In colon cancer, wingless (Wnt)/β-catenin signaling is frequently upregulated; however, the creation of a molecular therapeutic agent targeting this pathway is still under investigation. This research aimed to study how nitazoxanide can affect Wnt/β-catenin signaling in colon cancer cells (HCT-116) and a mouse colon cancer model. Our study included 2 experiments; the first was to test the cytotoxic activity of nitazoxanide in an in vitro study on a colon cancer cell line (HCT-116) versus normal colon cells (FHC) and to highlight the proapoptotic effect by MTT assay, flow cytometry and real-time polymerase chain reaction (RT-PCR). The second experiment tested the in vivo cytotoxic effect of nitazoxanide against 1,2-dimethylhydrazine (DMH) prompted cancer in mice. Mice were grouped as saline, DMH control and DMH + nitazoxanide [100 or 200 mg per kg]. Colon levels of Wnt and β-catenin proteins were assessed by Western blotting while proliferation was measured via immunostaining for proliferating cell nuclear antigen (PCNA). Treating HCT-116 cells with nitazoxanide (inhibitory concentration 50 (IC50) = 11.07 µM) revealed that it has a more cytotoxic effect when compared to 5-flurouracil (IC50 = 11.36 µM). Moreover, it showed relatively high IC50 value (non-cytotoxic) against the normal colon cells. Nitazoxanide induced apoptosis by 15.86-fold compared to control and arrested the cell cycle. Furthermore, nitazoxanide upregulated proapoptotic proteins (P53 and BAX) and caspases but downregulated BCL-2. Nitazoxanide downregulated Wnt/β-catenin/glycogen synthase kinase-3β (GSK-3β) signaling and PCNA staining in the current mouse model. Hence, our findings highlighted the cytotoxic effect of nitazoxanide and pointed out the effect on Wnt/β-catenin/GSK-3β signaling. According to the Global Cancer Repository 2018 records, colon cancer is the third most deadly cancer in the world [The development of gene mutations is thought to be the primary motivating factor in the early stages of colon cancer  such as Nitazoxanide [2-(acetyloxy)-N-(5-nitro-2-thiazolyl)benzamide] is an antiparasite medication marketed by Romark Laboratories in 2002 . NitazoxIt is important to find molecules and signaling pathways that are crucial for colon cancer and to create novel medications to target them. Wnt signaling was recently considered as a target for treating colon cancer. The current study was planned to test the cytotoxic activity of nitazoxanide in an in vitro colon cancer cell line and in vivo chemically induced colon cancer. Furthermore, the scope of this paper was extended for exploring the impact of nitazoxanide on Wnt/β-catenin signaling and tumor apoptosis.Testing nitazoxanide for its cytotoxic activity against HCT-116 colon cancer cells and FHC  is shown in Nitazoxanide (IC50 = 11.07 μM) was added to the HCT-116 cancer cells for 48 h. We investigated its apoptotic activity using the cell cycle analysis. Nitazoxanide significantly increased apoptotic cell death with 15.86-fold (28.72% versus 1.81% for the control). It encouraged the early, intermediate, and late apoptotic cell death by 4.88%, 15.26%, and 8.58%, respectively. Moreover, DNA flow cytometry was employed for analysing the kinetics of the cell cycle in HCT-116 cancer cells treated with nitazoxanide. As seen in http://string-db.org, accessed on 10 April 2021), we selected multiple protein query and wrote our desired set of proteins  sequentially then; we got a network view (After accessing the website (ork view A using tork view B.HCT-116 cells treated with nitazoxanide (IC50 = 11.07 μM) for 48 h were used for performing the real-time polymerase chain reaction (RT-PCR) assays. In HCT-116 cells, the mRNA expression of the pro-apoptotic proteins (P53 and BAX), caspases , and the anti-apoptotic protein (BCL-2) was measured. Nitazoxanide significantly activated the mRNA expression of P53 (≈4.09-fold) and BCL-2-associated X protein . Further, nitazoxanide significantly increased the mRNA levels of caspases 3 (≈8.49-fold), 8 (3.06-fold), and 9 (5.90-fold) genes. By contrast, nitazoxanide significantly inhibited the BCL-2 mRNA expression (≈0.28-fold) .Using the online bioinformatic KEGG and Reactome databases we found that Wnt signaling regulates various developmental and adult process containing stem cell maintenance, cell proliferation, and cell death ,18. Wnt protein kinase C; this Wnt calcium pathway stimulates cell migration and prevents the canonical β-catenin reliant transcriptional pathway , GSK-3β (11B9): #sc-81462 [1:1000] and actin (C-2): #sc-8432 [1:500] . In addition, β-catenin antibody (#9562) [1:1000] was obtained from Cell Signaling Technology, Inc. (USA). The next step was the incubation in the antibody solutions at 4 °C overnight with gentle vortexing. After each incubation period, the blots were washed 3 to 5 times with TBST; each wash was maintained for five minutes. Compatible horseradish peroxidase conjugated secondary antibodies were applied to the blotted proteins for 1 h. Then, the blot was washed four times using 1 × TBS, 0.1% Tween 20 Detergent (TBST) for 5 min. Visualization of the target proteins was achieved by a detection kit from Amersham BioSciences . ImageJ software (NIH) was employed to quantify the immunoreactivity based on a densitometry method and normalizing the readings against β-actin housekeeping protein.Colonic specimens were homogenized in radioimmunoprecipitation assay (RIPA) buffer containing inhibitors for proteases and phosphatases. Then, samples were cold-centrifuged at 13,000× The colonic tissue sections were H&E stained, and microphotographed a digital camera (Tucsen ISH1000) on a CX23 Olympus light microscope at original magnification ×100 and ×400. Colon specimens were blindly examined for general crypt architecture and features of dysplasia  was processed overnight. The next step was by the addition of biotinylated secondary antibodies to the colon specimens for 1 h. Then, counterstaining was achieved by staining with Mayer’s hematoxylin. After that, PCNA immunostaining within the cells was imaged at ×100 and ×400. Blind quantification of the immunostaining was undertaken using the ImageJ software (NIH) for counting the PCNA positive nuclei in 4 sections imaged at ×400 from each animal. A molecular docking towards the β-catenin protein was done for demonstrating the probable interaction. First, nitazoxanide structure was optimized energetically and chemically and subjected to docking within PDB = 3SL9 whose structure was manipulated following a previous method . The molp < 0.05 was the accepted significance level. Inhibitory concentration 50 (IC50) values were estimated employing nonlinear regression dose-inhibition curve fit practiced by GraphPad prism 7.Using the SPSS program, the normality of the distribution of the current data was confirmed first by the Kolmogorov–Smirnov test. Data that passed the test were analyzed employing one-way analysis of variance (ANOVA) and Tukey’s post-hoc test and presented in mean ± standard deviations. Data of colon cancer histologic grading was demonstrated in medians and quartiles and analyzed by non-parametric ANOVA. Because the mechanism of antitumor activity of nitazoxanide was not completely studied, the present study aimed to further explore this activity focusing on the inhibitory effect on Wnt/β-catenin signaling and the consequent impact on tumor proliferation and apoptosis. We found that nitazoxanide robustly reduced Wnt/β-catenin-dependent tumor proliferation suggesting the promising profits of nitazoxanide in colon cancer treatment especially those with identified Wnt mutations. Future studies are warranted to confirm these results in other colon cancer cell lines and rodent models of colon cancer. In addition, clinical trials are needed to use nitazoxanide in the safe dose ranges and decide its ability to treat colon cancers.


Over the years, leaked fluids from aircraft have caused severe deterioration of airfield pavement. The combined effect of hot exhaust from the auxiliary power unit of military aircraft and spilt aviation oils have caused rapid pavement spalling. If the disintegrated concreted pieces caused by spalling are sucked into the jet engine, they may cause catastrophic damage to the aircraft engine or physical injury to maintenance crews. This study investigates the effectiveness of incorporating hybrid fibres into ordinary concrete to improve the residual mechanical and thermal properties to prevent spalling damage of pavement. Three fibre-reinforced concrete samples were made with micro steel fibre and polyvinyl alcohol fibre with a fibre content of zero, 0.3%, 0.5% and 0.7% by volume fraction. These samples were exposed to recurring high temperatures and aviation oils. Tests were conducted to measure the effects of repeated exposure on the concrete’s mechanical, thermal and chemical characteristics. The results showed that polyvinyl alcohol fibre-, steel fibre- and hybrid fibre-reinforced concrete suffered a 52%, 40% and 26.23% of loss of initial the compressive strength after 60 cycles of exposure to the conditions. Moreover, due to the hybridisation of concrete, flexural strength and thermal conductivity was increased by 47% and 22%. Thus, hybrid fibre-reinforced concrete performed better in retaining higher residual properties and exhibited no spalling of concrete. Concrete is a versatile building material of the 21st century. It is a durable material with excellent mechanical and thermal properties and has broad structural application. However, it has a significant drawback, being a quasi-brittle material, and an increase in the strength also increase its brittleness . Modern The production of HSC concrete requires the use of supplementary cementitious materials, such as ground granulated blast furnace slag, silica fume and fly ash as a partial replacement of ordinary Portland cement (OPC) ,7. The aEarlier studies ,13,14 haf) and properties of fibres matrix in the concrete mixture [Researchers in the last few decades saw a sharp rise in the use of different fibres in concrete to increase its mechanical properties such as flexural strength, toughness, tensile strength and durability ,22,23,24 mixture ,26. Amon mixture . Althoug mixture ,29,30.Most aprons and runways of military airbases are constructed using OPC concrete. These aprons and runways face more severe operating conditions than ordinary commercial airports because of the powerful modern aircraft such as the Harrier jet, F/A-18 and B-1. These pavements are repeatedly subjected to hot exhaust from an auxiliary power unit (APU) of modern aircraft, and aviation oils spill either in conjunction or separately, as seen in A few earlier studies also reported the causes of the spalling damage of airfield pavements exposed to repeated high temperature and HC fluids. However, these studies focused on causes like vapour pressure, residual mechanical and strength degradation for the chemical reactions. Currently, there are no research data on spalling damage, residual mechanical and thermal properties of FRC under similar conditions. Such data play a significant role in selecting fibre type, volume fraction, fibre matrix and geometry while designing for airfield pavements. To fill this knowledge gap, this study investigates the effectiveness of incorporating hybrid fibres into ordinary concrete to improve the residual mechanical and thermal properties to prevent spalling damage. In this investigation, the different combination of micro steel fibre (SF), polyvinyl alcohol fibre (PF) and hybridisation of PF and SF are produced to examine the effect of two fibres in FRC in comparison with ordinary concrete. Moreover, to study the effect of hybridisation of concrete using PF and SF, three mixed fibre-reinforced concrete are produced with a fibre content of 0.3%, 0.5% and 0.7% from each type. All fibre-reinforced samples are compared with the control specimen that contains no fibre. The residual compressive strength, flexural strength, mass loss and spalling effect after repeated exposure to high temperature and HC fluids are evaluated. This study also explored the thermal performance of FRC and its effect on spalling due to repeated exposure to HC fluids and high temperature. w/c) ratio of 0.42. Fresh M70 grade concrete samples were prepared using Boral general-purpose (AS 3972) OPC with a water-cement  flexural testing machine of 150 KN capacity with a deflection rate of 0.3 mm/min was used to measure the concrete beams’ flexural strength. The specimens were assessed for thermal properties like specific heat and thermal conductivity each after 20 exposures. As per ASTM C518 , the NetThe XRD test was used as a non-destructive method to determine crystal phases and mineral compounds present in the specimens . The samAfter 20 cycles of high-temperature exposures, the differential scanning calorimetry (DSC) and TG tests for the specimens were conducted using NETZSCH (manufacturer) STA 449C Jupiter, Selbu, Germany. The DSC and TG spectra were collected in an inert nitrogen environment with a heating rate of 10 °C/min from 20 to 800 °C. The Zeiss Axio Imager  optical microscope was used to analyse fibre reinforced samples’ microstructures at the original condition and after 60 cycles of high-temperature and HC fluid exposures. This machine analyses the microcrack and voids development in the samples due to high temperature and HC fluids’ simultaneous effect. For microstructural analysis, samples were collected from the top (up to 20 mm) surface of the specimens. The samples’ microstructure is also analysed by combining two main techniques: Direct observation with an optical microscope and scanning electron microscope (SEM). This combination method allows a better understanding of links between microstructure, composition and engineering behaviour.Various factors govern the behaviour of samples exposed to higher temperature and HC fluids. For repeated exposure to the high temperature and HC fluids’ combined effect, residual compressive strength loss was more than only heat-exposed samples, as seen in In summary, PF fibres in HB concrete created additional microchannels allowing the release of vapour pressure created by exposure to HC fluids. The inclusion of SF also increases the tensile capacity ; thus, tf = 0.7% used in this study was low enough to cause any significant mass loss due to fibres’ presence. Specimens containing 0.7% PF fibres and 0.7% SF suffered a mass loss of 12% and 7.7%, respectively. At the same time, HB samples lost 8.4% of the mass after 60 cycles. However, Lee et al. [The mass loss of specimens after recurring exposure to high temperature and HC fluids is shown in e et al.  suggestee et al. ,41 also In summary, initial mass loss occurs due to the evaporation of initial free water for exposures to high temperature and HC fluids. Subsequent mass loss occurs due to the evaporation of chemically bonded water, decomposition of C-S-H gel and calcium hydroxide, which is also identified in the XRD and TG analysis paragraphs of this paper.f further improved the flexural load capacity of concrete. For samples without any heat and HC fluids exposures (E0), the inclusion of 0.3%, 0.5% and 0.7% PF fibre led to the flexural strength increasing by 4.5%, 15.89% and 21.82%, respectively. With the inclusion of 0.3%, 0.5% and 0.7% SF fibre, the flexural strength increased by 15.5%, 17.89% and 22.82%, respectively. Similarly, with the inclusion of 0.3%, 0.5% and 0.7% HB fibre, the flexural strength increased by 13.13%, 17.89% and 32.29%, respectively. The flexural strength and descending branch after peak load were significantly improved in concrete reinforced with SF and HB compared to PF fibre.Control and FRC samples were evaluated for flexural strength after E0 and E60 cycles of high temperature only and combined high temperature and HC fluid exposures. The average of three sets of data was used to calculate the flexural strength. The midspan deflection against the applied load under four-point bending is shown in The flexural capacity of samples exposed to a high temperature and HC fluids decreased significantly, as shown in In summary, the residual flexural strength and the post-peak deformation behaviour of FRC were significantly improved with PF and SF. Due to the hybridisations, high-temperature and HC fluids exposed samples’ maximum residual flexural strength loss was 23% for control and 11.59% for 0.7% HB sample.The ruptured sections of the FRC were carefully inspected after the flexural test. The increase in fibre fraction resulted in the smoothness of ruptured sections for FRCs but was reduced with an increase in high temperature and HC fluids exposures. The fracture energy between the cement pastes and aggregates interface decreased with high temperature and HC fluid exposures because high temperature decreases the bond between the cement paste and aggregates. However, PF FRC samples were split entirely into two parts since fibres were melted after repeated heating as also reported in SEM results, thus behaving like ordinary concrete. The SF has been seen protruding from the concrete matrix after the specimen has ruptured, as seen in Spalling of concrete has a significant influence on concrete fire performance and can be a governing factor in determining the fire resistance of an RC structural member . Some reConcrete is an anisotropic and non-homogenous material where hydrated cement paste helps to keep aggregates held together. Due to its porosity, moisture content affects the pore conductivity of concrete. Thermal properties of concrete have a significant role in retaining its strength because the concrete structure deteriorates quickly once exposed to high temperature. In this study, the thermal conductivity and specific heat of FRC and control specimens subjected to recurrent higher temperatures and HC fluids were measured.The experiment involves measuring the amount of heat flow q through the sample once the equilibrium condition is achieved. Thermal conductivity is k, the sample thickness is Δx, the temperature difference across the sample is ΔT and cross-sectional area is A through which heat flows influences the magnitude of the heat flow q. Fourier’s law of conduction gives the relation between these parameters: Two heat flow transducers of the HFM 436, the heat flow instrument used to calculate the amount of heat flow (in volts) through the sample, is shown in N is the calibration factor related to the heat flow transducer’s voltage to the heat flux through the sample. Solving Equations (1) and (2) for k, the equation of thermal conductivity may be expressed in-unit W/m.k:For calculation of thermal conductivity and specific heat, ASTM C518 and IS EN 12667/12939  was follThermal conductivity measured for specimens exposed to high temperature only, and high temperature and HC fluids is shown in A similar separate test was done to measure the value of specific heat Cp. The specific heat measured for specimens exposed to high temperature only and high temperature and HC fluids is plotted in Moreover, the deterioration of concrete due to repeated high temperature and HC fluids exposures results in hairline cracks, which increased PF porosity and other FRC porosity. In contrast, ordinary concrete has lower specific heat because of its lower permeability and dense microstructure, requiring additional heat to convert moisture into vapours.3S = 3CaO·SiO2, mullite = 3Al2O32SiO2 and belite C2S = 2CaO·SiO2, similar results were also reported by other researchers [The XRD peaks for control and FRC specimens appeared to be similar in original condition. This trend reveals that fibres do not contain any crystalline mineral compounds. Nevertheless, the intensity height of the ordinary concrete and FRC sample in XRD was found to be different in some cases. The addition of SF and PF in the concrete matrix might have caused the increase/decrease in the peak intensity height and peak shift for the crystalline compound in the XRD, as shown in earchers ,47. Accoearchers ,48, whenSimilarly, when exposed to 200 °C, physical and chemical decomposition in mineral compounds usually occurs. Recurrent exposure of control and FRC samples to 175 °C might cause the ettringite dehydration and decomposition. Similarly, the peak position of quartz, ettringite and portlandite have shifted to a lower degree (2θ), as shown in However, a few of the picks like alite, mullite and calcite did not shift their position but a significant reduction in peak intensity was observed. Most mineral compounds in FRCs were affected by combined actions of HC fluid and a high thermal cycle.The thermogravimetric (TG) tests were conducted for control and FRC specimens after HC fluid and high-temperature exposure, as shown in The primary chemical reactions in different temperature range are given below:The decomposition of the C–S–H and carboaluminate hydrates cause the loss of bound water from .3.4CaO·Decomposition of portlandite:Decarbonation of calcium carbonate :CaCO3 → After the initial rapid decline, the actual weight loss rate stabilised between 200 °C and 350 °C. The second significant weight loss was observed between 350–600 °C, where portlandite started decomposing until completion of the process at around 550 °C ,55. The The DSC plots of the control, PF, and HB specimens are shown in 2 occurred with peak shifts with increased heat exposures. For recurrent exposure of FRC samples to high temperature, a significant reduction in peak intensity at 440 °C (in 3) decomposes, thus permitting CO2 to liberate from the concrete. According to Noumowé and Li et al. ,60, cont40 °C in a was recSEM/optical analysis was done on the polish surface taken from the specimen’s core (up to 20 mm depth) to understanding the fibre–matrix interactions after repeated high temperatures and HC fluid exposures. For HB FRC, a better result was observed due to the combined effect of PF and SF, where melting of PF created a microchannel, which helps to release moisture pressure developed for HC fluids exposure. Simultaneously, SF’s presence helps prevent thermal cracks in concrete; thus, HB FRC showed better performance in high temperatures and HC fluid exposures.Airfield concrete pavements face different severe loading conditions during their service life. The most significant one is repeated thermal shock from APU’s exhaust of jet engines and chemical attack from the leaked HC fluids. This effect causes the spalling of the concrete surface, which requires additional maintenance and replacement costs. Recent investigations showed that the inclusion of fibres improves the residual mechanical properties of concrete exposed to high temperatures and HC fluids. This study includes an experimental investigation on adding PF fibre and SF in the FRC mixes to improve the residual mechanical and thermal properties. The following conclusions are drawn as a result of this study.The compressive strength loss was more significant in specimens exposed to the combined high temperature and HC fluids than to the high temperature only. Specimens with PF showed slightly more strength loss than control specimens under similar loading conditions. The addition of SF resulted in more residual compressive strength than PF and control specimens. However, hybrid FRC performed much better in retaining residual compressive strength.The hybridisation of concrete using PF and SF was slightly more effective in enhancing the flexural properties of FRC than control and PF reinforced concrete. The specimens’ flexural strength decreased gradually with an increase in the number of high-temperature exposures due to the degradation of the tensile strength of fibres and bonding between the fibres and the matrix. Besides, PF’s melting created extra pores in the matrix to reduce the vapour pressure due to heating. Moreover, SF improves the FRC post-peak behaviour and reduced the crack propagation and the risk of spalling compared to OPC concrete.The thermal properties of FRC improved with the addition of SF and PF fibres. However, recurrent exposure to heat and HC fluids caused a gradual decrease in thermal conductivity and specific heat. Due to the excellent thermal conductivity, SF had the highest positive impact above HB FRC, and PF fibres exhibited the most negligible impact on thermal properties.Mass loss was prominent among PF and control samples than SF and HB samples. TG and DS test also confirmed the decomposition of concrete at the higher temperature besides loss of free and bound water, which has contributed to mass loss.Microstructure analysis revealed that the PF’s melting created extra pores in FRC that release the extra vapour pressure due to high-temperature exposures. The addition of SF reduces the microcracks propagation in the concrete by the bridging effect, thus enhancing the tensile capacity of FRC specimens.In Brief, the above tests showed that the addition of fibres has a positive impact on the residual thermo-mechanical properties of FRC, except for PF fibre. Therefore, incorporating 0.7% HB fibres seems to be a promising way to enhance concrete resistance to thermally induced explosive spalling. In this experiment, concrete specimens were exposed to high temperatures from all directions, but the airfield APU exhaust applies one-directional heat. It will be worth considering that exposing concrete samples to one direction (1D) heating as it happens under the APU exhaust. It will reveal the effect of uneven thermal stress distribution developed from 1D exposure compared to this research’s all-directional heating.


The aim of this cohort study was to identify resident-related factors that influence antibiotic treatment decisions for urinary tract infections (UTIs) in nursing home residents and to provide an overview of the appropriateness of antibiotic treatment decisions according to the updated Dutch guideline for UTIs in frail older adults. The PROGRESS study dataset, consisting of 298 suspected UTI episodes in Dutch nursing home residents, was used. The presence of dysuria was associated with the highest frequency of antibiotic prescription (87.8%). Positive leukocyte esterase dipstick results showed the greatest increase in the risk of antibiotic prescription . Treatment decisions were considered adequate in 64.1% of the suspected UTI episodes. Overtreatment occurred more often than undertreatment. Of the inadequate treatment decisions, 29.3% was due to treatment of UTI episodes in which solely non-specific symptoms were present. A high proportion of nitrofurantoin prescriptions were incorrect in UTIs with signs of tissue invasion (54.8%), indwelling catheter-associated UTIs (37.5%), and UTIs in men (29.2%). Although this is considered inadequate, non-specific symptoms were associated with antibiotic prescription for suspected UTIs in Dutch nursing home residents and nitrofurantoin was inadequately prescribed in particular groups, such as men.  Urinary tract infections (UTIs) are one of the most common infections in nursing home residents worldwide ,2,3. ConClostridium difficile infections and allergies [Unnecessary antibiotic prescriptions increase the risk of adverse events at the individual level  and allergies ,5,9.The prevalence of asymptomatic bacteriuria (ASB), defined as significant bacteriuria without (specific) symptomatology of a UTI, in the older population is high (up to 50%). Treatment of ASB in older adults is not considered useful since the patient is asymptomatic, and more importantly, treatment does not improve survival and it is associated with adverse events and AMR . ASB is Distinguishing ASB from UTIs in nursing home residents is difficult. First, cognitive impairments limit the ability to express symptoms, including specific UTI symptoms . Second,The recently updated Dutch guideline for UTIs in frail older adults aims to reduce inappropriate antibiotic treatment of UTIs to prevent unnecessary adverse events and to combat the occurrence of AMR ,17. SimiDespite the recommended guideline, inappropriate antibiotic prescriptions persists. A strategy to enhance appropriate antibiotic prescriptions in this setting is to improve the diagnostic process of suspected UTI in older adults, for example, by implementing a decision tool that automatically generates treatment advice into the electronic health record . For anyThis study is a secondary analysis of the PROGRESS study with the primary aim of assessing the sensitivity of blood C-reactive protein and procalcitonin, measured by point-of-care tests, to diagnose UTIs in nursing home residents. The full study protocol was published previously . The datThe main outcome of this study was the antibiotic prescribing rate per resident-related factor and the corresponding relative risks (RR). The resident-related factors were gender, the presence of an indwelling catheter, signs and symptoms (specific and non-specific), and dipstick urinalysis results (leukocytes and nitrite). Other outcome measures were (1) the proportion of adequate antibiotic treatment decisions (initiating or withholding) based on the latest Dutch UTI guideline , where aFor the analysis of the proportion of adequate antibiotic agents based on susceptibility results, episodes were excluded if the urine was collected >24 h after initiation of antibiotic therapy to reduce the risk of false-negative urine cultures.A complete case analysis was performed. When clinical symptoms or the presence of an indwelling catheter were reported to be unknown by the attending physician or nurse, this was considered an absence of the symptom or catheter.For the main outcome, RR and 95% confidence intervals were calculated in order to obtain insight into the relationship between antibiotic prescription and the resident-related factors. The percentages of adequate and inadequate treatment decisions were calculated from all suspected UTI episodes in which antibiotics were prescribed. The percentages of adequate and inadequate withholding of antibiotics were calculated from all suspected UTI episodes in which no antibiotics were prescribed. The calculation of the proportion of adequate antibiotic agents prescribed based on the type of UTI in accordance with the guideline  was performed differently. Firstly, suspected UTI episodes were only included if they fulfilled the guideline definition of either cystitis, UTI with signs of tissue invasion or indwelling catheter-associated UTI . Then, an = 163), the median age was 87 years (range 66–107), and over 70% (n = 146) were residents of psychogeriatric wards.The dataset consisted of 298 suspected UTI episodes identified in 206 residents (30.9% recurrent infections) . The majn = 215)  . In 60 sEscherichia coli (E. coli) was most commonly often identified (n = 90). Other uropathogens found were Proteus mirabilis (n = 15), Enterococcus faecalis (n = 3), Klebsiella pneumoniae (n = 3), Kelbsiella variicola (n = 3), and Klebsiella oxytoca (n = 1).In 120 of the 298 suspected UTI episodes (40.3%), an uropathogen was identified (data not shown). Among these episodes, In total, 185 suspected UTI episodes were treated with antibiotics (62.1%) . In 8 ofThe proportion of treated UTI episodes was higher when multiple specific UTI symptoms were present: in 61.5% (40/65) of the suspected UTI episodes antibiotics were prescribed when one specific symptom was present, while in 14 out of 15 (93.3%) of the suspected UTI episodes, antibiotics were prescribed when 4 specific UTI symptoms were present (data not shown). Antibiotics were most frequently prescribed in episodes with reported dysuria , followed by suprapubic pain  . DysuriaThe presence of positive leukocyte esterase results was associated with more than a two-fold increase in the risk of antibiotic prescription  . When bon = 10), regardless of the additional resident-related factor.In episodes presenting with a combination of dysuria and several other resident-related factors, the proportion of antibiotic prescription was high (up to 100%) . EspeciaOverall, 64.1% of the treatment decisions were adequate (191/298): 50.3% of the decisions to prescribe antibiotics were adequate (93/185) and 86.7% of the decisions to withhold antibiotics were adequate (98/113) . InadequAmong the suspected UTI episodes, nitrofurantoin was the most commonly prescribed antibiotic agent , followed by amoxicillin-clavulanic acid  (data not shown). Nitrofurantoin was inadequately prescribed for seven men with suspected UTIs (29.2%). Three suspected catheter-associated UTI episodes (37.5%) and seventeen of the suspected UTI episodes (54.8%) with signs of tissue invasion were inadequately treated with nitrofurantoin.Of the 298 suspected UTI episodes, 108 (36.2%) fulfilled the guideline’s UTI definitions: 80 cystitis (74.1%), 22 UTI with signs of tissue invasion (25.0%), and 1 indwelling catheter-associated UTI (0.9%) (data not shown). Of these guideline-based UTIs, 86.1% (93/108) were treated with antibiotics. The adequate antibiotic agent (nitrofurantoin or fosfomycin) was used in 57 of the 69 treated cystitis episodes (82.6%). In 9 of the 23 treated guideline-based UTIs with signs of tissue invasion (39.1%), the adequate antibiotic agent  was prescribed.E. coli isolates were mostly susceptible , while P. mirabilis isolates were only susceptible in 6 of 13 (46.2%) UTI episodes for the antibiotic agents prescribed.Among all treated suspected UTI episodes with urine specimens collected <24 h after initiating antibiotics and a positive urine culture, 84.5% (87/103) of the identified uropathogens were susceptible to the prescribed antibiotic agent (data not shown). This study shows that dysuria and positive leukocyte esterase dipstick results increased the risk of antibiotic prescription for suspected UTI in Dutch nursing homes. Moreover, the proportion of treated UTI episodes increased when increasing numbers of leukocytes were found, especially in combination with the presence of specific UTI symptoms. These data confirm that, against guideline recommendations, the presence of non-specific symptoms resulted in treatment of a UTI. A third of the antibiotic treatment decisions were either inadequately prescribed or inadequately withheld, according to the Dutch guideline for UTIs in frail older adults . OvertreThe reluctance to prescribe antibiotics for only non-specific symptoms is not new. Previous guidelines, including the former Dutch guideline, recommend refraining from antibiotic treatment for episodes without specific UTI symptoms ,18,23. TWe found that positive leukocyte esterase results were associated with a more than doubled risk of antibiotic prescription. This is in line with an earlier study in nursing homes that reported a positive dipstick result as the most important resident characteristic prognosticating antibiotic prescription for suspected UTIs . On the In our study, inadequate treatment decisions were made in approximately one third of the suspected UTIs and overtreatment occurred more often than undertreatment, which is in concordance with previous findings in Dutch nursing homes . SurprisE. coli comprised the majority of the isolated uropathogens and were susceptible to the prescribed therapy in 92.3% of UTI episodes. The overall uropathogen susceptibility in this study was higher (84.5%) than the uropathogen susceptibility in an American nursing home study (77.4%) [In our study,  (77.4%) .A strength of this study is that it provides an overview of the individual and combined influence of a wide range of resident-related clinical and demographic factors in antibiotic treatment decisions in suspected as well as guideline-based UTIs. In addition, because of our prospective study design in which residents were included based on the clinical suspicion of a UTI, both treatment decisions to prescribe and to withhold antibiotics were assessed. Hereby, this study gives a complete overview of the management of suspected UTIs in nursing homes in terms of overtreatment and undertreatment. Previous studies in this field had a retrospective study design in which the treatment decision to prescribe antibiotics could only be assessed ,24 or inThe main limitation of this study is that more than two thirds of the UTI episodes were enrolled before publication of the new Dutch guideline for UTIs in frail older adults and the remaining episodes were enrolled within a year after publication. Although the proportions of adequate treatment decisions did not differ between the subgroups enrolled before and after guideline publication, this may have resulted in an overly stringent assessment of the proportion of adequate treatment decisions. However, the previous guideline already recommended careful exclusion of other infections in case of non-specific symptomatology before initiation of antibiotics . Second,This study showed that unnecessary antibiotic prescriptions in suspected UTI episodes were driven by dipstick results and the presence of solely non-specific symptoms, and it revealed inadequate nitrofurantoin use in particular risk groups, such as men. When re-evaluating the current guidelines, a greater focus on these pitfalls causing overtreatment as well as undertreatment should therefore be considered. Due to the interdependence of symptoms and symptom complexes characterising UTIs, causality between each resident-related factor and the occurrence of antibiotic prescription could not be determined. A principal component analysis with a larger sample could further determine the causal relationship between antibiotic prescription and its influencing factors. The results of this study could, however, encourage a greater focus on guideline adherence. Furthermore, it could be used for educational matters targeted at nursing home nurses and physicians to reduce the gap between guideline recommendations and daily practice to improve antibiotic treatment decisions in this frail population.


Few studies have explored the health and development of AIDS orphans using the positive youth development (PYD) framework. Grounded in this framework, the main objective of this study is to examine how internal assets  and external assets  affect subjective well-being among Yi AIDS orphans in the Liangshan Yi Autonomous Prefecture, Sichuan province, China.A cross-sectional survey was conducted by interviewing 571 AIDS orphans and 979 non-orphans of Yi ethnic minority from 5th-10th grades. Structural equation models (SEM) were utilized to identify and estimate the direct and indirect effects of internal and external assets on subjective well-being.P < 0.05). Resilience, school connectedness, peer support , and self-rated physical health had significant and positive direct effects on subjective well-being. In addition, the effects of school connectedness, and peer support on subjective well-being were mediated by resilience.The average score of subjective well-being was significantly lower for AIDS orphans than for in non-orphans (Positive individual and school-related contextual assets can bolster subjective well-being among AIDS orphans. The design of health intervention programs for AIDS orphans should incorporate these positive development assets.The online version contains supplementary material available at 10.1186/s12888-022-03833-2. Since the first cases of acquired immunodeficiency syndrome (AIDS) were reported in 1981, human immunodeficiency virus (HIV) infection has become a global pandemic, which has exacted a heavy toll on both adults and children. It has been estimated that 36.3 million people have died from AIDS-related illnesses since the onset of the pandemic . With reA growing body of research has suggested that AIDS orphans are more susceptible to internalizing problems, such as depression, anxiety, and suicidal ideation than non-orphans –7. WhileSince school-age AIDS orphans spend most of their time in school, factors such as school connectedness and peer support are deemed important external development assets for subjective well-being . School Peer support, defined as the process of giving and receiving emotional and practical assistance, sharing knowledge, teaching and learning life skills, and connecting people with resources and opportunities within a network of friends or peers, is another important positive development asset for children and adolescents' subjective well-being , 17. ResResilience has recently come to light as one of the most salient internal development assets and individual strengths that plays a vital role in recovering and maintaining a well-functioning adaptive system in the context of trauma, tragedy, and other adverse life events. Resilience can be divided into three dimensions: tenacity , strength , and optimism  , 21. A sMoreover, unhealthy physical conditions can hinder children and adolescents' participation in daily learning and activities, which can in turn reduce social connections and life satisfaction. On the other hand, healthy physical conditions can be regarded as a positive health asset that is beyond the mere absence of disease for subjective well-being . Such a In summary, few studies have explored the health and development of AIDS orphans using the PYD framework. Grounded in this framework, the present study examines the subjective well-being of AIDS orphans in the Liangshan Yi Autonomous Prefecture, located in the southwestern part of Sichuan province, China. AIDS orphans in this study refer to children and adolescents under the age of 18 who have lost one or both parents due to AIDS related causes. The vicious circle of intravenous drug use and the high prevalence of HIV/AIDS, coupled with severe economic underdevelopment and chronic poverty, have resulted in a large number of deaths of young adults, thus leaving behind approximately 25,000 AIDS orphans . In addist grade to 10th grade. Based on the information available through the school management system, AIDS orphans were selected as the study subjects. To ensure accuracy, all AIDS orphans were verified by the school teachers or administrators who were familiar with the student participant's family circumstances. In addition, 1–3 non-orphans were randomly selected from the orphans' classes in each selected school to compose a quasi-comparison group. Both the participants and their guardians were provided with both oral and written consent prior to the study. Before the survey was conducted, all investigators received professional training. By virtual of their professional qualifications, several investigators served as counselors for the student participants throughout the data selection process. In total, 1,912 students ranging from 1st grade to 10th grade were recruited. Because of their limited literacy and proficiency, the students in 1st-4th grades were excluded from this study. As a result, 1,550 participants with an average age of 14.3 years [standard deviation (SD): 1.77 years] from 5th grade to 10th grade constitute an analytic subsample for the present study. Out of the 1,550 Yi adolescents, 571 were AIDS orphans and 979 were non-orphans.A cross-sectional survey on the well-being of Yi children and adolescents was conducted from September 20 to October 10, 2018. Among the 17 counties in the Liangshan Yi Autonomous Prefecture, Sichuan province, China, four counties that have been seriously affected by HIV/AIDS were selected. Four schools, one from each county, were identified and selected for this study, including one primary school, one middle school, and two schools with mixed grades ranging from 1Subjective well-being was measured by the Index of Well-being , consistThe School Connectedness Scale came from the Resilience Youth Development Module of the California Healthy Kids Survey. There were 5 items : (1) I fTwo items from the Social Support Rating Scale were utilized to represent peer support . ParticiIn addition, a single item was included to measure self-rated physical health. Participants were asked: "How do you feel about your physical health?” The five-point Likert response options were: 1 = very unhealthy, 2 = unhealthy, 3 = moderately healthy, 4 = healthy, and 5 = very healthy.The Connor-Davidson Resilience Scale developed by Connor and Davidson include 25 items, for example, "I can adapt to change" and "I make my best effort no matter what". This scale was adapted and divided into three dimensions: (1) tenacity, (2) strength, and (3) optimism. The items were rated on a 5-point scale  and summed to form an index variable , with hiDemographic characteristics included age (years) and gender (dummy-coded). The housing condition was used to approximate family economic status. The mud-brick house, brick house, and storied house indicated poor, medium, and good family economic status, respectively.For descriptive statistical analysis, percentages, means and standard deviations (SD) were calculated and reported. The differences between AIDS orphans and non-orphans in sociodemographic characteristics, subjective well-being, school connectedness, peer support (number of friends and caring friends), resilience and self-rated physical health were analyzed. The partial correlation coefficients among subjective well-being, school connectedness, peer support, resilience, housing, and self-rated physical health were examined, adjusting for age and gender among AIDS orphans.P-value (two-sided) ≤ 0.05 was considered statistically significant.One structural equation model (SEM) with maximum likelihood estimation was estimated to test both the direct and indirect effects of the exogenous variables on subjective well-being among AIDS orphans. The mediating effects of resilience on subjective well-being was tested using the bootstrapping method. The following indicators were used to evaluate the goodness-of-fit of the model: the goodness-of-fit index (GFI) of 0.90 or better; the comparative fit index (CFI) of 0.90 or better; the normed fit index (NFI) of 0.90 or better; the adjusted goodness-of-fit index (AGFI) of 0.90 or better; and the root mean square error of approximation (RMSEA) of less than 0.08 . The staP < 0.05). With reference to peer support, 44.5% of AIDS orphans reportedly had more than 6 friends and 31.3% of orphans reported being cared for very often by friends, both of which were lower than non-orphans, 59.2% and 40.5%, respectively. Additionally, nearly 35% of AIDS orphans reported being very healthy, which is also lower than non-orphans (40.9%). Lastly, AIDS orphans reported significantly poorer housing conditions than non-orphans.As shown in Table The adjusted partial correlation coefficients of the study variables are presented in Table P-value associated with each path coefficient was less than 0.05, the exact times of the bootstrap method was 5000. Table P < 0.05). These mediation effects account for 10.5% of the total effect of school connectedness, 8.3% of the total effect of the number of friends, and 6.7% of the total effect of caring friends on subjective well-being, respectively. The same model was also estimated for non-orphans  are well aligned with supportive ecological assets . This means that as a central construct in the framework of developmental assets and mental health promotion, subjective well-being has considerable implications for positive adolescent outcomes in their transition to young adulthood , 38, 39.To cultivate ecological assets, this study found that school connectedness, as a crucial external asset, positively affected AIDS orphans' subjective well-being. School connectedness is the perception developed by students about the care and respect they received from their teachers and other adults in the school context. A higher level of school connectedness would reflect positive attitudes toward school, a strong sense of belonging, and a positive connection with adults and peers. This sense of belonging can help reduce AIDS orphans' psychological distress , 15. TheAs anticipated, peer support surfaced as another external asset that significantly bolstered AIDS orphans' subjective well-being. Results from this study showed that having more friends, especially caring friends, might imply frequent information sharing and emotional support AIDS orphans elicited from their peer networks. Such intangible peer support could meet basic psychological needs and make up for the lack of familial support for AIDS orphans, which underscored the importance of peer support as a positive development asset for children and adolescents' subjective well-being.As an internal development asset, results pertaining to resilience are in line with the prior literature. That is, resilience could play a vital role in strengthening subjective well-being even when AIDS orphans encountered a significant amount of adversity and stress . Put difFor children and adolescents, self-rated physical health reflects self-perceived health conditions . Under the PYD framework, self-reported health can be viewed as health asset. As such, good healthy conditions can be positively associated with subjective well-being , which iSeveral research limitations should be recognized. First, this study utilized a cross-sectional survey. As such, it is impossible to draw any causal conclusions regarding the associations between school connectedness, peer support, or resilience, and subjective well-being among AIDS orphans. Longitudinal studies are needed to establish possible causal relationships in future research. Second, all variables used in this study were self-reported, which might be subject to a certain degree of self-report bias. However, it is important to note that our SEM analysis has corrected some of the measurement errors  by design. Finally, several important measures that are associated with AIDS orphans' subjective well-being, such as self-esteem, relationship with the caregiver, and physical activity, were not included in the survey. Future research should incorporate these factors as developmental assets and link them to AIDS orphans' subjective well-being.Despite these limitations, there are some strengths to this study. The most notable strength is the contribution to the study of AIDS orphans' subjective well-being from a positive development perspective. We venture to suggest that the PYD framework has the potential to become a leading theoretical framework in studying AIDS orphans. Additionally, the sample size of this study is reasonably large, and the findings are generalizable to AIDS orphans of Yi ethnic minority in the region. Finally, this study has laid a compelling backdrop for (1) future intervention work that can help AIDS orphans thrive by increasing both external assets  and internal assets  and (2) mobilizing and orchestrating government and public efforts and resources to improve AIDS orphans' and non-orphan adolescents' subjective well-being among ethnic minority populations in China.The PYD framework is essential for scholars and practitioners to identify school-related contextual and individual assets that can bolster AIDS orphans' subjective well-being. Practitioners are strongly encouraged to offer health promotion and health education programs so that school-age children and adolescents, especially AIDS orphans, can receive the necessary training to improve their health-related, problem-solving, and coping skills. Meanwhile, school administrators and teachers can utilize these training opportunities to promote subjective well-being for AIDS orphans.Additional file 1.Additional file 2.


Understanding the evolution of mechanical properties and microscopic pore structure of concrete after freeze–thaw cycles is essential to assess the durability and safety of concrete structures. In this work, the degradation law of mechanical properties and damage characteristic of micro-structure of concrete with two water-cement ratios (w/c = 0.45 and 0.55) is investigated under the condition of freezing–thawing cycles. The influence of loading strain rate on dynamic compressive strength is studied. The microscopic pore structure after frost damage is measured by low-field nuclear magnetic resonance (LF-NMR) technique. Then, a damage model based on the porosity variation is established to quantitatively describe the degradation law of macroscopic mechanical properties. The test results show that the relative dynamic modulus of elasticity (RDME), dynamic compressive strength, flexural strength, and splitting tensile strength of concrete decrease with the increase of freeze–thaw cycles. Empirical relations of concrete dynamic increase factor (DIF) under the action of freeze–thaw cycles are proposed. Moreover, the experimental results of NMR indicate that the porosity as well as the proportion of meso-pores and macro-pores of concrete gradually increased with the increasing of freeze–thaw cycles. The research results can provide reference and experimental support for the anti-frost design theory and durability life prediction of hydraulic concrete structures in cold regions. Material degradation caused by freeze–thaw cycles is one of the major durability problems of concrete structures in cold regions ,2,3, wheIn the past few decades, numerous studies have been conducted on the evolution laws of mechanical deterioration ,10 and dThe porosity and pore size distribution (PSD) are significant parameters of the pore structure, which directly affect the permeability, mechanical properties, and durability of concrete ,22,23. KCurrently, LF-NMR technique is gradually and widely used as a new and rapid method to detect the microstructure of rocks , concret−5/s to 10−2/s. The porosity, transverse relaxation time T2 distribution, and PSD after freeze–thaw cycles are obtained. The empirical relations of concrete DIF under the action of freeze–thaw cycles are proposed. The relationship between NMR porosity damage and strength are established, which can provide data support and reference for the durability prediction and safety assessment of concrete structures in cold regions.The goal of this study is to investigate the mechanical properties and pore structure degradation of concrete with different water–cement (w/c) ratios under the action of freezing–thawing cycles. The attenuation rules of mass loss rate, RDME, compressive strength, flexural strength, and splitting tensile strength after frost damage are analyzed. The dynamic compressive properties of concrete are experimentally investigated at the strain loading rates ranging from 103, the specific surface area is 330 m2/kg. The initial and final setting times are 155 and 215 min, respectively. The compressive strengths at 7 and 28 days are 26.2 and 48.8 MPa, the flexural strengths at 7 and 28 days are 5.6 and 8.5 MPa, respectively. The common natural river sand was used with a fineness modulus of 2.66, and its particle size distributions are illustrated in 3 and continuous gradation from 5 to 31.5 mm were chosen as coarse aggregates. In addition, a modified FDN superplasticizer was used with a mixing amount of 0.8% (by the weight of cement), the pH value of the FDN superplasticizer  was 8.19, and the water reducing rate was 21%.Ordinary Portland cement P.O 42.5 was used for preparing concrete specimens, which is produced by Yatai Group Co., Ltd . The density of the cement is 3105 kg/mPrevious studies have shown that the water–cement ratio and loading rate have a great influence on the compressive strength of concrete. Therefore, two different water–cement ratio (w/c) concrete mixtures were designed and prepared in the laboratory conditions. The mix proportions of concrete are given in The flow chart is shown in The rapid freeze–thaw method used in this test was based on the Chinese national standard GB/T 50082-2009 , which iN freeze–thaw cycles (kg); The mass loss rate . The relative dynamic modulus  Two displacement sensors were placed on the two sides of the cube specimen to record their deformation during the loading process. The flexural strength and splitting tensile strength of concrete are another key property for evaluating the durability of concrete. In this test, the flexural strength and splitting tensile strength of the concrete specimens with different w/c ratios under freeze–thaw cycles were tested, according to Chinese standard specification GB/T 50081-2019  and ASTMN freezing and thawing cycles; N freeze–thaw cycles, MPa.To better evaluate the effect of freeze–thaw cycles on the frost durability of concrete with different water–cement ratios, the loss of flexural strength under freeze–thaw cycles (0–225 cycles) was calculated according to Equation (3) based on the test results.In this experiment, a MesoMR23-060H-I instrument  was used to test the pore structure of concrete drill core samples after frost damage. The NMR analysis equipment has a resonance frequency of 21.3 MHz, a magnet strength of 0.5 ± 0.08 T, a coil diameter of 60 mm. Additionally, the measurement parameters were set as follows: P1 = 13.00 μs, P2 = 26.00 μs, SW = 200 kHz, TR = 1000 ms, NS = 32, Echo spacing time = 0.26 μs, Echo count = 18,000. During the NMR tests, the temperature of the magnet and probe assembly was maintained at 32 ± 0.01 °C. The room temperature was set at 25 ± 1 °C by air conditioning. The size of concrete sample used for NMR test was 50 × 100 mm (diameter × height). Prior to the test, the drill core sample was wiped to clean the surface mortar and was vacuum-saturated with water for 24 h by using a ZYB-II vacuum saturator . Compared with CT technique, the LF-NMR test needs more preparation and time. The experimental procedure is shown in T2 is the transverse relaxation time of water in the pore, ms; ρ2 is the strength of transverse surface relaxation (μm/ms); S/V is the surface–volume ratio of the pores; sF is the shape scale factor; R is the pore radius.According to the theory of NMR, the Carr–Purcell–Meiboom–Gill (CPMG) sequence is usually used to test the relaxation time information of cement-based materials ,34,35. BS/V, and T2 is positively correlated with pore radius. The short relaxation times have smaller pore sizes, while longer times have larger pore sizes. Therefore, the transverse relaxation time T2 distribution curve is consistent with the pore size distribution curve, which can reflect the distribution of moisture in the internal pores of concrete.It can be seen from Equation (4) that the transverse relaxation time is only related to The figure also shows that the cubic specimens after 200 freeze–thaw cycles present more serious surface scaling and more damage characteristics than the prism specimens after 200 freeze–thaw cycles. This can be explained in two ways: (1) influence of size effect; (2) since the ratio of surface area to volume around the cubic specimen is 1.33 times that of the prismatic specimen . This alThe relationship curves of mass loss rate of concrete specimens with the number of freeze–thaw cycles for different water–cement ratios are shown in In addition, it is clear that the relationship between mass loss rate and freeze–thaw cycles exhibit the two distinct stages. In the first 0–125 freeze–thaw cycles, it can be identified that in the damage accumulation stage, the weight of concrete specimens shows a slightly increasing trend or is basically unchanged. However, after 150 freeze–thaw cycles, the mass loss rate increases significantly for the 0.45, 0.55 water–cement ratio specimens, which can be identified as the damage acceleration stage.The RDME can reflect the state of micro-crack development inside the concrete, the lower the RDME means the more serious degree of freeze–thaw damage. The change of RDME can reflect the change of internal microstructure and overall compactness of concrete after frost damage, therefore, it can be used to characterize the degree of damage deterioration of freeze–thaw concrete ,42. It icuf) was tested for characterizing the mechanical properties of concrete under different freeze–thaw cycles. −5/s to 10−2/s. Furthermore, it is noted that the peak compressive strength of concrete shows a decreasing trend with the increase of freeze–thaw cycles at the same strain loading rate.In this study, the cubic compressive strength  and splitting tensile strength (stf) tests were also performed to evaluate the durability of the concrete specimens after freeze–thaw cycles. The average experiment results of ff and stf are listed in ff and stf decreased continuously with the increase of the number of freeze–thaw cycles. This phenomenon might probably be due to the internal damage gradually accumulated during the freeze–thaw cycles, which indicates the micro-cracks have gradually expanded and penetrated in the concrete specimen.In this test, the flexural strength , the 3rd peak is not obvious, and with the increase of the number of freeze–thaw cycles, the pore structure of the concrete core sample changes, and the proportion of the 2nd and 3rd peaks gradually increases, while the 1st peak gradually decreases, which means that the freeze–thaw cycles make the internal micro-pores gradually expand and penetrate, making the micro-pores gradually evolve into medium and large pores. After 200 freeze–thaw cycles, the increase of the 2nd and 3rd peaks on the right side of the T2 relaxation time curve was significantly higher than that of the 1st peak, indicating that the micro-pores and meso-pores inside the concrete continuously expand and penetrate into macro-pores. This indicates that with the accumulation of frost damage, the external moisture continues to migrate into the newly generated pores, generating the internal frost heaving pressure and osmotic pressure of concrete increasing, the pore structure continues to deteriorate, small pores continue to develop, expand, and even penetrate, forming medium and large pores [ge pores ,44.Concrete is a typical porous material, and the internal porosity and pore size distribution are closely related to the mechanical properties. According to the results of , the porIn The porosity is a significant property used to quantify the pore structure of concrete. It can also be seen from the figure that at the early stage of freeze–thaw (0–25 cycles), the porosity hardly changed, while at the stage of 50–125 freeze–thaw cycles, the growth of NMR porosity was significantly accelerated. Subsequently, at the stage of 125–175 freeze–thaw cycles, the growth of porosity was slower. The analysis concluded that at the beginning of freeze–thaw cycles, the concrete is relatively compact inside and the overall degree of compactness is high; as the number of freeze–thaw cycles increases, the repeated action of periodic freezing and expansion forces and hydrostatic pressure on the pores inside the concrete causes the pores inside the concrete to gradually expand, penetrate, and form connected pores . At the In previous studies, most of the literature has focused on the variation of macroscopic mechanical properties of concrete under the condition of freeze–thaws cycles. In fact, the microscopic pore structure and pore size distribution inside concrete are closely related to the macroscopic mechanical properties and durability ,24,44. TD to evaluate the damage of concrete with different water–cement ratios after frost damage, and this damage variable can quantitatively reflect the degree of damage to the internal microstructure of concrete specimens, and the relationship between the damage variable D and porosity can be defined asn freeze–thaw cycles, %; The most direct result of the damage caused by freeze–thaw cycles on concrete is the increase of porosity. Therefore, the change in porosity is introduced as the basis for establishing the damage variable The damage variables of porosity of concrete after different number of freeze–thaw cycles were calculated according to Equation (5), as shown in ff) and splitting tensile strength (stf) of concrete specimens gradually decreased with the increase of the porosity damage. This indicates that the degree of deterioration gradually increases with the increase of the number of freeze–thaw cycles, and the accumulation of damage to the microscopic pore structure leads to different degrees of deterioration of the macroscopic mechanical and mechanical characteristics of the concrete specimens.In order to further analyze and explore the quantitative relationship between microscopic pore structure changes and macroscopic damage characteristics of concrete, a fitted regression analysis was performed on the porosity damage variables and macroscopic damage characteristics indicators. As shown in the ff and damage variable D all satisfy the quadratic parabolic equation, and the correlation coefficient R2 is greater than 0.964. This fully indicates that there is a good quantitative correspondence between the microstructural changes of concrete pores and macroscopic damage characteristics under different freeze–thaw cycles.According to The main reason for the concrete failure under freezing and thawing cycles is the generation, expanding, and developing of micro-cracks inside the concrete. The test results of Luan et al.  showed tAccording to the experimental results, all of the RDME, dynamic compressive strength, flexural strength, and splitting tensile strength decrease with the increase of freeze–thaw cycles, which is shown in (1)With the increase of the number of freeze–thaw cycles, the appearance characteristics of concrete became more and more rough, and the apparent damage of cubic specimens was more serious than that of prism specimens. The change rule of concrete mass loss varying with freeze–thaw cycles shows obvious two-stage distribution. Before 125 freeze–thaw cycles, the mass increases slightly due to the capillary pore water absorption and further hydration of cement paste. After that, the mass loss rate increases gradually become larger.(2)The concrete specimen with 0.45 water–cement ratio has better performance of frost resistance and durability. The RDME, flexural strength, and splitting tensile strength of concrete decrease 22.66%, 66.1%, and 53.1% after 200 freeze–thaw cycles, respectively.(3)The results of dynamic loading tests show that there is a good linear relationship between the DIF and the log strain rate under the different freeze–thaw cycles. With the increase of strain rate, the peak stress of concrete with the same degree of freeze–thaw deterioration gradually increases. In addition, the sensitivity of the peak stress to the strain rate gradually increases with the increase of the number of freeze–thaw cycles.(4)The porosity as well as the proportion of meso-pores and macro-pores gradually increase, which indicates that the deterioration of concrete interior is gradually serious with the increase of the number of freeze–thaw cycles. After 200 freeze–thaw cycles, the NMR porosity of 0.45 and 0.55 water–cement ratios increased by 53.49% and 59.67%, respectively.(5)Finally, a damage model based on the porosity variation was established to quantitatively describe the degradation law of macroscopic mechanical properties, which matches well with the experimental results.(6)The results in this work can provide data support and reference for the durability prediction and safety assessment of concrete structures in cold regions, such as concrete dams, sluices, and canals. To improve the durability and service life of the concrete structures in cold climates, the porosity and water–cement ratio should be reduced.In this study, the dynamic evolution of mechanical properties, durability, and pore structure of two types of water–cement ratio  concrete under freeze–thaw cycles were systematically investigated, and the degradation mechanism of concrete was explored based on porosity damage variables. Based on the experimental results analysis above, the following conclusions were drawn:


To observe efficacy of Timolol maleate 0.5% by topical and surface application in infantile superficial capillary hemangioma of eyelid. This multi-centered clinical case series was carried out at Ophthalmology Department of Bilawal Medical College and Institute of Ophthalmology, LUMHS, Jamshoro from November 2019 to May 2020. We included 14 subjects. All the patients were subjected to detailed clinical examination. Before starting the topical beta blockers, the enrolled subjects had obtained the expert opinion by pediatrician to rule out any preexisting developmental cardio vascular disease. Topical beta blockers 0.5% drops were thus started with, against the ongoing finding of superficial capillary hemangioma of eyelid.There was significant regression in size of infantile hemangioma after treating with topical timolol maleate 0.5%. We included 14 subjects in this study. Mean±SD age of patients was 4.94. Complete regression was seen in 08 subjects at the end of 12 weeks (64%) while 03 were completely cured at 08 weeks (21%) and 01 patient lost follow up with us. No significant ocular and systemic side effects were noted. Topical timolol maleate 0.5% can be the first-line treatment modality for superficial capillary hemangiomas due to its better safety and efficacy. Infantile hemangiomas (IH) are benign proliferation of endothelial cells mostly arising in first 08 weeks of life.2The cycle of disease is characterized by early proliferative phase, followed by involution and results in complete regression in most cases. During first few months aged, the lesion grows aggressively, followed by stabilization. Involution is complete in most youngsters by four years of age.5Previously hemangiomas were treated with ultrapotent topical corticosteroids, which were potent but were causing side effects like skin hypopigmentation and atrophy.12Topical β-blockers timolol maleate 0.5% are best substitute in managing superficial IHs asthey will improve the therapeutic efficacy and reduce systemic adverse effects of beta blockers.15Topical timolol has been reported to inhibit the expansion and promote regression of superficial IH’s.This multi-centered case series was conducted at Bilawal Medical College and Institute of Ophthalmology, LUMHS, Jamshoro from November 2019 to May 2020 after approval from ethical committee (LUMHS/REC/-828). Fourteen patients aged two months to 18 months were included during this study after an informed written consent.All the subjects underwent detailed ocular and systemic examination and patients having superficial capillary hemangioma of eyelid were included. Subjects having hypertension, visceral involvement, respiratory problem & cardiovascular abnormalities were excluded from the study. Opinion of pediatrician to rule out developmental cardiovascular abnormalities was obtained before the commencement of treatment. Topical Timolol Maleate 0.5% 2 drops were applied over the lesion twice each day. Follow up was done at two weeks, eight weeks and 12 weeks respectively during which color and size of lesion were assessed. Statistical analysis was through with help of SPSS version 21.0. p-value was not calculated due to single group study.Fourteen (14) subjects received timolol maleate with a total mean±SD age of 4.94 (Male = 6.5 and female mean age = 4.08 months, respectively. Gender distribution of patients was 64% male and 36% female. The most common indication of treating IH’s was to prevent cosmetic disfigurement, ulceration, astigmatism and amblyopia. Clinical characteristics of patients are mentioned in Inafantile hemangiomas grow in early period of life that mostly resolves spontaneously. The proliferative phase commences during a week or two of life, that’s followed by a plateau phase. The involution phase is noticed to be commenced at a primary year of life and remains until 4-6 years aged. In our study, the initial age for the looks of IH’s was eight weeks, as compared with previous studies. Xu et al found that the therapeutic response of youngsters who started treatment with propranolol ointment had a big difference.Ariwibowo, Danarti et al. and associates found that Timolol maleate 0.5% the answer was better than corticosteroids in reducing the dimensions of superficial IH.Regression of IH’s using 0.5% timolol maleate drops occurred before spontaneous regression which occurred at 9-12 months.Despite our success of treating IH’s with topical timolol maleate 0.5%, the underlying mechanism of timolol maleate remains elusive. Further work should be administered and comparison of regression between children and adults should be investigated on large scale.we could not consider the presence of multiple and deep hemangiomas and their regression with topical timolol maleate 0.5 %. Moreover, we measured short term post treatment effect of 12 weeks.Topical timolol maleate 0.5% instead of oral propranolol could be the first-line approach for superficial capillary hemangiomas due to its good efficacy and improved safety. However, a comparative study between children and adult’s regression of hemangiomas must be conducted and evaluated at a larger scale.JMS: conceived, designed and did statistical analysis & editing of manuscript, is responsible for integrity of research.JMS, R, MMN: did data collection and manuscript writing.SPS: did review and final approval of manuscript.


In early-onset FRI, 100.0% efficacy would be achieved by meropenem + vancomycin, gentamicin + vancomycin, co-amoxiclav + glycopeptide, ciprofloxacin + glycopeptide and piperacillin/tazobactam + glycopeptide. For patients with delayed FRI, the highest susceptibility was revealed for meropenem + vancomycin, gentamicin + vancomycin and ciprofloxacin + glycopeptide (96.7%). Meropenem + vancomycin was the most effective empiric antimicrobial in patients with late-onset of infection with 92.1% coverage. No subgroup differences in antibiotic sensitivity profiles were observed except for the combination ciprofloxacin + glycopeptide, which was significantly superior in early FRI . Across all subgroups meropenem + vancomycin was the most effective empiric treatment in 95.7% of patients with confirmed susceptibility. Meropenem + vancomycin, gentamicin + vancomycin, co-amoxiclav + glycopeptide are the best therapeutic options for FRI, regardless of the onset of infection. To avoid multidrug resistance, established antibiotic combinations such as co-amoxiclav with a glycopeptide seem to be reasonable as a systemic antibiotic therapy, while vancomycin + gentamicin could be implemented in local antibiotic therapy to reduce adverse events during treatment.Antibiotic treatment strategies for fracture-related infections (FRI) are often extrapolated from periprosthetic joint infections (PJI), although, in contrast to PJI, detailed analysis of pathogens and their antibiotic resistance is missing. Therefore, this study aimed to investigate antibiotic susceptibility profiles to identify effective empiric antibiotic treatment for early-, delayed-, and late-onset FRI. Patients treated for FRI from 2013 to 2020 were grouped into early (<2 weeks), delayed (3–10 weeks), and late (>10 weeks) onset of infection. Antibiotic susceptibility profiles were examined with respect to broadly used antibiotics and antibiotic combinations. In total, 117 patients (early  In trauma surgery, reduction and internal fixation is applied to restore skeletal integrity. One of the major complications after fracture fixation utilizing metallic fracture fixation devices, is implant-related infection. Rates of developing a posttraumatic infection are reported to be around 1–2% for closed fractures ranging up to exceeding 30% for Gustilo–Anderson type III open tibia fractures ,5. The mTo classify FRI, the time of onset of symptoms after fracture fixation is commonly applied, representing time-dependent pathophysiological changes such as biofilm maturation. Thus, FRIs are differentiated as early (< 2 weeks), delayed 3–10 weeks) and late (> 10 weeks) . This cl0 weeks aRecently, the microbiologic etiology in FRI has been analyzed, suggesting a similar spectrum of pathogens in early, delayed, and late FRI . HoweverWhat is the best possible empirical antibiotic treatment for FRI cases with early-, delayed- and late-onset of infection, respectively?2. Patients had comorbidities with a mean CCI of 1 (range 0–6) and a mean ASA score of 2 (range 1–4). FRI mainly occurred at the tibia (39.3%) followed by infections of the ankle (18.8%) and femur (14.5%). The mean delay from initial fracture care to onset of infection symptoms was 34.5 ± 93.5 weeks and the mean delay from symptom onset to surgical treatment for FRI was 1.3 ± 2.5 weeks. The cohort was grouped into 19 patients (16.2%) with early-onset of infection, 60 patients (51.3%) with delayed-onset of infection and 38 patients (32.5%) with late-onset of infection (p = 0.8), age (p = 0.738), ASA score (p = 0.929), CCI (p = 0.590), BMI (p = 0.885) or fracture site (p = 0.301).In total, 117 patients diagnosed with FRI were included. Overall, 85 (72.6%) of the patients were male and 32 (27.4%) were female. Mean age was 55.5 ± 16.8 years. The mean BMI was 27.4 ± 5.2 kg/mnfection . The subStaphylococcus aureus was the most frequently detected pathogen (39.7%), followed by Staphylococcus epidermidis (17.2%) and Gram-negative bacteria (16.4%). Difficult-to-treat microorganisms with a biofilm-active antibiotic resistance were present in 12 cases (10.3%) (Methicillin-sensitive  (10.3%) . The patbacteria .4%. DiffEscherichia coli and Pseudomonas aeruginosa, respectively. The highest resistance rates were found for ceftriaxone (29.1%), which could be reduced to 6.8% by an additional combination with a glycopeptide. For co-amoxiclav or piperacillin/tazobactam 22.2% of the patients would have shown resistance , ciprofloxacin + glycopeptide and piperacillin/tazobactam + glycopeptide (92.3% each). The lowest rates of resistance were evident for the combination gentamicin + vancomycin and meropenem + vancomycin, for which only two patients (1.7%) remained resistant due to infections with sistance .F = 3.304, p = 0.04), for which more patients with an early-onset of infection would have been susceptible.Comparing the predicted efficacy of empiric antimicrobial regimens between the subgroups, the combinations meropenem + vancomycin, gentamicin + vancomycin, co-amoxiclav + glycopeptide, ciprofloxacin + glycopeptide and piperacillin/tazobactam + glycopeptide would have covered all detected pathogens in early FRI and achieved 100% sensitivity in these patients . MonotheFor patients with delayed-onset of infection, meropenem + vancomycin, gentamicin + vancomycin and ciprofloxacin + glycopeptide were slightly superior (96.7% coverage) than co-amoxiclav + glycopeptide (93.3%) and piperacillin/tazobactam + glycopeptide (95.0%) . For antFor patients with a late-onset of infection, highest susceptibility was found for meropenem + vancomycin (92.1%). This was followed by the combinations: ciprofloxacin + glycopeptide (89.5%); gentamicin + vancomycin (86.8%) and piperacillin/tazobactam + glycopeptide (84.2%) . The higThe present study compared antibiotic susceptibility testing of FRI cases with distinct onset of infection treated at a center specializing in bone and joint infection management with the purpose of evaluating best treatment options for empirical antibiotic therapy. Overall, no significant differences in the efficacy of empiric antimicrobial regimens were observed between early, delayed, and late FRI, except for early FRI, in which the combination ciprofloxacin + glycopeptide was superior compared to delayed and late FRI.Current recommendations of an initial empiric broad-spectrum therapy include a lipopeptide or glycopeptide and an agent covering Gram-negative bacilli . HoweverSpecific data on the consumption of antibiotics in orthopedics and trauma surgery are lacking. European surveillance data suggest that 39% of infections including surgical site infections are caused by bacteria resistant to last-line antibiotics such as carbapenems . In EuroA further aspect when choosing an appropriate antimicrobial agent is the consideration of possible adverse events associated with the respective drugs, especially in the setting of required long-term antimicrobial therapy. Thereby, patient-related factors such as age, concomitant diseases  and allergies should be taken into account . Valour ® G+V), whereby an individual mixture is also possible [A feasible approach to bypass unwanted side effects of systemic antibiotics, while reaching high local concentrations, is administration of local antibiotic carriers . Especiapossible ,34. Basepossible . Local cpossible . Hence, possible ,38,39. HThe limitations of this study are the usual suspects. First, data analysis of only one orthopedic center may lead to a local epidemiological bias. In addition, the retrospective design restricts analysis to already existing antibiograms. In some cases, antibiotic testing for certain antibiotics was sometimes not performed which leads to it being listed as “unknown” antibiotic susceptibility. This is mainly due to different panels of antibiotics available for automated and manual susceptibility testing according to the interpretative criteria released by the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Further, the retrospective file analysis did not consistently allow identification of antibiotic pretreatment and its effect on the detection of infection-causing pathogens. In addition, subgroup analysis regarding the relevance of distinct anatomical localization would have been underpowered due to the low number of participants.A retrospective cohort study of patients treated for FRI was conducted in a level 1 trauma center in Germany. The inclusion period was defined from 1 January 2013 to 31 December 2020. Eligible patients aged 18 years or older were screened by international classification of disease (ICD) 10 diagnosis “T84.6 infection and inflammatory reaction due to internal fixation device”. Afterwards, patients’ medical charts, surgery protocols, laboratory findings as well as microbiological and histopathological reports were retrieved for inclusion criteria of FRI.Following the 2018 international consensus meeting on musculoskeletal infection , FRI wasPatient characteristics  , ASA scoTissue samples were homogenized and seeded on solid and liquid culture media. All samples were incubated for 14 days. Bacteria were identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI TOF MS) using a Microflex LT mass spectrometer and BioTyper software . Antibiotic susceptibility testing followed guidelines from the European Committee on Antimicrobial Susceptibility Testing (EUCAST).p-values ≤ 0.05 were considered statistically significant.Descriptive and statistical data analysis was performed using the IBM SPSS Statistics software . Frequencies were expressed as numbers and percentages. Continuous parameters were presented as means ± standard deviation (SD). One-way ANOVA with Tukey- and Games–Howell post-hoc test was conducted after ensuring homogeneity of variances using Levene’s test and normal distribution by Shapiro–Wilk test. For all tests, In conclusion, the retrospective analysis of potential antibiotic regimens indicates that for empiric antibiotic therapy, a combination of meropenem + vancomycin, gentamicin + vancomycin, co-amoxiclav + glycopeptide, ciprofloxacin + glycopeptide or piperacillin/tazobactam + glycopeptide achieves the best hypothetical sensitivity for antimicrobial therapy in FRIs regardless of the onset of infection. Due to hitherto unknown effects on multidrug-resistance development, empirical antibiotic therapy in FRI should avoid use of reserve antibiotics such as meropenem, whenever reasonable. Established antibiotic combinations such as co-amoxiclav with a glycopeptide as systemic antibiotic therapy and vancomycin + gentamicin as local antibiotic combination should be considered as an effective antibiotic combination therapy. Meropenem instead of co-amoxiclav should be considered in patients with a septic course of infection, previous antibiotic treatment or a high risk of infection with multidrug-resistant pathogens.