The properties assessed were splitting tensile, compressive and flexural strengths, workability, porosity, water absorption, and density. Furthermore, the correlations between the properties considered were also evaluated. The outcomes reveal that the foamed concrete mix with 4% PFF attained the highest porosity, with approximately 13.9% and 15.9% for 600 and 1200 kg/m3 densities in comparison to the control specimen. Besides, the mechanical properties  increased steadily with the increase in the PFF percentages up to the optimum level of 3%. Beyond 3%, the strengths reduced significantly due to poor PFF dispersal in the matrix, leading to a balling effect which causes a degraded impact of scattering the stress from the foamed concrete vicinity to another area of the PFF surface. This exploratory investigation will result in a greater comprehension of the possible applications of PFF in LFC. It is crucial to promote the sustainable development and implementation of LFC materials and infrastructures.Foamed concrete is considered a green building material, which is porous in nature. As a result, it poses benefits such as being light in self-weight, and also has excellent thermal insulation properties, environmental safeguards, good fire resistance performance, and low cost. Nevertheless, foamed concrete has several disadvantages such as low strength, a large amount of entrained air, poor toughness, and being a brittle material, all of which has restricted its usage in engineering and building construction. Hence, this study intends to assess the potential utilization of polypropylene fibrillated fiber (PFF) in foamed concrete to enhance its engineering properties. A total of 10 mixes of 600 and 1200 kg/m In the context of global climate change, the construction industry is mulling over an alternative for normal-strength concrete as a means of mitigating the extreme self-weight of the material as well as the substantial carbon discharge connected with the production of cement . As a re3 . This di3 .Foamed concrete is broadly applied in the construction industry as a filling material, as a non-loadbearing wall constituent, and as insulation material for exterior panels . To deliIn spite of this, it is commonly believed that foamed concrete has poor physical, mechanical, and durability properties, which is principally due to its high porosity and void connectivity, both of which allow harmful substances to enter foamed concrete media . In addiDespite this, a few studies have demonstrated that the uneven inclusion of steel fiber in concrete can have a negative effect on the workability of the fresh mix, leading to porous concrete and a reduction in the strength parameter ,16. By iPolypropylene fibrillated fiber (PFF), one of the synthetic fibers, has the potential to be utilized as an additive in foamed concrete to improve its qualities. All the PFF membrane’s exceptional mechanical qualities, alkali resistance, and thermal properties contribute to its superior performance. In addition, the PFF membrane is acknowledged as a fiber that may be incorporated into a cement-based composite material which has a high resistance to cracking. The incorporation of PFF into concrete permits the formation of a three-dimensional dispersion network, which effectively suppresses the development of microcracks in cement-based materials. 3 and 1200 kg/m3 were achieved. On the basis of the preceding review, it can be concluded that the influence of PFF inclusion in foamed concrete on the enhancement of engineering qualities has not been explored and discussed in detail. Consequently, the fundamental objective of this study is to determine the engineering characteristics of foamed concrete, reinforced with a PFF membrane. By altering the weight percentages of PFF in the production process, densities of 600 kg/m3 and particle sizes ranging from 0.15 to 2.36 mm, as well as Portland cement that complied with the specifications of the British Standards Institution (1996). The entire required fine river sand quantity underwent a sieve examination to fit the coarse aggregate standard specification, as per what was stated in ASTM-C33. 3 was produced. It was attenuated in the mortar slurry at a ratio of 1:34 and then aerated using a TM-1 foam generator. Then, four different weight fractions of polypropylene fibrillated fiber . This apparatus was used following Brewer’s open-ended cylinder spread procedure ,23. OnceThe number of pores in foamed concrete is commonly stated as a percentage of volume. The porosity of foamed concrete affects many different aspects of its mechanical, thermal, and durability properties. Additionally, it allows several dangerous substances into the foamed concrete. Salt will corrode the reinforcing bar in reinforced foamed concrete, and rust will grow and cause the foamed concrete to crack. Determining the porosity of foamed concrete with a polyformaldehyde monofilament membrane is therefore critical. As shown in The ability of foamed concrete to absorb water is directly related to its ability to repel water, something which is essential in many weakening mechanisms and prevents many harmful factors from entering the environment. The movement of oxygen, chlorine, and carbon dioxide, which start the corrosion of the reinforcing steel in foamed concrete, is made possible by the water absorption capacity of foamed concrete. The water absorption test was performed in this study in conformity with the BS 1881-122 specification . ConcretThe purpose of the axial compression test was to determine the potential strength of the foamed concrete mixtures from which the samples were taken. It evaluates the capacity of a foamed concrete specimen to withstand a load before failing. It permits the verification of whether the correct mix proportions of various foamed concretes and various ingredients were used to achieve the requisite strength. In this investigation, the axial compression test was conducted at a constant rate of 0.03 mm/s in accordance with the BS 12390-3 standard . Cubic sFlexural testing was performed to confirm the rigidity of foamed concrete and determine the force required to bend a prism. In a flexural test, ultimate stress represents the last stress level before failure. A three-point flexural test, as indicated in Foamed concrete’s splitting tensile strength is one of the essential and crucial qualities that significantly affects the depth and breadth of cracks in the material. Because of its brittleness and poor tensile strength, a foamed concrete specimen is not often anticipated to bear direct tension. In this research, the splitting tensile strength test was carried out in line with BS EN 12390-6 specifications . The tes3 densities of the control specimens, respectively. Spreadability was reduced by adding PFF to foamed concrete, and this effect was proportional to the amount of PFF added. Foamed concrete mixes with 4% PFF had the lowest spreadability when compared to the other foamed concrete mixes. Spreadabilities were measured to be 206 mm for 600 kg/m3 and 187 mm for 1200 kg/m3. Because PFF tends to absorb water, there is a consistent decrease in spreadability when it is are present; the external segment of PFF presents significant porosity, which benefits the bond to the matrices, and thus the spreadability of the foamed concrete decreases. In addition, the cementitious matrices aggregate on the PFF’s large specific surface area, increasing the foamed concrete’s viscosity and causing a decrease in spreadability at greater PFF weight fractions. As the air bubbles are forced out of the cementitious matrix, the slump diameter of the foamed concrete will decrease as a result of the free flow of the intermittent stage above the capacity of the stable spreading form. Mortar must additionally cover the smooth PFF membrane in addition to the fine filler (sand). The spreadability of foamed concrete was reduced as the percentage of PFF was raised from 1% to 4%, indicating that greater quantities filling mortar was required to cover the additional zone of PFF. Furthermore, PFF increases the inner abrasion between foamed concrete components, which in turn causes more cement matrix to diminish the inner resistance, hence reducing the workability of foamed concrete. A similar finding, that increasing the fiber’s weight fraction in concrete reduced its workability, was previously described by Mohseni et al. [i et al. . 3 for all foamed concrete mixes that included PFF in different percentages. For instance, for mixes PF0%, PF1%, PF2%, PF3% and PF4%, the discrepancies between final dry densities and planned dry densities of 600 kg/m3 density were ±2 kg/m3, ±5 kg/m3, ±10 kg/m3, ±19 kg/m3 and ±24 kg/m3, respectively. The foamed concrete properties are entirely reliant on the dry density [Differences in the dry density of foamed concrete as a function of PFF weight % are shown in  density .3 densities, respectively. It is possible that this is because of the high packing capacity that PFF has in the cementitious matrix of foamed concrete. A porosity value of 64.9% was observed for the foamed concrete mix, with a density of 600 kg/m3 and a percentage of PFF of 4%, whereas a porosity value of 75.4% was recorded for the control sample. Microcracks formed on the surface of the foamed concrete while it was still in its fresh state condition. At the same time, the surface moisture was rapidly evaporating, which resulted in significant dry shrinkage. When PFF is added to foamed concrete mixes, the segregation can be reduced, and this also helps to reduce the amount of water that is lost through evaporation. In addition to this, the use of PFF has been shown to effectively stop the spread of cracks in foamed concrete that start on the surface and move inward [3, is shown in The porosity of foamed concrete with increasing PFF percentages is represented graphically in e inward . The morThe findings of foamed concrete’s water absorption with various PFF percentages are shown in 3 densities, correspondingly.The correlation between foamed concrete water absorption capacity and its level of porosity is seen in 3 densities, corresponding with the insertion of various percentages of PFF, are shown in 3) and 4.34 MPa (1200 kg/m3), the optimal compressive strengths achieved on day 56 were 2.26 MPa and 7.83 MPa, with the inclusion of a 3% and 4% weight fraction of PFF for the 600 and 1200 kg/m3 densities, respectively. When an optimal percentage of PFF is evenly scattered in foamed concrete cement paste, the hydrated products of cement amass around the PFF. This is due to their superior surface energy, as their surface behaves as a nucleation site. As the foamed concrete contracts, the PFF membrane absorbs tensile energy through the boundary between the PFF and the foamed concrete cementitious matrix. It then transfers this energy to the neighboring matrix, thereby reducing the amount of concentrated tensile stress and increasing the foamed concrete’s resistance to cracking [The compressive strength results of 600 and 1200 kg/mcracking . Poor PF3 are shown in 3) and 1.04 MPa (1200 kg/m3), the ideal flexural strengths that were attained at day 56 were 0.63 MPa and 1.66 MPa, with the addition of a 3% of PFF for the 600 kg/m3 and 1200 kg/m3. PFF is a hydrophilic substance, and as a result, it possesses great adhesion when combined with cement paste. After the PFF percentage was increased to 4%, the flexural strength of foamed concrete drastically dropped for both densities that were taken into consideration for this investigation. Because it is difficult to disperse the PFF evenly and because it might cause agglomeration, the flexural strength will be lowered if the percentage of PFF is too high. This is because PFF can cause agglomeration. During the process of the crack spreading out, the PFF will gradually become separated from the matrix until the bond strength is completely exceeded. This will continue until the fracture has completely spread out. Although the matrix is damaged, it is still capable of maintaining its fundamental form. The presence of PFF in foamed concrete plays a significant role in both the strengthening of the foamed concrete cementitious matrix, and the modification of the material’s physical characteristics from a brittle state to a ductile one. Both of these effects are the result of the material’s transition from a brittle to a ductile state. Because an appropriate percentage of PFF can bond with the hydration products and unhydrated constituents in the foamed concrete matrix to build a three-dimensional grid structure, incorporating an appropriate weight fraction of PFF can efficiently increase the flexural strength of foamed concrete. This is because the three-dimensional network structure can create a subsidiary effect and boost the foamed concrete flexural strength [The results of the flexural strength tests at densities of 600 and 1200 kg/mstrength . 3 (the dataset can be found in 3) and 0.64 MPa (1200 kg/m3), the optimal splitting tensile strengths attained at day 56 were 0.39 MPa and 0.93 MPa, with the inclusion of a 3% PFF for the 600 and 1200 kg/m3 densities. Because of the enhanced foamed concrete robustness, helped along by the presence of PFF, the enhancement of splitting tensile strengths was accomplished for both materials that were taken into consideration throughout this investigation. PFF will gradually form a fiber grid skeleton inside the foamed concrete as it goes through the process of hardening. This can improve the brittle state of the foamed concrete matrix by governing the growth and propagation of cracks when it is subjected to external tensile stress, preventing the cracks from leading to an explosive failure. It became apparent that the PFF could be uniformly disseminated when the PFF percentage was 3%, which resulted in a growth in the bonding strength between the cement matrix and the PFF. The PFF is dispersed throughout the foamed concrete matrix in a manner that is nearly homogeneous and does not show any significant signs of buildup. In the presence of a tensile load, foamed concrete demonstrates elastic linear tension prior to the onset of plastic deformation, which occurs after the appearance of the first crack in the material. The addition of PFF membrane to foamed concrete, on the other hand, causes the membrane to take on the role of fastening when the foamed concrete cracks. This ensures that the matrix elastic modulus does not immediately drop to zero when the direct boundary strain is reached [ reached ,39,40. W reached ,43,44,453 of foamed concrete was used in the execution of a correlation between the compressive and flexural strengths of the material. For the purpose of this investigation, all curing periods were taken into account. The connection between the flexural and compressive strengths of foamed concrete with various percentages of PFF is demonstrated in The density of 600 kg/m3 density foamed concrete with different PFF percentages is shown in The relationship between the splitting tensile and compressive strengths of 600 kg/m3 densities were made. Compressive, splitting tensile and flexural strengths were assessed. Additionally, the workability, porosity, water absorption, and density of products were evaluated as well. Additionally, the correlations between the considered properties were analyzed. When PFF is added to foamed concrete, spatial networks are formed and cement paste is incinerated to cover the PFF, resulting in reduced spreadability versus foamed concrete without fibers. However, all foamed concrete mixes exhibited spreadabilities greater than 187 mm, indicating a significant capacity for self-flow. In contrast to the control specimen, the dry density of the foamed concrete decreases as the PFF weight fractions rise from 1% to 4%. The control specimen had the highest dry density of foamed concrete, whereas the 4% PFF inclusion product had the lowest density. Due to the intricacy of the compaction process, which produces porous foamed concrete, the dry density decreased at larger weight fractions of PFF. With the presence of PFF, the foamed concrete porosity grows gradually up to 4%. Foamed concrete mixes containing 4% PFF achieved the optimal porosity with a reduction of around 13.9% and 15.9% for 600 and 1200 kg/m3 densities correspondingly. This is most likely because foamed concrete’s cement matrix has strong PFF packing capabilities. As the PFF percentages rose from 1% to 4%, foamed concrete water absorption was increased. With the addition of 4% PFF, the highest water absorption capacity was achieved. When PFF is added to foamed concrete, the fissures are less noticeable and finer than they are in foamed concrete that does not contain PFF. The foamed concrete flexural, compressive, and splitting tensile strengths were increased by the addition of PFF. The ideal percentage of PFF for both densities was 3%. The foamed concrete’s compressive, flexural, and breaking tensile strengths considerably decreased above the 3% PFF. It is difficult to spread the PFF uniformly, and agglomeration is caused if the PFF weight fractions are too large.This laboratory investigation aims to evaluate the possible use of polypropylene fibrillated fiber (PFF) to enhance the foamed concrete engineering properties. With the inclusion of four different PFF percentages , ten mixes of 600 and 1200 kg/m


This study examined the impact of microorganism intrusion on concrete's physical and mechanical properties and efforts to minimize the effect by using nickel waste as a partial substitute for cement. The microorganisms resulted from the natural fermentation of coconut water which intruded into the concrete material, harming the concrete's physical and mechanical properties. Physical and mechanical properties observed were porosity, permeability, and compressive strength. The results indicated that the intrusion of microorganisms into the concrete material increased porosity and permeability and decreased the compressive strength of the concrete. Using nickel slag as a partial cement substitution material with an optimal percentage of 15% was employed to overcome these impacts. It becomes one of the best choices because it is durable, malleable, and able to be fabricated with good physical and mechanical properties, such as low porosity and high compressive strength.Damage to concrete structural components is not only caused by excessive loading but also due to the influence of the surrounding environment . Damage Various ways to overcome the damage of concrete's structural components include; using water-resistant and high-quality concrete by using new material innovations. In the last few decades, new materials in concrete construction have been used, such as industrial waste like fly ash, silica fume, blast furnace slag, and others , 4, 5.2) or abbreviated S chemical compounds .Data included in article/supp. material/referenced in article.The authors declare no competing interests.


The rapid rise of antibiotic resistance is a serious threat to global public health. The situation is exacerbated by the “antibiotics dilemma”: Developing narrow-spectrum antibiotics against resistant bacteria is most beneficial for society, but least attractive for companies, since their usage and sales volumes are more limited than for broad-spectrum drugs. After developing a general mathematical framework for the study of antibiotic resistance dynamics with an arbitrary number of antibiotics, we identify efficient treatment protocols. Then, we introduce a market-based refunding scheme that incentivizes pharmaceutical companies to develop new antibiotics against resistant bacteria and, in particular, narrow-spectrum antibiotics that target specific bacterial strains. We illustrate how such a refunding scheme can solve the antibiotics dilemma and cope with various sources of uncertainty that impede antibiotic R &D. Finally, connecting our refunding approach to the recently established Antimicrobial Resistance (AMR) Action Fund, we discuss how our proposed incentivization scheme could be financed. The Medical Problem. According to the World Health Organization (WHO), antibiotic resistance is a serious threat to global public health  consequences of increased resistance  of the UK established a subscription-based payment model in 2019 Antibiotic (ii)Antibiotic The higher effectiveness of antibiotic We assume that antibiotic We will later turn to costs and chances associated with the development of antibiotics n antibiotics is provided in Appendix A.In this section, we formulate the population-level resistance dynamics for both types of antibiotics X and x denotes the proportion of susceptible individuals and d. For infected individuals, the death rate is c. The antibiotic-induced recovery rates are b of different strains is justified by corresponding empirical findings  model (Keeling and Rohani mentclass2pt{minimmentclass2pt{minimsh). If one wishes to adjust the distribution of the probability of having acquired resistance to a specific antibiotic at a certain time after the initiation of therapy, one can explicitly account for the time since the start of antibiotic therapy and formulate an age-structured version .The performance of the proposed treatment protocols can be compared in terms of different measures including the total stationary populationG(T) and Finally, we may wish to calculate the time at which half of the infected individuals are infected by bacterial strains that are resistant against any antibiotic. This “half-life” of non-resistance isG, half-life of non-resistance, We now compare treatment protocols I–IV for G, G of the 50/50 treatment is smaller than the gain of the 100/0 treatment.We first study differences between the evolution of the wild-type and fully resistant compartments under 50/50 and 100/0 treatment. Figure We complement the above comparison of 50/50 and 100/0 treatments by monitoring the use of antibiotics antibiotics dilemma: Developing a narrow-spectrum antibiotic against resistant bacteria is most attractive for society, but least attractive for companies, since usage should be limited, so that sales are low.Our analysis highlights a fundamental dilemma. Developing a narrow-spectrum antibiotic The situation is further complicated by additional properties of antibiotics development and usage. First, the development costs are enormous, in the range of about one billion USD, and second, the chances to succeed are low. This is true in general for new drugs ). This part is in the spirit of Kremer , as it iresistance premium.The refund is strongly increasing with the use of the new antibiotic for currently resistant bacteria, compared to other newly developed antibiotics for this purpose. This part is the non-resistance penalty.The refund is declining in the use of the antibiotics for non-resistant bacteria, compared to other antibiotics used for this purpose. This part is the The refund for a particular antibiotic is calculated with a formula that satisfies the following three properties:The objective of our refunding scheme is to financially incentivize pharmaceutical companies to reorient their R &D efforts and sales strategy toward narrow-spectrum antibiotics, using a minimum-size antibiotics fund. As we will demonstrate below, all above elements (1–3) are necessary to achieve this purpose.To overcome the antibiotics dilemma and associated complications, we propose a refunding scheme to incentivize the development and appropriate use of antibiotics. The main properties of the refunding scheme are as follows: Several remarks are in order to summarize the application areas of refunding schemes and the challenges arising in the context of antibiotic resistance. First, refunding schemes are widely discussed in the environmental literature. These schemes are meant to provide incentives for firms to reduce pollution  biotech companies cannot raise enough capital in the market to finance the initial development, as financiers prefer immediate over future rewards. Hence, such companies would need to achieve profits above break-even levels in order to be attractive for investors, as the investment is long term.Second, we have neglected many sources of uncertainty about the future revenues the new antibiotic will generate, such as uncertainties about prices, volume, life time (including new antibiotics produced by competitors), and production costs. Such uncertainties will typically call for additional risk premia that have to be added to the break-even condition. Or, in other words, the break-even condition in expected terms has to be achieved in a shorter time period. Typically, such time periods can be in the range of five to ten years or a bit more, but not much longer.To derive the critical refunding parameters, we assume that the parameter entclass1pt{minimaentclass1pt{minimaentclass1pt{minimaentclass1pt{minimamentclasspt{minimamentclasspt{minimamentclasspt{minimaThird, we need to make sure that a narrow-spectrum antibiotic entclass1pt{minimamentclasspt{minimaT after developing and effectively using a narrow-spectrum antibiotic, without (primarily) focusing on the development of broad-spectrum antibiotics.Together, Eqs.  and 12)12) deterWe now focus on an example to illustrate how our refunding scheme can incentivize the development of narrow-spectrum antibiotics. For this purpose, we use the parameters listed in the last column of Table Case IIf mentclasspt{minimaCase IIIf mentclasspt{minimaCase IIIIf mentclasspt{minima For the parameters of Table We first determine the critical refund per unit g to Eq.  and showmentclass2pt{minimFor intermediate consumption of entclass1pt{minimamentclasspt{minimamentclasspt{minimaWithin the orange-shaded regions of Fig. If the expected return associated with the entclass1pt{minimaTo summarize:N antibiotics has the index We now generalize the refunding scheme of the previous sections to account for possible treatment options with more than two antibiotics. We assume that j is The generalized refunding scheme is given byThe break-even conditions can be established as for the model with two antibiotics, but now with adjusted total consumption per antibiotic and with the generalized refunding scheme.Similar to the extension to more than two antibiotics, the refunding scheme can be generalized when more than one pharmaceutical company should be given incentives to pursue R &D on narrow-spectrum antibiotics. In such cases, the refunding parameters have to be adjusted, such that with lower sales volumes for each company, it is still profitable to undertake R &D investments.Using a refunding scheme as designed above in practice requires a series of additional considerations which we discuss in this section. In particular, the scheme must work under a variety of sources of diagnostic, treatment, and R &D uncertainty. It should also promote the development of the R &D ecosystem and should not discourage the development of broad-spectrum antibiotics if it is impossible to develop a narrow-spectrum antibiotic.The development and usage of antibiotics are subject to a variety of uncertainties. In particular, companies may not know at the start of a development process against which type of bacterial strains the drug that might emerge will be effective. Such uncertainties can be taken into account as follows. Suppose a pharmaceutical company starts an R &D process for an antibiotic, but does not know initially whether it will turn out to be broad-spectrum or narrow-spectrum, as this will only become clear during or, in the worst case, at the end of the development process.A possible solution to this issue is setting the value of the refund per unit, With these parameters, starting the R &D investment is profitable and the incentives for a narrow-spectrum antibiotic are maximal. If during the R &D process, a narrow-spectrum opportunity emerges, it will be chosen, since expected profits will be higher than for a broad-spectrum antibiotic. However, the company also breaks even for a broad-spectrum antibiotic if such an opportunity emerges. Hence, investing in R &D remains profitable even if it is impossible at the start to evaluate whether a broad-spectrum or narrow-spectrum antibiotic will result from the R &D investment, as such uncertainty does not generate additional profit risk.The refunding scheme relies on the ability of doctors to rapidly identify the strain of bacteria that caused a certain infection. For a fraction of such treatments, this may be impossible—in particular in emergency situations or when rapid, high-throughput diagnostic devices are unavailable. Yet, certain bacterial strains can already be identified in a few hours by using peptide nucleic acid (PNA) fluorescent in-situ hybridization (FISH) tests, mass spectroscopy, and polymerase chain reaction (PCR)-based methods  and regulatory approval is expected this year or the next.New diagnostic approaches are currently developed by several companies to significantly improve the speed and comprehensiveness of diagnostics of pathogens that cause a disease. These approaches are based on sequencing a targeted part of the DNA/RNA of an infected patient. Then, with machine learning tools, the sequenced data are analyzed and a diagnostic report on the pathogen causing the infection is produced. The aim is to have a diagnosis within less than 24 hours. At the moment, test kits are already available for some multi-drug resistant bacteria  incentives for biotech companies to develop fast diagnostic tests that help identify the sources of infections.A further refinement would be to provide a refund in case a newly developed antibiotic is used and turns out to be effective. Such success targeting would be desirable, but may not be easily implementable in practice. As long as the success rates of an antibiotic that is effective against particular bacterial strains are known or can be estimated with sufficient precision, collecting the usage and bacterial strain data would be sufficient to provide desirable incentives to engage in R &D for narrow-spectrum antibiotics.Both small biotech companies and large pharmaceutical companies play a significant role in developing new antibiotics. The flexibility, nimbleness, and flat organizational structure of smaller biotech companies that specialize in innovative antibacterial treatments can be very effective for the development of new antibiotics. Therefore, while refunding will mostly benefit large pharmaceutical companies, the anticipation of such refunds is expected to also motivate smaller biotech companies to increase their R &D efforts. These smaller companies can expect significant rewards when they sell or license their patents to larger companies. Moreover, in the presence of a refunding mechanism, small biotech companies may receive much more start-up funding both from venture capitalistsA necessary condition for the functioning of our refunding scheme is the existence of an antibiotics fund with sufficient equity to cover R &D incentives. Similar to the recently established AMR Action Fund, which aims at bridging the gap between the pipeline for innovative antibiotics and patients, an antibiotics fund should be started by initial contributions from industry and public institutions. Since it is in the collective self-interest of the pharmaceutical industry to solve the antibiotics dilemma—as otherwise, many other business lines and their reputation will be harmed—, a significant contribution from the industry can be expected to set up the antibiotics fund, as it was the case for the AMR Action Fund. In addition, a continuous refilling of the fund can be achieved by levying a fee (or Pigouvian tax, see Hollis and Maybarduk As in the context of slowing down climate change, the ideal implementation would involve a global refunding scheme administered by an international agency, because reducing resistance is a global public good. However, also similar to implementing climate change policies, worldwide adoption is expected to be extremely difficult and might be impossible to achieve. As a starting point, a set of industrialized countries should agree to a treaty that fails if any of them does not participate. Once an antibiotic fund has been initiated, a treaty should establish the continuing financing of the antibiotics fund and the refunding scheme. The gains would be large and may lead to long-standing self-enforcing incentives to substantially and continuously increase the chances to develop antibiotics against resistant bacteria. If attempts to build a larger coalition fail, the European Union or the USA could take the lead and become the first country, or coalition of countries, that implements a refunding scheme for antibiotics.One could also achieve sufficiently strong incentives to develop new antibiotics without a refunding scheme, by allowing for very high prices when an antibiotic is used against bacterial strains that are resistant against other antibiotics. We do not pursue this approach, since enormously high prices for a treatment would raise ethical and health concerns. For instance, with high prices, certain therapies might then only be affordable to high-income households. Moreover, many infections by bacteria strains may not be treated appropriately and this may fuel the spreading of resistant germs.The rapid rise of antibiotic resistance is a serious threat for global public health. No new major class of antibiotics has been registered or patented for more than three decades see Fig. . One impn antibiotics. We then used this framework to develop a market-based refunding scheme that can solve the antibiotics dilemma. That is, it can incentivize pharmaceutical companies to reallocate resources to antimicrobial drug discovery and, in particular, to the development of narrow-spectrum antibiotics that are effective against multiresistant bacterial strains. We describe how such a refunding scheme can cope with various sources of uncertainty inherent to R &D for antibiotics, as well as with diagnostic and treatment uncertainties.We introduced a new framework to mathematically describe the emergence of antibiotic resistance in a population that is treated with Our study opens up several avenues for future research. One worthwhile direction for future work is to combine our methods with control theory (Chehrazi et al.


Epoxy resin, CFRP (Carbon Fiber Reinforced Polymer) sheet, and concrete flexural specimens are selected to study the durability of carbon fiber strengthened cementitious materials in a cold region. Two exposure environments, chloride immersion and salt-freeze coupling, are set up, and the mechanical deterioration is discussed utilizing a microscopic observation mechanical test and finite element analysis. The damage to the epoxy resin, CFRP sheet, and concrete exerts a more severe performance degradation in the salt-freeze coupling environment when compared with the chlorine salt immersion environment. The freeze–thaw action destroys the bonding surface of CFRP and concrete based on the microscope observation. The flexural strength of the specimens strengthened with CFRP is 3.6 times higher than that of the specimens without CFRP, while the degradation rate is only 50%. These observations show that the strengthened CFRP effectively improves the cementitious material’s flexural performance in the cold region. The finite element model of epoxy and CFRP subjected to chloride immersion and salt-freeze coupling environment is established. The degradation formula of bond performance between CFRP and concrete is proposed. In addition, the flexural mechanical numerical model is established with and without CFRP strengthened concrete, respectively. Research results provide a technical reference for applying CFRP reinforced cementitious materials in a cold region. Concrete buildings are simultaneously subjected to the coupling effect of chloride erosion and freeze–thaw cycle  in the marine environment of the cold region. In the salt-freeze coupling environment, concrete buildings deteriorate seriously, making it challenging to ensure their performance and safety. The actual service life of buildings is far from reaching the designed service life ,2. The cThe durability of CFRP reinforced concrete structures is influenced by the following factors: the durability of concrete materials, the durability of epoxy resin, the durability of CFRP, and the durability of the interface between CFRP and concrete. However, most researchers only discussed the durability of the above objects in a single chloride salt immersion environment or a single freezing-thawing environment. Therefore, limited research focus on a comprehensive study of the coupling effect of influencing factors .The carbon fiber sheet is presoaked with epoxy resin adhesive on both sides and bonded along the tensile direction for the concrete structure strengthened with CFRP. The CFRP and concrete are stressed together, giving full play to the compressive performance of the concrete and the high tensile performance of the CFRP. This improves the bearing capacity of the concrete structure and achieves the purpose of strengthening the original concrete structure. The factors influencing stress transfer between carbon fiber sheets and concrete include the interface bonding performance between CFRP and concrete and the mechanical properties of the epoxy resin itself. Therefore, it is necessary to study their durability in a chloride environment. Lu et al.  studied CFRP itself has a tremendous advantage of tension, which can improve the bearing capacity of the concrete structure. Therefore, it is necessary to study the durability of CFRP chloride salt and salt-freeze coupled environment, respectively. Hong et al.  studied The durability of CFRP reinforced cementitious materials also needs to be further investigated. Nasser et al.  studied The durability of epoxy resin, CFRP sheet, and cementitious materials specimens is investigated in this study. Two corrosive environments are set up: the chlorine salt immersion and the salt-freeze coupling environment. The damage degree of the exposed environment to the above specimens is investigated by microscope observation. The tensile properties of epoxy resin and CFRP sheet (including the ultimate tensile strain of tensile strength and stress–strain curve) are measured by tensile test, and the degradation of the tensile properties of the sheet in the exposed environment is discussed. The flexural properties  of specimens subjected to bending are measured by a four-point flexural tension test. In addition, the degradation law of flexural properties of specimens subjected to bending is discussed. A finite element model is proposed to analyze the internal force distribution characteristics, failure modes, and mechanical properties.A unidirectional carbon fiber sheet with a thickness of 0.167 mm is used in the test, as shown in The mix ratio of epoxy resin and curing agent is 2:1, and curing for 7 days at room temperature of 25 °C. The epoxy specimen size and strain gauge layout point are shown in Concrete design strength is 30 MPa in this test, and its composition materials include water, cement, sand, and gravel, as shown in The unreinforced and CFRP reinforced concrete prism specimens are selected, and the dimension of a specimen is 100 mm width by 100 mm height by 400 mm length. A notch of 30 mm height is prefabricated on the midspan’s tension side to guarantee bending failure, and a rectangle shape of 100 mm × 300 mm CFRP strip bonded on the tensile side of CFRP reinforced concrete specimen, as shown in There are two kinds of exposure environments: chlorine immersion and salt-freeze coupling effect, respectively. The epoxy resin, CFRP sheet, and concrete specimens are grouped and numbered when subjected to various environments and duration. The definition of numbering information is shown in A digital microscope is used to observe the damage degree of epoxy resin, CFRP sheet, and concrete specimens, respectively. The typical epoxy resin of EPND, EPSI-400, and EPSF-100 is selected to observe its surface deterioration. Similarly, CFRPND, CFRPSI-400, and CFRPSF-100 are selected for CFRP; URFND, URFSI-400, and URFSF-100 are selected for the unreinforced specimen; and RFND, RFSI-400, and RFSF-10 are selected for the reinforced specimen, as shown in In order to investigate the mechanical performance deterioration in a corrosive environment, tensile tests are carried out on epoxy resin and CFRP sheets. The tensile test process is composed of mechanical control and data acquisition system, and the loading rate is 2 mm/min, as shown in The microstructure of epoxy resin is shown in Similarly, All these observations can be explained; the epoxy resin contained an ether bond due to a chemical reaction between resin and curing agent. Some uncured epoxy resins contain hydrophilic hydroxyl groups, and curing agents contain tertiary amines and a small amount of incomplete primary and secondary amines. These groups will be hydrolyzed to varying degrees in a salt solution, which leads to some depressions on the surface of epoxy resin and CFRP sheet. Furthermore, low temperature and chlorine ion environment can destroy the inner structure of epoxy resin, and the internal micro-cracks occur. The epoxy resin deterioration is derived from group hydrolysis and chloride ions erosion in the chlorine salt immersion environment. However, the coupled effect of the group hydrolysis, chloride ion erosion, and freeze–thaw cycles caused the damage to epoxy resin in the salt-freeze environment. In addition, the microcracks caused by freeze–thaw cycles promote the penetration of sodium chloride solution, leading to further damage to epoxy resin and CFRP sheet.The appearance and morphology of the epoxy resin and CFRP sheet are observed in the tensile test. The tensile strength and ultimate tensile strain of epoxy resin and CFRP sheet are shown in The entire cement mortar matrix surface is observed for URFND and RFND specimens without environmental effect, as shown in The failure mode of URFND is shown in The failure modes of the reinforced specimen are different in various exposure to environmental conditions. The failure mode is inclined section failure for RFND, and the upper and lower ends of the inclined crack are located near the loading and support points, respectively. As a result, the CFRP sheet and interface are not damaged, as shown in For unreinforced bending specimens, the cracks initially occurred at the notch location  and thenff is flexure strength (MPa); F is specimen failure load (N); l is distance between supports (mm), l = 300 mm; b is specimen width (mm), b = 100 mm; and h is specimen height (mm), h = 70 mm.The bending strength of specimens can be calculated by Formula (1) as follows:The flexural strength and deflection of specimens subjected to bending are shown in After the salt-freeze coupling effect, the unreinforced and strengthened bending specimens exert a similar decrease trend. The whole concrete structure becomes loose under the repeated action of frost heaving force, resulting in a higher reduction than in the chlorine salt environment. The bond force between CFRP and concrete is also the main factor affecting the mechanical properties of the flexural specimens. The degradation of the bond force reduces the bearing capacity of the flexural specimens in the salt-freeze coupling environment.For CFRP reinforced flexural specimens, the tensile strain of CFRP strips at various positions is shown in CFRPE is modulus of elasticity for CFRP tension (MPa); and CFRPε is ultimate tensile strain for CFRP.EPE is modulus of elasticity for epoxy resin tension (MPa); and EPε is ultimate tensile strain for epoxy resin.ABAQUS r2021x is used to simulate the tensile process of epoxy resin adhesive and CFRP sheet. The CFRP is regarded as a linear elastic material, and only the tensile stress in the fiber direction is considered in the finite element analysis. The CFRP is considered a failure when the CFRP reaches the ultimate tensile strain. There is no difference in damage form concerning different chlorine salt environments. Thus, the internal stress distribution and plasticizing effect can be ignored. The linear elastic model is selected to consider the limit tensile strength and the change in the chlorine salt environment. Similarly, the mechanical properties fitting curve equation is described above for CFRP and epoxy resin in a chloride environment, and the specific parameters of constitutive models are determined. The expressions are as follows:The epoxy resin finite element model is a three-dimensional solid structure, and the mesh division is shown in The CFRP finite element model is a three-dimensional plane structure, and the mesh division is shown in Reinforcement sections are reserved at both ends of epoxy resin and CFRP models. In order to approach the actual situation, the reinforcement The failure modes of epoxy resin in different environments are the same no matter the environmental effect. tσ is concrete tensile stress; εt is concrete tensile strain; dt is evolution parameters of concrete uniaxial tensile damage; cσ is concrete compressive stress; εc is concrete ultimate compressive strain; dc is damage evolution parameters of concrete under uniaxial compression; and E is elastic modulus of concrete.According to ‘Concrete Structure Design’ (GB50010-2010), the CDP model and the determination method of concrete material parameters under uniaxial loading are used to simulate the mechanical behavior in this study. The stress–strain relationship of concrete under uniaxial tension and compression can be calculated by Equations (4) and (5), respectively. Furthermore, the concrete degradation law of mechanical properties is proposed under a salt-freeze coupling environment, and the concrete material is also simulated based on this law ,25.(4)σFor the flexural specimen model of concrete, the constitutive relation of CFRP and the interface between CFRP and concrete are consistent with the axial compression specimen model. Therefore, the C3D8R solid element is used to simulate concrete material, and the S4R shell element is used to simulate CFRP material. The mesh division of concrete and CFRP is shown in K is bond stiffness (N/mm3); τ is bond stress (MPa); ε is relative slip distance (mm); and G is fracture energy (N/mm).nε is normal strain of bond layer; n0ε is limit normal strain of bond layer; sε and tε are tangential strain of bond layer; and s0ε and t0ε are limit tangential strain of bond layer.The ABAQUS software provides two methods for establishing a cohesion model based on traction–separation law: cohesive element and cohesive surface interaction method. Most studies often use the latter ,27. For τ is bond strength without deterioration (MPa); Itτ is bond strength after t hours of chlorine salt immersion (MPa); and FTnτ is bond strength after n times of salt freeze coupling (MPa).The degradation law of the bond force between CFRP and concrete in different environments is shown in Equations (9) and (10).The underlying block’s four degrees of freedom  are fixed to keep the loading scheme consistent with the experiment. Similarly, the upper block is coupled with the reference point RP-1, and all five degrees of freedom  of the reference point are fixed to obtain output load and displacement. Hard contact and no friction are used between concrete and the loading point. The reference points of the above two loading points are applied concentrated linear force in the Z direction, which is converted into a stress rate of 0.05 MPa/s.The stress and crack damage distribution of URFND, URFSI-400, and URFSF-100 are shown in The stress distribution, prefabricated crack damage, and CFRP-concrete interface bond damage of RFND, RFSI-400, and RFSF-100 are shown in (1)Groups of the hydrolysis reaction and the erosion of chloride ions causes the apparent structure damage of epoxy resin and CFRP sheet. The coupling effect of chloride ion erosion and the freezing-thawing cycle leads to the further aggravation of the damage to the sheet. The apparent structural damage directly leads to the decrease of the tensile property of the sheet. The tensile strength exerts a higher degradation rate in the salt-freeze coupling environment when compared with the chlorine salt immersion environment. For epoxy resin, the degradation rate of tensile strength in a salt-freeze coupling environment is 327% higher than that in a chloride salt environment, while the value is 78% for the CFRP sheet.(2)The finite element model of the tensile mechanical model is developed for epoxy resin and CFRP. The simulated and experimental values for tensile strength have a good agreement; the maximum error of epoxy resin is only 1.24%, and of CFRP is only 1.77%.(3)Concrete is damaged by the crystallization extrusion pressure caused by the precipitation of sodium chloride crystal in a chlorine immersion environment. The specimens’ damage in the salt-freeze coupling environment is severe, and the flexural strength degradation rate is higher than in the chlorine salt immersion environment. For the specimens without reinforcement, the flexural strength degradation rate in the salt-freeze coupling environment is 187% higher than that in the chlorine-salt immersion environment. However, the degradation rate reaches 202% for the reinforcement specimens.(4)The degradation law of bond performance between CFRP and concrete is discussed, and a finite element mechanical model is established. The maximum error between simulation and experimental data is only 5.52%, and the failure mode is basically consistent with the test data. It can be explained that the CFRP improved the tension capacity of the specimen, which inhibits the development of prefabricated cracks and improves the bearing capacity.


What is the rate of exposure to antibiotics and the incidence of early-onset sepsis (EOS) and sepsis-associated mortality among late-preterm and full-term newborns?In this cross-sectional study of 757 979 neonates born in 13 networks from 11 countries, 2.86% received antibiotics during the first postnatal week . The incidence of EOS was 0.49 cases per 1000 live births , and the EOS-associated mortality rate was 3.20%.Early postnatal antibiotic use was high compared with the rate of sepsis and varied across networks, suggesting it could be lowered safely. This cross-sectional study compares early postnatal exposure to antibiotics, incidence of early-onset sepsis, and mortality among different networks in high-income countries. Appropriate use of antibiotics is life-saving in neonatal early-onset sepsis (EOS), but overuse of antibiotics is associated with antimicrobial resistance and long-term adverse outcomes. Large international studies quantifying early-life antibiotic exposure along with EOS incidence are needed to provide a basis for future interventions aimed at safely reducing neonatal antibiotic exposure.To compare early postnatal exposure to antibiotics, incidence of EOS, and mortality among different networks in high-income countries.This is a retrospective, cross-sectional study of late-preterm and full-term neonates born between January 1, 2014, and December 31, 2018, in 13 hospital-based or population-based networks from 11 countries in Europe and North America and Australia. The study included all infants born alive at a gestational age greater than or equal to 34 weeks in the participating networks. Data were analyzed from October 2021 to March 2022.Exposure to antibiotics started in the first postnatal week.The main outcomes were the proportion of late-preterm and full-term neonates receiving intravenous antibiotics, the duration of antibiotic treatment, the incidence of culture-proven EOS, and all-cause and EOS-associated mortality.A total of 757 979 late-preterm and full-term neonates were born in the participating networks during the study period; 21 703 neonates , including 12 886 boys (59.4%) with a median (IQR) gestational age of 39 (36-40) weeks and median (IQR) birth weight of 3250 (2750-3750) g, received intravenous antibiotics during the first postnatal week. The proportion of neonates started on antibiotics ranged from 1.18% to 12.45% among networks. The median (IQR) duration of treatment was 9 (7-14) days for neonates with EOS and 4 (3-6) days for those without EOS. This led to an antibiotic exposure of 135 days per 1000 live births . The incidence of EOS was 0.49 cases per 1000 live births . EOS-associated mortality was 3.20% . For each case of EOS, 58 neonates were started on antibiotics and 273 antibiotic days were administered.The findings of this study suggest that antibiotic exposure during the first postnatal week is disproportionate compared with the burden of EOS and that there are wide (up to 9-fold) variations internationally. This study defined a set of indicators reporting on both dimensions to facilitate benchmarking and future interventions aimed at safely reducing antibiotic exposure in early life. Large data sets are required to compare antibiotic use and monitor time trends in networks and countries using different strategies to prevent and treat EOS, to provide a basis for interventions aiming at safely reducing neonatal antibiotic exposure.The Antibiotic Exposure for Suspected Neonatal Early-Onset Sepsis (AENEAS) study is an international, cross-sectional, retrospective study investigating exposure to intravenous antibiotics in the first postnatal week in late-preterm and full-term neonates. Thirteen networks from 11 high-income countries contributed to the study (eTable 1 in STROBE) for Newborn Infection (STROBE-NI) guideline.16A network was defined by use of a common strategy for preventing and managing suspected EOS and the ability to provide data on at least 25 000 live births within the 5-year study period. Networks from Europe, North America, and Australia were eligible if they met the expected sample size  or cultures considered as a contamination by clinicians with a decision to treat with antibiotics for less than 5 days. Cultures with growth of coagulase-negative staphylococci (CoNS) and antibiotic therapy for more than 5 days were considered proven infection. Neonates without proven EOS (no EOS) were those who received antibiotics but did not have a diagnosis of EOS. Indication for antibiotic treatment was obtained from electronic medical records and patients’ records. Neonatal death was defined as death before discharge or death before 28 days for patients who were hospitalized for more than 28 days. EOS-associated mortality was defined as death within 28 days after a positive blood or CSF culture. The cause of death was reported as free text and was then classified into categories  by the principal investigators.EOS was defined as culture-proven EOS, by positive blood and/or cerebrospinal fluid (CSF) culture, within the first postnatal week.18The proportion of newborns treated with antibiotics was calculated by dividing the number of newborns receiving at least 1 dose of intravenous antibiotics within the first postnatal week by the number of live births. Duration of antibiotic therapy was defined as calendar days with at least 1 dose of antibiotics. Antibiotic exposure was calculated as the sum of antibiotic days of each treated newborn divided by the number of live births and was reported as the number of antibiotic days per 1000 live births. Incidence of EOS was defined as the rate in all live-born neonates. Incidence was reported for all EOS episodes and for episodes excluding CoNS. Mortality was defined as all events of death for all live-born neonates independent of antibiotic therapy and EOS , and in subgroups (EOS and no EOS). We analyzed the whole cohort and each network separately. We conducted subgroup analyses of data from Stockholm County, Sweden, a large population-based network with the lowest exposure to antibiotics, stratifying data by level of care at place of birth.We presented descriptive statistics as median (IQR) for continuous variables and as frequencies (percentages) with 95% CIs for categorical variables. We calculated odds ratios (ORs) with 95% CIs using the Mantel-Haenszel method for stratification, as measures of association where binary outcomes were compared between groups. For the comparison of quantitative outcomes between groups, we calculated median differences with 95% CIs. If appropriate, these effect measures were calculated in a stratified manner, using network as strata. Correlations between quantitative metrics were assessed using Spearman correlation coefficient. We performed analyses using R version 4.0.2 . Data were analyzed from October 2021 to March 2022.Escherichia coli (62 of 375 cultures [17%]) , including 12 886 boys (59.4%) with a median (IQR) gestational age of 39 (36-40) weeks and median (IQR) birth weight of 3250 (2750-3750) g, were started on intravenous antibiotics within the first postnatal week . The medThe number of deaths for all live births was 622, leading to an all-cause mortality rate of 0.82 per 1000 live births . The all-cause mortality rate was 1.10%  in all neonates treated with antibiotics, 3.20%  in those with EOS, and 1.06%  in those without proven EOS. Among EOS cases, mortality was 7.7%  in late-preterm and 2.0% in full-term newborns . Culture-proven EOS accounted for 1.9% of all-cause mortality. Altogether, 1 neonate died from EOS per 63 165 births .r = 0.77; 95% CI, 0.39-0.93 for all EOS episodes; r = 0.69; 95% CI, 0.23-0.90 for EOS episodes without CoNS)  .Over time, when analyzing data without Norway (which provided only 2015-2018 data), the proportion of neonates treated with antibiotics decreased from 3.4%  in 2014 to 2.7%  in 2018, with no change in the duration of treatment  in neonates born in level I and II facilities and 63 antibiotic days per 1000 live births  in neonates born in level III and IV facilities  proportion of all live births started on antibiotics, (2) duration of therapy, and (3) number of antibiotic days per 1000 live births. The proportion of neonates started on antibiotics in our study is at the low end of the up to 14% described in the literature.27 Three of the 13 networks reported treatment rates below 2% with the lowest rate of 1.18% in Stockholm County. To our knowledge, this is the lowest rate reported in literature. Most recent publications on the proportion of neonates treated with antibiotics reported on the impact of using the neonatal EOS calculator, a risk stratification and decision-making tool that recommends starting antibiotics when the estimated risk of EOS is 3 cases or more per 1000.17 Although the proportion of neonates started on antibiotics was reduced by this tool, the lowest rate of antibiotic exposure reported after implementing the EOS calculator is 3.0%.27 In our study, the only network using the EOS calculator decreased antibiotic treatment rates, but treatment rates after the intervention remained above all other networks. Seven networks used the serial physical examination approach, a strategy that has been associated with safe reduction of antibiotic use.30Precise data on antibiotic utilization are needed to improve antimicrobial prescription practices promoting quality of care and patient safety. Given the specificities of neonatal care and the importance of AMS in early life, relevant indicators are required to identify antibiotics utilization practices that should be promoted or avoided.31 showing wide variations in antibiotic use across neonatal units but no correlation between the proportion of neonates exposed to antibiotics and the incidence of EOS at each site. Population-based networks include all neonates born in a given geographical area . In contrast, hospital-based networks include only neonates born at participating hospitals and are, therefore, not representative of a region or a country. Moreover, comparisons between hospital-based networks are limited by the specific patients’ case mix at each institution that may influence the risk of EOS and antibiotic prescription patterns. In our study, tertiary care hospitals (levels III and IV) which are characterized by higher patient acuity and volume, were overrepresented in hospital-based networks. To address these limitations, we performed analyses stratifying neonates born in Stockholm County  by the level of care at the place of birth. The burden of disease and the burden of treatment were higher for neonates born in level III and IV facilities compared with level I and II facilities. This is not unexpected given the mission of level III and IV facilities to take care of the most vulnerable and most ill patients. However, in Stockholm County, the proportion of neonates treated with antibiotics and number of antibiotic days per 1000 live births was lower both in level I and II and in level III and IV facilities compared with all other networks. This indicates that antibiotic exposure can be minimized even in high-risk tertiary care facilities, without increasing all-cause mortality.Networks performed differently at minimizing the proportion of neonates started on antibiotics, limiting the duration of treatment in those without proven infection, and at preventing and/or diagnosing EOS. Networks with higher antibiotic exposure also had higher EOS incidence. This contrasts with findings from studies32 but could not identify a common pattern of approaches associated with a lower burden of disease and/or treatment. Therefore, we are not able to generate a hypothesis regarding which strategy may work best. We speculate that education of staff, leadership, and AMS culture might have an important impact on clinical decision-making.34We observed substantial heterogeneity among networks regarding the strategies used to prevent EOS and manage newborns at risk of EOS23 Culture-proven EOS accounted for 1.9% of all-cause mortality, and all-cause mortality was more frequent than EOS. This is in line with literature showing that perinatal asphyxia and congenital malformations cause a greater number of deaths in late-preterm and full-term neonates than sepsis.35Given the relatively low incidence of EOS and sepsis-associated mortality in late-preterm and full-term newborns, the burden of treatment is disproportionate to the burden of disease. This imbalance is bigger in full-term neonates, who have a lower sepsis-related mortality than late-preterm neonates.36 focused mainly on 1 dimension and/or did not provide important baseline information, such as the proportion of all live-born neonates treated with antibiotics and/or the duration of treatment. To facilitate benchmarking and guide clinicians regarding AMS and future research, we propose a new minimal standard including 7 key indicators for reporting data on EOS and antibiotic use: (1) incidence of culture-proven EOS per 1000 live births, (2) EOS-associated mortality rate, (3) proportion of neonates started on antibiotics per 100 live births, (4) duration of antibiotic therapy, and (5) number of antibiotic days per 1000 live births, and the whole study population needs to be described by (6) gestational age and (7) all-cause mortality.Large cohorts reporting on the burden of disease along with the burden of treatment are scarce. Previous studies4 Given that more than 95% of antibiotic courses initiated within the first postnatal week were started within the first 3 days, it is unlikely that the choice of a 7-day rather than a 3-day cutoff affected our results.Although the strengths of our study are grounded in the large, international, high-quality data set promoting new standards to quantify the burden of disease along with the burden of treatment, our study has limitations. Owing to the retrospective design, we could not collect data on prenatal exposure to antibiotics, risk factors for EOS, biomarkers, and long-term morbidity. In addition, data on management strategies are descriptive, whereas clinical practice may substantially deviate from guidelines. The heterogeneity between and within networks and the selection bias of participating networks limits the generalizability of our findings. Population-based networks are representative of a region or a country, but hospital-based networks depend on the level of care and case selection at each site. The difficulty in distinguishing CoNS-related infections from contamination is a limitation that we addressed by showing results with and without CoNS-related infections. There is no clear-cut difference in the definition between perinatal (EOS) vs nosocomial (late-onset) infections. Including neonates started on antibiotics within the first postnatal week leads to some overlap between the 2 conditions. From an AMS perspective, this has the advantage of capturing all antibiotic courses started within a well-defined period.The burden of treatment is considerable in comparison to the burden of disease, and there are wide variations internationally. We defined a set of indicators reporting on both dimensions to facilitate benchmarking and guide AMS programs and future research. A neonatal antibiotic treatment rate less than or equal to 1% appears achievable. Decreasing unwarranted neonatal antibiotic exposure may help reduce the risk of antimicrobial resistance and preserve the developing microbiome to improve long-term health.


Cryotherapy is widely applied to relieve pain and improve functional outcomes after total knee arthroplasty (TKA). New cryotherapy devices have recently been developed to guarantee a fixed temperature for a prolonged time. Therefore, we conducted a systematic review and meta-analysis to compare continuous cryotherapy and traditional cryotherapy (ice bag or gel pack) for patients after TKA.This study was conducted according to a predefined protocol registered on PROSPERO. Two independent reviewers performed an electronic database search of PubMed, Embase, Cochrane, Web of Science, Google Scholar, and ClinicalTrials.gov. Dichotomous outcomes were reported as risk difference (RD) with 95% confidence intervals (CIs), and continuous outcomes were reported as mean difference (MD), or standardized mean difference (SMD) with 95% CIs.P = 0.30), analgesics consumption , postoperative range of motion , swelling of the knee joint, blood loss, change in hemoglobin, or transfusion rate. Meanwhile, there were no differences in length of hospital stay  and adverse events . In addition, continuous cryotherapy leads to extra costs and resources than traditional cryotherapy.Seven trials enrolling a total of 519 patients were included. There were no differences in pain intensity (MD: −0.54, 95% CI: −1.55 to 0.47; Continuous cryotherapy does not appear to offer significant benefits for TKA when compared with traditional cryotherapy. Based on currently available evidence, traditional cryotherapy is still recommended as continuous cryotherapy is not cost-effective. Further well-designed studies with larger sample sizes are warranted to further confirm these preliminary results.PROSPERO Registration: Identifier [CRD42022308217]. DespCryotherapy, also known as cold therapy, was utilized for inflammation and infection treatment as early as 3,000 BC, and was utilized for anesthesia before operations and amputations for its analgesic and numbing effects in the 1800s , 12. At A broad scope of the literature has suggested that the volume of randomized controlled trials (RCTs) specifically focusing on continuous cryotherapy vs. traditional cryotherapy has increased, and findings are conflicting –22. The 2.http://www.cochrane-handbook.org) and completed according to a predefined protocol, which has been listed on the International Prospective Register of Systematic Reviews   .2.1https://clinicaltrials.gov/) and checked the reference lists of all included full-text articles and previous systematic reviews to identify any additional eligible studies. Corresponding authors of included articles were contacted, where possible, to obtain detailed information or numerical data.We searched the following electronic bibliographic databases from inception to March 2,022 to capture all recent relevant studies: PubMed, Embase, The Cochrane Library (Cochrane Database of Systematic Reviews), Web of Science, and Google Scholar,. We performed electronic searches using exploded Medical Subject Headings (MeSH) terms with corresponding keywords. The search was broad and applied no language restriction. A detailed description can be found in 2.2Two investigators independently conducted the initial electronic databases search and carefully reviewed all yielded records for inclusion using pre-determined eligibility criteria. All records were screened by title, abstract, and keywords for possible inclusion, and subsequently, identified as “included”, “excluded”, or “required further retrieval” to identify eligibility. No language or publication database filter was applied. Any discrepancies were resolved through discussion by the review team.(i)Population: adult patients undergoing TKA;(ii)Intervention: received continuous cryotherapy (without compression) after TKA;(iii)Comparison: received traditional cryotherapy after TKA;(iv)Outcomes: reporting at least one of the outcomes of interest listed below;(v)Study type: RCT.Exclusion criteria were non-RCT interventional studies, observational studies, conference abstracts, editorials, correspondence, expert opinions, case series or reports, and unavailable full texts.The inclusion criteria were:2.3Two independent reviewers extracted details pertaining to the participants from each included trial. The following data were extracted from each included study: first author; year of publication; study location; publication journal; study design; clinical settings; study population; demographic data; intervention management; control management; outcomes of interest. These extracted data were entered into a standardized data extraction form. When the information was unclear or missing, we attempted to contact the corresponding authors of the original studies. The differences in the extracted data were discussed and resolved by referring to the original article by the panel of all the reviewers. The main outcomes of interest were the efficacy, safety, and cost-effectiveness of continuous cryotherapy when compared with traditional cryotherapy. In detail, the primary outcomes include pain intensity, analgesics consumption, postoperative range of motion (PROM), and swelling of the knee joint; while the secondary outcomes include blood loss, change in hemoglobin, transfusion rate, adverse events, length of hospital stay, and cryotherapy costs.2.4via discussion and consensus.Two reviewers independently evaluated the risk of bias of each study using the assessment tool from the Cochrane Handbook . The maj2.5via three means: visual inspection of overlapping confidence intervals, the statistical heterogeneity across studies quantified using I2 statistics, with P ≥ 0.05 considered statistically non-significant. Heterogeneity will be considered to be substantial if the I2 value > 50%. All P values were two-sided, and a P value < 0.05 was considered to be statistically significant evidence.This meta-analysis was performed using Review Manager version 5.3 (Nordic Cochrane Center) for all prespecified outcomes if three or more studies reported the outcome . The ris3.3.1In total, 1,387 articles were obtained from the electronic search strategy, with an additional 16 articles identiﬁed through other resources. After the removal of duplicates and irrelevant references, 35 publications were thought to be potentially eligible for inclusion and further assessed for eligibility. Overall we excluded 28 publications for not meeting the inclusion criteria, and seven RCTs were included. The flow diagram with the number of and reasons for exclusions at each stage is provided in 3.2n = 263) and traditional cryotherapy (n = 256). These studies were published between 2012 and 2019, with a sample size ranging from 44 to 100. Notably, the application protocols between the continuous and traditional cryotherapy groups differed significantly with respect to the applied time and intervals, and the difference is even more significant among studies.The characteristics of included studies can be found in the study characteristics tables , 2. Seve3.3No trials were considered to be at low risk of bias. Three studies were judged to be at high risk of bias, and four studies were felt to be at unclear risk of bias , 3. More4.4.14.1.1n = 241 vs. n = 234 in the continuous cryotherapy group and traditional cryotherapy group, respectively). Meta-analysis was performed on studies that reported a pain score for participants at 48 h postoperatively (P = 0.30). A high level of heterogeneity was observed (I2 = 96%). Data for analgesics consumption were reported by three trials that recruited 268 patients . SMD was used as there were differences in the calculating conversations of analgesics consumption. There was no statistically significant difference in analgesics consumption between the continuous cryotherapy group and the traditional cryotherapy group  (I2 = 92%).Data for pain intensity were reported by six trials that recruited 475 patients (ratively . There w = 0.43) . A high 4.1.2n = 241 vs. n = 234 in the continuous cryotherapy group and traditional cryotherapy group, respectively). There was no statistically significant difference in the PROM between the continuous cryotherapy group and the traditional cryotherapy group  (I2 = 84%).Data for PROM were reported by six trials that recruited 475 patients ( = 0.84) . A high Knee circumference is another parameter that reflects swelling of the knee joint and was reported in three trials. Meta-analysis was not performed as two trials reported the postoperative knee circumference while one trial reported the difference in knee circumference. Overall, all three trials found no statistically significant difference in knee circumference between the continuous cryotherapy group and the traditional cryotherapy group.4.24.2.1Only one study reported blood loss and there was no statistically significant difference between the continuous cryotherapy group and the traditional cryotherapy group.4.2.2Three trials reported data for hemoglobin changes, and meta-analysis was not performed because two trials reported the preoperative and postoperative hemoglobin while one trial reported the change in hemoglobin. Only one study detected a statistically significant difference between the continuous cryotherapy group and the traditional cryotherapy group .4.2.3Data for transfusion rate was reported by three trials, and meta-analysis was not performed as two trials reported the number of transfusions while one study reported the number of units of allogeneic blood transfusions. Overall, all three trials found no statistically significant difference in transfusion rate between the continuous cryotherapy group and the traditional cryotherapy group.4.2.4n = 187 vs. n = 178 in the continuous cryotherapy group and traditional cryotherapy group, respectively). There was no statistically significant difference in the length of hospital stay between the continuous cryotherapy group and the traditional cryotherapy group  (I2 = 84%).Data for the length of hospital stay were reported by four trials that recruited 265 patients ( = 0.07) . A high 4.2.4n = 184 vs. n = 178 in the continuous cryotherapy group and traditional cryotherapy group, respectively). There was no statistically significant difference in the incidence of adverse events between the continuous cryotherapy group and the traditional cryotherapy group   .4.2.4. reported that the cost of continuous cryotherapy is $ 520, Schinsky et al. reported that continuous cryotherapy costs $97.34 than traditional cryotherapy per patient, while Karaduman reported that they found no significant additional costs associated with the use of continuous cryotherapy.Data for cryotherapy costs were reported by three trials. Thienpont et al5.5.1Our meta-analysis comprehensively and systematically reviewed the currently available literature, and the study results suggest that continuous cryotherapy does not appear to offer significant clinical benefits for TKA compared with traditional cryotherapy. There were no significant differences in pain intensity, analgesics consumption, postoperative range of motion, swelling of the knee joint, blood loss, change in hemoglobin, transfusion rate, length of hospital stay, and adverse events. In addition, continuous cryotherapy may lead to extra costs and resources than traditional cryotherapy.5.2Although TKA shows long-lasting clinical and structural improvement for the management of severe osteoarthritis, patients in the immediate postoperative period are often associated with acute pain, hidden bleeding, severe edema, and reduced range of motion. Cryotherapy has been shown to appreciably reduce the intraarticular temperature, especially in the knee, blood flow by vasoconstriction, the local inﬂammatory reaction, postoperative bleeding and swelling, pain transmission, and the length of hospital stay –29. In tOn the other hand, as healthcare providers, it is our duty to appropriately allocate finite resources to evidence-based approaches that are efficacious in an era of increasing expenses. Therefore, apart from the convenience that continuous cryotherapy devices provide prolonged continuous cooling and do not need to change the ice/gel pack, which does not offer any extra clinical advantage for patients undergoing TKA when compared with traditional cryotherapy . HoweverIn addition, the current available RCTs only applied continuous cryotherapy and traditional cryotherapy during hospitalization and not after discharge, which is a relatively short duration, and the minimal difference between continuous cryotherapy and traditional cryotherapy may not be detected , 29. The5.3To the best of our knowledge, this is the first systematic review and meta-analysis that systemically and comprehensively reviewed currently available evidence to compare the efficacy, safety, and cost-effectiveness of continuous cryotherapy vs. traditional cryotherapy for TKA.Our study also has several potential limitations. First of all, in more than half of included studies, neither patients nor healthcare providers were blinded to group allocation and outcome assessment, hence, subjective assessments such as pain level are subject to potential bias. Second, the comparison of continuous cryotherapy vs. traditional cryotherapy was specialized to the TKA procedure, which may not be generalizable to other surgical procedures, such as arthroscopic surgery. Third, substantial heterogeneity across studies was noticed, which may be explained by the considerable difference in cryotherapy protocols. Lastly, almost all eligible trials included in the meta-analysis had relatively modest sample sizes (<100 patients), and overestimation of the treatment effect is more likely than in larger trials.6.Our systematic review and meta-analysis suggested that continuous cryotherapy showed no superiority in reducing pain intensity, analgesics consumption, swelling, blood loss, length of hospital stay, and improving ROM compared with traditional cryotherapy in the acute postoperative setting after TKA. Continuous cryotherapy may further lead to extra costs and resources, so the currently available evidence does not support continuous cryotherapy could be added as an adjunct therapy. Additional well-designed studies with larger sample sizes are needed to confirm these preliminary results.


E. coli resistance. Therefore, based on our important findings in Finland, methods other than the restriction of antibiotic use, such as new anti-infective innovations, including antibacterials, are needed as soon as possible to tackle this major global health threat—a silent pandemic.The objective of this study was to describe the prevalence of outpatient use and costs for systemic antibacterials by age and sex among adults in Finland from 2008–2019. Data from the Finnish statistical database Kelasto, containing information concerning all reimbursed medicines for 18+-year-olds during 2008–2019, were analyzed. In addition to the decreased (26%) use of systemic antibiotics, decreased use was observed in all antibiotic categories, notably including several wide-spectrum antibiotics. The use of quinolones decreased by 49% and of tetracyclines by 39%. The 10 most frequently used antibiotics covered 89% of all adult antibiotic prescriptions. Antibiotic use also decreased in every age group during the study period. Although the overall yearly costs of outpatient antibiotics during the 10-year study period decreased from EUR 36.4 million to EUR 30.7 million, the cost per prescription increased slightly. In conclusion, according to the findings of this study, concerning adults and the results of our previous study concerning children and adolescents (2008–2016), there has been a decreasing trend of outpatient antibacterial use among the whole Finnish outpatient population over the duration of nearly one decade. However, during the same time period, there has been a specific increasing trend for the Gram-negative AMR threat regarding  Escherichia coli being the leading pathogen for death associated with resistance [Antimicrobial resistance (AMR) is a major health threat around the world . AMR causistance . The facsistance  further Escherichia coli and Klebsiella pneumonia ESBL findings were published in the early 2000s [In Finland, like in many other countries, ly 2000s , with anly 2000s ,8. Howevly 2000s . There ily 2000s . Therefoly 2000s ,19,20,21ly 2000s ,23. The ly 2000s  on the uly 2000s . With thThe overall antibiotic prescription rate use decreased by 26% from 582 prescriptions per 1000 adults in 2008 to 428 prescriptions per 1000 adults in 2019 . The antDuring the entire research period (2008–2019), antibiotic use was substantially higher in females compared to males, but the decrease was similar in both sexes . The decThe most used antibiotic groups during the research period were beta-lactam antibacterials, penicillins (J01C) (195 prescriptions per 1000 adults in 2019), other beta-lactam antibacterials (J01D) (104 prescriptions per 1000 adults), and tetracyclines (J01A) (52 prescriptions per 1000 adults) . The mosThe 10 most frequently used individual antibiotics covered 89% of all antibiotic prescriptions from 2008–2019. Cefalexin was the most common antibiotic throughout the research period , coverinWhen comparing the antibiotic prescription rate between 2008 and 2019, a decrease was observed for 8 of the 10 most common antibiotics: the prescription rate of azithromycin decreased by 55%, doxycycline 39%, ciprofloxacin 36%, phenoxymethylpenicillin 32%, clindamycin 24%, cefalexin 18%, trimethoprim 8%, and amoxicillin/beta-lactamase inhibitor use 3%. However, a slight increase was seen in the use of doxycycline and azithromycin from 2010–2011.Use of antibiotics decreased notably in adults in every age group during the research period . The greThe antibiotic prescription rate was lowest in adults aged 18–29 years (357 prescriptions per 1000 adults in 2019) and highest in adults aged ≥80 years (731 prescriptions per 1000 adults in 2019). The prescription rate increased with age with relative stability until the age of 80 years, after which a steep increase in prescription rate was detected . The preThe annual total costs of antibiotic use in adults decreased by 16% from EUR 36.4 million in 2008 to EUR 30.7 million in 2019, although the average cost per prescription increased . The higThe costs per prescription increased by 8% from EUR 14.76 in 2008 to EUR 15.99 in 2019, being highest in 2016 (EUR 17.16) and lowest in 2013 (EUR 14.29) . The cosThe most used antibiotic cefalexin incurred the highest total costs: 22% of all antibiotic costs during the study period . The totFor the 10 most used antibiotics, the costs per prescription increased for cefalexin, amoxicillin, phenoxymethylpenicillin, doxycycline, clindamycin, and ciprofloxacin and decreased for the other substances. Of the 10 most used antibiotics, clindamycin was the highest-priced (EUR 32.60 per prescription in 2019). Of all antibiotics, phenoxymethylpenicillin (EUR 6.84 in 2019) and doxycycline (EUR 9.21 in 2019) had the lowest costs per prescription. The average cost per prescription of all the antibiotics in group J01 was EUR 16.27 in 2019.This study includes all the adults aged 18 years and over residing in Finland who purchased their antibiotics in community pharmacies.In Finland, all oral antibiotics are prescription-only medicines. Antibiotics that are prescribed and granted reimbursement status by the Pharmaceuticals Pricing Board (Hila) are partially reimbursed to the patient under National Health Insurance, which covers all residents of Finland  ,26. The The research data was retrieved from the Finnish statistical database Kelasto administered by the Social Insurance Institution of Finland (Kela) . The staThe research data were analyzed using Microsoft Excel software (version 2008). The antibiotic prescription rate was expressed as the number of prescriptions per 1000 adults per year and the proportion of adults who filled at least one antibiotic prescription. The population figures were based on the population data, including the total Finnish population maintained by The Social Insurance Institution. The analyses were performed separately for both sexes and for all age groups . In addition to the overall use of antibiotics, the prescription rate of the most common individual antibiotics and antibiotic groups was also examined. The 10 most frequently used antibiotics were chosen based on the total number of antibiotic prescriptions over the course of the entire study period.The research data include only aggregated register data and does not identify individuals. According to Finnish legislation, ethical approval was not required for this study.In this nationwide register-based study, we found a decreasing trend in the prescribing of antibacterial drugs during the study period (years 2008–2019) among the total adult outpatient population in Finland. The findings of the present study are similar to that of a previous study by Parviainen et al. [Our result is conflicting when compared to the global antibiotic use during the 2000s, but Finland seems to follow the recent decreasing direction of the other high-income countries . To contMycoplasma pneumoniae epidemic observed in Finland from 2010–2011 [In this work, we found that, in addition to a 26% decrease in overall antibiotic use, this decrease was also found in all antibiotic categories, including wide-spectrum antibiotics, e.g., quinolones (decreased by 49%) and tetracyclines (decreased by 39%). This finding is also in line with the goals of the NAP in Finland [010–2011 .Antibiotic use decreased in every age group during the study period. However, the antibiotic prescription rate was notably higher among those people over 80 years of age than in the other age groups throughout the whole study period, despite the overall decrease in antibiotic use in older adults. Specifically, the prescription rates of trimethoprim and pivmecillinam were considerably higher in the oldest adults compared to those of other age groups. Since these narrow-spectrum antibiotics (trimethoprim and pivmecillinam) are used only for treating cystitis, it can be concluded that the higher antibiotic prescription rate found among the over 80 years old most likely was due to older patients’ increased susceptibility to urinary tract infections . In SwedThe overall annual costs of the use of outpatient antibiotics decreased but the antibiotic cost per prescription increased slightly. A similar phenomenon was found in our previous study concerning children and adolescents. This can be a result of, e.g., the increased price of antibiotics or increased use of more expensive antibiotics. According to both of our studies, antibiotic costs per prescription were highest in the elderly and children . AlthougE. coli strains in Finland, reflecting an increasing Gram-negative AMR health threat [E. coli resistance, despite decreasing antibiotic use in Finland, is travel; studies by Kantele et al. from Finland have shown ESBL-carriers after traveling  outside the EU area [We have now found that outpatient antibiotic use, especially the use of broad-spectrum antibiotics, has decreased among the entire Finnish population. Overall, the results of our studies show that Finland has succeeded in reducing outpatient antibiotic use, which is in line with the AMR action plans ,3,4. Howh threat ,8, as wah threat . Based o EU area ,38. It c EU area . The eff EU area . Accordi EU area , AMR is The main strength of the present study is that it is nationwide, covering the reimbursed antibiotic purchases in outpatient care for the whole adult population in Finland. The other important strength is that the period covered by the study is fairly long, which provides the possibility of studying the long-term trends in the prevalence of antibacterial prescriptions and also cost change trends. However, there are also some limitations in this work. This work does not include nonreimbursable antibacterial drugs. However, the majority of antibacterial drugs used in adults in Finland have a reimbursement status. However, according to pharmaceutical sales, data recovered from the Finnish Medicines Agency Fimea for the total consumption of antibiotics in outpatient care showed a similar decreasing trend to that observed in our study, which indicates that the nonreimbursable drugs have minor relevance in terms of the reliability of the study. Furthermore, there are no data on the dosage or indication of the drugs, nor information on the actual use of the drugs after purchasing.In conclusion, our findings show the decreasing trend of the use of antibacterial drugs in Finland among the whole outpatient population for one decade and are in line with AMR action plans. However, during the same time period, there has been an increasing trend of the Gram-negative AMR threat in Finland. Our important results from Finland further support the significance of the recent EMA, ECDC, EFSA, and OECD joint reports. According to the joint report, the global AMR health threat can only be tackled by increased coordination within the EU and worldwide by developing new innovative treatments, including antibacterial drugs with new mechanisms of action and using existing therapies responsibly around the world to ensure effective treatment for infectious diseases in the future. The new innovations are needed as soon as possible.