The objective of this research was to study the effect of an optimal mechanical treatment method to reduce the mortar adhered on recycled aggregates (RCA) on the long-term mechanical properties and durability of concretes containing RCA at different replacement levels. It was found that concretes incorporating treated RCA exhibited sharper and more significant increase on 90- and 365-day compressive strengths than any other investigated mixture. The same mixtures also benefitted from a ‘shrinkage-controlling’ effect, where strains and mass losses were reduced by almost 15% and 10%, respectively, compared to the reference concrete. While sulfate resistance and carbonation resistance are predominantly defined by the hydration products available within the cement paste and not to a large extent by the aggregate type and quality, the incorporation of either treated or untreated RCA in concrete did not appear to expose RACs to significant durability threats. The growth in global urbanization has resulted in an increase in construction and demolition waste (CDW), with concrete being the predominant construction material. In 2018, CDW constituted 35.9% of all total waste in the European Union (EU) 14] whereGenerally, the durability properties of mixtures containing RCA are reported to be impaired in comparison with conventional concretes ,16. HighComparable results were reported for drying shrinkage experiments when RCA were added ,19. Inco2SO4 aqueous solution and examined after 6 months, observing a maximum weight loss of 2.8% [2SO4 solution. In particular, at a w/c ratio of 0.35 the expansion of samples was decreased, while a relatively high w/c ratio (0.55) had an adverse effect on the expansion was observed.In other studies , RAC mix of 2.8% . For con of 2.8% , the w/cOverall, when RCA were introduced to concrete mixtures, substantially increased values of carbonation depths were observed in contrast with natural aggregate-based concretes. Specifically, for 25% and 50% RCA replacement, the mean carbonation depth was 1.07 and 1.18 times respectively higher compared to conventional concrete . FurtherTo improve the quality of RCA that affects the mechanical and durability properties of RAC mixtures, several treatment methods were developed that mainly focused on the removal of the remnant mortar and/or paste attached to the aggregate’s surface. Removal methods include mechanical treatment ,31,32, tThe treatment method adopted for the removal of adhered mortar was studied in  and opti2 carbon footprint, quantitative energy consumption), and the overall performance yielded from the experimental data.In light of the previous research work, it is necessary to establish an understanding on the effect of the adhered mortar paste as well as how its quality characteristics could impact the properties of commonly used concrete. Utilizing of the abovementioned methodologies indeed highlights useful information and such methodologies are included in comprehensive reviews. However, there are several concerns embedded with each methodology, such as the energy consumption throughout the treatment procedure, the cost of necessary equipment for running the relevant experiments, the scarcity of facilities for conducting essential rigorous advanced techniques, as well as risks of jeopardizing the existing aggregate properties used in the aforementioned research. It is therefore imperative, when utilizing a particular methodology towards enhancing RCA, to determine an optimum balance between the cost embedded with the usage of relevant equipment ; the environmental impact associated with the conducting of experimental procedure , A = the cross-section area exposed to propanol (mm2), t = the time (min) and k = the sorptivity coefficient (mm/s0.5).The study includes evaluating the mechanical properties and durability of the concretes incorporating RCA at strategic replacement contents. d), following by placing them in a vacuum desiccator subjected to a pressure of 2.0 ± 0.7 kPa for a duration of 2 ± 0.2 h. The procedure included filling the desiccator with demineralized water following which the atmospheric pressure was restored. The samples (three samples for each tested formulation) were maintained within the desiccator for 24 h and both immersed (mh) and saturated surface dry (ms) masses were measured. The open porosity (%) was then determined by calculating the ratio of the open pore volume and the apparent volume of the samples, based on the equation below:The open porosity  of concrChloride resistance of 28, 56, 90 and 365-day cylindrical concrete disc specimens of 100 mm diameter and 50 mm height (cut from 100Φ200 mm cylinders) was determined in accordance with ASTM C-1202  using a For measuring the drying shrinkage of RAC, specimens of 300 × 75 × 75 mm dimensions were prepared and water cured for 28 days at 20 °C. The specimens were then placed in a conditioning environment  throughout the remaining period of investigation and dimensional changes were obtained at weekly intervals using a length comparator apparatus for up to 20 weeks.2SO4 solution at 20 °C. This exposure is approximately 5.6 times stronger than the most severe environment in EN 206-1 that suggests a SO4- concentration of 6 g/L. The solution was changed every 28 days, to maintain the concentrations through immersion period. Sulfate expansions were monitored throughout a period of 40 weeks.The sulfate resistance of the RAC was determined using a method proposed by Dhir et al.  which in2 atmosphere, 20 °C and 65% RH. Longitudinal slices of 50 mm were cut from the sample by using chisel and hammer at weekly intervals for the determination of carbonation depths. Phenolphthalein indicator solution was sprayed on the internal surface of the 50 mm slices while the remainder of the specimen was re-sealed and placed in the CO2 chamber. A total of 12 points were used to obtain the average carbonation depth, one hour after spraying.Carbonation resistance of hardened concrete was measured in accordance to the EN 12390-12:2010 standard, where 300 × 75 × 75 mm samples were water cured at 20 °C for 28 days, followed by being conditioned in advance  for a period of 14 days and placed in a carbonation chamber set to 4% CO3 and 864 kg/m3 in order to evaluate the effect of RCA in both normal and high strength concretes. The target consistency class was S3 in accordance with EN 206-1 [“R” denoting recycled concrete aggregate“F” denoting the fine aggregates replacement “C” denoting the coarse aggregates replacement“F” denoting the aggregate to be field, non-treated “T” when aggregate is treated.“100”, “50” or “25” represent the replacement percentage of natural aggregatesIt should be noted that throughout the paper, the w/c ratio is suffixed at the end of each code name.A total of 17 mixtures were developed based on the mix proportions shown in EN 206-1 . For achMixes were produced in accordance with BS 1881-125:2013  by usingcu/fct ratio was maintained relatively constant for all mixes from the 28th day to the 90th day, albeit at a lower value at higher w/c ratio mixtures . An interesting point was nevertheless observed at higher w/c ratios. When treated coarse aggregates were incorporated at 25%, the 90-day strengths surpassed the compressive strengths of the reference by 5%. On the 50% replacement of the same, compressive strength was still 2% higher than those of the reference mixture, and this denotes that the treatment method enhanced the overall microstructural and density characteristics of the matrix, though such beneficial effect was restricted only up to a 50% replacement.The relationship between compressive and splitting tensile strength, porosity and chloride resistance of all investigated mixtures is shown in Treated recycled coarse aggregates, when incorporated in RAC of 0.25 w/c ratio, resulted in reduced compressive strengths at 90 days (up to 15% reduction from the reference) however, they caused more apparent reductions in splitting tensile strengths (up to 26.9% reduction compared to reference). The opposite appeared to occur in untreated fine/coarse RAC mixtures at low w/c ratios, where splitting tensile strengths at 90 days were maintained close to the reference, although compressive strengths were more drastically decreased, i.e., by 23.1%. Such behaviour would be probably related to the presence of unhydrated cement particles in the matrix as these low w/c ratio values incorporate inadequate water for hydration within the mixture. For the high w/c ratio concretes, where the differences in splitting tensile strengths was higher, this would be attributed to the presence of a double ITZ . The results suggest that the effect of mechanical treatment of recycled aggregates on the bonding characteristics of RACs may be more beneficial to mixtures of higher w/c ratios where the cement content was lower, however, such effect had evidently benefited all treated RCA combinations at all w/c ratios when reached 90 days. In low w/c ratios at early ages, this effect was less apparent, which may indicate a possibility that the effect of geometrically altered aggregates in concrete could be somewhat hindered by the significantly high cement contents in the mixes. Nevertheless, the effect still appeared to have benefited even these mixtures at 90 days. When considering longer-term strengths (365 days) against porosity evolutions of the mixtures as shown in Significant outcomes were observed in the chloride resistance, resistivity and porosities investigation of the mixtures. All RAC mixtures appeared to have reduced the chloride penetration by up to 52% at low w/c ratios and 40% at high w/c ratios compared to the reference mixtures while having, interestingly, higher porosities than those of the reference mixtures. The addition of higher amounts of RCA in concrete mixes seemed to have increased the porosities of the mixtures, due to the presence of higher amounts of adhered mortar—which is a highly porous material. The reductions in both porosity and RCP values were well correlated with the reduction in w/c ratio as seen from Drying shrinkage strains and mass loss of concretes examined for up to 20 weeks are shown in 2 and the available Ca(OH)2 in concrete in the presence of humidity, to yield CaCO3 and alter the molar volume of the matrix while further minor phases may additionally incur such as calcium carboaluminates produced from the AFm phases. When considering the investigated mixtures, the amounts of alkalis present are significantly high as of the large volumes of CEM I 52.5N and these are backed by the high pH values in the pore solution. This fact appears to be the major and most predominant factor controlling the carbonation resistance of concrete while the w/c ratio, based on the figures, seemed to be evidently the second parameter that defines the magnitude of the carbonation depths. Even though the carbonation depths of concretes at w/c 0.5 were higher than their corresponding RefC1 concrete and higher those of w/c ratio of 0.25, still however, these values may be considered insignificant (less than 0.25 mm) when comparing to previous research, and the carbonation resistance of RACs is considered comparable to that of their REF equivalents. An interesting fact noted was that the incorporation of treated aggregates at 25% by mass within w/c 0.5 mixtures improved the carbonation resistance making it comparable to that of RefC2 concrete, although the aforementioned differences were not significant compared than the rest of the mixtures with w/c ratio of 0.5. Furthermore, the results showed that the w/c ratio along with the cement content were more predominant factors defining the carbonation resistance than incorporating and/or treating RCA within the concrete. Any formations of secondary ITZs or any weaker bonding between RCA and mortar did not occur to a degree that would hinder the beneficial effect that the present alkali hydroxyls provided within the concrete.Another observation made was that in most mixtures, shrinkage became dormant approximately at the 8th week of testing, although mass losses were still continuing to occur up to even the 10th week in some mixtures. Based on The sulfate resistance of concretes investigated up to 40 weeks of exposure at both w/c ratios is shown in 2, C3A and AFm phases in concrete to form expansive ettringite, which in turn increases the molar volume of the matrix causing internal stresses, cracking and mass loss. The permeability of concrete is a significant factor affecting the penetration of sodium sulfate solution in the matrix [Fundamentally, the mechanism of sulfate attack is based on the reaction between sulfate ions and the available Ca (OH)e matrix . Becausee matrix ,62.The incorporation of 3-h mechanically treated RCA at 25%, 50% and 100% replacement levels offered a sharper increase in long-term compressive strengths than any other combination or reference mixture investigated in the study. The uprises in strength from 28 to 90 to 365 days reached a range of approximately 25%. Such differences were more drastic than those in porosities of the same combinations.An optimal mechanical treatment process appeared to offer a ‘shrinkage-controlling’ effect in treated RACs, where shrinkage strains of up to 20 weeks were reduced by almost 15% compared to reference concrete, and this was also reflected in the mass loss measurements.Optimal treatment of RCA in concrete initially appeared to have, to a lesser extent, affected the early-age compressive strengths and porosities of the investigated mixtures; then, it appeared to be benefitting only the strengths of high w/c ratio mixtures; and finally, it enhanced the long-term mechanical properties of both w/c ratios.The carbonation resistance and sulfate resistance of RAC appeared to be comparable to those of reference mixtures. As these two aspects are predominantly defined by the hydration products available within the cement paste and to a lesser extent by the aggregate quality, it follows that the incorporation of either treated or untreated RCA in concrete did not appear to expose RACs to any durability concerns.The reductions in both porosity and RCP values were well correlated with the reduction in w/c ratio. In mixtures containing 100% replacement with either treated coarse RCA or untreated fine RCA, the reduction in the RCP at 28 and 90 days was significant, ranging between 40–50%, although as the samples matured (365 days), reductions were less . The same behaviour was observed in mixtures of high w/c ratio although improvements in chloride resistance were not as significant.A comprehensive long-term mechanical properties and durability assessment was conducted on RAC mixtures incorporating untreated, as well as treated RCA that had undergone mechanical treatment. Following the treatment process, the aggregates were utilized in concrete combinations at w/c ratios 0.50 and 0.25, with strategic replacement percentages of fine, coarse treated and untreated aggregates at 25%, 50% and 100% by mass. The following conclusions were drawn:


Background: Pharyngitis is 1 of the most common conditions leading to inappropriate antibiotic prescriptions. When personal protective equipment (PPE) was at first constrained during the COVID-19 pandemic, Intermountain Healthcare recommended limiting rapid group A streptococcal pharyngitis (GAS) testing in urgent-care clinics to preserve PPE. Notably, the percentage of pharyngitis encounters prescribed an antibiotic and that underwent GAS testing is a key Healthcare Effectiveness Data and Information Set (HEDIS) measure. We have described our experience with urgent-care pharyngitis encounters and the impact of temporarily reducing GAS testing on antibiotic prescribing before and during the COVID19 pandemic. Method: We identified all urgent care encounters between July 2018 and August 2021 associated with a primary diagnosis of pharyngitis using ICD-10 CM codes and a validated methodology. Pharyngitis encounters were assessed for antibiotic prescriptions ordered through the electronic health record (EHR) and the use of point-of-care rapid GAS tests. Pharyngitis encounters were analyzed monthly. We assessed the percentage of encounters associated with an antibiotic prescription regardless of testing and the percentage of encounters associated with an antibiotic prescription when a GAS test was or was not performed. We examined 3 periods relating to COVID-19 and GAS testing recommendations: the prepandemic period (July 2018–March 2020), the pandemic onset period (April 2020–June 2020), and the pandemic period (July 2020–August 2021). Results: Prior to the pandemic, the monthly percentage of pharyngitis encounters for which rapid GAS testing was performed was nearly 90% (Fig. Conclusions: Limited PPE in our urgent care centers during the initial months of the COVID-19 pandemic was associated with a mandated substantial decline in rapid GAS testing. As testing volume decreased, we noted a simultaneous relative increase of >30% in antibiotic prescribing for pharyngitis. These findings suggest that rapid streptococcal testing promotes appropriate antibiotic prescribing.Funding: NoneDisclosures: None


Nitrofurantoin is the first-choice antibiotic treatment for uncomplicated urinary tract infections (UTIs) in males according to the Dutch primary care UTI guideline. However, prostate involvement may be undetected and renders this treatment less suitable.To compare the nitrofurantoin failure fraction with that found with use of other antibiotics in adult males diagnosed by their GP with an uncomplicated UTI, as well as GP adherence to the Dutch primary care UTI guideline.Retrospective observational cohort study using routine healthcare data for males seeking care at GP practices participating in the Julius GP Network from 2014 to 2020.Medical records were screened for signs and symptoms of complicated UTIs, antibiotic prescriptions, and referrals. Treatment failure was defined as prescription of a different antibiotic within 30 days after initiation of antibiotic therapy and/or acute hospital referral. The effects of age and comorbidities on failure were assessed using multivariable logistic regression.n = 6805/10 055 episodes, 68%). Nitrofurantoin  was prescribed in 3788 (56%) of uncomplicated UTIs, followed by ciprofloxacin , amoxicillin/clavulanic acid , and trimethoprim/sulfamethoxazole . Antibiotic failure occurred in  25% , 10% (95% CI = 9 to 12), 20% (95% CI = 16 to 24), and 14% (95% CI = 10 to 19) of episodes, respectively. The nitrofurantoin failure fraction increased with age. Comorbidities, adjusted for age, were not associated with nitrofurantoin failure.Most UTI episodes in males were uncomplicated (Nitrofurantoin failure was common in males with uncomplicated UTI and increased with age. Internationally, there is ongoing debate about whether males can actually have an uncomplicated UTI. Some experts argue that the prostate is always involved to some extent indicating a complicated UTI, but evidence to support this is lacking. In some countries, such as the UK, Sweden, and the Netherlands, the distinction between complicated and uncomplicated UTIs in males is made in the national guidelines, although definitions differ slightly across guidelines.2Although UTIs are much less common in males than in females, the incidence increases considerably with age. The annual incidence rises from 11 per 1000 person–years in males aged <65 years to 174 per 1000 person–years in males aged  ≥85 years, corresponding to around 165 000 males with UTIs in the Netherlands annually.2 This is mainly based on expert opinion, extrapolation from scientific evidence related to uncomplicated UTIs in females, and low Escherichia coli (E. coli) nitrofurantoin resistance rates in the Netherlands.2 However, a higher risk of nitrofurantoin treatment failure in males than in females could be anticipated for two main reasons: first, males with uncomplicated UTIs may have undetected involvement of the prostate and nitrofurantoin hardly reaches therapeutic concentrations in the prostate;4,5 and second, although most UTIs in females are caused by E.coli, UTIs in  males  are  often  caused  by  non-E.coli uropathogens. A study from the Netherlands showed that approximately half of UTI episodes in males are caused by E. coli, with Klebsiella spp found in 6%, Proteus mirabilis in 5%, Enterococcus spp in 5%, other  Gram-negatives  in  11%,  and  other  Gram-positives in 12%.6 Nitrofurantoin is less effective against non-E. coli uropathogens, . GPs may therefore intuitively deviate from current Dutch guideline recommendations and prescribe other antibiotics such as the second-choice antibiotic trimethoprim, or antibiotics that are only recommended for complicated UTIs: ciprofloxacin, amoxicillin/clavulanic acid, and trimethoprim/sulfamethoxazole. However, antimicrobial resistance rates for E. coli in males in Dutch primary care are 22% for trimethoprim, 17% for ciprofloxacin, 33% for amoxicillin/clavulanic acid, and 20% for trimethoprim/sulfamethoxazole.2 Furthermore, ciprofloxacin use is associated with a risk of serious adverse events.7 Nitrofurantoin treatment causes less resistance than these other antibiotics and has a favourable safety profile.Evidence for optimal treatment of uncomplicated UTIs in males is scarce. The Dutch primary care UTI guideline recommends nitrofurantoin 100 mg slow release twice daily for 7 days as the first-choice antibiotic for males with an uncomplicated UTI.The aims of this study were to inform the Dutch primary care UTI guideline by comparing the failure fractions of the various commonly GP-prescribed antibiotics in uncomplicated UTIs in males, and to assess GP adherence to the current Dutch guideline.8 The study population consisted of adult males (aged ≥18 years) with uncomplicated UTI, as diagnosed by their GP,  who  received  a  UTI-related  antibiotic  prescription for that UTI episode. Patients were able to contribute multiple UTI episodes to the dataset.This retrospective observational cohort study was conducted using anonymised routine healthcare data from the Julius General Practitioners’ Network (JGPN) collected from January 2014 to December 2020. The network covers 84 general practices providing care during office hours in Utrecht and surrounding areas. Participating practices and their registered patients  are representative of the Dutch population as a whole.the patient had an indwelling urinary catheter;no information on patient-reported symptoms and GP-assessed signs was available;one UTI episode was associated with two prescriptions for different antibiotics on the same day;the antibiotic prescription was for prophylactic or future use, andthe patient was anatomically female.GPs participating in the JGPN register a diagnosis for each consultation using International Classification of Primary Care (ICPC) codes. As a first step, medical record data were collected from all consultations of adult males with ICPC codes U01 (dysuria/painful urination), U02 (urinary frequency/urgency), U70 (pyelonephritis/pyelitis), U71 (cystitis), and Y73 (prostatitis) for which a UTI-related antibiotic  was prescribed within 7 days before and after the start date. A UTI episode after a UTI consultation-free interval of 30 days was considered a new UTI episode. Second, UTI episodes were excluded if:2 A UTI was considered uncomplicated when all of these signs and symptoms were absent. If a sign or symptom was not recorded it was considered absent. Screening and scoring of 400 variables regarding signs and symptoms of complicated UTI was done in duplicate by two independent investigators with an agreement of 99% .Next, medical records of all remaining UTI episodes were manually screened and scored for patient-reported symptoms and GP-assessed signs of a complicated UTI, namely fever reported by patients and/or assessed  by  GPs,  patient-reported  malaise  and/or cold shivers, and GP-assessed ‘clinically severely ill’, costovertebral angle tenderness, perineal pain, and/or signs of delirium.The following data were extracted for each uncomplicated UTI episode: age, comorbidities , number and type of antibiotic prescriptions using Anatomical Therapeutic Chemical codes, and hospital referrals.Treatment failure was defined as an antibiotic prescription for a different antibiotic >1 day after the initial prescription or an acute hospital referral to urology or internal medicine >1 day after the antibiotic prescription.2 GPs were therefore considered adherent to the guideline if they prescribed one of those antibiotics. If treatment failure had occurred in the year before the current UTI episode, ciprofloxacin, amoxicillin/clavulanic acid, and trimethoprim/sulfamethoxazole were considered adherent as well.The Dutch UTI guideline recommends nitrofurantoin (first choice) or trimethoprim (second choice) for treatment of uncomplicated UTI in males.As data on UTI episodes from 2013 were not available, treatment failure in the year before 2014 could not be determined. The year 2014 was therefore excluded from the adherence analysis.Uncomplicated UTI incidence rates in males were calculated by dividing the number of UTI episodes by the number of person–years available in the JGPN database, overall and stratified by age group. Baseline characteristics were described descriptively. Treatment failure fractions for the various antibiotic regimens were expressed as percentages with 95% confidence intervals (CIs). Only the first course of antibiotics given for a UTI episode was included to determine ‘prescribed antibiotic’ statistics. Guideline adherence by GPs was calculated by dividing the number of uncomplicated UTI episodes in which the GP prescribed an antibiotic according to the guideline recommendation by the total number of uncomplicated UTI episodes. A secondary analysis was performed to assess GPs’ adherence with the recommended nitrofurantoin or trimethoprim treatment duration of ≥7 days.9A random intercept model was performed to determine the effect of age and comorbidities on nitrofurantoin failure. Statistical analyses were performed with MedCalc Version 20.110 and IBM SPSS Statistics (version 26.0.0.1).Between 2014 and 2020, an annual mean of 150 450 adult males were registered in the JGPN database. These males experienced 12 846 UTI episodes, of which 2791 episodes (22%) were excluded for various reasons, leaving 10 055 episodes in 6903 individual males suitable for inclusion .Of the 10 055 episodes, 6805 episodes (68%) in 4876 individual males were defined as uncomplicated UTI episodes. The baseline characteristics associated with these 6805 episodes are shown in The overall incidence of uncomplicated UTI was 6.5/1000 person–years. The incidence increased with age: (data not shown).n = 3788, 56%), followed by ciprofloxacin , amoxicillin/clavulanic acid , trimethoprim/sulfamethoxazole , and other antibiotics   . The secn = 87) of episodes treated with nitrofurantoin, 3% (n = 6) treated with trimethoprim, 3% (n = 62) treated with ciprofloxacin, 1% (n = 7) treated with amoxicillin/clavulanic acid, and 4% (n = 10) of episodes treated with trimethoprim/sulfamethoxazole (data not shown).Acute hospital referrals occurred in 2% (Nitrofurantoin failure occurred in 25% (95% CI = 23 to 26) of the nitrofurantoin-treated episodes   (data noAge (in years) was statistically significantly associated with a higher odds of nitrofurantoin failure . Comorbidities, when adjusted for age, were not significantly associated with nitrofurantoin failure (see Supplementary Table S2).The trimethoprim, ciprofloxacin, amoxicillin/clavulanic acid, and trimethoprim/sulfamethoxazole failure percentages were 25% , 10% , 20% , and 14% , respectively . Age  were available for assessing guideline adherence . In 3712n = 234) did not result in a higher treatment failure risk compared with a prescription for 7 days in males with an uncomplicated UTI  (data not shown).Data on antibiotic treatment duration was available for 3358 nitrofurantoin and 164 trimethoprim prescriptions. Prescriptions adhered to the recommended length of 7 days for nitrofurantoin in 3052 of 3368 (91%) episodes and for trimethoprim in 133 of 164 (81%) episodes. Nitrofurantoin prescriptions for ≤5 days . The failure percentage of  trimethoprim,  the  second-choice  treatment, was also 25%, but the number of trimethoprim prescriptions was small. Nitrofurantoin failure significantly increased with age, ranging from 13% in those aged 18–39 years to 29% in those aged >80 years. GPs were shown to deviate from the Dutch UTI guideline in 38% of uncomplicated UTI episodes, mostly prescribing ciprofloxacin instead of nitrofurantoin or the infrequently prescribed second-choice trimethoprim.Major strengths of the current study are the large sample size allowing robust age-specific subgroup analyses and the use of well-documented primary care electronic routine care data for 7 consecutive years. Using the medical text from UTI consultations it was possible to discern uncomplicated from complicated UTI episodes and to not only take antibiotic switches but also treatment failures leading to an acute hospital referral into account.Some limitations deserve further discussion. First, as this was a medical record study, it was not possible to ascertain whether tissue invasion was definitely absent. Tissue involvement might have gone undetected by the GP. This is, however, no different than in actual routine care. Besides, not only ICPC codes for cystitis, but also for prostatitis and pyelonephritis were included to obtain consultation data for all types of UTIs. As free medical text entered by the GP is more reliable than ICPC coding, all signs and symptoms of tissue invasion were scored manually to distinguish uncomplicated from complicated UTIs. Episodes with ICPC codes for prostatitis and pyelonephritis accounted for 4% of all uncomplicated UTI episodes. Even if the inclusion of such episodes would have introduced some misclassification, it was anticipated this would be of minor influence on the findings.Second, data from out-of-hours services, such as prescriptions and referrals, and deaths were not available, which might have led to an underestimation of the observed treatment-failure fractions. It is, however, unlikely that a potential bias would differ for the various UTI-related antibiotic prescriptions. Also, no data were available on intolerances, allergies, or interactions with other medications, which might justify some non-adherent prescriptions. Besides, GPs might have other good reasons to deviate from guideline recommendations, for example, initiating a more aggressive treatment in vulnerable patients with clinically uncomplicated UTIs.Third, by classifying all re-prescriptions with a different antibiotic and all acute referrals to urology or internal medicine as a treatment failure, some overestimation of treatment failure might have occurred. Some re-prescriptions might have been issued for other reasons than treatment failure, such as adverse effects. Also, patients might have been referred to urology or internal medicine for another reason but, as the time window for referrals was short and the number of referrals low, the authors believe that the potential impact of such misclassification will be minor.Fourth, this study is observational  and confounding by indication may therefore be present: the groups of males treated with nitrofurantoin versus another antibiotic might not be comparable regarding disease severity and other factors contributing to treatment failure. This may, for example, explain why hospital referrals were less common in males treated with nitrofurantoin compared with males treated with ciprofloxacin. It seems likely that patients with more severe symptoms are prescribed ciprofloxacin more often than patients with milder complaints.10,11 According to the Dutch primary care UTI guideline, nitrofurantoin is contraindicated in patients with an eGFR <30 mL/min/1.73 m2.2 Unfortunately, information about patient’s actual eGFR was not available in the current study. As GPs as well as pharmacies receive an alert if nitrofurantoin is prescribed to a patient with an eGFR <30 mL/min/1.73 m2, the authors consider it unlikely that many patients would have had a eGRF <30 mL/min/1.73 m2. However, it cannot be excluded that nitrofurantoin failure was more likely in males with eGFR between 30 and 90 mL/min/1.73 m2. Further research into this potential association is warranted.Fifth, in line with clinical practice, it was not know whether patients used their antibiotics as prescribed. Sixth, there is ongoing debate whether the effectiveness of nitrofurantoin is reduced in patients with a low estimated glomerular filtration rate (eGFR).5 However, the current study adds valuable information. First, in the previous study, data on signs and symptoms were not available, making a distinction between complicated and uncomplicated UTIs impossible. Second, only nitrofurantoin prescription data from older males were available as opposed to all antibiotic types in all age groups in the current study, making comparisons between antibiotic regimens possible. Additionally, the Dutch primary care UTI guideline cites an unpublished study by the Netherlands Institute for Health Services estimating the nitrofurantoin failure percentage to be 27% in males of all ages.2 However, their treatment failure definition also included antibiotics that were likely not prescribed for UTIs, and the failure period was defined as 60 days. A third Dutch outpatient study showed that 5.4% of male patients treated with nitrofurantoin were prescribed a different antibiotic within 3 days across all ages.12 This much lower treatment failure risk may likely be explained by the 3-day treatment failure period as opposed to the 30-day period in the current study.The Netherlands is one of few countries worldwide recommending nitrofurantoin as a first-choice treatment for uncomplicated UTIs in males. Most available studies are therefore of Dutch origin. A previous smaller study from the same author group showed a similar nitrofurantoin failure percentage (27%) as this study.13 However, 32% of the males had a catheter inserted at the time nitrofurantoin was prescribed, making it difficult to generalise the results to males with uncomplicated UTIs. Another retrospective study from Sweden in 69 males with a lower UTI showed nitrofurantoin failure in only one patient, but the sample size was very small.14To the authors’ knowledge, only two studies on nitrofurantoin efficacy in males from outside the Netherlands have been published. A retrospective study in 485 American male veteran patients with lower UTIs showed a clinical cure fraction of 77%.15 That study included 169 Dutch males with an uncomplicated UTI. Also comparable is the very low prescription fraction of 3% in the current study and 4.4% in Ganzeboom et al15 for the second-choice trimethoprim. This might be related to the failure fraction of 25%, which is comparable with nitrofurantoin.The 62% guideline adherence observed in the current study was comparable with the 50% adherence in the only other study, to the authors’ knowledge, that has been published about adherence to the guidelines for males.The current study shows higher rates of nitrofurantoin failure compared with ciprofloxacin, amoxicillin/clavulanic acid, and trimethoprim/sulfamethoxazole in males with uncomplicated UTI, especially in those of older age. As this is based on observational data causal inferences cannot be drawn and the implications for what the consequences are for clinical practice remains to be elucidated.Based on the current findings, a randomised controlled trial comparing various antibiotic regimens is warranted to robustly determine the optimal treatment strategy for males with an uncomplicated UTI.In conclusion, nitrofurantoin failure was common in males with an uncomplicated UTI and this increased with age. GPs deviated from the Dutch UTI guideline in 38% of the uncomplicated UTI episodes, mostly prescribing ciprofloxacin instead of nitrofurantoin.


This review is devoted to self-healing materials (SHM) containing polyhedral oligomeric silsesquioxanes (POSS) as building blocks. The synthetic approach can vary depending on the role POSS are expected to play in a given system. POSS  can be grafted in side chains of a polymer backbone or used as segments of the main chain. Appropriate functionalization allows the formation of dynamic bonds with POSS molecules and makes them an active component of SHM, both as crosslinking agents and as factors that enhance the dynamics of macromolecules in the polymer matrix. The latter effect can be achieved by reversible release of bulky POSS cages or by the formation of separated inclusions in the polymer matrix through hydrophobic interactions and POSS aggregation. The unique properties of POSS-based self-healing systems make them interesting and versatile materials for various applications . Polymeric self-healing materials (SHM) are of great interest due to their dynamic properties that can stabilize their performance extending the service life and thus reduce the impact of synthetic materials on the environment. SHM can self-heal spontaneously or stimulated by environmental conditions, after a fracture or external mechanical damage ,2. The l1.5)n, where n = 6, 8, 12; R is a hydrogen atom or an organic or heterorganic group  are the smallest known silica-like hybrid particles (1–3 nm diameter) with a well-defined inorganic framework made of silicon and oxygen atoms, and the empirical formula (RSiOic group  36]. Th. Th1.5)nic group  that opeg) and improvement of mechanical strengths. The composites were microphase-separated due to the aggregation of POSS units into nanodomains, which become the reinforcing net points of the physically crosslinked network  elastomer, were introduced into a rubber matrix filled with fumed silica . Amic acReversible hydrogen bonds resulting from interactions between the epoxy resin and POSS additives that were functionalized with different numbers of oxirane rings  as well as dodecaphenyl-POSS (DPHPOSS), were used to activate self-healing mechanisms in a thermosetting multifunctional resin containing embedded multi-walled carbon nanotubes (MWCNT) . GPOSS nIt should be noted that in some cases the phase separation caused by the propensity of POSS to aggregate can be creatively exploited to alter unwanted effects caused by excessive supramolecular interactions. An example can be the alternating supramolecular thermoplastic poly(lactide)/poly(ε-caprolactone) triblock copolymers admixed with 1,2-propanediol-heptaisobutyl-POSS. PLA-PCL-PLA were functionalized at their end positions with 2-ureido-4[1H]-pyrimidinone (UPy) groups, which are capable of forming self-complementary quadruple hydrogen bonds . The useIt has been also shown that the scratch resistance and healing ability of an acrylic melamine clearcoat can be improved upon the addition of hyperbranched polymer (HBP) and POSS bearing eight (3-hydroxy 3-methyl butyl) groups  60]. Th. Th60]. Liquid-repellent surfaces , which are able to perform non-stick, self-cleaning, and anti-pollution functions, have recently attracted much attention in materials engineering. Unfortunately, most super-repellent surfaces exhibit poor durability after exposure to chemical environments (including air oxidation), UV radiation, or physical damage . It would be a significant advantage if synthetic coatings could recover their intrinsic hydrophobicity without modification or the addition of low surface energy substances. Recently, significant progress has been made in developing robust, self-healing superhydrophobic surfaces and fabrics with enhanced durability. Functionalized polyhedral oligosilsesquioxanes can help maintain these special properties of self-repairing coatings . The selThe incorporation of highly perfluorinated compounds into the coating allows for achieving low surface energy without the need for specific chemical surface grafting. It was found that superhydrophobic and superoleophobic fabrics coated with tridecafluorooctyl triethoxysilane (FAS) hydrolysate with embedded but well-dispersed particles of octaocta-silsesquioxane (FD–POSS) can self-regenerate during heating, showing excellent durability against physicochemical  and mechanical  factors . The pro2 nanoparticles that occurred after heating the abraded surface at 140 °C for 30 min. A similar effect was obtained for self-healing waterborne superhydrophobic coatings prepared from a polysiloxane emulsion containing fluorinated POSS and modified SiO2 nanoparticles  copolymers prepared by RAFT copolymerization of butyl acrylate (BA) with 2-ureido-4[1H]-pyrimidinone acrylate (UPyA) using trithiocarbonate derivative of 3,13-dihydroxypropyl DDSQ [co-UPyA)] the double-decker silsesquioxanes aggregated into much smaller microdomains with dimensions of 10–20 nm. All the studied samples showed high elongation at break, which increased with the content of UPyA groups in the material, e.g., 450% for DDSQ[P(BA-co-UPyA10)]2 and 350% for DDSQ[P(BA-co-UPyA20)]2. The UPyA content also affected the shape recovery rate—the higher it was, the faster the samples reformed (shape recovery time was 85 s for DDSQ[P(BA-co-UPyA10)]2, 74 s for DDSQ[P(BA-co-UPyA20)]2, 65 s for DDSQ[P(BA-co-UPyA30)]2 and 48 s for DDSQ[P(BA-co-UPyA40)]2).Similar results were obtained for self-healing DDSQ[P(BA-pyl DDSQ  or polyupyl DDSQ . The hybco-UPyA40)]2.The self-healing properties were tested by cutting the samples into two halves and then contacting them at elevated temperatures (40 °C). The incision in the material gradually decreased and disappeared completely after about 15 h a. Tests 1H NMR, and GPC analyses, while its thermoreversible nature was demonstrated by DSC studies. DSC thermograms of FPU and FPU-POSS-MI showed  and retro-DA  reactions were observed with increasing POSS-MI content, which is due to the increasing effect of rigidity of the polymer chains. The hybrid materials showed a significant increase in the wetting angle from 84° to 141.3°, owing to the combined effect of grafting of hydrophobic POSS-MI units and increased micro- and nanoscale surface roughness. There was no change in the WCA values after the samples were heated to rDA temperature (130 °C) and then annealed for another 15 h at 70 °C. The surface structure was evaluated by atomic force microscopy (AFM) and field emission scanning electron microscopy (FESEM). An interesting sphere-like morphology with small nanopatterns on the surface was observed on the FESEM micrographs  were used in the synthesis of a new class of hydrophobic self-healing polyurethane-POSS hybrids based on the dynamic furan-maleimide Diels-Alder “click” reaction  74]. Th. Th74]. I showed  that therographs . With inThe self-healing characteristics of this organic–inorganic hybrid SHM were evaluated by a tensile test and also by monitoring the crack disappearance by optical microscopy after annealing at 130 °C for 3 h, then cooling to 70 °C and maintaining at this temperature for 15 h. Heating at 130 °C caused cleavage of the DA adducts. The bonds reconnected via the DA reaction, which occurred at 70 °C, and the scratch was healed. In the case of FPU, the scratch remained visible after the healing process, whereas the addition of POSS-MI resulted in some enhancement of the self-healing properties even after the thermal treatment was stopped. An additional slight change in the scar could be noted. For the FPU-POSS-MI hybrids, almost no change in the surface roughness value (±3 nm) was observed after the healing process.The presence of POSS also improved the thermal and mechanical characteristics compared to those of pure FPU . The FPUg > 90 °C). Moreover, the incorporation of hydrophobic silsesquioxane moieties significantly improved the thermal stability of the copolymers as well as the surface hydrophobicity (WCA ≈ 101° for the parent fluoro-polymer and WCA 135° for the modified polymers) due to the increased micro/nano-surface roughness.The reversible addition-fragmentation chain transfer copolymerization of furfuryl methacrylate (FMA) and 2,2,2-trifluoroethyl methacrylate (TFEMA), with silsesquioxane side units grafted by dynamic DA cycloaddition reactions , yieldedTrDA) in the first heating curve indicates a retro-DA reaction, whereas the exothermic peak within the temperature range of 60 °C–155 °C was attributed to the reinstallation of the cleaved DA linkages. The reappearance of the glass transition and the presence of the rDA endotherm in this temperature range in the second heating curve confirmed the reversible dynamic behavior of the DA structures in the hybrid material. The enthalpic effects observed for sample P1C with the number of reactive furan units in the copolymer chain: POSS-MI = 38:40 are higher than in the other polymers studied . These observations were confirmed by FTIR studies.The thermoreversible behavior of the furan-POSS-M linkages facilitated the self-repairing of the hybrid polymethacrylates, as confirmed by DSC measurements  and optiThe cut and heal tests showed that the polymers were not suitable for healing at room temperature due to the poor segmental movement of the polymer chains inhibited by POSS and the lack of reversible exchange characteristics. However, self-healing of the studied system was possible at higher temperatures. Thermal treatment of the notched sample  resulted in a fourfold reduction of the scratch width. At temperatures suitable for retro-DA reactions, segmental motion and local diffusion of polymer chains are facilitated by cleavage of DA linkages, which releases bulky molecules of POSS-MI. The structural integrity of the sample was achieved by reconnecting the cleaved functional groups at 65 °C. The self-repairing performance of DA-modified polymers was significantly improved after increasing the content of reversible DA conjugates with POSS-MI. For the P1C polymer, the relatively low repair efficiency (EH ≈ 17%) of the original parent polymer was increased to EH ≈ 78%.g in POSS-modified ENR compared to the original sample indicates that also in this case the incorporation of bulky POSS-MI inhibits the mobility of macromolecular chains in hybrid DA elastomers. The self-healing characteristics were investigated by cut-and-heal test using optical microscopy. Due to the presence of nano-sized POSS, the DA-modified elastomer exhibits significantly better hydrophobicity (WCA > 140°), thermal stability, surface hardness, mechanical properties, and adhesion to metal substrates.The Diels-Alder reaction was also used to introduce self-healing and ultrahydrophobic features into a commercially available epoxidized natural rubber (ENR)  76]. Fu. Fu76]. TrDA plays a significant role in enabling segmental movement of polymer chains through the release of POSS-MI molecules. This effect was confirmed by the lap-shear test. The increased segmental movement of polymer chains caused by the release of POSS-MI facilitated the flow of the released polymer chains (Tg < TrDA because furfuryl groups acted as a plasticizer). Consequently, the healing process was enhanced by increased mobility of macromolecular chains. Again, the healing performance of DA elastomers improved significantly with increasing POSS-MI content.A gradual increase in surface roughness of the hybrid elastomers with increasing POSS-MI content was demonstrated on FESEM micrographs and 3D AFM images illustrating the surface morphology . The 0.5−1 attributed to ν(SH) disappeared and a new peak assigned to ν(S–S) vibrations appeared at 472 cm−1, resulting from the oxidation of -SH groups.The application of SHM, which can potentially be used as coatings, low-electrical insulating materials for microelectronics, or automotive clearcoats, is related to the type of polymer matrix. For example, self-healing silicones, in addition to their high thermal stability, hydrophobicity, biocompatibility, and electrical resistance have recently received special attention, especially due to new emerging applications in stretchable electronics ,78. MoleThe mechanical properties of crosslinked SEs can be adjusted by changing the amount and type of components used as crosslinking agents. Too low amount of crosslinkers resulted in poor elastomeric properties. Using POSS and higher amounts of PETMP as linkers between macromolecules led to the formation of hard SEs with numerous cracks. POSS-SH is a bulky molecule and, therefore, free rotation of bonds in the formed crosslinked network is difficult. Unlike molecular crosslinkers, such as PETMP and POSS-SH, PMMS with high molecular weight cannot effectively bond the polysiloxane matrix. The reason is the crosslinking between PMMS chains, leading to unsuccessful hybrid network formation. Moreover, POSS-SH could provide more crosslinking sites than PETMP. As a result, more rigid and dense networks were formed, which was reflected in the mechanical properties. As the amount of POSS-SH increased, the elongation at break gradually decreased from 545% to 85%, while the change of the tensile strength trend was rather irregular, and the sample with a moderate amount of crosslinking agent showed the highest tensile strength (0.23 MPa).Another method for obtaining hybrid polymer coatings with self-healing properties is based on the use of complementary interactions between nucleobase pairs. A novel system containing adenine end-capped three-arm polycaprolactone oligomer (PCL-A) and POSS bearing eight uracil groups (POSS-U) was successfully used to prepare stable, physically crosslinked structures via the formation of complementary uracil–adenine (U–A) pairings . POSS-U 1H NMR, UV, and FT-IR spectroscopy. The degree of conversion of the epoxy groups was found to be about 98%. The formation of DA bonds between furan and maleimide groups was indicated by shifting the carbonyl doublet characteristic IR peak (1770 cm−1) and the imide C=O stretching vibrations (1709 cm−1) to higher wavenumbers of 1774 and 1713 cm−1, respectively. The conversion of maleimide to DA adduct could be also observed as a decrease in absorption at about 300 nm due to the loss of O=C–C=C–C=O conjugation.Self-repairing hybrid coatings can be also formed from mixtures of functionalized POSS and complementarily reactive small molecules. For example, a tough, transparent, and self-healing POSS nanocomposite was prepared by a thermally reversible Diels–Alder reaction between furan-end octafunctionalized POSS (FG-POSS) and bismaleimide molecules  81]. Th. Th81]. Good transparency of the crosslinked material indicated the molecular level of FG-POSS dispersion in the rigid nanocomposite at room temperature. The compressive modulus value was 1.0 GPa and the yield strength (118 MPa) was comparable to those obtained for commercially available crosslinked epoxy resins (102–170 MPa) . From thThe cracked sections of the POSS nanocomposite could be thermally repaired. After heating at 135 °C for 30 min and then cooling, the cracks were successfully healed without leaving a scar . HeatingA crosslinked, thermally stable (up to 300–350 °C) nanohybrid material (MMA-POSS/FA) was prepared using commercially available octafunctional POSS containing methacrylate groups (MMA-POSS) and furfurylamine (FA) . In the 8) by reverse vulcanization  bynization a. The menization . The obtnization b. MoreovAn alternative method to obtain self-healing hybrid systems is based on the use of metal−ligand (M−L) interactions. The thermodynamic and kinetic properties of M−L complexes may enable the synthesis of new hybrid materials with tunable mechanical properties . Moreove2 was used as a metal salt due to its good thermal stability and fairly weak interactions between zinc and chloride ions  were prepared by in situ crosslinking of self-assembling colloidal poly(acrylic acid) micelles functionalized with POSS . The addThe POSS-AH/PAA hydrogel had the ability to self-heal due to reversible physical crosslinks. The cut samples were stored in a closed vessel at 37 °C for 48 h and sealed almost completely. Tensile tests performed on the original and self-healing samples showed that the POSS-AH content, AA monomer concentration, and AA neutralization degree had significant quantitative effects on the self-healing process. POSS-AH were effectively crosslinking PAA, but an increase in the silsesquioxane concentration led to a decrease in the ability of hydrogels to self-heal. This effect may be due to the fact that as the amount of POSS increases, the lengths of the flexible chains on the cut surface decrease. The results of the tensile test illustrate the effect of POSS-AH on the self-healing process . A determining factor in the self-healing process is thus the appropriate amount of long polymer chains that must be present on the cut surfaces . Accordi−1 as well as stretching and bending vibrations of N-H bonds . The ν(N-H) were sharper in CS/HPC/POSS than those in CS/HPC hydrogels, indicating that hydrogen bonding interactions between CS molecules have been reduced in the hybrid hydrogels. X-ray diffraction studies revealed that the incorporation of OCAPS also affects the ordered arrangement of HPC molecules and makes the hydrogels more amorphous. Cross-sectional SEM images of freeze-dried CS/HPC/POSS showed that the internal structure of the hydrogels consists of pores with thin walls. Energy dispersive X-ray spectroscopy (EDS) showed that OCAPS molecules were well dispersed and uniformly distributed throughout the matrix.An injectable and self-healing POSS-based hydrogel was also prepared using water-soluble octa(γ-chloroammoniumpropyl)-silsesquioxane (OCAPS), which was mixed with a chitosan (CS) solution and then reacted with the aldehyde groups of oxidized hydroxypropyl cellulose (HPC) . OCAPS aThe readily formed dynamic Schiff bonds were responsible for pH sensitivity and self-healing, while the incorporation of OCAPS improved the mechanical properties of the hydrogel. The gelation time, degree of swelling, degradation, compressive modulus, and strength of CS/HPC/POSS hydrogels were regulated by changing the amount of OCAPS. In general, CS/HPC/POSS hydrogels exhibited a faster swelling than CS/HPC hydrogels. Their equilibrium swelling ratio first increased and then decreased with increasing OCAPS content. The reversible sol-gel transition for CS/HPC/POSS could be controlled by adjusting the pH value. When the pH of the environment was lower than 4.2, the crosslinking density of CS/HPC/POSS was low (Schiff base bond cleavage). When the pH value was increased then the initially liquid CS/HPC/POSS mixture gradually transformed into a solid gel. It was also demonstrated  that the hydrogel was suitable for drug loading and release. It should be noted that drug release from hybrid hydrogels improved after the introduction of OCAPS. The self-recovery of the hybrid hydrogel was evaluated by continuous step strain measurements according to the strain amplitude results B. The re−2) that can be adjusted by the feed ratio.Due to electrostatic interactions and the formation of hydrogen bonds between OCAPs and amide linkers in poly(N-isopropylacrylamide) (PNIPAM) chains, silsesquioxane molecules could also act as effective physical crosslinkers in a nanocomposite hydrogel (OCAPS-PNIPAM), which significantly reduced the loading of N,N′-methylenebisacrylamide (BIS) (50–100 ppm) used as a chemical crosslinking agent . Water-sOCAPS-PNIPAM hydrogels of low loading of the hybrid silsesquioxane crosslinker (<< 7%) can self-heal under certain conditions. This suggests that at very low concentration of BIS, chemical crosslinking of PNIPAM is limited and occurs in microscopic domains. Additionally, the higher OCAPS content limits interactions between PNIPAM macromolecules, which is essential for efficient healing. The 3% OCAPS-PNIPAM0.005 hydrogel, which exhibited self-repairing properties, was subjected to a continuous step-strain sweep test. It was found that the material self-healed as a result of periodic changes in continuous step strain, consistent with the process of damage and reconstruction of the physically crosslinked network.N,N′-methylenebisacrylamide. Morphological studies showed that the pore size and swelling of these materials were a decreasing function of POSS content. A thermally activated and reversible shape memory behavior was observed for PNIPAm-POSS, which involved swelling-deswelling and can be used for drug delivery.Viscoelasticity and smart bidirectional shape-memory behavior of hydrogels formed from N-isopropylacrylamide (NIPAm) and (propyl methacrylate)heptaisobutyl)-POSS copolymers were also investigated . PNIPAm-Another approach to a POSS-hydrogel hybrid system was based on the formation of supramolecular complexes through structural relationships and non-covalent binding . Supramo2) and acrylic acid (2–AA) can be mixed with other monomers methacrylamide (DMAPMA)] to obtain molecularly dispersed systems. The presence of POSS, acting as an amphoteric and noncovalent macro-crosslinker in radical copolymerization, reinforced the hydrogel structure. The synthetic hydrogel is sensitive to pH changes and exhibits a rapid self-healing ability (stress of 8 kPa) and excellent tensile mechanical properties (strain of 4683% and stress of 37.8 kPa). The swelling index of the material under acidic and alkaline conditions was higher than that under neutral conditions. The hydrogel also showed good cohesion with plastics, glass, and metal. The inorganic core of POSS units molecularly dispersed in the hydrogel matrix strengthened it by enhancing the intermolecular forces. Moreover, the electrostatic interactions in these hydrogels, favorably influenced the self-healing properties.A highly stretchable and self-healing ampholytic hydrogel was prepared using octa(aminopropyl)silsesquioxane (POSS-NHlic acid  106]. T. T2) andThe review covers the literature reports on POSS-containing self-healing materials published within the last 14 years. The number of papers devoted to this topic is growing which proves a significant potential of POSS in this area. Such self-healing systems connect nanotechnology and smart materials and despite being, at the moment, a relatively small niche, compared to the large number of papers devoted to polymeric-self healing materials, the specific properties of polyhedral silsesquioxanes may present a unique opportunity for next-generation self-healing and dynamic systems, including materials designed for biomedicine and biotechnology. SHM containing polyhedral oligomeric silsesquioxanes as building blocks can have unique properties. Their design should take into account both the chemical structure of POSS derivatives and the specific application area for a given SHM. Various factors may influence the self-repairing activity of POSS-based polymer nanocomposites, hydrophobic coatings, or hydrogels. Appropriate functionalization enables, for example, the formation of dynamic bonds with POSS molecules as reactive components or can influence the intrinsic properties of SHM . The macromolecular dynamics required for effective self-healing can be achieved by reversibly releasing bulky POSS cages through DA reactions, metal-ligand interactions, or thiol/disulfide chemistry. Another approach is the formation of separated inclusions in the polymer matrix through hydrophobic interactions and POSS aggregation. The specific chemistry of some of the interactions occurring in POSS-based SHMs makes them interesting next-generation materials with improved mechanical properties, suitable for applications in sensors, nanostructured superhydrophobic coatings, and objects with shape recovery properties.


Esophageal cancer (EC) is one of the most common cancers worldwide, especially in China. Despite therapeutic advances, the 5-year survival rate of EC is still dismal. For patients with resectable disease, neoadjuvant chemoradiotherapy (nCRT) in combination with esophagectomy is the mainstay of treatment. However, the pathological complete response (pCR) rate to nCRT of 29.2% to 43.2% is not satisfactory, and approximately half of the patients will develop either a locoregional recurrence or distant metastasis. It is, therefore, necessary to explore novel and effective treatment strategies to improve the clinical efficacy of treatment. Immunotherapy utilizing immune checkpoint inhibitors (ICIs) has significantly changed the treatment paradigm for a wide variety of advanced cancers, including EC. More recently, increasing clinical evidence has demonstrated that neoadjuvant immunotherapy can potentially improve the survival of patients with resectable cancers. Furthermore, accumulating findings support the idea that chemotherapy and/or radiotherapy can activate the immune system through a variety of mechanisms, so a combination of chemotherapy and/or radiotherapy with immunotherapy can have a synergistic antitumor effect. Therefore, it is reasonable to evaluate the role of neoadjuvant immunotherapy for patients with surgically resectable EC. In this review, we discuss the rationale for neoadjuvant immunotherapy in patients with EC, summarize the current results of utilizing this strategy, review the planned and ongoing studies, and highlight the challenges and future research needs. Esophageal cancer (EC) is the sixth leading cause of cancer-related mortality worldwide, with approximately 544,000 deaths from EC in 2020 . In contst-line therapy resulted in significantly longer OS and progression-free survival (PFS) than chemotherapy alone. These results suggest that ICIs have promising prospects for EC treatment.In recent years, immune checkpoint inhibitors (ICIs) have made significant advances in a variety of tumors , 8. In ECurrently, ICI neoadjuvant therapy has been tried in a variety of tumors, such as lung cancer , 19, melAntitumor immune responses can be driven by mutation-associated neoantigens that are recognized as nonself-foreigners by T cells that have escaped negative selection during T-cell development . Tumor mAnti-PD-(L)1 antibodies block the inhibitory signals between tumor cells and T cells in the tumor microenvironment (TME), reversing the exhausted state of T cells –49. Dendvia the stimulator of interferon genes pathway. Type I interferon is a well-known mediator of DC recruitment and maturation  rate. Five studies did not report MPR , 108. ThWhen compared with the classic CROSS 49%)  or NEOCR9%  or NEThe safety results are graphically summarized in In the two studies that added ICI to CRT, the incidence of grade 3 and higher AEs was 65.0% and 42.5%, respectively , 100. MoMore clinical trials can be found at ClinicalTrials.gov Table 2.In addition to these phase 2 studies, several phase 3 studies deserve special attention. Hong et al. designed a randomized controlled trial (RCT) to compare PD-1 inhibitors combined with preoperative CRT versus neoadjuvant CRT for locally advanced ESCC (NCT05357846). The KEYSTONE-002 study was designed to evaluate the efficacy and safety of pembrolizumab in combination with chemotherapy for preoperative neoadjuvant therapy and then the continued use of pembrolizumab as adjuvant therapy postoperatively compared with neoadjuvant CRT and surgery for locally advanced ESCC (NCT04807673). Two other studies are comparing the efficacy of neoadjuvant chemotherapy combined with immunotherapy versus neoadjuvant chemotherapy in resectable ESCC . Immunotherapy plus neoadjuvant chemotherapy versus immunotherapy plus neoadjuvant CRT is also being studied (NCT05244798).In summary, neoadjuvant chemoradiotherapy remains the standard treatment for locally advanced esophageal cancer, and neoadjuvant immunotherapy is in the clinical trial stage. No indications for neoadjuvant immunotherapy are currently authorized.Neoadjuvant immunotherapy in EC is still in its infancy, and many unanswered questions remain. Here, we summarize the challenges and future directions Figure 4ICIs might cause specific toxicity profiles, i.e., immune-related AEs, different from those of chemo- or radiotherapy , 115. InIn neoadjuvant immunotherapy for EC, a combination of CRT with ICIs increased the pCR rate, but the incidence of grade 3 or worse AEs was high, and deaths during treatment were reported , 119. InThe current available toxicity data were all collected from single-arm studies with limited numbers of patients. Large randomized controlled studies are warranted to establish the safety of ICI neoadjuvant treatment of EC. From the above reports, lung injury is a concern when CRT and ICIs are used concurrently. In clinical practice, the extent of cancer lesions or lymph node metastases and the dose of radiation delivered to the lungs should be clearly defined for patients receiving CRT in combination with ICIs. In addition, delayed toxicities remain elusive due to insufficient follow-up.Pathologic response is the most common surrogate endpoint for relapse-free survival and OS in cancer neoadjuvant therapy . pCR is It is highly appreciated when the pathological response is reported in a uniform and reproducible manner to allow for valid cross-study comparisons. However, the pathological response criteria that were developed for chemotherapy and/or radiotherapy may not be suitable for neoadjuvant immunotherapy. In addition, OS was reported to be correlated with the response spectrum of RVT, implying that if assessments beyond pCR and MPR could be performed, prognostication could potentially be available for all patients , 124.Recently, immune-related pathologic response criteria (irPRC) have been developed, that is, scoring 0 to 100% irRVT in 10% intervals . This apAdditionally, neoadjuvant immunotherapy may bring difficulties to radiological response evaluation since the tumor regression pattern seems different from what may happen during chemo- or radiotherapy. Radiographic responses such as pseudoprogression or a delayed response to immunotherapy have been frequently reported –129 and In neoadjuvant immune combination therapy, the chemotherapy regimens were mainly paclitaxel and platinum , 112 F, 131. InTheoretically, chemotherapy may induce lymphopenia and selectively deplete immunosuppressive cells , while IFrom these reported results, ICI combined with CRT achieved higher rates of pCR and MPR over chemotherapy . It shouIn the NADIM study, patients with resectable stage IIIA NSCLC received neoadjuvant treatment with platinum-based chemotherapy plus nivolumab before surgical resection, followed by adjuvant nivolumab monotherapy for 1 year. This study showed that the treatment regimen was well tolerated, and at 24 months, the PFS was 77% and the OS was 90% . Based oTheoretically, postoperative adjuvant ICI therapy is a reasonable option to prevent postoperative recurrence and metastasis. However, there are some issues that deserve our attention. As one example, in patients with HER2-positive early-stage breast cancer, neoadjuvant anti-HER2 therapy plus chemotherapy followed by surgery and adjuvant therapy with anti-HER2 therapy was beneficial only for patients without a pCR . These rAdditionally, prolonged use of ICIs may lead to increased AEs. In mouse tumor models, compared with mice given 2 doses of neoadjuvant immunotherapy, mice treated with 2 doses of neoadjuvant immunotherapy plus 4 adjuvant immunotherapy did not display any significant increase in OS but they did have an increase in immune-related AEs . FurtherPD-L1 expression could be used to predict the efficacy of pembrolizumab in advanced EC . HoweverGenomic analysis showed that in some studies, TMB was higher in the pCR group compared to the nonpCR group , 108. HoIn summary, TCF-1+ CD8+ T cells, TMB and immune-related genes deserve further exploration in larger-scale clinical studies for predicting the response to neoadjuvant immunotherapy for EC. Going forward, the identification of biomarkers reflecting complex tumor-immune system interactions and immune system-host interactions will help us to identify patients who will truly benefit from neoadjuvant immunotherapy. In addition, although traditional imaging techniques cannot accurately reflect the pathological changes of tumor tissue during neoadjuvant therapy, with advances in imaging technology, particularly positron emission tomography technology, we may be able to label specific immune cells, checkpoint molecules, or markers of metabolic processes associated with the neoadjuvant treatment response or resistance to guide or adjust clinical decision-making , 143.Although the use of immunotherapy for preoperative neoadjuvant therapy versus adjuvant therapy may be theoretically more effective, and neoadjuvant immunotherapy has shown preliminary positive results in resectable EC in some clinical studies, further validation of the feasibility, safety, and efficacy of neoadjuvant immunotherapy in large randomized clinical studies is still needed. In addition, a number of unresolved issues must be addressed before neoadjuvant ICIs strategies can be widely adopted as the standard of care. Identifying predictive biomarkers will be key to selecting appropriate populations, and the role of adding adjuvant therapy must be fully understood. Furthermore, long-term follow-up is needed to determine the long-term outcomes and assess any delayed toxicity. We are confident that neoadjuvant immunotherapy will move forward into a new chapter.


Long-term continuous cropping may result in the outbreak and proliferation of soil-borne diseases, as well as reduction in annual crop production. Overcoming the obstacles of continuous cropping is critical for the long-term growth of modern agriculture. Soil microbes are essential for plant health, but the consequences of continuous cropping on soil microbiome are still poorly understood.This study analyzed changes in soil bacterial community composition of Aksu (AKS) and Shihezi (SHZ) in Xinjiang Province during 1–20  years of continuous cropping by 16S amplicon sequencing. The results showed that the incidence of cotton Verticillium wilt rose with the number of cropping years. The bacterial alpha diversity in the AKS soil grew as the number of continuous cropping years increased, however it declined in the SHZ soil.Streptomyces decreased with the increase of continuous cropping years in the AKS and the SHZ soils. In addition, Actinobacteria, Propionibacteriales, and Nocardioidaceae were significantly enriched during the early stages of continuous cropping. Network analysis showed that long-term (≥8  years) continuous cropping interfered with the complexity of soil bacterial co-occurrence networks and reduced collaboration between OTUs.The results of beta diversity analysis showed that there were significant differences in soil bacterial communities between different continuous cropping years and between different soils. The results of community composition changes at the level of main phyla and genus showed that the relative abundance of Actinobacteria, Bacteroidetes and Streptomyces in Actinobacteria might be one of the reasons of continuous cropping obstacles.These findings suggested that continuous cropping and soil origin jointly affected the diversity and structural of bacterial communities, and the loss of Nocardioidaceae and  The region of Xinjiang is China’s most significant cotton-growing site , owing tOvercoming continuous cropping obstacles is an urgent task for the sustainable development of modern agriculture. According to research, changes in soil microbial populations are one of the primary drivers of continuous cropping obstacles . The soiRecently, increasing numbers of studies have indicated that continuous cropping resulted in the disruption of soil microbial community and structure. For example, Verticillium dahliae, is one of the worst plant diseases. V. dahliae can survive as microsclerotia in soil without host plants for more than 14 years. V. dahliae is exceedingly difficult to control due to its long survival time in soil, strong variability, and complex infection process of cotton  region of southern Xinjiang and the Shihezi (SHZ) region of northern Xinjiang over a period of 1–20 years. This study aimed to investigate the response of soil microbial community to continuous cropping, which would provide useful guidance for improving continuous cropping obstacles using microbial techniques in the future.The two study sites are located in Aksu and Shihezi, Xinjiang, China. Aksu belongs to the temperate continental arid climate; the annual average temperature is between 9.2 and 11.5°C, the annual average total sunshine hours are between 2,571 and 2,967 h, and the annual frost-free period is between 183 and 250 days; the annual average rainfall is only 64 mm, while the annual evaporation amounted to 1,890 mm; the distribution of rainfall within the year was extremely uneven, with the main rainfall distributed in summer and almost no rainfall in winter . ShiheziA total of 14 treatments were conducted in this experiment: the farmland with continuous planting of cotton for 1, 3, 5, 8, 10, 15, and 20 years in two sites (Aksu and Shihezi), named AKS1, AKS3, AKS5, AKS8, AKS10, AKS15, AKS20, SHZ1, SHZ3, SHZ5, SHZ8, SHZ10, SHZ15, and SHZ20, respectively. Two cotton fields were selected in each continuous cropping year at each location. There were three blocks in each cotton field and six blocks in each treatment. At the boll formation stage (late August 2020), the incidence of cotton Verticillium wilt was investigated and the incidence rate was calculated . Soil samples were collected with a sampler  using the five-point sampling method, and five soil cores collected in each block were pooled into one sample, with 6 mixed samples per treatment. A total of 84 soil samples were collected. Prior to DNA extraction, the obtained soil was sieved (2 mm) and stored in a refrigerator at −80°C.® High-Fidelity PCR Master Mix (New England Biolabs), 0.2 μM forward primer, 0.2 μM reverse primer, and 10 ng template DNA  was used to generate sequencing libraries, and the quality of each library was assessed using Qubit 2.0 Fluorometer . Finally, the library was sequenced using an Illumina HiSeq 2500 and 250 nucleotide paired-end reads were generated.Soil samples (250 mg) were resuspended in 500 μL of MoBio PowerSoil bead solution, and total genomic DNA was extracted from all 84 soil samples using the MoBio PowerSoil DNA Isolation Kit  following the manufacturer’s instructions. Successful DNA extraction was checked on a 1% agarose gel and DNA concentration was assessed using a spectrophotometer NanoDrop ND-2000 . Barcode primers 341F (5′-CCTAYGGGRBGCASCAG-3′) and 806R (5′-GGACTACNNGGGTATCTAAT-3′) were used to amplify the V3-V4 hypervariable region of 16S rRNA. PCR reactions were performed in a 30 μL reaction mix containing 15 μL Phusionlate DNA . PCR conPaired-end reads were assembled using FLASH (v1.2.7) . Qualityp < 0.05 was considered significant) in SPSS 22.0. Beta diversity analysis was performed based on the Bray–Curtis dissimilarity distance matrix and visualized by principal coordinate analysis (PCoA). Analyzes of similarity (ANOSIM) were performed using the vegan package in R to identify significant differences in beta diversity across groups. The effects of continuous cropping years, soil origin and their interactions on bacterial alpha diversity and beta diversity were evaluated through the two-way ANOVA using SPSS 20.0. Linear discriminant analysis (LDA) effect size (LEfSe) was performed on the Galaxy platformr| > 0.8 and p < 0.05 were retained and visualized using ChiPlot.Community alpha diversity was evaluated by Chao1 estimator and Shannon diversity index calculated by QIIME, and visualized using R software (v3.5.0). The alpha diversity index among the groups was statistically analyzed using one-way analysis of variance (ANOVA) and Tukey’s multiple comparison test  (p < 0.05) (p < 0.001) (p < 0.01) (p < 0.001). Two-way ANOVA showed that alpha diversity indexes (Chao1 and Shannon) were significantly affected by the continuous cropping years and soil origin as well as their interactions  were annotated to the genus level. The dilution curves demonstrated that the sequencing data accurately represented the diversity present in the samples from each treatment group . Alpha d < 0.05) . In the  < 0.05) . However< 0.001) ; the Sha < 0.01) ; the Sharactions .R = 0.6621, p = 0.001), and there were also significant differences in community structure between AKS and SHZ soils . In both soils, the distance between samples of continuous cropping for 1 and 3 years was closer, and the distance between the samples of continuous cropping for 5 and 8 years was closer. In particular, the samples of continuous cropping for 15 and 20 years clustered together and separated from the samples of other continuous cropping years. Two-way ANOVA showed that beta diversity indexes (PCo1 and PCo2) were significantly affected by the continuous cropping years and soil origin as well as their interactions  effect size (LEfSe) method was used to analyze the bacterial taxa with significant abundance difference between different continuous cropping years in two soils. A total of 28 taxa were found to be significantly different in relative abundance among continuous cropping years in the AKS soils , and theCo-occurrence networks were constructed to evaluate the co-occurrence patterns of bacterial communities in short-term and long-term continuous cropping in the two soils. In the AKS soil, compared with short-term (≤8 years) continuous cropping, long-term (≥8 years) continuous cropping decreased the network total nodes, total links, average degree, average clustering coefficient and density, while the average path distance increased . In the In this study, the incidence of Verticillium wilt in cotton field soil with different continuous cropping years was assessed in AKS and SHZ, and it was found that the incidence of Verticillium wilt rose with the continuous cropping years, especially after 5 years of continuous cropping. Similar phenomena have been observed in many crops, including cucumber, potato, tomato and vanilla, with an increased incidence of soil-borne diseases and severely stunted growth after years of continuous cropping .Microbial diversity and community structure are important indicators affecting soil health, and many microbes have the potential to improve crop yield and disease suppression . This stStreptomyces belonging to Actinobacteria decreased with the continuous cropping year in both the AKS and the SHZ soils. Streptomyces are the most abundant and important Actinomycetes, which contribute to the maintenance of soil fertility and homeostasis to promote plant growth and to help plants resist biotic and abiotic stresses  of continuous cropping, suggesting that these groups may be important species to maintain soil health in the early stage of continuous cropping. At the same time, we found that some taxa were enriched in the AKS soil with 1–5 years of continuous cropping and also in the SHZ soil with 15–20 years of continuous cropping, which might be due to the differences in the two soils origin and the composition of the native microbial communities.Network analysis has been widely applied to explore the complex inter relationships and co-occurrence patterns of soil microbial communities . PreviouStreptomyces, Propionibacteriales, and Nocardioidaceae, and these taxa that were lost due to the continuous cropping might be one of the causes for continuous cropping obstacles. These findings extend our understanding of the mechanisms by which continuous cropping of cotton affects soil microbes and provide useful guidance for overcoming continuous cropping obstacles through the application of beneficial microbes in the future.The results of this study indicated that continuous cropping and soil origin jointly affected the diversity and structural of the soil bacterial population. The relative abundance of some beneficial bacterial taxa in both soils decreased with increasing years of continuous cropping, such as: Actinobacteria, Bacteroidetes, https://www.ncbi.nlm.nih.gov/), SRP412954.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: NCBI Sequence Read Archive .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Building practices began with human civilization. Cement is the most commonly used building construction material throughout the world. These traditional building materials have their own environmental impact during production, transportation, and construction, but also have limitations on building quality and cost. Biological construction materials are currently emerging technology to combat emissions from the construction sector. Different civil and biotechnology researchers have turned to microorganisms for the production of bio construction materials that are environmentally friendly, socially acceptable, and economically feasible but can also produce high strength. Scanning electron microscope (SEM) and X-Ray diffraction (XRD) are the most characterization methods used to observe and ensure the production of calcite precipitate as bacterial concrete. As compared to conventional concrete, bacterial concrete was greater by 35.15% in compressive strength, 24.32% in average tensile strength, and 17.24% in average flexural strength, and it was 4 times lower in water absorption and 8 times lower in acid resistivity than conventional concrete. Genetic engineering has great potential to further enhance the mechanical strength of bacterial concrete for use in crack repairs in existing buildings. Building construction is not a recent technology; it began with human civilization. In 3000 BC Sumerians used a mixture of clay and straw complexes as biocomposite materials . NowadayNowadays conventional construction practice such as material production, construction, and demolition holds a role in environmental pollution. During cement manufacturing, varying gases are released to the environment due to heating of clay and limestone. About 2.7 billion tons of carbon dioxide released from manufacturing of cement in 2021 . SimilarThe other drawback of cement-based construction is crack formation. Concrete crack is widespread phenomenon in concrete-based buildings. Cracking causes a decrease in engineering properties and construction material strength in the surface layers of concrete. It often happens due to the pore size between the materials, low tensile strength of the material , overloaStudies show that, to enhance the durability and prevent penetration of aggressive materials, it can be treated through passive (exterior) and active (interior and exterior) methods . ExternaThe idea of microbial application for construction materials were first introduced in 1990 by the US research group Prof Sookie Bang, Eben Bayer, and Gavin McIntyre . MicrobeDifferent studies have shown that varying species of bacteria and fungi have the capacity to mineral precipitation, mainly calcium carbonate, which plays a great role in concrete strengthening.Microorganisms that can induce carbonate precipitation are: (i) sulphate reducing microorganisms, (ii) photosynthetic microorganisms, and (iii) microorganisms involved in the nitrogen cycle . The maiBiocementation is a process of production of carbonate precipitate (MICP) from microbes . As showBacillus is most widely used species for bacteria-based crack healing [μm [Studies show that, the genus  healing , 34, 35.ling [μm , could sling [μm , 36, forling [μm , has thebacillus spp. can remain dormant up to 200 years in harsh environment [Other studies show that the spores of ironment . When crironment , 36, 37.ironment , 33. TheThe day taken to accomplish the crack healing mainly depends on the length of width of the crack and the number of curing days. Most bacterial strains are efficient in crack healing with crack widths 0.15 mm ; 0.2 mm;Most extra ingredients for self-healing concrete include bacterial strains, hydrogels, and different carbon sources such as manganese, peptone, calcium glutamate, and calcium lactate ; corn stBiobricks can be produced through calcite precipitation of alkaline resistant spores forming microbes, bacterial and fungus metabolism as well as chemical reactions , 41.Xanthomonas campestris and gellan gum produced from Sphingomonas elodea are used to replace cement for soil strengthening. Their findings show that soil containing 0.5% (5 Kg) biopolymer resulted in a higher compression strength than that of 10% (100 kg) soil without biopolymer which is about 6.31 MPa. Soil mixed with biopolymer has twice the adhesive capacity of ordinary cement [Biopolymers are polysaccharides produced by microorganisms such as bacteria, algae, and fungi as a result of metabolic activity. Chang et al.  concludey cement . Using by cement .There are four methods in which bacteria are mixed with other healing agents: (i) by direct method, bacteria and other agents are mixed with water to produce calcite , 43;  to visualize the precipitates; X-ray diffraction (XRD) to confirm the production of calcite; thermo-gravimetric analysis (TGA) to determine the moisture, ash, and volatile matter; compressive strength and tensile strength testing to test strength and tensile of the product [From the figure above, direct application of  product .the concentration of calcium sources,pHdissolved inorganic carbon concentration (DIC), andThe availability of nucleation sitesStudy done by Jin et al.  and MenoThis process is the simplest pathway for microbe-based calcite precipitation as part of metabolism . Urease 32−).According to the following equationstated in Seifan et al. ; reactioAs illustrated in 4+) through the ureolytic activity [However, this process of calcium carbonate precipitation has some drawbacks in nitrogen oxide emission into the atmosphere through production of ammonium ions 2)) present in the cement, producing even more calcite precipitate as shown in the following equation[In addition, calcium carbonate was also obtained by the reaction of carbon dioxide with calcium hydroxide. The CO equation, 36. Bec equation.(8)CO2+CCompared to the ureolysis pathway, metabolic conversion is more sustainable due to the absence of emission from ammonium production through hydrolysis of urea .3−) to different oxides of nitrogen , nitrous oxide (N2O), nitric oxide (NO), and nitrogen gas (N2)). This is another pathway to produce biology-based calcium carbonate precipitates [Diaphorobacter nitroreducens and Bacillus sphaericus which are mentioned in (3−). The primary results of organic compound denitrification are carbon dioxide, water, and nitrogen It is a respiratory process that results in the reduction of nitrate . Due toequation ). Finallequation )(9)OrganHowever, different factors can accelerate or decelerate the biomineralization of calcium carbonate. Selection of low risk bacteria with high ability of calcium carbonate precipitation, optimum amount of nutrients, enzyme activity and growth rate, and inoculum size are preferred for maximal precipitation . Among t3. A similar study done by Sidiq et al. [Different studies show that the budget allocated for concrete crack repair and maintenance is more than for concrete production. Silva et al.  cost comq et al. . The cosq et al. ; the ecoq et al. ).  FigurAutogenously and encapsulation self-healing mechanisms are automatic healing cracks without human intervention or interference. During the encapsulation of polymeric material, the filler released from hollow fibers embedded in the concrete matrix is not usually compatible with concrete compositions, which could cause the enlargement and propagation of the existing cracks . It needHowever, the bacteria-based self-healing approach can reduce all drawbacks observed in autogenous and encapsulation methods. There is no need of filler . Instead, it uses microbe-based mineralization. Successful implementation of the biological approach treatment methods will result in a longer lifespan of concrete structures, low cost, and increased environmental sustainability, as well as significant reduction in cement production and structural replacement . Further5 cell/ml concentrations of bacterial species Sporosarcina pasteurii species show better compressive strength of concrete followed by Bacillus aerius as shown in Compressive strength mainly depends on factors such as type of bacteria, concentration of bacteria, application method , and num5 cell/ml bacteria concentration with 28 curing days shows better compressive strength.The addition of more number of bacteria negatively affects the quality of concrete . This is5 cell/ml concentration of bacteria for 7, 14, and 28 curing days results in 14.89, 16.42, and 19.26 Mpa compressive strength, respectively, which is higher than conventional concrete, having a compressive strength of 10.03, 11.38, and 12.49 Mpa as shown in According to Borse et al.  experime5 cell/ml bacterial concentration, the tensile and flexural strength increase with increasing number of curing days [Tensile strength in the case of a concrete specimen is defined as the stress developed by the application of a load due to compression at which the concrete specimen may crack. The result illustrated in ing days . 28 curiing days  also shoing days .2SO4. They conclude that conventional concrete at 36.5 N/mm2 reference age and bacterial concrete at 46.4 N/mm2 reference age at 28 curing days, only 10.7% strength is loosed from bacterial concrete and 16.4% from conventional concrete. As the number of curing days increases, the durability decreases in both conventional and bacterial concrete at a constant concentration and type of acid. However, the rate of loss of strength is higher in conventional concrete than in bacterial.The other advantages of bacteria-based construction materials are resistance to acids and less water absorption. It can decrease water absorption by four times , six timThere are some drawbacks to biologically mediated crack self-healing technology such as spore dormancy period, narrow crack repair, loss of concrete compressive strength due to incorporated capsule . Even thE. coli bacteria (BKH2) through bioremediase-like protein incorporation was increasing the mechanical strength and durability of the mortar samples due to its capacity to leach silica from silicate substrates. However, this modified gene lacks the ability to adapt to an alkaline environment. In contrast to this, most Bacillus species can survive in an alkaline environment and form large spores. Studies done by Sarkar et al. [Bacillus subtilis (B. subtilis) through T-vector can increase the mechanical strength of the concrete, and the new modified gene has the capability to live a long life span, produce more calcite, and have a high self-healing capacity. A similar study was also done by [Short lifetime is one of the limitations of bacteria inside the concrete matrix which restricts it from behaving as a true self-healing activator over sustained duration. It is possible to enhance the bacterial survival period in the harsh environment through genetic transformation of alkaliphilic bacteria and thermophilic anaerobic bacteria. A study done by Sarkar et al.  concluder et al.  showed t done by .Pseudomonas aeruginosa MJK1 and Escherichia coli MJK2 to study MICP [Sporosarcina pasteurii were transfected to bacteria naturally capable of producing large amounts of extracellular polymeric substances, Pseudomonas aeruginosa strains 8821 and PAO1, to get new genes with high alkaline adaptive capacity and good calcite precipitator [3 precipitation for sealing wide cracks. However, attention should be paid during the release of the new gene into the environment.Similar studies done by Lee and Park  revealedudy MICP . This tripitator . The newBuilding construction is not a new technology. It has begun since human civilization. However, the design and construction materials become vary. Currently, cement is the most widely used construction material in the form of concrete or blocks. Besides its high compressive strength and low water absorption, cement has its own social, economic, and environmental problems. About 2.7 billion tons of carbon dioxide will be released from the manufacturing of cement in 2021. If no action is taken on the use of cement, business as usual can eventually lead to significant environmental pollution. To combat this drawback, different studies were done to develop sustainable construction materials. Microbes such as bacteria and fungi play a great role in the application of sustainable construction.Direct and indirect application of bacteria in the construction sector is the one which most researchers argue is the most sustainable. Biocement, bioblock, and bioconcrete as self-healing, bioplastic, and biopolymer are the most well-known microbe-based construction materials. Compared to conventional concrete, bacterial concrete increases 35.15% in compressive strength, 24.32% in average tensile strength, and 17.24% in average flexural strength. And it is 4 times lower in water absorption and 8 times lower in acid resistivity than conversional concrete.