increase the area bond between the concrete parts and thus negatively affect diffusion ,53.th), the chloride concentration on the surface (C0), the depth of reinforcement (Z) and the diffusion coefficient (D) as inputs on one side, and the results of the reliability function on the other side. The chloride threshold for corrosion initiation has a significant correlation factor with the reliability function values in the case of all results. With increasing the chloride threshold, the reliability function decreases, and vice versa. For the chloride concentration at the surface, the opposite linear correlation occurs, i.e., positive and also significantly high. The concrete cover thickness and diffusion coefficient have a low correlation, and it is not possible to estimate what effect they have on the result.The last results are from the significance analysis, which is shown in The opposite trend was then observed for SCC with 1% and 2% fibres, where the influence of reinforcement depth and diffusion coefficient was reduced, and even for the last mixture with 2% fibres, it is the thickness of the cover that had the least influence.A global view of all results showed that OPC and SCC did not differ much in the evaluation of input sensitivity and significance analysis. However, the inclusion of fibres in the concrete affects the outcome differently and, therefore, needs to be taken into account in the case of other probabilistic analyses.This paper provided new insights into sensitivity analysis, which is the ideal tool for demonstrating which input parameters influence or do not influence the design outcome of reinforcement failure probability with respect to aggressive environments.The current study was limited to plain ordinary concrete and self-compacting concrete with and without fibres. This concrete can be used as a part of the load-bearing structures in aggressive environments, such as road bridges. The present findings may help to solve the problem of having to use more simulations when applying the Monte Carlo method, and therefore lower the computational power requirements. The appropriate determination of input parameters, that do not highly affect the results, may also significantly speed up the calculation. The reported results provide further evidence that different concretes and their different properties affect probabilistic analyses, and therefore, the sensitivity analysis must be an integral part of any calculation. Furthermore, the assumption that SCC reports better chloride diffusion protection properties has been confirmed and, on the contrary, fibres can negate such positive properties. Similar conclusions and hypotheses may be applied to other structural components and models. Therefore, this aspect needs to be analysed by more extensive preparation of sensitivity analysis with different concrete fibres.


Nanocomposite modification has attracted much attention in improving properties of bio-based polymer coating material for coated fertilizer. Herein two comparable polyhedral oligomeric silsesquioxanes (POSS), with eight poly(ethylene glycol) (PEG) and octaphenyl groups attached to the cage, respectively, were successfully incorporated into thin castor oil-based polyurethane coatings via in-situ polymerization on the urea surface. The nanostructure coatings are environmentally friendly, easy to prepare, and property-tunable. The results show that the vertex group of POSS had a pronounced influence on dispersion level and interaction between polyurethane and POSS that well-tuned the release pattern and period of coated urea, even at the coating rate as low as of 2 wt%. The liquid POSS with long and flexible PEG groups had better compatibility and dispersibility in polyurethane matrix than the solid POSS with rigid octaphenyl groups, as evidenced by SEM/EDS. The unique properties were resulted from the different extents of physical crosslinkings. This modification of bio-based polyurethane coating with POSS provided an alternative method of regulating and controlling the properties of coated fertilizer. Its nutrient release pattern demonstrates a strong dependence on the used coating material5. Polyurethane (PU) made by the reaction of polyol and isocyanate is a kind of block copolymer composed of soft chain segment and hard chain segment. By changing the composition and proportion of the two phases, its microstructure is adjusted and the specific property is improved. Therefore, currently polyurethane coatings are favored by the researchers and manufacturers of non-solvent in-situ reaction coated fertilizers8.Coated fertilizer is widely used in agriculture because it increases nutrient utilization efficiency and decreases pollution to air and groundwater9, lignin10, cellulose11 and vegetable oil12, are considered to be green, sustainable and low-cost. Thus they have shown great potential as a substitute for conventional synthetic polymer coatings. Bortoletto-Santos et al.13 prepared castor oil-based polyurethane coated fertilizer. The nitrogen release period of fertilizer with the coating rate of about 4 wt% was 40 days. Zhang et al.16 designed a series of coated fertilizers by curing liquefaction products of starch, wheat straw and waste paper to the fertilizer surface, and the resulted coatings had the good biodegradability in soil. The effect of coating microstructure on fertilizer performance is particularly obvious especially for the ultrathin coating. Therefore, the researchers tried some methods to optimize the microstructure, such as blend and nanocomposite19. Reportedly Yang et al.21 modified the bio-based polyurethane coating material using epoxy or polyester resin to form interpenetrating network structure, which enhanced the slow-release properties of coated fertilizers. Zhao et al.22 filled nanobentonite to the soybean oil-based polyurethane coating. When the addition content of polyethylene glycol-intercalated bentonite was 5 wt%, the nutrient release period of coated urea was 74 d. Till now, when the coating rate of fertilizer was lower than 2.5 wt%, the nutrient release period was not longer than 30 d yet. A simple and efficient approach still brings a challenge in designing microstructures and tuning release properties of fertilizers with ultrathin bio-based polyurethane coatings.Bio-based polyurethane coatings from natural materials such as starch24, which offers alternative choices for the microstructure optimization of coatings. POSS, a cagelike molecule containing RSiO3/2 units, is an environmentally friendly nanomaterial developed in recent years25. Not only does POSS combine the advantage of both inorganic and organic components, but it also has some new properties produced by synergistic effect26. POSS with eight PEG groups attached on the cage (POSS-PEG) was ever used to modify MDI-PTMG-based polyurethane. The POSS-PEG dispersed well on the molecular level and acted as a diluent to plasticize the molecular dynamics27. Huang et al.28 prepared an environmentally friendly polyurethane nanocomposite with POSS as a chain extender. Its surface hydrophobicity was significantly improved in comparison with that without POSS. What’s more, it was reported that the degradation controllability of polyurethane coating for controlled release of drug was improved by the incorporation of POSS30. To our best knowledge, the effect of POSS on the release behavior of fertilizer from polymer coated fertilizer is an unknown field. Since the preparation process and raw material type directly affect the combination mode of nanoparticle with polymer matrix and the topology of nanocomposite32, it is necessary to specially conduct the in-depth research on the solvent-free in-situ polymerization of bio-based polyurethane coating on the fertilizer surface.The synthesis of nanomaterials gains growing attention2CH2O– as polyether polyols, and the size of POSS-PEG is longer than that of silicon cage or castor oil. PEG vertex groups improve the compatibility by the hydrogen bonding interaction between the hydroxyl groups on castor oil and the ether oxygens on PEG. For comparative purpose, POSS with octaphenyl groups (POSS-BEN) was selected, where no chemical links bound the POSS molecules to polyurethane matrix. The formation of the nanocomposite coatings is illustrated in Fig. In the present study, the castor oil-based polyurethane nanocomposite coating containing the commercial liquid POSS-PEG was firstly designed. Wherein the PEG vertex groups possess the same repeated unit of –CHn and PCU/PEGn (n refers to the weight percentage of POSS in the coating liquid). A control sample designated as PCU was prepared in a similar manner except that pure polyurethane was used to coat the urea granules. Water resistance and controlled release properties of the coatings were evaluated. The exact interaction mechanism of POSS and PU matrix was further investigated by a combination of thermal, mechanical and morphological analyses.In the study, two comparable polyurethane/POSS nanocomposite coatings were synthesized via in-situ polymerization on the urea surface. The preparation process of the nanocomposite coated urea is shown in Fig. −1 corresponding to the Si–O–Si bond, which is the characteristic signal of POSS33. The characteristic absorption band was further assigned to stretching vibration of C–O bond of PEG chain34. The peak of 2867 cm−1 was associated with the CH2 and CH3 symmetric and antisymmetric stretching vibrations, and the peaks located at 1456 cm−1 and 1352 cm−1 were attributed to C–H bending vibrations, which indicated the existence of PEG chain. In the case of POSS-BEN, both 3019 cm−1 and 1593 cm−1 were the characteristic absorption peaks of benzene ring framework.Figure TG/DTG was performed to study the thermal properties of the coating materials. The curves are shown in Fig. 35. Besides, the shape and position of tanδ peaks were obviously affected by POSS. Compared with pure PCU, the peaks of composite coatings clearly revealed POSS-relevant broadening, which implied that the interaction of POSS with PU introduced the heterogeneity. The Tg of PCU was 42 °C while that of composite coatings was increased up to above 50 °C. The shift of Tg was due to the formation of more physical crosslinking points from hydrogen bond interaction, formation of POSS domain and so on36, which restricted the movement of PU chain and POSS cage.The DMA spectra were performed to explore the effect of POSS on storage modulus E′ and tanδ of the coating materials. Figure 37. PEG vertex groups improved the compatibility between POSS-PEG and PU. POSS-BEN was surrounded by PU matrix to form a sea-island structure, which indicated a strong affinity38. It is worthy noted that after the POSS-BEN number increased with the loading increase, some particles were aggregated into a larger size than 1 μm. The detached particles and holes appeared as a result of a strong aggregation effect of POSS-BEN through physical interactions assigned to benzene ring being hydrophobic and inert to PU similar to the report by Cheng39. The coating part was involved in reducing the rates of both water diffusion into the core and urea diffusion outside the core. To intuitively understand the coating thickness, a low magnification SEM image of PCU is given in Fig. To follow the effect of POSS on PU matrix, the cross-section morphologies of the coatings were studied by SEM and are depicted in Fig. To understand the surface elemental distribution on coated urea, SEM images and corresponding EDS mappings of C, N and Si were shown in Fig. 40, the prepared coatings were analyzed to see whether the surface property was changed. The static water contact angles of coatings are shown in Fig. 41. Therefore, the existence of POSS cage and three-dimensional network structure had an influence on the surface property of coating material. However, no significant differences were observed between nanocomposite coatings (P < 0.05), which was the result of the limited POSS addition. This behavior implies that the hydrophobicity of coatings was not evidently changed by increasing the POSS content in the experiment.Considering POSS is a derivative of organosilicon compound for lowering free energy of polymer42. In the case of PCU/PEG1, the total nitrogen release rate with 2 wt% coating rate reached 80% near 60 d. The urea with 2.5 wt% coating rate released still less than 60% after the same time seen in Fig. The nitrogen release behaviors of coated urea in water at 25 °C were measured. The effects of POSS with different vertex groups on the nitrogen release behaviors of PCUs were studied and the results are shown in Fig. Castor oil-based polyurethane nanocomposite thin coatings were successfully prepared via in-situ polymerization by incorporating two types of polyhedral oligomeric silsesquioxanes, POSS-PEG and POSS-BEN, respectively, to develop controlled release fertilizer. The liquid POSS-PEG was evenly dispersed on the surface of coating due to the long and flexible PEG segment similar to castor oil, while the solid POSS-BEN was not well-dispersed as a result of benzene ring being hydrophobic and inert to polyurethane. The mechanical and thermal stability of coatings were improved as a result of the formation of physical crosslinking points after the addition of POSS. The coating PCU/PEG showed much better controlled release performance than PCU/BEN and pure PCU, and the release pattern and period were tunable by the vertex group type of POSS and coating rate of urea. In terms of practical application in agriculture, it is necessary to further study the nitrogen release in slightly acidic and alkaline environments. The POSS with different functional groups is going to optimize the polyurethane for coated fertilizer. In addition, more attention will be paid to the leaching study, so as to provide a release mechanism and give a basis for the performance optimization of nanocomposite coatings. All in all, the very thin nanocomposite coatings not only open up a new way to the property improvement of bio-based polyurethane coated fertilizers, but also extend other applications of polymer/POSS hybrid materials.w = 5576 g/mol), a viscous liquid, was supplied by Hybrid Plastics, USA. Octaphenyl POSS (denoted by POSS-BEN), a white powder, was supplied by Shanghai Macklin Biochemical Co., Ltd. China.Castor oil was supplied by Tianjin Fucheng Chemical Reagent Factory, China. Polyaryl polymethylene isocyanate  was supplied by Bayer, Germany. Microcrystalline wax was supplied by Cangzhou Forest Wax, China. The regular urea granule containing 46.6% N with 2–4 mm diameter was supplied by Shandong Hualu-hengsheng Chemical Co., Ltd. China. POSS-PEG  were mixed at 70 °C, and then the mixture and 12 g of PAPI were stirred evenly to form the coating liquid. 1 kg of urea granules in a coating machine were preheated to 70 °C. 10 g of the coating liquid was sprayed uniformly onto the urea surface and cured for about 5 min to form the coated urea with 1 wt% coating rate. After repeating the above coating process for 2 or 3 times, the coated urea granules with different coating rates were cooled to room temperature, and used for analysis. To analyze Dynamic Mechanical Analysis (DMA) of coating material, the formed coating liquid was poured into a polytetrafluoroethylene mold (20 cm × 20 cm × 0.5 cm) and kept in an oven at 70 °C overnight to conduct curing of polyurethane. Table 46. ATR-FTIR was recorded on a BRUKER TENSOR 27 spectrometer  in a scan range from 4000 to 500 cm−1 with a resolution of 4 cm−1.The chemical structure of POSS was analyzed by Attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR)47. Finally, the obtained coating was further analyzed by thermogravimetry and derivative thermogravimetry (TG/DTG).The coated urea was cut up and immersed into a water bath so that urea was dissolved to obtain the coating. The coating was cleaned with deionized water and then oven-dried at 35 °C for 10 h47.TG/DTG analysis was performed on a NETZSCH STA449C simultaneous thermal analyzer . Samples with a weight of ~ 5 mg were heated from 40 to 600 ºC at a heating rate of 10 ºC/min under flowing argon atmosphereDMA was carried out on a TA Q800 dynamic mechanical analyzer  in the temperature range from − 100 to 150 ºC at the frequency of 1 Hz.The water contact angle was determined using a HARKE-SPCAX2 goniometer .46.The coating was observed by using a Zeiss Supra 55 field emission scanning electron microscope  equipped with an energy-dispersive X-ray spectroscopy (EDS) at an accelerating voltage of 20 kV. The coated urea was split into two halves, and then adhered to the sample holder with double side adhesive tape. The sample was sprayed with gold before observation46.D7 is the cumulative release rate in the first seven days and D1 is the release rate on the first day.Nitrogen release of the prepared coated urea was evaluated based on International Standard ISO 18644. The detailed process is as follows: 10 g of the coated urea sample was immersed in 200 mL of distilled water in a plastic bottle. The temperature of incubation was 25 ºC. The solution in the plastic bottle was removed after a certain interval , and replaced by another 200 mL of distilled water until N release rate reached 80%. The differential release rate was measured according to the following equation P < 0.05. All data were expressed as mean ± standard deviation (SD).Statistical analysis was conducted using Excel 2010 and SAS 9.2 . Three duplicates were conducted for each sample. Comparison among samples was evaluated by one-way analysis of variance (ANOVA), followed by Tukey test at a significance level of Supplementary Information


Clostridioides difficile infection, and the spread of antimicrobial resistance). In prescribing SAP, surgeons should have both the awareness necessary “to handle antibiotics with care”, and the knowledge required to use them appropriately.Surgical antibiotic prophylaxis (SAP) is one of the peri-operative measures for preventing surgical site infections (SSIs). Its goal is to counteract the proliferation of bacteria in the surgical site during intervention in order to reduce the risk of SSIs. SAP should be administered for surgical interventions where the benefit expected (prevention of SSIs) is higher compared to the risk (serious side effects, such as acute kidney injury,  One of the goals of best practice across surgical pathways is to prevent surgical site infections (SSIs). SSIs are infections that occur up to 30 days after surgical operation or up to one year after surgical intervention in patients receiving prosthetic materials. They can affect either the superficial tissues or the deep tissues at the operation site. Superficial SSIs can affect both the skin and subcutaneous tissues, while deep SSIs can involve tissues under the skin such as muscle, fascia, and organs/space opened during the surgical operation .SSIs are the costliest and second most common healthcare-associated infections (HAIs), being the first among surgical patients. They are associated with a longer post-operative hospital length of stay and result in higher post-operative mortality and morbidity. Most SSIs can be preventable by basic infection prevention and control measures ,3.Preventing SSIs should be considered a global priority since in the latest few decades bacteria have become resistant to antibiotics, making the prevention of SSIs very important in the containment of antibiotic resistance.Despite great progresses in infection prevention and control in the previous years, nowadays SSIs continue to represent one of the most frequent adverse events in surgical departments worldwide, and their prevention requires the integration of basic measures before, during, and after the surgical operation.Surgical antibiotic prophylaxis (SAP)  is one oClostridioides difficile infection, and spread of antimicrobial resistance).SAP should be administered for surgical interventions where the benefit expected  is higher compared to the risk , the Infectious Diseases Society of America (IDSA), the Surgical Infection Society (SIS), and the Society for Healthcare Epidemiology of America (SHEA) . HoweverClostridioides difficile infection [The guidelines recommend that SAP should be administered to prevent infections before and only during surgical intervention. Antibiotics should not be administered after surgical operation, as often happens. Probably the most common mistake made by surgeons in prescribing SAP is to prolong its administration in the post-operative period. However, it is well known that long duration of SAP (more than 24 h) does not result in an additional decrease in SSIs rate in any procedures but, on the contrary, are associated with increasing adverse effects, such as the risk of acute kidney injury and the risk of nfection . Moreovenfection ,15.For many surgeons, SAP is not a priority. The poor awareness of surgeons about SAP is well demonstrated in the literature. Broom et al. , in a stClostridioides difficile infection, (5) reducing consequences for the patient’s microbial flora, and (6) reducing the emergence of antibiotic resistance.Ideally, an appropriate SAP should have six main characteristics: (1) preventing SSIs, (2) improving the patients’ outcomes, (3) reducing the duration and related cost of health care, (4) reducing adverse effects, such as acute kidney injury or the risk of The selected antibiotic for SAP should be: (1) active against the bacteria that most likely can contaminate the surgical site, (2) administered in an appropriate dosage and at the correct time, in order to obtain appropriate tissue concentrations during the period of potential contamination during the surgical intervention, (3) safe, and (4) administered for the shortest period to minimize the adverse effects, the emergence of antibiotic resistance, and costs and, at the same time, to maximize its efficacy.In the next section of our paper, we briefly outline the principles that a surgeon should follow in prescribing SAP correctly.SAP should be administered for all of those operative procedures having a high risk of post-operative SSIs, or when prosthetic materials are implanted. The surgical interventions can be divided into four classes according to the degree of bacterial contamination and the consequent incidence of post-operative infections . For eleThe implantation of any prosthetic material increases the risk of infection of the surgical site, as it reduces the host’s defenses . In factSAP should be effective against the bacteria that most likely contaminate the surgical site. Contamination of the surgical site is a frequent occurrence during surgery. In many cases it is the inevitable consequence of a surgical technique. In other cases, it is the consequence of a violation of asepsis techniques. Contamination can be both endogenous and exogenous.Staphylococcus aureus and Staphylococcus epidermidis or normal flora colonizing the incised mucosae such as Escherichia coli, or another Enterobacterales or anaerobes. Exogenous contamination is caused by microorganisms that meet the patient accidentally, generally coming from the surgical team, the operating room environment, and the instruments, and cannot be predicted a priori.Endogenous contamination occurs when the responsible microorganisms are the commensals present on the skin such as The antibiotic chosen for prophylaxis should have a spectrum of action that guarantees efficacy against the most probable contaminants. It has been shown that the effectiveness of prophylaxis is limited to endogenous contaminants; only these pathogens can, in fact, be reasonably predicted and therefore “covered” by antibiotic prophylaxis.It is crucial to choose antibiotics with the narrowest spectrum of activity required, since broad spectrum antibiotics may be required later if the patients develop serious post-operative infections and may induce the spread of antibiotic resistance.Intravenous “first generation” cephalosporins such as cephazolin are the most common antibiotics used in SAP. Intravenous ‘second generation’ cephalosporins, such as cefoxitin improving coverage against anaerobic and aerobic Gram-negative antibiotics, can be used as alternative to the combination of “first generation” cephalosporin and metronidazole in elective abdominal surgery.Staphylococcus aureus (MRSA) colonization or at high risk for MRSA colonization, such as patients with recent hospitalization or patients coming from nursing-home residents. However, even if vancomycin is commonly recommended when the risk for MRSA is high, it is important to point out that the evidence suggests that vancomycin is less effective than first generation’ cephalosporins for preventing SSIs caused by methicillin-susceptible Staphylococcus aureus [Routine use of vancomycin in SAP is not generally recommended. Vancomycin should be always considered for SAP in patients with known methicillin-resistant s aureus .Intravenous administration of the antibiotic within 120 min is generally recommended. Administration of the first dose of antibiotic 30 to 60 min before surgical incision is usually suggested for most used antibiotics  in order to ensure appropriate tissue concentrations during the operative period. A single dose is generally sufficient. Additional intra-operative doses should be administered for procedures exceeding two half-lives of the antibiotic or with associated significant blood loss (more than 1.5 L).It is generally accepted as good clinical practice that the dose of the antibiotic used for prophylaxis is the same as that used for therapy. This dose must guarantee appropriate tissue concentrations at the time of the surgical incision .Intravenous administration of the antibiotic within 120 min prior to incision is generally recommended. However, for the most used antibiotics, such as cefazolin, intravenous administration 30–60 min prior to incision is the most reliable method to ensure an effective concentration of the antibiotic in the tissues at the site of the intervention .Many of the antibiotics used in SAP have relatively short half-lives (1–2 h) calculated in healthy volunteer studies. It is therefore logical to administer an additional dose of antibiotic if the surgical procedure lasts more than 2–4 h to ensure adequate serum and tissue concentrations of the antibiotic. Additional intra-operative doses are generally recommended if the duration of the operative procedure exceeds two half-lives of the antibiotic or there is excessive blood loss (more than 1.5 L) .The shortest effective duration of SAP for preventing SSI is not known. However, evidence have shown that post-operative antibiotic administration is not for most procedures and should be less than 24 h for most procedures.Erroneously, the surgeon believes that prolonging antibiotic “coverage” can protect the patient from infections that can develop after surgery and protect from possible medico-legal repercussions in case of infectious complications. However, the surgeon often ignores that all of the studies that have demonstrated the efficacy of antibiotic prophylaxis were aimed exclusively at preventing peri-operative infections (and SSIs), not infections that occur in the post-operative course and nosocomial infections that develop away from the surgical site.The shortest effective duration of antibiotic prophylaxis for preventing SSI is not known. Evidence has shown that post-operative antibiotic administration is not for most procedures and should be less than 24 h for most procedures .In conclusion, SSIs continue to pose an important clinical challenge in surgical departments worldwide. It is essential to recognize that much of the burden of prolonged hospitalizations, increased healthcare costs, mortality, and morbidity associated with SSIs is preventable through the integration of basic measures before, during, and after the surgical operation. SAP is one of the most important peri-operative measures for preventing SSIs; the principles of SAP are clearly established, and several guidelines for them have been published. However, high rates of inappropriate SAP, in terms of timing and duration, has been demonstrated across the surgical pathway. Adherence to evidence for SAP should be improved by multidisciplinary intervention strategies, both intra-specialties, actively involving surgeons, and inter-specialty, directly connecting surgeons, anesthetists, infectious diseases specialists, epidemiologists, and pharmacologists.One way to engage surgeons in guideline development and implementation is to translate recommendations into a protocol or pathway that specifies and coordinates responsibilities and timing for actions among the multi-disciplinary team. Moreover, since the choice of SAP and its spectrum also depends on local epidemiology, a local adaptation, of evidence-based guidelines for SAP should be developed and implemented in each acute health care facility around the world.Finally, surveillance of HAIs including SSIs is pivotal for infection prevention and control because it can provide quality data that can be used in monitoring and alert system reducing the incidence of preventable HAIs ,28,29,30


The aim of this research was to test the potential of applying a flow cytometric procedure to evaluate the impact of concrete compounds’ release to the freshwater microbiome. Cells from the collected samples were stained with a fluorogenic redox indicator dye that measures the redox potential of microbial cells. This novel approach was combined with the assessment of microorganisms’ penetration into the internal structures of concrete using the Rose Bengal sodium salt staining. Rose Bengal staining revealed an intense fouling of the upper and side walls of the concrete cubes and also indicated the penetration of microorganisms inside the concrete as observed for the cubes’ cross-sections. Flow cytometric cellular redox potential measurement revealed high percentages of active cells within the concrete’s porous structures and in non-exposed water (32.7% and 30.2% of active cells) versus samples from exposed water and concrete’s outer surfaces . The results demonstrated a detrimental impact of hydro-technical concrete on the vitality of microbial cells within the freshwater environment. Tested protocol by analyzing the physiology of microbial cells improved the functional description of complex communities to evaluate the fate of contaminants present in the concrete-based hydro-technical infrastructure. Traditional concrete components such as cement and mineral aggregate do not pose a threat to the environment. Recently, increasing changes in concrete technology and the use of new components are being observed. Specific chemical additives and admixtures adequate to outside conditions and the size of the concrete elements are used , anti-washout admixtures (AWA), and superplasticizers, e.g., high-range water-reducing admixture (HRWR), increasing the washout resistance of underwater concretes, keeping the water in the concrete mixture to prevent high leaching of cement paste . The components used to prepare concrete samples and the chemical composition of concrete components are listed in Tables In order to reduce the toxicity of concrete, the cubes were placed in the lake , in the coastal and wave zone, 5 m from the shore, at a depth of 1 m, for 9 months (from September 2016 to June 2017)  were placed in tubes with 1 ml of 1% PBS  solution. Both types of samples were transferred to the Department of Biotechnology and Food Microbiology laboratory for direct staining and analysis.Sample no. 1—water from aquaculture with concrete cubeSample no. 2—sample containing swabs collected on the side wallSample no. 3—sample containing swabs collected on the underside wallSample no. 4—sample containing swabs collected from porous structures on concrete cube wallsSample no. 5—water from control aquaculture, without the concrete cubeWater samples were collected using a pipette (sample volume 2 mL), and swab samples  was employed according to a method described previously . The BD FACS Aria™ III  flow cytometer (cell sorter) was employed to analyze the vitality of microbial cells within the samples. The distinct and demonstrating low CV (coefficient of variation) values in measured parameter (CRP) sub-populations of microbial cells were defined by gating in the dot plots of green fluorescence (FITC detector from RSG) versus side scatter signals (SSC). Each sample was analyzed in triplicates. The calculation of CRP was performed using the medians of green fluorescence (FITC-A) signals. P4 (active), P5 (mid-active), and P6 (non-active) sub-populations of analyzed cells were defined based on the differences in the levels of metabolic activity measured as CRP. To each sub-population, the arbitrary selected mean CRP ranges were attributed as follows: 280–1000 relative fluorescence units (RFU), 1500–7500 RFU, and 8700–70,000 RFU for P4 (non-active), P5 (mid-active), and P6 (active) sub-populations, respectively.After 9 months of BP cube exposition to lake water, the Rose Bengal staining was performed to reveal the concrete interaction and observed that concrete cubes strongly interacted with BP-associated microbes. The penetration of microorganisms into the internal structures of concrete varied, and deposition outside was evaluated .Concrete cubes after exposition were transferred to tanks of water from the lake (aquariums). During the experiment, the measurements of pH and electrolytic conductivity (C) of water in the tanks were performed. The temperature was about 20 °C. Basic physical–chemical parameters pH = 7.667 and C = 251 μS/cm indicated I class of according to the current standards . After exposition, a significant increase of electrolytic conductivity (from 251.0 to 1570 µS/cm) was observed, and pH value increased slightly, while the oxygen level dropped significantly (from 86.7 to 18.7% of OFlow cytometric measurement (FCM) of fluorescently labeled microbial cells from tested samples provided a fingerprint of the cellular vitality, which expands the concept of live and dead cell discrimination. It enables the evaluation of the metabolic activity of microbial cells by the measurement of cellular redox potential (CRP). The CRP enabled the discrimination between different physiological states of microbial cells from tested samples to resolve the non-active (P4), intermediate (P5), and active (P6) bacterial sub-populations Fig. . Thus, tAs demonstrated in diagram B of Fig. Pseudomonas aeruginosa cells  could be toxic for living organisms  and algae  also contributed to the protection of the reinforcement layer and corrosion inhibition , and mid-active, including the viable but non-culturable cell (VBNC) forms of microbial cells (Juzwa et al., In this study, a Rose Bengal sodium salt staining to assess the microorganisms’ penetration into the internal structures of concrete was combined with a single cell–based approach—fluorescent staining and FCM. Flow cytometry was applied to measure the cellular metabolic activity and investigate the in situ dynamics of the planktonic and concrete-associated microbial cells within the complex aquaculture microbiome. The evaluation of the physiology of microbial cells revealed the potential to develop a routine protocol for assessing the degree of environmental contamination with reference to microbiological balance within different ecological niches. The tested protocol enabled us to evaluate the impact on the condition of environmental microbiomes exerted by the specific components of hydro-technical infrastructure. As the work refers to the toxicity of hydro-technical infrastructure to freshwater microbiome, the application potential of the developed procedure is strongly related to environmental diagnostics. The combination of Rose Bengal sodium salt staining and a single cell-based flow cytometric approach may provide a tool for the precise and fast detection of interferences within freshwater microbiome and diagnose the processes taking place on the surface and inside of concrete. The method allows for the standardization of measurements. The procedure may provide a new quality in the current works in the field of concrete technology, concrete-environment interaction, and in the analysis of the microbiome/consortia of microorganisms emerging for specific types of concrete.