To test and compare the efficacy of methenamine hippurate for prevention of recurrent urinary tract infections with the current standard prophylaxis of daily low dose antibiotics.Multicentre, open label, randomised, non-inferiority trial.Eight centres in the UK, recruiting from June 2016 to June 2018.Women aged ≥18 years with recurrent urinary tract infections, requiring prophylactic treatment.Random assignment  to receive antibiotic prophylaxis or methenamine hippurate for 12 months. Treatment allocation was not masked and crossover between arms was allowed.Absolute difference in incidence of symptomatic, antibiotic treated, urinary tract infections during treatment. A patient and public involvement group predefined the non-inferiority margin as one episode of urinary tract infection per person year. Analyses performed in a modified intention-to-treat population comprised all participants observed for at least six months.Participants were randomly assigned to antibiotic prophylaxis (n=120) or methenamine hippurate (n=120). The modified intention-to-treat analysis comprised 205 (85%) participants ; methenamine hippurate, n=103 (86%)). Incidence of antibiotic treated urinary tract infections during the 12 month treatment period was 0.89 episodes per person year  in the antibiotics group and 1.38 (1.05 to 1.72) in the methenamine hippurate group, with an absolute difference of 0.49  confirming non-inferiority. Adverse reactions were reported by 34/142 (24%) in the antibiotic group and 35/127 (28%) in the methenamine group and most reactions were mild.Non-antibiotic prophylactic treatment with methenamine hippurate might be appropriate for women with a history of recurrent episodes of urinary tract infections, informed by patient preferences and antibiotic stewardship initiatives, given the demonstration of non-inferiority to daily antibiotic prophylaxis seen in this trial.ISRCTN70219762. Recurrent urinary tract infection (UTI) is defined as repeated UTI with a frequency of at least two episodes in the preceding six months or three episodes in the past year.The urgent need for demonstration of effective non-antibiotic treatments is underlined by the UK antimicrobial resistance strategy, which comments that “we are heading rapidly towards a world in which our antibiotics no longer work” and recommends a “strong focus on infection prevention.”Methenamine hippurate has been evaluated in previous Cochrane systematic reviews,This pragmatic, multicentre, randomised, open label, non-inferiority trial compared clinical effectiveness of low dose antibiotic prophylaxis, the current standard treatment for recurrent UTI prevention, with the urinary antiseptic methenamine hippurate. The ALTAR trial  recruited women from secondary care urology and urogynaecology centres in the UK from June 2016 and incorporated a 12 month treatment period followed by a six month follow-up period. Recruitment was completed in June 2018 and the final follow-up visit took place in January 2020. The study protocol has been published elsewhere.Adult women aged 18 years and over with recurrent UTI who had decided, in conjunction with their responsible clinician, that prophylaxis was appropriate, were eligible for inclusion. Recurrent UTI was defined as at least three episodes of symptomatic UTI in the previous 12 months or at least two episodes in the past six months. We excluded women with correctable urinary tract abnormalities contributory to recurrent UTI  and those with neurogenic dysfunction of the lower urinary tract. Women already taking antibiotic prophylaxis or methenamine hippurate were allowed to take part, but a washout period of three months without preventive treatment was required before randomisation. All participants provided written informed consent.v peri-menopausal/post-menopausal) and UTI frequency in the preceding year (<4 v ≥4). Randomisation lists were generated by an individual not otherwise involved in the trial and administered centrally via a web based service. This pragmatic trial was designed to reflect contemporary practice, and there was no masking of participants, clinicians, or local research staff.Participants were randomly assigned (1:1) to receive antibiotic prophylaxis or methenamine hippurate. Permuted blocks of variable length (2/4/6/8) were used, stratified by menopausal status , trimethoprim (100 mg), or cefalexin (250 mg) given orally once daily, depending on previous urine culture results and individuals’ history of allergy or intolerance. Methenamine hippurate was prescribed as a twice daily oral dose (1 g). Participants were allowed to switch between antibiotic drugs or between treatment strategies, however, the need to adhere to the allocated intervention was emphasised. Participants experiencing symptomatic UTI episodes were advised to seek discrete treatment courses of antibiotics in their usual way, typically via their general practitioner.Follow-up assessments took place every three months until month 18. At each visit, participants were asked about the occurrence of any UTIs, treatment adherence, and adverse events. Information on UTI episodes was confirmed where necessary from healthcare records. Blood samples were taken to monitor kidney and liver function in all participants. Urine samples were submitted to the central laboratory at baseline, at scheduled three monthly visits and at the time of UTI episodes. Optional perineal swabs were submitted at baseline and at six monthly routine visits. Participants completed symptom questionnaires every three months and at the time of symptomatic UTI.The primary clinical outcome measure was the incidence of symptomatic, antibiotic treated, UTI episodes self-reported by participants over the 12 month treatment period. An episode of UTI was defined as the presence of at least one symptom reported by patients or clinicians from a predefined list produced by Public Health England,Escherichia coli isolated from urine and perineal swabs; asymptomatic bacteriuria; total antibiotic use; and hospital admissions due to UTI. Participant satisfaction with treatment was measured using the treatment satisfaction questionnaire for medication, which assessed four domains of treatment satisfaction: effectiveness, side effects, convenience, and global satisfaction.Secondary outcomes were the incidence of symptomatic, antibiotic treated UTI in the six months after treatment; microbiologically confirmed UTIs; antibiotic resistance profiles in 4 colony forming units/mL or two species of uropathogens isolated at ≥105 colony forming units/mL.E coli was defined as resistance to at least one antibiotic drug in at least three antimicrobial categories .Microbiologically confirmed UTIs were episodes defined as per the primary outcome but with an additional criterion of positive urine culture at the time of UTI. A positive urine culture was defined as one isolate of a potential uropathogen at a concentration of ≥10The trial was powered to assess non-inferiority of the absolute difference in UTI incidence over the 12 month treatment period. The non-inferiority margin, defined after a series of patient focus group meetings, was a difference of one UTI episode per year. Two meta-analyses of antibiotic prophylaxis and methenamine hippurateFor the primary outcome, the incidence rate in each group was the total number of UTI episodes divided by the total follow-up (exposure) time, reported with 95% confidence intervals calculated using a resampling procedure (bootstrap). The absolute difference between groups was calculated and reported with a 90% bootstrap confidence interval. Non-inferiority would be concluded if the upper limit of the confidence interval was below one UTI episode/year. We estimated relative treatment differences using a negative binomial model with follow-up time included as an exposure variable, recruiting centre as a random effect, and baseline stratification factors  as fixed effects. This model yielded an estimate of the incidence rate ratio, presented with a 95% confidence interval. Sensitivity analyses excluded days when participants took therapeutic antibiotics for UTI from the follow-up time. We analysed a binary indicator of at least one UTI episode using a mixed effects logistic regression model adjusted for centre and baseline stratification factors. Analyses were primarily conducted in a modified intention-to-treat population, which included all participants observed for at least six months, because these participants were assumed to provide a reliable estimate of UTI incidence. Prespecified sensitivity analyses were conducted in intention-to-treat and per protocol populations . We also conducted a post hoc sensitivity analysis in a strict per protocol population that included only those participants achieving ≥90% adherence with initially randomised treatment.2 or Fisher’s exact tests. These analyses are considered exploratory and should be interpreted with caution. We made no adjustments for multiple testing. Domain scores of the treatment satisfaction questionnaire for drug treatment were compared between groups using a two sample t test and an analysis of covariance model adjusted for baseline stratification factors. To account for switching between treatment strategies, adverse events were reported according to treatment received at the time with data summarised by numbers of participants receiving each intervention. All analyses were conducted using Stata version 16. Independent trial steering and data monitoring committees had oversight throughout the trial. The trial was registered with the ISRCTN registry (ISRCTN70219762).Symptomatically diagnosed UTI incidence in the post-treatment period and microbiologically confirmed UTIs were analysed as for the primary outcome measure. Secondary outcomes were analysed according to the intention-to-treat principle and included all participants with data available. Rates of asymptomatic bacteriuria and antibiotic resistance were compared by χThe host institution has an established UTI patient group and as such patient and public involvement began at the planning stage of this trial. Patient representatives were included on the trial steering committee. The patient and public involvement group helped define the main outcome measure and in particular stressed the importance of a practical UTI definition rather than sole reliance on microbiological tests. The non-inferiority margin was exclusively defined by the patient group who stressed the severity of UTI symptoms and advised a non-inferiority margin of one UTI in a year. This margin was considered a clinically meaningful difference by our patient and public involvement group based on an appreciation of the likely numerical reductions in UTI frequency in both of our trial arms. During recruitment, the study was advertised via patient representatives from Bladder Health UK and results will be disseminated widely among patients including via this groups’ regular publications.Between 23 June 2016 and 20 June 2018, 240 participants were recruited and randomly assigned to antibiotic prophylaxis (n=120) or methenamine hippurate (n=120). For those allocated to antibiotic prophylaxis, 66 (55%) received nitrofurantoin, 30 (25%) trimethoprim, 24 (20%) cefalexin. A total of 22 (18%) participants allocated to methenamine hippurate switched to receive antibiotic prophylaxis and seven (6%) vice versa. Patient follow-up was completed in January 2020. The modified intention-to-treat analysis included 205 (85%) participants; 102 (85%) in the antibiotic arm and 103 (86%) in the methenamine hippurate arm . SupplemIn the modified intention-to-treat population, 90 symptomatic, antibiotic treated UTI episodes were reported over 101 person years of follow-up in the antibiotic group, and 141 episodes over 102 person years of follow-up in the methenamine hippurate group (supplementary fig S1A). The incidence of symptomatic antibiotic treated UTI over the 12 month treatment period was therefore 0.89 episodes per person year  in the antibiotic group and 1.38 (1.05 to 1.72) in the methenamine hippurate group ). With the upper limit of the 90% confidence interval below the non-inferiority limit of one, we can conclude methenamine hippurate to be non-inferior to antibiotic prophylaxis in this setting. This result was confirmed in all sensitivity analysis populations . To faciIn the six month post treatment follow-up period, the UTI incidence rate was 1.19  and 1.72 (1.27 to 2.18) episodes per person year in the antibiotic prophylaxis and methenamine hippurate groups, respectively ; supplementary table S4).Overall, 183 (79%) of 231 UTI episodes reported in the modified intention-to-treat population were accompanied by a urine sample, and during the 12 month treatment period a positive urine culture was observed in 96 (52%) of these episodes. Incidence of microbiologically confirmed UTIs was 0.41  in participants allocated to antibiotic prophylaxis and 0.53 (0.34 to 0.72) for those allocated methenamine hippurate (absolute difference 0.11 (−0.12 to 0.35); supplementary table S5). In the six months after treatment, 93 (66%) of 141 UTI episodes were associated with a urine sample, of which 65 (70%) were positive. Incidence of microbiologically confirmed UTI episodes was 0.48 (0.28 to 0.68) and 0.86 (0.59 to 1.14) in the antibiotic prophylaxis and methenamine hippurate groups, respectively (absolute difference 0.38 (0.04 to 0.72)).v 22 (7%) of 323; χ2 test, P=0.0048; supplementary table S6).During the 18 month trial period, the rate of asymptomatic bacteriuria was similar between treatment groups, however, a post hoc analysis of urine samples submitted during the 12 month treatment period identified a significantly higher rate in the methenamine hippurate group than in the antibiotic prophylaxis group (44 (14%) of 326 samples v 7.5 (4-15)). Similarly, antibiotics for other infections were received by 28 (29%) of 98 participants receiving methenamine hippurate compared with 15 (15%) of 97 receiving antibiotic prophylaxis (supplementary table S7).Therapeutic antibiotics for UTI were received during the 12 month treatment period by 51 (43%) and 67 (56%) participants allocated to the antibiotic prophylaxis and methenamine hippurate groups, respectively. In the six month observation period, the total number of days spent taking therapeutic antibiotics was higher in the methenamine hippurate group than in the antibiotic prophylaxis group (13.5 (interquartile range 6.5-23) E coli isolated from perineal swabs was similar between randomised groups at baseline. At six or 12 month follow-up, this proportion was higher in the antibiotic prophylaxis group than in the methenamine hippurate group (46/64 (72%) v 39/70 (56%); χ2 test, P=0.05, E coli isolated from perineal swabs was higher in the methenamine hippurate group than in the antibiotic prophylaxis group (9/45 (20%) v 2/39 (5%), Fisher’s exact test, P=0.06, Availability of optional six monthly perineal swabs over the 18 month trial period is presented in supplementary table S8. The proportion of participants demonstrating resistance to at least one antibiotic in E coli was isolated from the urine samples of 41 participants during 67 episodes of symptomatic UTI  over the 12 month treatment period, and from 21 participants during 26 symptomatic episodes over the six months after treatment. The proportion of participants showing resistance to at least one of the antimicrobial drugs tested in E coli isolated from symptomatic urine samples was similar between randomised treatment groups (supplementary fig S2A), as were the rates of multidrug resistance (supplementary fig S2B). However, a higher proportion of participants in the antibiotic prophylaxis group than in the methenamine hippurate showed resistance to co-trimoxazole (6/13 (46%) v 3/14 (21%)) during the 12 month treatment period, and resistance to trimethoprim (6/8 (75%) v 5/13 (38%)) during the six months after treatment . In contrast to the numbers of positive samples collected during symptomatic episodes, E coli was isolated from only a small proportion of urine samples collected routinely at three month intervals from asymptomatic participants (supplementary table S9A). All isolates identified from urine samples are listed in supplementary table S9B.A substantial growth of reatment . Similarv 82.2 (18.4); t test, P=0.001; supplementary table S10).On average, treatment satisfaction was high and generally comparable between treatment groups, although the antibiotic prophylaxis group reported higher scores in the convenience domain than the methenamine hippurate group (mean 91.4 (standard deviation 12.7) Rates of adverse events and adverse reactions were low and comparable across treatment groups . Two serThis trial has demonstrated that the non-antibiotic preventive treatment for UTI (methenamine hippurate) is not inferior to the current guideline recommended standard . This trial adds to the evidence base for the use of methenamine hippurate for prophylactic treatment in adult women with recurrent UTI. Although the methenamine hippurate group had a 55% higher rate of UTI episodes than the antibiotics group, the absolute difference was just 0.49 UTI episodes per year, which has limited clinical consequence.Clostridium difficile infection, and concluded that the risks of long term antibiotic prophylaxis might outweigh the benefits in older patients with UTI. Our results could support a change in practice in terms of preventive treatments for recurrent UTI and provide patients and clinicians with a credible alternative to daily antibiotics, giving them the confidence to pursue strategies that avoid long term antibiotic use. The observed numerical difference in clinically diagnosed UTI between the two trial arms, which favoured antibiotic prophylaxis, was small and did not exceed the predefined non-inferiority margin of one episode per person year. This finding was consistent across the modified intention-to-treat, strict intention-to-treat, per protocol, and modified per protocol (post hoc) analyses. The information provided by this trial will allow clinicians and patients to undertake a shared decision making process relating to UTI preventive treatments. The study showed a small numerical difference in UTI incidence between the daily antibiotics and methenamine hippurate groups, but the potential trade-off includes the avoidance of antibiotic consumption, which is closely associated with antimicrobial resistance development.The risks of long term prophylactic antibiotic treatment have been well recognised in a recent study,Reductions in clinically diagnosed UTI during the treatment period were in line with previously published results from systematic reviewsMicrobiological testing of urine samples during the treatment period showed that the use of positive urine culture as a criterion for UTI diagnosis would have resulted in a failure to capture around half (48%) of all patient reported episodes treated with antibiotics. This proportion is in line with results from another trial that reported only 58% of clinical UTIs confirmed by a positive urine culture.The two trial treatments are licensed for UTI preventionDuring the six month follow-up period after treatment, UTI rates increased but remained substantially lower than rates before treatment. These findings contrast those from a Cochrane review of antibiotic prophylaxis,In this trial, the use of methenamine hippurate as a preventive treatment against recurrent UTI was associated with a reduction in overall antibiotic use and equivalent levels of treatment satisfaction compared to daily antibiotics. Treatment satisfaction domains explored were effectiveness, side effects, convenience, and global satisfaction, and we saw no differences between arms in individual domain scores apart from convenience. Participants scored once daily antibiotics as more convenient than twice daily methenamine hippurate (supplementary table S10). In the methenamine hippurate arm, 44% of women did not receive any therapeutic antibiotics during the 12 month treatment period, which is directly aligned to current antibiotic stewardship strategies designed to reduce antimicrobial resistance.E coli isolates from perineal swabs than patients allocated to methenamine hippurate. Results from urine cultures revealed higher rates of resistance to trimethoprim, co-trimoxazole, and cephalosporins in E coli isolated from urine samples from women in the antibiotic arm than in the methenamine hippurate arm. The described differences in antimicrobial resistance rates suggest that the use of continuous, low dose, antibiotic prophylaxis is a contributory factor to the development of antimicrobial resistance and is similar to findings from a previous randomised controlled trial exploring antibiotic prophylaxis in patients with recurrent complicated UTIs.E coli isolates from perineal swabs was higher in the methenamine hippurate arm than in the antibiotics arm. This difference could be due to a sustained effect of daily antibiotics on the faecal microbiome or the greater incidence of antibiotic treated acute UTIs in the methenamine hippurate group during follow-up.Antimicrobial resistance development associated with both trial treatments was explored in cultures from both perineal swabs and urine samples collected throughout the trial. Overall rates of resistance to nitrofurantoin were very low . During This trial was conducted in line with current best practice and all outcomes were defined a priori and reflected those important to both patients and clinicians. Primary outcome allocation was verified from healthcare records and a random sample group of participants was examined by an independent clinician, blinded to treatment allocation. This independent verification agreed with the allocation of primary outcome in all cases.The adherence of participants to their allocated treatment was regularly assessed, and results showed that the vast majority of participants were over 90% adherent with the allocated treatment. A realistic attrition rate, given the 18 month trial period, was incorporated into the sample size calculation and the number of withdrawals was in line with predicted rates. All pre-set thresholds regarding numbers of participants contributing to the primary analysis were met.The trial was designed in a pragmatic fashion to allow for widespread applicability and generalisability. A broad range of eligible participants accurately represented women with recurrent UTI seen regularly in routine NHS practice. Women from a range of geographical and socioeconomic areas were included in the trial and shared decision making between patients and clinicians regarding choice of antibiotic was in line with good clinical practice. Patients were allowed to crossover between trial arms, which again reflects usual care.Limitations of the ALTAR trial included the lack of blinding, which would have increased the certainty of results but would have hugely increased trial costs. The treatment of any breakthrough UTIs was decided by healthcare providers who were not involved in the study and had no influence on trial results. Another limitation was the heterogeneity of prophylactic antibiotics prescribed, which alongside the wide inclusion criteria prevented meaningful subgroup analysis that could identify differences in efficacy of individual antibiotic drugs or specific subgroups of patients who might gain particular benefit from either of the trial treatments. Further research should focus on the use of methenamine hippurate as a preventive treatment for recurrent UTI in more narrowly defined patient groups. In addition, the added value of urinary acidification was not explored in this study despite the practice of some clinicians who prescribe vitamin C alongside methenamine hippurate to encourage acidic urine. Finally, data regarding long term safety of methenamine hippurate are scarce, and this question was outside of the scope of the current trial. Increased adoption of this treatment as prophylaxis against recurrent UTI will allow for the generation of long term safety data now that efficacy has been demonstrated in our study.E coli might encourage patients and clinicians to consider methenamine hippurate as a first line treatment for UTI prevention in women.In the ALTAR trial, we have demonstrated high levels of efficacy from methenamine hippurate in terms of UTI prevention, and have shown that this efficacy is comparable to the current guideline recommended prophylaxis . The increased rates of antimicrobial resistance development associated with the antibiotic arm as shown in the primary uropathogen Long term, low dose daily antibiotic treatment is the current standard of care for prophylaxis in women with recurrent urinary tract infection and is recommended by national and international guidelinesDespite the reported success of prophylactic antibiotics, antimicrobial resistance has been directly linked to antibiotic consumption; as a result, the importance of research into non-antibiotic alternatives has been highlightedSystematic reviews have concluded that the non-antibiotic option of methenamine hippurate could be effective in preventing urinary tract infections, but outlined the need for further large, well conducted randomised trialsThe ALTAR randomised trial compared use of methenamine hippurate with low dose antibiotics in a predefined cohort of women with recurrent urinary tract infection presenting to secondary careEfficacy of both treatments in the primary and sensitivity analyses was found to be comparable, suggesting that methenamine hippurate might be appropriate for women with a history of recurrent urinary tract infectionThe range of a priori outcomes reported confirm clinical utility of methenamine hippurate as a non-antibiotic option for prevention of urinary tract infection in this pragmatic trial, which allows generalisability of results


Oil palm shell (OPS) is an agricultural solid waste from the extraction process of palm oil. All these wastes from industry pose serious disposal issues for the environment. This research aims to promote the replacement of conventional coarse aggregates with eco-friendly OPS aggregate which offers several advantages, such as being lightweight, renewable, and domestically available. This paper evaluates the mechanical and thermal performances of renewable OPS lightweight concrete (LWC) reinforced with various type of synthetic polypropylene (SPP) fibers. Monofilament polypropylene (MPS) and barchip polypropylene straight (BPS) were added to concrete at different volume fractions (singly and hybrid) of 0%, 0.1%, 0.3% and 0.4%. All specimens were mixed by using a new mixing method with a time saving of up to 14.3% compared to conventional mixing methods. The effects of SPP fibers on the mechanical properties were investigated by compressive strength, splitting tensile strength and residual strength. The strength of the oil palm shell lightweight concrete hybrid 0.4% (OPSLWC–HYB–0.4%) mixture achieved the highest compressive strength of 29 MPa at 28 days. The inclusion of 0.3% of BPS showed a positive outcome with the lowest thermal conductivity value at 0.55 W/m °C. Therefore, the results revealed that incorporation of BPS fiber enhanced the performance of thermal conductivity tests as compared to inclusion of MPS fiber. Hence, renewable OPS LWC was proven to be a highly recommended environmentally friendly aggregate as an alternative solution to replace natural aggregates used in the concrete industry. The world’s population is projected to reach approximately nine billion in the next 30 years . The blo3 [The oil palm trees are grown abundantly in tropical regions, such as Indoensia, Malaysia, Thailand, Colombia, Ecuador and Papua New Guinea . Malaysi3 . The adv3 . It has been reported that mechanical properties such as compressive strength, splitting tensile strength, flexural strength and modulus of elasticity of oil palm shell lightweight concrete (OPSLWC) are lower than other lightweight aggregate concrete (LWAC) ,11. TherThis paper evaluates the effects of two different SPP fibers on the mechanical and thermal properties of OPSLWC. The fibers were added singly and hybrid in different volume fractions . This study focuses on investigating the mechanical characteristics, namely the compressive strength, splitting tensile strength, flexural strength and residual strength (compression and tension), and the thermal conductivity of OPSLWC.Type 1 Ordinary Portland Cement (OPC) manufactured by Tasek Corporation Berhad, in compliance with MS EN 197–1:2014, was used for all the mixing in this research. The technical specifications of the OPC used are summarized in 3. High performance water reducer, Master Glenium® SKY 8808 manufactured by BASF was added to all the mixes at a constant amount of 2.0% of the cement weight to enhance the workability of fresh concrete.Potable water from a municipal tap supplied by the local water supplier was utilized for mixing and curing. The quality of water was monitored to ensure it was free from any contaminants or impurities, as these contaminants/impurities can adversely affect the hydration of cement and the properties of concrete. The specific gravity of the mixing water was taken at 1 g/cm3, 2.75, 0.95% and 4.75 mm, respectively. Sieve analysis was performed according to ASTM C 136–01 in order to obtain the grading of fine aggregate used in this study. Average distribution of sand was obtained by performing two sieve analyses, using a similar source, as shown in In this research, conventional coarse aggregates for all the mixes were fully substituted by crushed older OPS, which had been thrown out for more than 180 days. The fiber content in the surface of old OPS is less than 2%, which offers a stronger bonding between the cement and OPS grains resulting in a better strength performance ,24. Befo3H6, which has a low specific gravity of 0.91 g/cm3. The good mechanical properties of SPP fibers offer a tensile strength of 600 MPa and Young’s modulus of 4.11 GPa. The mode of polymerization gives polypropylene a sterically regular atomic arrangement that results in its chemical inertness. Hence, it can be added into a highly alkaline matrix without any adverse effects on its properties. In addition, SPP is a good thermal insulator, and has a low thermal conductivity of 0.1–0.22 W/mK. In this research, two different types of SPP fibers, monofilament polypropylene straight (MPS) and barchip polypropylene straight (BPS), were added to the OPSLWC. The properties of these polypropylene fibers are tabulated in Synthetic polypropylene (SPP) fiber is derived from monomeric hydrocarbon C3, 170 kg/m3, 1000 kg/m3, 290 kg/m3 and 2.0% of the binder weight, respectively. Different types and volume fractions of fibers were added to different mixes. Each mix was given a mix code for the ease of identification. Four different mixes were prepared as shown in . This mixing method was developed by modifying the mix proportion of self-compacting concrete (SCC), which comprises a liquid phase and solid phase with a total mixing time of 360 s [The preparation procedures of all the mixes are described in this section. The trial mixing method was conducted to make a comparison between conventional mixing method (CMM) and new mixing method (NMM). From the results, NMM, in terms of total mixing time, could save up to 60 s compared to CMM. Therefore, a new mixing method was used to produce all the mixes , as showFigure 2of 360 s . The fibA 3000 kN capacity compression test machine was used and was manufactured by Unit Test Scientific Sdn. Bhd. It was set to a constant loading rate of 3.0 kN/s in compliance with BS EN 12390–Part 3: 2009. The same machine was used for the splitting tension tests with a loading rate set to 1.5 kN/s in accordance with BS EN 12390–Part 6: 2009. For each mixture sample, cubes with dimensions of 100 mm × 100 mm × 100 mm were cast to test the compressive strength for 1, 7, 28, 90 and 180 days. Three cylinders with dimensions of 100 mm × 200 mm were cast to test the splitting tensile strength of the mixture samples at 7, 28 and 90 days. Furthermore, the residual strengths of the cube compressive and splitting tensile strengths were determined by loading the specimens for a second and third time and set at a 10% failure rate.The thermal conductivity was determined by using a guarded hot plate and a heat flow meter methods according to BS EN 12664: 2001, as shown in The workability of concrete plays an important role in determining the homogeneity at which it can be blended, placed, compacted, and finished. In this research, the workability of mixes was measured through a slump test and Vebe test. The results collected from both tests are tabulated in 2 value of 0.845. Hence, Equation (1) was proposed to predict the slump value with the given Vebe time.S denotes the slump value in cm and V indicates the Vebe time in s. The slump value can be correlated to the Vebe time, as shown in 3 and 1936.7–1976.5 kg/m3, respectively. The outcome fulfilled the objective of obtaining OPSLWC with an ODD less than 2000 kg/m3. The samples also met the requirements for structural applications as structural lightweight concrete (SLWC), defined as concrete with an ODD no greater than 2000 kg/m3 [Demolded density (DD) and oven-dried density (ODD) were measured for all mixes, as shown in 00 kg/m3 .The compressive strength of each mix at 1, 7, 28, 56, 90 and 180 days is shown in When a compressive load is applied to a specimen, lateral tension is produced randomly throughout the sample. Minor cracks will start to develop due to volumetric changes in the heterogenous mixture of concrete and can lead to hairline cracks. Minor cracking will continue to occur and eventually major cracks will form when the advancing minor cracks meet each other. The cracking will take place in the direction parallel to the applied load. The presence of PP fibers blocks the propagation of the crack and acts as a resistance to lateral tension. As a result, additional compressive loading can be withstood, and thus the capacity of concrete to withstand compression was improved. This showed the attributes of fibers in arresting cracks and bridging concrete more effectively ,28,29.The residual compressive strength (RCS) is a streamlined method to evaluate the effects of fibers on the toughness of concrete. This test was conducted by further loading the specimens a second and third time at 28 days. RCS shows a clearer comparison and the positive effects of the different types of PP fibers on the post-cracking of fiber-reinforced oil palm shell lightweight concrete (FROPSLWC). The values of the first loading compressive strength (FLCS), second loading compressive strength (SLCS) and third loading compressive strength (TLCS) are tabulated in Without the incorporation of fibers, OPSLWC–CTR–0% failed at 64.8% of FLCS and 40.9% of FLCS for the second and third loadings, respectively. The inclusion of fibers showed a remarkable improvement of 17.8% to 24.2% for SLCS and 33.5% to 42.4% for TLCS. Comparing OPSLWC–BPS–0.3% and OPSLWC–MPS–0.1%, the former produced higher SLCS and TLCS of 87% and 74.7%, respectively. The latter retained SLCS of 82.6% and TLCS of 74.4%. This could be due to the higher volume fraction and different geometry of BPS . The mixThe failure pattern of OPSLWC with fibers and without fibers is illustrated in Splitting tensile strength was tested at 7 days, 28 days and 90 days for all mixes. The splitting tensile strength increased with the ages of concrete, as shown in Splitting tensile strength of OPSLWC was relatively lower than that of concrete with normal aggregate due to the weak bonding between the OPS and cement matrix . TherefoResidual splitting tensile strength (RSTS) is another method to investigate the effects of fibers on the integrity of concrete. Without the presence of fibers, OPSLWC–CTR–0% split in half after the first loading, as shown in From The failure mode of the specimen differed from the control mix in fiber-reinforcement, as shown in The thermal conductivity increased when curing age increased. The thermal conductivity of the 28-day mix was higher than the thermal conductivity of a similar 7-day mix. Voids were present in the mix at 7 days due to the cement being in a partially hydrated state . FurtherAs shown in The inclusion of synthetic polypropylene fibers deteriorated the workability. The slump value reduced from 165 mm to 96 mm and the Vebe time increased from 9.46 s to 12.26 s.Incorporation of synthetic polypropylene fibers in OPSLWC offered a positive effect on the mechanical properties. The bridging effect of fibers contributed to arresting the propagation of cracks, enabling stress transfer, providing an extra energy-absorbing mechanism, and was thus able to accommodate larger deformations. The presence of fibers also modified the failure mode of OPSLWC under compression and splitting tensions.The positive effect of fibers on the compressive strength was more pronounced in OPSLWC–HYB–0.4% with the highest volume fraction. Enhancements of 4.8% to 17.4% and 11.9% to 17% were observed in 28 days and 180 days, respectively.The inclusion of fibers improved the splitting tensile strength in the range of 0.5–3.4% at 28 days and 1.4–8.7% at 90 days.The hybrid synthetic polypropylene fiber showed the most pronounced effect in enhancing residual strength for both compressive strength and splitting tensile strength.The effect of fibers on thermal conductivity varied depending on the type of fiber added. Monofilament polypropylene straight (MPS) increased thermal conductivity, while barchip polypropylene straight (BPS) lowered the thermal conductivity.The flexural strength of OPSLWC was improved by 24.3% to 38.8% with the reinforcement of fibers.Based on the results acquired from the properties of synthetic polypropylene fiber-reinforced renewable OPSLWC, the following conclusions can be made:It can be concluded that the findings of synthetic polypropylene fiber-reinforced renewable OPS lightweight concrete demonstrated a great potential application in building construction.


Ternary Portland cements are new cementitious materials that contain different amounts of cement replacements. Ternary Portland cements composed of granulated blast-furnace slag (GBFS), coal fly ash (CFA), and clinker (K) can afford some environmental advantages by lowering the Portland cement clinker use. Accordingly, this is an opportunity to reduce carbon dioxide emissions and achieve net-zero carbon emissions by 2050. Furthermore, GBFS and CFA possess pozzolanic properties and enhance the mechanical strength and durability at later ages. Compressive strength and natural carbonation tests were performed in mortar and concrete. Cement-based materials made with GBFS and/or CFA presented a delay in the compressive strength development. In addition, they exhibited lower carbonation resistance than that of mortar and concrete made with plain Portland cements. Concrete reinforcement remains passive in common conditions; however, it could be corroded if the concrete pore solution pH drops due to the carbonation process. Service life estimation was performed for the ternary cements regarding the carbonation process. This information can be useful to material and civil engineers in designing concretes made with these ternary cements. Ternary cements are binders composed of Portland cement clinker and two other components, which are usually blended at the cement mill. Ground granulated blast-furnace slag and siliceous coal fly ash are two major constituents in Portland cements due to their good durable properties in aggressive environments. By contrast, these cements carbonate faster than plain Portland cement . This coSome studies on ternary cements made with coal ash and rice husk ash  or made 2/g), the compressive strength gain for all ages was improved [Similar studies were performed with ground granulated blast-furnace slag and coal fly ash ,10; whenimproved . By contimproved  did not The cement industry is a significant carbon dioxide emitter mainly due to the calcination process and combustion of fuels . TherefoSteel reinforced concrete structures must be durable to ensure the intended service life is reached . The steAccordingly, reinforcement corrosion induced by carbonation plays a key role in the reinforced concrete structure’s service life, primarily when it is coupled with chloride attack , which i2) with calcium phases (Ca2+) and water (H2O) to form calcium carbonate in Portland cement paste. Furthermore, carbon dioxide (CO2) can produce other carbonates depending on the reacting species [The physico-chemical process known as carbonation consists of the reaction of carbon dioxide (CO species .2) in water (H2O) in terms of the Equation (1) and the dissolution of Ca(OH)2 according to Equation (2). Afterwards, carbon dioxide reacts primarily with calcium hydroxide (Ca(OH)2) and other calcium phases [The early stage begins with the dissolution of the carbon dioxide 2 is partially consumed, leading to a C–S–H gel formation [Carbonation of cements made with coal fly ash or ground granulated blast-furnace slag has some peculiar characteristics. Due to the pozzolanic reaction, Ca(OH)ormation  with a lormation . In geneormation . ConsequWrapping up, while carbonation is being developed, the microstructure becomes denser, and the pore solution pH lowers.Different models were proposed to outline the cement paste carbonation process ,20,25,262 diffusion coefficient, D, given in Equation (6).B = carbonation coefficient (mm/year0.5)x = carbonation depth (mm)t = natural carbonation exposure time (year)xC = CO2 concentration at discontinuity (kmol/m3)C1 = CO2 concentration in surroundings (kmol/m3)C2 = CO2 concentration in the cement paste (kmol/m3)D = Diffusion coefficient of the CO2 (m2/s)This physico-chemical process primarily proceeds by diffusion and the carbonation depth is normally used to calculate the carbonation coefficient, B, as shown in Equation (5) , and the2 concentration, and pore size distribution (PSD), among other factors.Both parameters, B and D, are assumed to be constant , but theThe European standards series known as Eurocodes specifies how structural design in buildings and civil engineering works should be conducted in Europe (EU). In Eurocode 2: Design of concrete structures (EN 1992), Part 1-1: General rules, and rules for buildings (EN 1992-1-1) , describ2 diffusion and concrete cover. Four carbonation exposure classes (XC) and a design service life of 100 years are defined , coal fly ash (CFA), and clinker (K) with regard to their carbonation resistance and mechanical strength development. Natural carbonation testing on ternary cement concretes will be used to assess the potential for improvement of this material. Accordingly, the minimum concrete cover required to prevent corrosion against carbonation given by the Eurocode 2 will be taken as reference value. These results will be useful to material and civil engineers in designing reinforced concrete made with ternary cements.2, Al2O3, Fe2O3, CaO, MgO, SO3, Na2O, K2O, loss on ignition (LOI), insoluble residue (IR), and Cl− was conducted following the methodology of the European standard for chemical analysis of cement, i.e., EN 196-2 [The raw materials used to prepare the ternary cements were a Portland cement CEM I 42.5 R—EN 197-1 , ground EN 196-2 .Free lime content in the Portland cement and coal fly ash were 1.31% and 0.5%, respectively. Reactive calcium oxide and reactive silica amount in the ground granulated blast-furnace slag were 3.84% and 44.78%, respectively. 2/g and 3772 cm2/g, respectively, whereas their densities were 3.12 g/cm3 and 2.4 g/cm3, respectively. The granulated blast-furnace slag was ground in a ball mill to reach two fineness values of 3489 cm2/g (SA) and 4630 cm2/g (SB). Portland cement (CEM I 42.5 R) and coal fly ash (VA) fineness measured according to EN 196-6  were 324In conclusion, coal fly ash and ground granulated blast-furnace slag fulfill the general requirements set out by the European standard EN 197-1 regarding the characteristics of the cement constituents.Ternary cements prepared for this study were manufactured by blending of coal fly ash (V), ground granulated blast-furnace slag (S), and Portland cement (CEM I 42.5 R) in the percentages presented in Both additions were provided by Cementos Tudela Veguín, S. A. , and the Portland cement by LafargeHolcim .A high range water reducing (superplasticizing) admixture for concrete was provided by Sika España, Madrid, Spain (Sika ViscoCrete-20 HE).Mortar mixes were elaborated by blending blast-furnace slag and coal siliceous fly ash contents of 25% or 40%. Accordingly, CEM I 42.5 R percentages were 20%, 35%, or 50% depending on each individual case (as illustrated in Prismatic mortar specimens (40 × 40 × 160 mm) were produced with CEN sand and distilled water following the methodology defined by the European standard EN 196-1 . TherefoTwo concrete mixes  were made and cured according to the European standard EN 12390-2:2019  and testThe mortar and concrete specimens were tested for natural carbonation following the technical specification CEN/TS 12390-10 . AccordiCarbonation depth measurements were taken in the prism mortar specimens at 20 months of natural exposure, and at 12 months in the concrete Ø75 × 100 mm cylinders.At the beginning of testing, samples were sawn up into 25 mm slices. It was assumed that the sawed cut is adequate for carbonation depth testing. Therefore, depth of carbonation was assessed on the freshly sawed area, which was cleaned of loose particles. The phenolphthalein indicator coloration was assessed visually in the laboratory. The cleaned surface was sprayed with a phenolphthalein indicator solution. In certain circumstances, when coloration was absent or very weak on the sprayed area, the surface was sprayed again after 20 min.2 diffusion coefficient, D, were calculated according to Equations (5) and (6), respectively.Carbonation depth readings were collected in four points of each mortar or concrete specimen. Later, carbonation coefficient, B, and COFinally, concrete carbonation coefficients were used to estimate the design service life regarding reinforcing steel corrosion.Compressive strength tests were performed in concretes A and B. The compressive strength of the concrete cylinder test can provide a general idea about all the characteristics of a concrete. By this easy test one judge that whether concrete mix design and execution was done properly or not. ck) for C30/37 concrete grade is 30 MPa, while for C45/55, concrete grade is 45 MPa.Concrete mix A—control is a concrete grade C30/37 according to the European standard EN 206 ; Concret2/g, SB: 4630 cm2/g). Furthermore, mixes B-SA25VA40, B-SB25VA40, and B-SA40VA40 presented higher 28-days concrete compressive strength results than that of the control concrete B. In addition, B-SA25VA25 mixture also had higher 28 days compressive strength than that of the control one. Concrete with a lower concrete grade does not exhibit similar improvements, i.e., only concrete mixes B-SA25VA25 and A-SA25VA40 had higher 28-days compressive strength.The effect of the ground granulated blast-furnace slag fineness at 28-days is more evident in concrete mixes B than in concrete mixes A. The finer the GGBFS is, the higher the concrete compressive strength is  SA provides similar compressive strengths than SB  fineness on the carbonation depth is negligible at 25% GGBFS levels. However, with 40% of GGBFS, the finer ground granulated blast-furnace slag (GGBFS) presents a better carbonation resistance. This fact could be attributed to the lower porosity in this last case .The effect of the partial replacement of coal fly ash in ternary cements decreasing the alkaline reserve and increasing the carbonation rate is lower than in the case of ground granulated blast-furnace slag (GGBFS) .Carbonation depth results obtained for concretes A and B were calculated with the results of three concrete samples  than that of concretes (until 3–5 mm).Concrete having the least amount of clinker (HA) presents the higher carbonation depth. In line with this result, concrete made without additions offers the best carbonation resistance.2) formed from cement hydration in the presence of water also accelerates lowering the alkaline reserve [In this case, the same as in the mortar’s case, the effect of the ground granulated blast-furnace slag (GGBFS) fineness on the carbonation depth is negligible at 25% GGBFS levels. By contrast, with 40% of GGBFS, the finer GGBFS presents a worse carbonation resistance. The fineness has an important bearing on the hydration rate, and hence, on the microstructural development and the strength gain. Finer GGBFS offers a greater surface area for reaction and, therefore, accelerates the microstructural development and its effect on the mechanical properties. Furthermore, the pozzolanic reaction of the GGBFS cement paste between reactive silica or alumina in the GGBFS particles and calcium hydroxide (Ca(OH) reserve . In addiFor concretes with a 28-days compressive strength lower than 45 MPa (concrete A), a clearer trend between the carbonation depth and the compressive strength at 28-days and 90-days was found. By contrast, mentioned correlation was not found in more dense and compact concretes, i.e., concretes with compressive strength at 28-days over 45 MPa (concrete B). In this last case, it would probably be necessary to have more testing time to achieve any correlation between these two parameters. In general, similar trends were reported in the literature . SummingConcrete carbonation-induced steel corrosion is one of the major issues of the durability and service life for reinforced concrete (RC) structures in atmospheric environment. Since the rate of carbonation depends on the concrete quality, assessment of the carbonation resistance and the service life estimation of the new ternary cements are necessary.The carbonation rate is inversely proportional to the square root of the age of the reinforced concrete structure, as shown in Equation (5) . AccordiConcrete with a larger quantity of GGBFS has a higher carbonation coefficient, particularly in the case of the finer GGBFS. Accordingly, a shorter service life period for reinforced concrete structures exposed to atmospheric environment can be expected.−8 and 3.38 × 10−8), which are slightly lower than those of the reference concretes A and B made with CEM I 42.5.Carbonation diffusion coefficients were quite similar for concretes A and B made with the ternary cements SA25VA25, SB25VA25, and SA40VA25 . Accordingly, an S4 structural class requires a minimum cover thickness of 25 mm  based on experience. This concept works well for traditional materials for which long experience is available; nevertheless, new additions need the assessment based on performance testing.Currently, exposure resistance classes (ERC) are proposed to classify reinforced concrete with respect to resistance against corrosion induced by carbonation (XRC class) following a performance-based concrete approach. The selection of concrete to resist deterioration and protect against corrosion for this exposure class is based on the exposure resistance classes given in EN 206 ,36. Tabl0.5 for all the concretes. Therefore, they can only be used in XRC 4–XRC 7 exposure resistance classes (ERC). This result is in line with the previous analysis.The carbonation coefficient is above 2.7 mm/yThese concretes may be applied in wide range of applications, such as reinforced concrete exposed to marine environment in harbours, building foundations, concrete pipes, self-compacting concrete, and so on. By contrast, it is not recommended for prestressed concrete.Furthermore, carbonation is considered by the cement sector as a way to achieve carbon neutrality by 2050 . TherefoThe use of GGBFS with coal fly ash, both as additions or as a partial replacement of Portland cement, results in the depletion of alkaline supply and, therefore, an increase in the carbonation rate.Ternary cements reduce compressive strength at 28-days of lower strength class concretes (C30). On the other hand, it sharply increases at 90 days. By contrast, concrete type B with a higher compressive strength exhibited a lower strength gain at 90-days. However, the effect of the additional content on the reduction of the compressive strength is more evident.There is an inverse relationship between the clinker content and concrete carbonation rate. The effect of the GGBFS fineness on the carbonation depth is negligible at 25% levels. Nevertheless, at 40% levels, the finer GGBFS showed better carbonation resistance due to a denser microstructure in this last case.Based on the carbonation and diffusion coefficients, the carbonation process is apparently better related with the alkaline reserve calculated by using the carbonation diffusion coefficient than the carbonation coefficient since it considers the CaO content in the calculations.Service life estimation related to carbonation was performed depending on the ternary cement used in the concrete mix. The ternary cement with the highest amount of blast-furnace slag yielded the lowest reinforced concrete service life.Concrete carbonation is a physico-chemical process influenced by the cement type. Data presented in this paper allow the drawing of meaningful and practical technical conclusions regarding the ternary cements used. However, such conclusions, as with any generalization, should be read with caution since results may change with variations in concrete mix design. Conclusions are listed next.All the above results should be considered by the civil engineers to design civil and building structures made of concrete with GGBFS and coal fly ash ternary cements.


Prosthetic joint infection (PJI) is a devastating complication of total joint replacement surgery. It affects about 2% of primary total joint replacements. Treatment aims at infection eradication and restoration of patient's mobility. Two-stage revision arthroplasty with an interim application of an antibiotic-loaded cement spacer (ALCS) is the widely accepted treatment for PJI. Spacers are powerful local carriers of antibiotics at the site of infection, effective against biofilm-protected microbes. On the other hand, spacers permit some mobility of the patient and facilitate final prosthesis implantation. ALCS's are either commercially available or prepared intraoperatively on prefabricated or improvised molds. Antibiotic elution from the spacer depends on the amount of the antibiotic used for cement impregnation, at the expense of mechanical stiffness of the spacer. The antibiotic should not exceed 4g per 40g of bone cement to preserve the mechanical properties of the cement. Spacers are frequently accompanied by local or systemic complications. The spacer may break, dislocate and compress vessels or nerves of the limb. Systemic complications are the result of excess elution of antibiotic and include nephrotoxicity, hepatotoxicity, ototoxicity, allergic reactions or neutropenia. Elderly patients with comorbidities are at risk to present such complications. Microbial resistance is a potential risk of long-lasting spacer retention. Persisting infection may require multiple spacer replacements. Prosthetic joint infection (PJI) is a major complication after total joint replacement surgery -3. In thPJI management is not easy, since there is no consensus among specialists in relation to PJI definition, diagnosis, the causative microorganism and the appropriate treatment ,3,5. DepTwo-stage revision arthroplasty is the widely accepted treatment for delayed and late PJI -3, 6-10.Systemic administration of antibiotics against isolated or expected microorganisms follows for the next 2-12 weeks. Elimination of the clinical and laboratory signs of infection signals transition to second stage surgery, when the final prosthesis will be implanted ,11. AntiHistory of ALCS applicationIn the past, PJI was an unsolved complication of primary joint replacement, leading in most cases to resection arthroplasty (Girdlestone) .In 1970, Hessert and Ruckdeschel  and BuchIn 1978, Carlsson  and, latIn 1979, Hovelius and Josefsson, taking into consideration of precedent experience on the management of chronic osteomyelitis with local application of antibiotic-loaded cement, described for the first time, in a case report, the two-stage replacement for hip PJI with insertion of gentamycin-infused cement spheres after first-stage prosthesis removal and debridement. The limb was immobilized by traction for three weeks, after which, the final prosthesis was implanted .Nevertheless, one-stage revision frequently fails to eradicate the infection, and two-stage revision implies prolonged bed rest, joint immobilization and a challenging second-stage surgery with poor functional results due to soft tissue contraction and muscle atrophy ,18.In 1987, Borden and Gearen commented on the role of antibiotic-loaded beads in two-stage revision for knee PJI, not only as antibiotic carriers, but also as a temporary implant to maintain the length of the extensor mechanism of the knee ..25].Systemic complications after ALCS implantation are attributed to the increased release of antibiotics immediately after the first-stage surgery. Such complications are nephrotoxicity, hepatotoxicity, and ototoxicity secondary to gentamycin or allergic reactions and neutropenia secondary to vancomycin ,38. OldeOther authors state that patients which undergo two-stage revision are usually elderly people with co-morbidities, such as chronic renal or hepatic disease. These patients should be monitored closely for systemic adverse effects after spacer implantation, particularly if the spacers are impregnated with high amounts of antibiotics , or non-Local toxic effect after high antibiotic release?Antibiotics used for cement impregnation may exert local toxicity on cells involved in tissue regeneration, such as osteoblasts, endothelial cells, ﬁbroblasts or skeletal muscle cells . It has Antibiotic-loaded cement leads to microbe resistance?The surface of the bone cement favors microbial adherence and colonization, even in the presence of antibiotics -70. The There are two aspects of this problem:Regarding cemented primary total joint replacement, it is not clear whether fixation of the implants with antibiotic-loaded cement could increase the risk of microbial resistance and subsequently predispose to future PJI with resistant microbes. Some authors support that prophylactic gentamycin cement impregnation increases the risk for subsequent PJI with gentamycin-resistant microbes , while oRegarding two-stage revision arthroplasty for PJI, there is controversy, whether the ALCS could lead to the bacterial resistance and secondary superinfection. Ma et al. showed that bacterial 16s rRNA was present on spacers retrieved at the second-stage surgery for PJI , indicatNevertheless, in the clinical setting it is not clear, whether prophylactic or therapeutic application of antibiotic-impregnated cement is a source of bacterial resistance that may predispose to PJI or compromise PJI treatment, respectively .Multiple spacer exchangeOne or multiple ALCS exchanges between the first-stage surgery and the final prosthesis insertion are reported in 12-17% of patients with PJI ,76,78.Spacer exchange is dictated by mechanical causes or because of persisting infection . MechaniPersisting infection is the most frequent cause of spacer exchange . It is mPatients, who undergo spacer exchange or have a history of multiple surgeries about the joint, usually present multiple comorbidities and have a higher prevalence of PJI due to resistant or difficult to treat microbes . In suchClinical application of ALCS: hip, knee, other jointsALCS's were introduced to deal with PJI’s after THR and TKR. Increasing total replacement surgery for other major joints, such as the shoulder or the ankle joint, has inevitably led to PJI’s of these joints as well. Thus, two-stage revision with ALCS has been recently described for PJI of the shoulder  and the Prosthetic joint infection is a serious complication after total joint replacement. Two-stage revision arthroplasty using an ALCS is the preferred method of treatment for delayed or late PJI and the last chance of the patient to restore a more or less satisfying quality of life. Suitably shaped antibiotic-loaded cement spacers fill the void, which is left after removal of the infected prosthesis and thorough debridement and irrigation of the joint. Various types of spacers are available, pre-manufactured or handmade, static or articulating. Spacers preserve limb anatomy and some function until the final prosthesis is inserted. Most important, ALCS’s are powerful carriers of antibiotics. Local antibiotic release from an ALCS exceeds by far the antibiotic provided after systemic administration, without the risk of systemic toxic effects. In direct contact with the infected bone and soft tissues, spacers release locally high amounts of antibiotics to eradicate biofilm-protected microbes. Systemic antibiotics “finish the job” to eradicate the remaining microbes. Proper choice of the type and the amount of antibiotics contained in the spacer is important to control infection. ALCS pharmacokinetics indicate that spacers sustain local antibiotic concentration above the MIC of most common microbes between the first- and second-stage surgery. Complications of the spacer, such as migration and breakage, soft tissue pressure, neurovascular compression, pain or persisting infection mandate spacer exchange. Patients with comorbidities, resistant bacteria or multiple previous surgeries at the joint are prone to fail final prosthesis insertion and are candidates for salvage surgery.


The objective of this study is to investigate the mechanical properties and the composite action of circular concrete-filled steel tube (CFST) columns subjected to compression-torsion load using finite element model analysis. Load–strain (T–γ) curves, normal stress, shear stress, and the composite action between the steel tubes and the interior concrete were analyzed based on the verified 3D finite element models. The results indicate that with the increase of axial force, the maximum shear stress at the core concrete increased significantly, and the maximum shear stress of the steel tubes gradually decreased. Meanwhile, the torsional bearing capacity of the column increased at first and then decreased. The torque share in the columns changed from the tube-sharing domain to the concrete-sharing domain, while the axial force of the steel tube remained unchanged. Practical design equations for the torsional capacity of axially loaded circular CFST columns were proposed based on the parametric analysis. The accuracy and validity of the proposed equations were verified against the collected experimental results. Concrete-filled steel tube (CFST) structures are widely used as compression members in bridges and building structures. Compared with conventional reinforced concrete columns, concrete-filled steel tube columns have the advantages of making full use of the material strength of steel and concrete, high bearing capacity and rigidity, and excellent seismic performance ,2,3,4,5.Extensive studies have been carried out on CFST columns subjected to axial compression ,17,18,19Xu et al.  performeIn terms of theoretical approaches, Lee et al.  establisIn recent years, Ding et al.  put forwThis paper is organized as follows: In The finite element (FE) models of circular CFST columns were established using ABAQUS version 6.14. The adopted plastic-damage constitutive model of concrete and the elastoplastic hardening model of steel can be found in Ding et al. . In the D is the column diameter, t represents the panel thickness of the steel tube, fs is the yield strength of the steel, fcu is the compressive strength of the concrete, N is the applied axial force, and n indicates the axial pressure ratio. The average ratio of test torsional moment  to simulation results  was 1.085. The corresponding variation coefficient was 0.106, indicating the efficacy of this FE model it calculating the torsional capacity of the circular CFST column. T–γ) curves obtained from the two approaches. The results show good agreement between test data and the finite element curve in the elastic section. Therefore, this FE model was applied to the investigation of compression-torsion properties.FE simulations of several related compression-torsion tests were conducted on the circular CFST columns, and the torsional moment comparisons with their corresponding test data are presented in N/Nu~T/Tu correlation curves from the FE results and test data. The FE results were slightly higher than the corresponding experimental values, but they followed similarly varying trends. For the specimens with a low steel ratio , as the axial compression ratio increased, the torsional bearing capacity increased at first and then decreased. Conversely, for specimens with a high steel ratio , the torsion strength decreased slowly, with an increase in the axial compression ratio. Since in practical projects the steel ratio of CFST columns is generally low (ρ < 10%), investigations on low-steel-ratio cases are critical. Hence, only the low steel ratio specimens we subject to further investigations in terms of compression-torsion properties.In compression-torsion problems, the applied axial load and torque are used as independent variables, then the loading process can be subdivided with different sequences, and the effects of different loading paths need to be identified first. Given a typical circular CFST column constructed with a Q235 circular steel tube and C40 concrete with a steel ratio of 0.05, a section diameter D of 400 mm, and a column length L of 2000 mm, the ultimate axial bearing strength could be obtained through Equation (1) :Nu = fcAφ is the confinement index coefficient, φ = Asfs/Acfc. The pure torsional strength of these circular CFST columns can also be obtained with Equation (2), proposed by Ding et al. [Aso is the area bounded by the centerline circle of the steel tube, calculated as π(rc + t/2)2. Ac is the core concrete area, fc is the compressive strength of concrete, rc is the section radius of the core concrete, and τcc is the maximum shear stress of the core concrete and equals (0.37 + 6.0ρ) × fcu0.62. In the equations presented in this paper, the units of the area and the material strength are mm2 and MPa, respectively.Here g et al. Tu = 1.1Nu and torsional strength Tu, we can realize different torque ratios (m = T/Tu) and axial pressure ratios (n = N/Nu) in numerical simulations by changing the applied axial and the torsional forces. N and the average longitudinal strain εL of the columns under different torque ratios (m = T/Tu). With different axial pressure ratios, the initial stiffness remained almost constant. Moreover, as the applied torque T gradually increased, the torsional capacity continued to decrease. γ (T–γ curve) under different axial pressure ratios (n = N/Nu). The shear stiffness of the column under combined compression-torsion conditions was nearly the same as that under pure torsion conditions. In addition, with an increase in the axial compression ratio, the ultimate torsional strength first increased and then decreased.With the axial capacity N/Nu~T/Tu correlation curves of a typical circular CFST column under the above two loading paths. The torsion-first loading case weakened the axial-force-resisting ability of the CFST column. In contrast, the compression-first loading path exerted a strengthening effect on the torsional strength. When the axial pressure ratio varied between 0.2 and 0.6, the torsional bearing capacity increased by 10–20%. As the ratio of axial force to compression strength increased to 0.8, the torsion resistance decreased slightly, but the torsional capacity remained nearly equivalent to that of the pure torsional column.n = 0), compression stress was induced at the core concrete. The maximum principal stress of the concrete was 12.6 MPa. Moreover, the internal stress followed a downward helical pattern, with the angle between the principal stress direction and column axis being smaller than 45°. At the same time, tension stress was induced in the steel tubes to ensure the forces’ equilibrium state. Thus, the mechanics of the circular CFST column in the pure torsion state is a combination of “pulling torsion” at the steel tube and “compressive torsion” at the interior concrete. For the n = 0.6 loading case, the angle between the concrete compressive stress and the column axis was about 30°. Compared to the pure torsion column, the internal compressive stress at the interior concrete was more uniform across the section, with the maximum principal stress reaching 28.9 MPa. Therefore, the internal stress state of the CFST column under compression-torsion state can be simplified as a combination of the “pulling (compressive) torsion” of the steel tube and the “compressive torsion” of the concrete. The stress state of the steel tube depended on the axial force condition. When axial force was low with an increase of applied torsional moment, the internal stress in the steel tube changed from compression to pulling. When the axial force level was high, the steel tube was always in a compression state.T to stain ratio υsc and the lateral compressive stress  of concrete. For axial pressure ratios of 0.2 and 0.4, the initial stain ratio was 0.285, which is close to Poisson’s ratio of steel. Therefore, the steel tubes presented little constraining effect on the interior concrete during the axial loading stage, and the core concrete had no lateral compressive stress. When the axial pressure ratios were 0.6 and 0.8, the initial stain ratios were 0.304 and 0.365, respectively, together with an increased lateral compression stress on the concrete. This indicates that when the axial pressure was relatively large, the steel tubes had a solid clamping effect on the core concrete, resulting in a three-axis compression state affecting the interior concrete. Compared to the pure-torsion column, the lateral compressive stress on the core concrete increased dramatically in the compression-torsion column, together with the restraining effect from the steel tubes on the interior concrete. Therefore, the torsional resistance of the compression-torsion column was generally more prominent than that of the pure-torsion column.In summary, the mechanics of a circular CFST column under compression-torsion can be regarded as a combination of “pulling (compressive) torsion” at the steel tube and “compressive torsion” at the concrete. Due to the composite effect of the steel tube and the concrete under axial force, the maximum shear stress at the core concrete increased significantly while shear stress at the steel tube gradually reduced. Therefore, as the axial compression ratio increased, the torsion capacity of the compression-torsion column initially increased and then gradually decreased.u~T/TuN/N correlation curves with different steel yield and concrete strength. Only minor differences are present between the different curves, which indicates that the strength of the steel and the concrete exert little influence on the ultimate torsional capacity of the CFST column.u~T/TuN/N correlation curves with different steel ratios. When the axial compression ratio was between 0.2 and 0.4, there was nearly no difference between the curves obtained with different steel ratios. When the axial pressure increased to 0.6–0.8, a greater steel ratio induced a larger torque share at the steel tube. The case with a greater axial force ratio had a more significant shear stress reduction at the steel tube and a reduced uT/T ratio.u~T/TuN/N correlation curves with 2000 mm and 6000 mm column length . Results indicate little influence of the slenderness ratio on the torsional bearing capacity of the column.u~T/TuN/N correlation curves with different column dimensions. The curves under different column dimensions are nearly coincident, indicating a small effect of column size on torsional strength.u~T/TuN/N curve of the compression-torsion column. Through the 36 FE u~T/TuN/N calculation results in Tu and Nu can be calculated according to Equations (1) and (2), respectively. To improve the practicability of Equation (3), it can be further simplified in favor of safety. The torsional ultimate bearing capacity of the circular CFST column at different axial compression ratios can be simplified as:Parameters like material strength, steel ratio, slenderness ratio, and column dimensions exerted little influence on the Tu,0) and 20 test values  with corresponding calculated values  using Equation (3). The average value of Tu,1/Tu,0 ratio was 1.001, and the variation coefficient was 0.093. The average value of Tu,c/Nu,1 ratio was 1.001, and the variation coefficient was 0.132. The comparisons verify the effectiveness and accuracy of the proposed formulas.u~T/TuN/N correlation curves calculated with each formula. In addition, u,cT), FE values , and the calculated values  together with the proposed formula and other formulas in scAscG is the composite shear stiffness and scG is the composite shear modulus. sG and cG are the shear moduli of the steel and the concrete, scA is the section area, and sA and cA are the areas of the steel tube and the concrete, respectively.According to Ding et al. , the comtk values of the compression-torsion columns with different axial compression ratios were still in agreement with the fitted curve, resulting in a minor effect of the axial compression ratio on the composite shear stiffness of circular CFST columns.The loading path can influence the compression or torsion strength performance. Torsion-first loading can weaken the axial-force-resisting ability of the CFST column, while the compression-first loading path has an enhancing effect on the torsional strength.Due to the composite action of the steel tubes and the concrete, the maximum shear stress is significantly increased at the core concrete and gradually reduced at the steel tubes. As the axial pressure ratio increases, the maximum shear stress at the core concrete increases at first and then decreases.As the axial pressure ratio increases, the axial load share of the steel tubes remains nearly unchanged, and the maximum shear stress share gradually decreases. The torque sharing in the circular CFST column changes from the tube-sharing domain to the concrete-sharing domain.Formulas for the torsion capacity of circular CFST columns are presented based on parametric analysis. The formulas can account for the contribution of axial force in a highly accurate yet simple form.In this study, systematic FE analyses of circular CFST columns subjected to axial compression-torsion were carried out. The main conclusions are as follows:


Due to its central role in coordinating nutrient and one-carbon metabolism along with immune responses of the newborn, the liver could be a key target of the programming effects induced by dietary methyl donors such as Met. To address this hypothesis, liver biopsies from 4-day old calves  transport, a reduction in metabolism of essential AA within the liver indicated an AA ‘sparing effect’ induced by maternal Met.FOXO1, PPARG, E2F1, and CREB1 appeared central in the coordination of effects induced by maternal Met. Overall, maternal Met supply induced better immunometabolic status of the newborn liver, conferring the calf a physiologic advantage during a period of metabolic stress and suboptimal immunocompetence.Despite greater global DNA methylation, maternal Met supply resulted in distinct alterations of hepatic transcriptome, proteome, and metabolome profiles after birth. Data underscored an effect on maintenance of calf hepatic Met homeostasis, glutathione, phosphatidylcholine and taurine synthesis along with greater efficiency of nutrient metabolism and immune responses. Transcription regulators such as The online version contains supplementary material available at 10.1186/s12864-021-07538-w. Maternal nutrient and metabolic stresses during pregnancy are important factors that can affect fetal and neonatal growth, development , 2, as wIn addition to being a substrate for protein synthesis, Met is a key component of one-carbon metabolism  where itEpigenetic control of gene expression, also induced by the intrauterine environment, is one of the underlying mechanisms of the ‘Fetal programming’ hypothesis , 16 thatThere are strong associations between Met supplementation during late-pregnancy and body weight and immune response in calves , confirmSince nutritional management of modern dairy cows entails dietary manipulation of energy density and nutrients such as essential AA during the last stages of gestation (~ 4–6 weeks prepartum) , a deepeIn the present work, a subset of calves from a larger cohort , 27 was P value = 0.04) and wither height . No significant differences were detected for body weight and length, and hip width   at day 2, whereas no significant differences were detected for other blood parameters  and Taurine  in MET calves compared with CON  global DNA methylation compared with CON calves  was greater in MET calves , an overall tendency toward lower abundance of Cysteine Dioxygenase Type 1 (CDO1) and greater abundance of Phosphatidylethanolamine N-Methyltransferase (PEMT) and Methionine Adenosyltransferase 1A (MAT1A) respectively  of Glycine, Adenosine, Serine, Taurine, Cystathionine, Glutamate, Fumarate, NAD, NADH, Taurocholic acid, Glycocholic acid, Lithocholic acid, and Glycochenodeoxycholic acid Table . MaternaA summary of sequencing read alignment and mapping is reported in Additional File The Dynamic Impact Approach (DIA) analysis yields the impact and flux of all the manually-curated pathways included in the KEGG database. The term ‘impact’ refers to the biological importance of a given pathway as a function of the change in expression of genes composing the pathway (proportion of DEG and their magnitude) in response to a treatment, condition, or change in physiological state. Consequently, the direction of the impact, or flux, characterizes the average change in expression as up-regulation/activation, down-regulation/inhibition, or no change. Considering DIA results with DEG at FDR ≤ 0.10, a broad effect on the transcriptome due to maternal MET was detected Fig. . All maiThe transcription factor enrichment analysis with the ChIP-X Enrichment Analysis 3 (ChEA3) tool generated a list of 72 TF significantly-associated (FDR ≤ 0.05) with our DEG at the FDR ≤ 0.10 threshold. The list of top 10-ranked upstream regulators is reported in Table The present findings were broadly consistent with our previous reports investigating the effect of feeding MET during late-pregnancy on cow and calf hepatic function , 34, 35.MAT1A abundance in MET calves  [FC = − 1.50] was also noteworthy. TYMS converts deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) in a 5,10-methylene-tetrahydrofolate (THF)-dependent reaction  was consistent with this scenario, as well as the upregulation of POLR3H (RNA Polymerase III Subunit H) [FC = 1.72] and POLR2I (RNA Polymerase II Subunit I) [FC = 1.71]  [FC = − 3.59] and cyclin-dependent kinase 1 (CDK1) [FC = − 3.15] was intriguing. These changes could potentially be biologically-relevant considering the role of these genes in oocyte meiosis , and the fact that at this age of the calf most of the supply of fatty acids (FA) are derived from consuming milk replacer.Studies in humans and mice suggest that DNA methylation plays a crucial role in tissue-specific insulin-induced gene expression . Both inPCK1 (Phosphoenolpyruvate Carboxykinase 1) [FC = − 1.99] is in line with the fact that most of the circulating glucose in newborn calves arises from lactose in the milk replacer fed. The downregulation of FOXO4 (Forkhead Box O4) [FC = − 1.44] also agreed with this idea, since the FOXO complex binds the PCK1 promoter [The lower phosphorylated S6K1  ratio in MET calves was intriguing considering that S6K1 is the predominant regulatory kinase of GSK3 (Glycogen synthase kinase 3)  and thatpromoter .GYS2 (Glycogen Synthase 2) [FC = − 1.39] and the simultaneous upregulation of G6PC3  [FC = 1.30].It is well-established that lactose intake on its own is not sufficient to meet the newborn glucose demands , thus, cPYGL (Glycogen Phosphorylase L) [FC = − 1.32], along with upregulation of NR0B2 (Nuclear Receptor Subfamily 0 Group B Member 2) [FC = 2.64] and PPP2R3C (Protein Phosphatase 2 Regulatory Subunit B″ Gamma) [FC = 1.68] was intriguing. These responses seemed to suggest a better capacity of MET calves in the utilization of lactose for meeting glucose requirements with a consequent reduction in depletion of glycogen reserves. The PYGL gene encodes a protein that catalyzes the cleavage of alpha-1,4-glucosidic bonds to release glucose-1-phosphate from liver glycogen stores and plays an important role in maintaining blood glucose homeostasis , CPT1A  [FC = − 1.46], and ACADM (Acyl-CoA Dehydrogenase Medium Chain) [FC = − 1.68] all of which are well-known to be crucial for mitochondrial and peroxisomal FA oxidation [PPARA (Peroxisome Proliferator Activated Receptor Alpha) [FC = − 1.33] that encodes a nuclear receptor controlling genes required for activation of mitochondrial and peroxisomal FA oxidation [Gamma-Butyrobetaine Hydroxylase 1 (BBOX1) [FC = − 1.51], which in non-ruminants is regulated by PPARA [MCAT  [FC = 1.42] agreed with the downregulation of CPT1A. Indeed, MCAT is a component of the fatty synthase complex [CPT1A and mitochondrial FA oxidation [MAT1A and PEMT  [FC = − 4.02] was also intriguing. This gene encodes the delta-6 desaturase enzyme, which catalyzes the first step in the desaturation and elongation of the dietary essential FA  was noteworthy. The protein encoded by this gene is part of the regulatory complex involved in AA sensing and activation of mTORC1  and GPX1 (Glutathione Peroxidase 1)  was noteworthy  [PANK3 [FC = − 1.87], which would be metabolically important because CoA is an essential cofactor supporting a multitude of oxidative and synthetic reactions, including those involved in FA biosynthesis and oxidation  with no added Met or CON plus ethyl cellulose MET  , 158. MeAfter parturition, neonatal calves were separated from their dams. Body weight (BW), hip and wither height , hip width (HW) and body length were measured. Heifer calves were kept in the experiment if they fulfilled all the following criteria previously described , 1) singCalves were offered 3.8 L of first milking colostrum from their mother within 6 h. If voluntary colostrum intake had not reached the 3.8 L required, calves were force-fed via an esophageal tube to ensure that all calves consumed the same amount of colostrum. Calves were housed in individual outdoor hutches bedded with straw and fed twice daily (AM and PM) with a milk replacer . More in detail, heifer calves received 4.54 kg/day of milk replacer mix (0.59 kg of milk replacer in 3.95 L of water) and had ad libitum access to starter grain mix  fed in the morning. All heifer calves remained clinically healthy during the study.n = 6 calves per group) from the jugular vein at 2 d of age using 20-gauge BD Vacutainer needles . Vacutainer tubes used contained lithium heparin, and plasma was obtained by centrifugation at 1900×g for 15 min at 4 °C and stored at − 80 °C until further analysis. Plasma was used to analyze the concentrations of a number of biomarkers associated with energy metabolism , immune function, liver function, and oxidant status according to protocols described in a number of publications from our group  with no added Met or CON plus ethyl cellulose Met .Additional File 3: List of all transcription factor (TF) obtained with ChEA3 transcription factor enrichment analysis tool and significantly overrepresented (FDR ≤ 0.05) in the differentially expressed gene (DEG) list from RNAseq data in liver tissue of 4-d old Holstein calves (n = 6/group) born to cows randomly assigned to receive a basal control (CON) diet from − 28 ± 2 d to parturition [1.47 Mcal/kg dry matter (DM) and 15.3% crude protein (CP)] with no added Met or CON plus ethyl cellulose Met . For each TF, the ranking (Rank), P value, false discovery rate (FDR), the overlapping genes among the DEG list, and the predicted state  calculated using the rationale underlying the Dynamic Impact Approach (DIA) analysis are reported.Additional File 4:. Extended discussion on methionine synthase (MTR) and cystathionine beta-synthase (CBS) activity, phosphatidylcholine (PC) and very low density lipoproteins (VLDL), and on single genes involved in immune status in MET calves.Additional File 5: KEGG pathways in ‘Lipid Metabolism’, ‘Amino Acid Metabolism’, and ‘Immune System’ subcategories resulting from the DIA analysis of RNAseq data from liver tissue of 4-d old Holstein calves (n = 6/group) born to cows randomly assigned to receive a basal control (CON) diet from − 28 ± 2 d to parturition [1.47 Mcal/kg dry matter (DM) and 15.3% crude protein (CP)] with no added Met or CON plus ethyl cellulose Met . The columns represent the effect (impact) and flux responses. The blue bars represent the effect value (0 to 300), and the flux columns represent negative (−) and positive (+) flux (− 300 to + 300) based on the direction of the effect. The positive flux (red bars) indicates an upregulation in treated (MET) liver tissue cells compared to control (CON) ones, while the negative flux (green bars) indicates a downregulation.Additional File 6:. Ingredient and nutrient composition of far-off (from − 45 to − 29 d) and close-up (from − 28 d to parturition) diets fed to Holstein cows used in the present study.Additional File 7:. Extended information about quantitative real-time PCR. Accession number, gene symbol, and forward and reverse primer sequences of genes analyzed in calf liver.Additional File 8:. Gene/pathway-based network visualization obtained with Pathway Network Visualizer (PANEV) tool, considering the entire list of differentially expressed genes (FDR ≤ 0.10). The network was created taking into account the main pathways of interest involved in ‘Glycolysis/gluconeogenesis’, ‘Lipid metabolism’, ‘Amino acid metabolism’ and ‘Immune system’, along with the list of their interconnected (i.e. up- and downstream) pathways based on information retrieved on KEGG pathway database.Additional File 9:. Transcription Factor/Gene/pathway-based network visualization matching the outcomes from Pathway Network Visualizer (PANEV) tool with the main results obtained by ChIP-X Enrichment Analysis 3 (ChEA3) software.