SPINE issuing the most publications (24 papers of the 100). Clinical research (73 of the 100 papers) outnumbered basic studies (14 papers) and systematic reviews (13 papers), and the most publications were published between 2000 and 2004. Co-citation analysis of the key words indicated that the top 5 focus areas were “complication,” “balloon kyphoplasty,” “vertebral compression fracture,” “biomechanics,” and “calcium phosphate cement.” The top 3 keywords with the strongest citation bursts were “compression fracture,” “cement,” and “balloon kyphoplasty.” The keywords with persistent strong citation bursts are “balloon kyphoplasty” and “augmentation.” There are still contrary opinions about vertebral augmentation; new research should be conducted with more deliberate design and longer follow-up.This study aimed to analyze the most influential publications on vertebral augmentation for treating osteoporotic vertebral compression fracture. The Web of Science database was searched using the key words “percutaneous vertebroplasty,” “percutaneous kyphoplasty,” “balloon kyphoplasty,” “vertebroplasty,” “kyphoplasty,” and “vertebral augmentation.” The top 100 publications were arranged by citations per year and descriptively and visually analyzed. The top 100 publications were cited 25,482 times, with an average of 14.4 citations per paper per year. The corresponding authors of the publications represented 17 nations, with most authors being American (46 authors). Thirty-two journals were involved, with  In recent years, new methods and software have emerged for the analysis of publications. More sensitive algorithms have been applied to reveal the relationships between publications, authors, institutions, and even countries. By these means, past trends, present hotspots, and future prospects could all be explored and exhibited. These new methods also enabled the ability to find the burst points of traditional research. The results of these analyses can be visualized using software such as CiteSpace and VOSviewer.Bibliometric studies refer to the statistical analysis of the particular group of publications that are associated with a specific field or subject. By this method, researchers can comprehend the subject more thoroughly and grasp the evolution of the subject more accurately. Meanwhile, influential authors and institutions can be identified by the number of times they have been cited. Although it has several limitations, the number of citations is still seen as the index that most commonly represents influence. Several bibliometric studies have been published focusing on issues from different perspectives, such as the particular subject, in 1987, it has been used extensively to treat several traumas and diseases, particularly osteoporotic vertebral compression fractures (OVCFs). Generally, vertebral augmentation includes 2 kinds of operations: percutaneous vertebroplasty (PVP) and percutaneous kyphoplasty (PKP). The core purpose of both operations is to insert bone cement into the vertebral body impacted by the fracture. Many clinical trials and basic research studies have attempted to explore the technology, indication, results, prognosis, and other factors associated with vertebral augmentation. Although most clinical trials exhibited excellent results in terms of pain relief and function restoration, some results were contradictory. Meanwhile, complications related to vertebral augmentation were observed, especially fatal pulmonary embolisms. In 2009, 2 level I evidence publications indicated that vertebral augmentation, especially PVP, was not more efficacious than conservative treatment when treating OVCF.,13 Both articles have been frequently cited thereafter. Based on these 2 articles and other level II evidence publications,–16 the American Academy of Orthopaedic Surgeons (AAOS) strongly recommended against PVP for treating OVCFs diagnosed on imaging with correlating clinical signs, whereas PKP was weakly recommended for patients with similar diagnoses.Vertebral augmentation is a type of operation used to restore the strength and stiffness of the vertebra after fractures caused by tumors, trauma, or osteoporosis. Since this technique was introduced by Galibert et alEven with the above AAOS recommendation, vertebral augmentation was still used in clinical practice. Many patients, especially some elderly patients, benefited markedly from these operations. Many new materials were invented to replace the traditional bone cement in order to overcome the disadvantages, and several new methods of operation were discussed, such as special puncturing routes. All these materials and technologies made the operations safer and more accurate. However, since there were still conflicting opinions about these technologies, it seemed necessary for researchers to explore vertebral augmentation further, especially the indications of this kind of operation.The treatment could present optimal results only when it was used to treat the most suitable patients. The details of the method, including the technology used in the course of the operation, the rehabilitation method used after the operation, and the characteristics of materials used to fill the vertebral body, should also be discussed. For these discussions, the publications that have been published in the last few years should be reviewed, with the most frequently cited articles analyzed using bibliometrics. By these means, the results could be assessed from different perspectives and exhibited visually using professional charts and figures.In this review, the most influential publications about vertebral augmentation, including PVP and PKP, were searched mainly in the database of the Web of Science Core Collection and analyzed. Additionally, the information in the publications was collected and researched thoroughly. The authors attempted the following: identify the 100 papers about vertebral augmentation that were cited most frequently; review the content of the papers to determine the focus areas in the field; analyze the internal relationships between the articles, such as the key word co-occurrence, paper co-citation, and key words time-zone. After discussing the results of the above analyses, the authors propose some suggestions about vertebral augmentation for consideration by researchers.In August 2021, the databases of the Web of Science Core Collection were searched using the keywords “percutaneous vertebroplasty,” “percutaneous kyphoplasty,” “balloon kyphoplasty,” “vertebroplasty,” “kyphoplasty,” and “vertebral augmentation.” Then, all the publications were reviewed by the first author and the co-first authors of the current study. The inclusion criteria of the publications were as follows: be associated with vertebral augmentation operations such as PVP or PKP, be searchable in the Web of Science Core Collection database because the information of this database was intact and suitable for the visual software analysis, and be published in English. Meanwhile, the exclusion criteria were as follows: be associated with other content such as the treatment principle of OVCF or discussion about the use of bone cement in the field of orthopedics; conference papers, letters, or other informal articles; and published in languages other than English. All articles searched were reviewed by the 3 coauthors separately to exclude the articles that were not closely associated with PVP or PKP. For example, research about the general treatment principles of osteoporotic fracture or some studies about the properties of bone cement were excluded. When there were differences in opinions about some articles, the corresponding authors discussed the articles with all authors and made the final decision. Since this research was a review of the publications and no patients were included, the requirement for ethical approval was waived.After determining the publications to be included in the analysis, the number of times a publication was cited per year  was calculated, and the top 100 papers were defined as the most influential publications about vertebral augmentation.The collected data included the journal and the year of publication, the nation of the corresponding author, total number of times cited, the number of times cited per year since publication, and the study type. When the publications were clinical studies, the evidence of the study was graded between 1 and 5 following the guidelines of the Oxford Centre for Evidence-Based Medicine (March 2009). Then, systematic reviews and meta-analyses were combined as a specific type. A visual analysis of the 100 papers was conducted using the CiteSpace software.Using the keywords mentioned above, a total of 6621 papers were found. Then, 2271 papers were selected by the screening step using the inclusion and exclusion criteria. The 100 most influential papers were then determined based on the number of citations per year, and the top 10 publications are listed in Table The 100 most influential publications were cited 25,482 times, and each paper was cited 14.4 times per year on average. The papers were cited 91–870 times, and the number of citations per year ranged from 7.25 to 66.92.SPINE at 24, followed by the European Spine Journal at 11, and the American Journal of Neuroradiology and Radiology with 8 each  about vertebroplasty in the same issue. These 2 RCTs were the 2 most frequently cited publications per year in our research. In the first article, Buchbinder et al performed a multicenter, randomized, double-blind, placebo-controlled trial to compare vertebroplasty and sham procedure in 78 patients >50 years old with painful, unhealed osteoporotic vertebral fractures that occurred <12 months prior to the procedure. The outcomes included overall pain, pain at night and at rest, physical functioning, quality of life, and perceived improvement at 1 week and 1, 3, and 6 months. The authors concluded that vertebroplasty did not have a significant advantage in all measured outcomes at all time points. Additionally, there were no differences in the incidence of vertebral fractures after operations. In this study, patients were randomly assigned to different groups before entering the operating room. For the patients in the sham intervention group, all procedures were similar to those in the PVP group until the needle was inserted into the lamina. Then gentle tapping was also performed to simulate the manipulation of PVP.In 2009,  compared vertebroplasty with the simulated procedure without cement for osteoporotic spinal fractures in 131 patients, and the follow-up period was 3 months. In their multicenter trial, the modified Roland-Morris Disability Questionnaire and ratings of average pain intensity were used as primary outcomes. The conclusions indicated that patients in the vertebroplasty group and control group experienced similar improvements, and there were no differences between the 2 groups. In this study, the patients were randomized after anesthetizing the skin and subcutaneous tissues. The blinding was implemented by verbal and physical cues; for example, pressure was applied on the back and the odor was similar to that of polymethyl methacrylate.In the second study, Kallmes et al–16 the AAOS strongly recommended against vertebroplasty for patients with OVCF based on imaging with correlating clinical signs, and kyphoplasty was recommended weakly for the same patients. The numbers of publications rapidly declined after 2009 resulting in obvious differences in our analysis for nearly all kinds of studies.These 2 articles were important as they changed traditional opinions about PVP and became the top 2 most frequently cited publications. Many surgeons and physicians began proposing conservative treatment for these kinds of operations, especially when they were used to treat osteoporotic spinal fractures. Based on these 2 articles, which were categorized as level I evidence, and the other 3 level II articles, published in 2016. There were 120 patients with acute OVCFs occurring <6 weeks prior to the study. Researchers simulated vertebroplasty by performing all the same procedures until the short needle reached the periosteum; then, skin pressure and tapping on the needle were applied to mimic vertebroplasty. Other factors, such as conversations about polymethyl methacrylate mixing and injection suggestion, were also used to simulate vertebroplasty. The authors concluded that vertebroplasty was superior to conservative treatment for patients with OVCFs that occurred <6 weeks prior to the procedure.Still, there were contrary opinions. Another level I evidence in our research was the study by Clark et al,20–22 or PKP–27 with nonsurgical treatments. Nearly all level II evidence studies achieved similar results, indicating that these 2 methods were more suitable for OVCF than conservative treatment. Even a publication with a nearly neutral opinion indicated that PKP can relieve pain more rapidly than conservative treatment. Two other publications compared PVP with PKP; one recommended PVP because of the higher cost of PKP, and the other one concluded that the results of PVP and PKP were similar, with a shorter procedure duration in PVP but fewer cement leakages and longer fracture-free survival in PKP. The last level II evidence publication compared PKP with conservative treatment in patients with vertebral compression fractures (VCF) and cancer and strongly recommended PKP.These level I evidence trials used careful designs and great effort to ensure blinding. This was also the most difficult aspect to assess in the evaluation of PVP and PKP versus conservative treatments for OVCF. Most of the publications were graded as level II evidence because of the absence of blinding. In these level II evidence publications, most still compared PVPIn our current study, systematic reviews and meta-analyses were combined as a specific kind of publication. There were 13 publications of this kind, all published after 2000, and most (13/15) were published after 2005. It is possible that this distribution indicated shift to stopping or pausing vertebral augmentation.–37 Some authors also mentioned providing information to the patients about the benefits and potential harms before operations. Taylor et al compared PKP with PVP and concluded that both procedures could achieve benefits in the treatment of OVCF, but PKP appeared to have a better adverse event profile. Other systematic reviews focused on complications such as pulmonary cement embolism. Contrary to these cautious recommendations in the treatment of OVCF, the applications of PVP and PKP for cancer-related VCFs have gained extensive recognition.Systematic reviews by different authors recognized the rapid pain relief of PVP and PKP generally, but recommended that comparative, blinded, RCTs should be performed and standardized evaluative methods should be adopted since there was not enough evidence to support the safety and effectiveness of these technologies. compared PVP and PKP in 2008 and concluded that both methods could provide improvement in visual analog scale pain scores, but PVP had a more significant improvement and also a greater risk of cement leakage and new fractures. Wang et al achieved similar results after comparing PVP and PKP for the treatment of single-level VCF. Lee et al considered PVP and PKP as minimally invasive procedures for VCF and evoked future prospective studies to validate the results. Anderson et al recommended cement augmentation in the treatment of symptomatic VCF. Chen et al also compared PVP and PKP with conservative treatment in elderly patients with OVCF and concluded that PVP achieved the best effect in relieving pain. Conservative treatment was associated with the lowest incidence of new fractures, and balloon kyphoplasty had the lowest risk of all-cause discontinuation.As for meta-analyses, Eck et al–54 or the method of finite-element analysis.–57 These studies reached similar conclusions that cement augmentation could restore the strength of the affected vertebrae but could increase the risk for fractures of the adjacent vertebrae. Some technology skills were discussed in these studies. Belkoff et al tested the effect of tamp treatment used in PKP and confirmed that this technology could restore the height of vertebrae better than PVP. Molloy et al related the strength and stiffness with the percentage of cement-filling volume during PVP. Steinmann et al compared unipedicular with bipedicular approaches and recommended the former for comprehensive consideration. Experimental models and cadaveric vertebral bodies,53 were also used to study the properties of some special kinds of cement or to compare different kinds of cement.The 14 basic studies were mostly biomechanical studies using cadaveric vertebral bodies multiple myeloma, or metastases. The follow-up period was within 1–24 months, and the number of cases reported was up to a hundred. The longest observation period was in a cohort study of Edidin et al at 4 years. This study indicated that patients in the nonoperated cohort had a lower adjusted survival rate than patients in the operation group. Meanwhile, kyphoplasty had a lower relative risk of mortality than PVP. This showed that longer follow-up might indicate different results for these procedures, especially considering the elderly patients who were possibly more affected by the OVCF than young patients. The cost of treating OVCF should also be considered in future studies. In 2013, Svedbom et al performed a cost-effectiveness analysis to compare balloon kyphoplasty, vertebroplasty, and nonsurgical management for the treatment of acute OVCF. The results revealed that PKP may be a cost-effective strategy for the treatment of OVCF. When considering the cost, some extra expenses should be included, such as nursing costs during the period of treatment.Most clinical studies were level III-V evidence publications, including case-control studies, retrospective comparative studies, case series reports, and reviews. The numbers of these publications decreased after 2009. These studies discussed PVP and PKP from different perspectives and reported different results about these 2 procedures. Nearly all studies were associated with OVCF treatment, and only 9 were about the use of these operations to treat vertebral fractures with tumors, such as angiomas,,68 cement leakage into the spinal canal, or catastrophic consequences caused by thermal necrosis (#8).–66 Adjacent fractures,70 were the most frequently discussed complications. The operation technique was an important issue in this field, since balloon kyphoplasty (#1) had been verified to be superior to PVP. Certainly, the indication of the operation was vital. This kind of operation might be suitable for older women (#7) when they were suffering from a vertebral compression fracture (#2). All the standards of this technology (#5) should be discussed seriously. Meanwhile, basic knowledge includes biomechanics (#3) and the material used to fill the vertebral body (#4), which could be considered to improve the result of the operations. All these trends can also be seen in the keyword with the strongest citation bursts. The keywords with the strongest citation bursts were augmentation and balloon kyphoplasty, which could be seen as an indication that researchers still had confidence in this technology, but there were still several workers before.The cluster categories of keyword co-citation indicated that the complications of vertebral augmentation were important to researchers. Although this kind of operation is minimally invasive, it could be associated with some severe complications such as fatal pulmonary embolism,Despite the number of publications decreasing since 2009 after the publication of 2 authoritative level I evidence studies, there are still contrary opinions about PVP and PKP. These procedures are being implemented worldwide, especially for treating OVCFs in elderly patients. It appears that there will be a long way to go before the different opinions reach a consensus. PVP and PKP should be performed cautiously, including choosing patients strictly and informing patients and their families of the results and potential risks thoroughly. Meanwhile, new methods should be explored for further research, which might be more deliberate and objective. With these methods, more patients with different baselines should be selected for longer follow-up. Additionally, the evaluation factors should be more extensive, covering relative fields including the treatment results in short and long term, the long-term survival rate, the costs associated with the treatment of the patients, and the nursing costs borne by medical institutions or families.The authors of the current article acknowledge all authors listed meet the authorship criteria according to the latest guidelines of the International Committee of Medical Journal Editors and that all authors are in agreement with the manuscript.Conceptualization: Yu Chen, Shuang Wang, Liang Zhang, Jun-Xiong Ma PanData: Yu Chen, Shuang Wang Formal analysis: Shuang Wang, Liang Zheng Methodology: Yu Chen, Jun-Xiong Ma PanfSoftware: Hong Wang, Bo-Hua Zhang Visualization: Shuang Wang, Shao-Tong Sun, Xin-Lei Guo Writing-original draft: Shuang Wang, Liang Zheng, Jun-Xiong Ma PanWrition-review&editing: Yu Chen, Liang-Bi Xiang.


Surf zone injuries include cervical spine injuries (CSI). Risk factors for CSI have not been extensively investigated. The objective was to examine risk factors associated with diagnosed CSI that occurred in a beach setting.This retrospective case series used manually linked data from Sunshine Coast Hospital and Health Service Emergency Departments, Queensland Ambulance Service, Surf Life Saving Queensland (SLSQ), and Bureau of Meteorology data from 01/01/2015-21/04/2021. Variables included victim demographics, mechanism of injury, scene information, and patient course.Seventy-nine of the 574 (13.8%) confirmed CSI occurred at the beach. Local residents and visitors were injured equally. Females represented a minority (12.7%) of those diagnosed with CSI but were a higher proportion of suspected spinal incidents reported to SLSQ (45%). Surfers were more likely to be injured through shallow water diving than swimmers (27.6% vs 2.2%). Females were more likely to be injured by shallow water diving than males (30.0% vs 8.7%). Visitors were more likely to be injured swimming and local residents surfing (68.2% vs 77.8% respectively). CSI occurred most commonly (40.0%) with a below average ocean wave height (0.75-1.25 m) and were most likely (45.3%) to occur in the second half of the outgoing tide. One beach had a statistically significant greater incidence of spinal incidents  and of CSI .Risk factors for CSI at the beach include male sex, smaller wave height and an outgoing tide. Shallow water diving among surfers and females should be addressed urgently.The online version contains supplementary material available at 10.1186/s12889-022-13810-9. Australia is renowned for its beaches and beach culture with eleven million people visiting the coast to wade, swim or surf in 2020, of which 3.9 million people did so frequently . BeachesThe energy per square meter of a wave is proportional to the square of the height of the wave . Thus, abeachsafe.org.au . Th. Th7]. TOur study is the second largest patient series globally to examine risk factors for CSI at the beach and the first to examine the influence of wave size and tide on the occurrence of CSI. The beaches of the Sunshine Coast stretch for approximately 60 km of coastline so data from a single wave buoy  may not be truly representative for each location. Secondly, the relationship between ocean wave height and the height and characteristics of waves in the surf zone is complex with shifting sand banks, rip currents, tidal currents and the wind all influencing the behaviour of waves in the surf zone. We were unable to access wave height predictions/measurements for each beach location for the duration of the study and hence relied on the wave buoy data.As mentioned earlier, our search strategy only identified patients with confirmed CSI, not the patients investigated for CSI but cleared of any injury. Given the comprehensive nature of the strategy (supplementary file Future research should examine the skill and experience levels of the swimmers and surfers involved, especially concerning the injuries occurring in smaller, but perhaps not safer, waves. Beach numbers have been used as a proxy for exposure and may not accurately reflect exposure, as it has been postulated that visitors will enter more hazardous surf whereas local will wait for better conditions. These figures are collected by lifeguards and lifesavers with no formal training in counting populations. As such, the accuracy of these figures cannot be ascertained. However, these figures have been collected several times a day, every day of the year, on patrolled beaches and are currently the best estimation of beach usage available.Our study demonstrates that the person most likely to sustain a cervical spine injury at the beach is a middle-aged male. However, we also found an unexpectedly high number of surfers and females injured by diving into shallow water. This must be addressed urgently with preventative measures. Swimmers and surfers were most likely injured on smaller than average waves and during the last half of the outgoing tide. A single hotspot location for both suspected spinal injuries and confirmed CSI was identified. Locals and visitors were injured equally, although they were injured doing different things. These findings should inform future injury prevention campaigns.Additional file 1.


Antimicrobial resistance (AMR) is a global problem that also includes countries of the Arabian Peninsula. Of particular concern, is the continuing development of extended-spectrum β-lactamases (ESBLs) in the countries of this region. Additionally, antibiotic treatment options for ESBL-producing bacteria are becoming limited, primarily due to the continuing development of carbapenem resistance (CR), carbapenems being frequently used to treat such infections. An overview of recent publications (2018–2021) indicates the presence of ESBL and/or CR in patients and hospitals in most countries of the Arabian Peninsula, although the delay between microbial isolation and publication inevitably makes an accurate analysis of the current situation rather difficult. However, there appears to be greater emphasis on CR (including combined ESBL and CR) in recent publications. Furthermore, although publications from Saudi Arabia are the most prevalent, this may simply reflect the increased interest in ESBL and CR within the country. Enhanced ESBL/CR surveillance is recommended for all countries in the Arabian Peninsula. Enterobacteriaceae family, which are part of the normal gut microbiota. However, these bacteria may become pathogenic when associated with urinary tract and bloodstream infections  and K. pneumoniae [8.1%]) isolated in 2020 from three government hospitals showed ESBL resistance, stating that patients with UTIs in the Najran region are at a high risk of antibiotic resistance, which may be leading to significant problems in outpatient department treatment outcomes  OR "extended-spectrum beta lactamase"[Title] OR "extended spectrum beta-lactamase"[Title] OR "extended-spectrum beta-lactamase"[Title] OR "extended spectrum β lactamase"[Title] OR "extended-spectrum β lactamase"[Title] OR "extended spectrum β-lactamase"[Title] OR "extended-spectrum β-lactamase"[Title] OR "ESBL"[Title] OR "ctx-m"[Title] OR "carbapenem"[Title] OR "carbapenemase"[Title]) AND ("Arabian peninsula"[Title] OR "bahrain"[Title] OR "iraq"[Title] OR "jordan"[Title] OR "kuwait"[Title] OR "oman"[Title] OR "qatar"[Title] OR "saudi arabia"[Title] OR "united arab emirates"[Title] OR "uae"[Title] OR "yemen"[Title]) AND ("2018/01/01"[Date - Publication]: "3000"[Date - Publication]). This generated 56 results, including one corrigendum. All publications were included in the current study and some publications  described research performed prior to 2018. Only English language articles were included , and wheThere is an inevitable lag between the initial isolation of microbial strains and the eventual publication of AMR results. Therefore, most of the studies published in 2018–2021 relate to isolates obtained several years before their publication. This makes an accurate analysis of the current state of affairs regarding the epidemiology of ESBL and CR in the Arabian Peninsula difficult, although this aspect of AMR epidemiological reporting is not restricted to this region of the world. However, recent publications have shown that there is an increasing interest in the epidemiology of CR in this region, most likely due to the increasing number of CR isolations from patients. Further, it is inevitable that the increasing use of carbapenem antibiotics to treat ESBL-related infections will lead to an eventual increase in CR globally, including in the Arabian Peninsula. As such, the steps required to help prevent or slow down the global emergence of CR infections include: i) recognition of the impact of carbapenem prescribing on regional infections and ii) ensuring that appropriate measures are taken towards the responsible prescription of antibiotics. In this respect, the need for a doctor’s prescription, a consultation with infection control teams, an accurate diagnosis of bacterial infections, and antibiotic sensitivity is essential . It is eFrom this review, it is obvious that most country-specific publications related to ESBL and CR infections were from Saudi Arabia. However, it should be remembered that this does not mean that Saudi Arabia has a larger AMR problem than other countries in the Arabian Peninsula, but suggests that the problem is potentially being more thoroughly investigated in this country . Focusing on publications in PubMed may mean that a few relevant publications could have been omitted from this review. However, we described data obtained from 56 relevant publications, and it is unlikely that the impression obtained by this review would be altered by the addition of any additional publications that may have been missed.Based on the current review, continued and expanded surveillance of ESBL and CR in hospitals and the environment is recommended for all countries in the Arabian Peninsula. Increased funding and the implementation of relevant AMR policies directed at non-specific and specific attributes associated with countries of the Arabian Peninsula, such as migration, religious pilgrimages, and food imports, are particularly recommended.


Concrete structures in cold regions are usually suffer from froze and thaw action. A combined investigation of nanoindentation technique and X-ray diffraction were adopted to demonstrate the microstructure change and micromechanical properties deterioration of concrete subjected to freeze–thaw (F-T) cycles in this study. The results showed that the indentation modulus and hardness of the main compositions in mortar, such as calcium-silicate-hydrates and calcium hydroxide, both gradually decreases as the F–T cycles increase, with the greatest reduction approximate 38% after 1500 F–T cycles, while the corresponding greatest reduction of the main compositions in interfacial transition zone (ITZ) is close to 50%. In addition, the micropores in mortar and ITZ both gradually converge and connect to form larger diameter pores, and the thickness of ITZ increased rapidly from 25 to 50 μm after 1500 F–T cycles. On this basis, the effective modulus of elasticity under different F–T cycles are analyzed through Mori–Tanaka scheme with consistent variation tendency of dynamic modulus of elasticity test. Subsequently, the mechanical properties deterioration of concrete under F–T cycles is mainly attributed to the decrease of mechanical properties (such as modulus and hardness) of microscopic components, and the increase and propagation of the internal micropores especially for micropores in ITZ. So far, investigations on the deterioration of concrete mainly focus on the mechanical properties at macro-scales such as stress characteristic, tensile properties, mechanical properties of flexural structure members, and have revealed a reduction in the mechanical resistance7.Freeze–thaw (F–T) action is one of the major causes for deterioration of durability performance of concrete structures in cold northern regions, such as bridge deck, dams and concrete ocean platforms etc. Many researchers have studied the effect and mechanism of F–T. The deterioration could be mainly attributed to hydraulic pressure, crystallization pressure and the mismatch of thermal effects between ice and solid phases10. In addition, the microstructure changes of concrete under F–T action have often been investigated by means of X-ray diffraction (XRD), scanning electron microscope, ultrasonic imaging, X-ray computed tomography and so on13. Generally, the macromechannical performance of concrete presents opposite changes as the porosity increases when exposed to F–T cycles condition and ITZ crack width14. The macroscopic deformation and the effect on pore size distribution could be analyzed through the link of thermodynamics and poromechanics16. Correspondingly, some measures and various additives which could improve internal pore systems, and conceptual designs were proposed to enhance the macromechannical performance18. As for the micromechanical properties of concrete, nanoindentation technology could provide an effective method to detect the nanomechanical properties of micro components. During indentation test, the nanoscale indenter tip is pressed into the surface of tested material, force and displacement are recorded, and a load–displacement curve is generated subsequently. According to the curve, stiffness, hardness and indentation modulus can be derived by applying continuum scale models, respectively19. Some researchers have studied the indent modulus and hardness of main components of hardened cement paste using this technique21. Subsequently, the elastoplastic and creep properties of calcium-silicate-hydrates (C-S–H) gels, and the influence of anaphases materials addition on the properties of cemented materials were investigated by means of through this technique24.The macro-mechanical properties of composites are dependent on microstructure and micromechanical properties. As a typical composite material, concrete has complex microstructure and presents multi-scale characteristics. Numerous recent papers have attempted to investigate the freezing behavior through numerical simulation method, and to investigate the deterioration of cemented materials at mesoscopic scale based on above frost damage mechanismThe relation between macromechannical performance and microstructure and micromechanical properties is relatively significant. Under the F–T cycles, the microstructure of concrete and the micromechanical properties of individual component could be changed. However, the corresponding researches of are indeed of scarce. Moreover, it is extremely important to study the changes of microstructure and micromechanical properties under F–T cycles for more in-depth understanding of the reduction mechanism of macroscopic performance. Therefore, in this study, a combination of nanoindentation and XRD is utilized to conduct a comprehensive investigation on the microstructure and mechanical properties of concrete subjected to F–T cycles. Firstly, the micromechanical properties of individual component of mortar, interface transition zone (ITZ) subjected to different F–T cycles were investigated. Secondly, through the analysis of the distribution and expansion of micropores, the thickness of ITZ was characterized. Finally, the effective modulus of elasticity of concrete under different F–T cycles are analyzed by means of homogenization theory based on nanoindentation test results. The causes of mechanical properties deterioration are analyzed comprehensively from the aspects of microstructure and micromechanics.The raw materials of concrete samples are Portland cement, sand, and coarse aggregate with black basalts. Table For the nanoindentation tests, six concrete groups of approximately 1.5 cm cubic specimens were cut from the beams after F–T cycles using diamond saws. Subsequently, the cubic specimens were put into the bottom of the plastic box, added the mixed solution of epoxy resin and curing agent, embedded in cylindrical shape. It is critical for obtaining more accurate indent test results to have a flat surface. Suitable grinding and polishing procedures are quite of importance. All cubic blocks were ground on 800, 1200, 2000 grit abrasive paper (Buehler) for approximate 3 min on grinding apparatus Buehler 250, respectively. Subsequently, they were polished with gradations 3 μm and 1 μm for about 3 min respectively, and 0.05 μm for 30 min. After grinding, the polished samples are shown in Fig. 26.Firstly, the basic principle of nanoindentation is recalled briefly. During indentation, the indenter tip is pressed into the surface of tested material, force and displacement are recorded, and a load–displacement curve is generated subsequently see Fig. . Accordi27.Polished samples were examined using a Hysitron Ti 950 Triboindenter to probe micro-structural changes on different phases. A pyramid-shaped diamond Berkovich indenter with a tip radius of 100 nm and angle of 142.3° was employed to reduce the pile-up phenomena around the indent area in this study. Prior to test, Z-Axis calibration in the air, machine compliance, and tip area function calibration after each group of indentation were carried out in order to reduce the influence of instruments. In addition, indentation experiments were usually carried out at night in order to reduce the influence of thermal drift. Load-controlled indentation measurements were performed up to a maximum load of 2 mN at a loading rate of 0.2 mN/s followed by a hold time of 10 s, which can minimize creep effects28 to detect possible transition zone more comprehensive  could determine the mineral compositions and provide quantitative information for most of the crystalline phases32, so the hydration products of the tested samples don't contain unhydrated cement clinker due to w/c = 0.48 of the tested samples. Table 5S6H5) with smaller amounts of xonotlite (C6S6H), dehydrated calcium aluminate hydrates (C3AH6) and quartz sand. The content of C-S–H and CH is approximately 15.7:1, which are in agreement with the results obtained by nanoindentation. Thus, it is reasonable to assume that the tested mortar compositions are mainly composed of micropores, low density calcium-The statistical analysis of the indent array on mortar and the deconvolution results are shown in Figs. silicate-hydrates (LD C-S–H), high density calcium-silicate-hydrates (HD C-S–H), calcium hydroxide (CH), and sand. Evidently, the two types of C-S–H are the major components of mortar with volume fraction of 58.9% and 15.45% respectively without F–T cycle and both the volume fraction of them have a certain downward trend with the increase of freeze–thaw cycles. The indent modulus of LD C-S–H, HD C-S–H, and CH in mortar decreased with the range of 15.9%, 37.7%, and 26.5% from 0 to 1500 F–T cycles respectively, while the hardness decreased with the range of 22.2%, 28.2%, and 39.3% from 0 to 1500 F–T cycles respectively.The propagation of micropores under different F–T cycles is presented in Fig. The statistical analysis of the indent array on ITZ and the deconvolution results are shown in Figs. 36.Noteworthy, the volume fraction of micropores increased rapidly to 59.52% after 1500 F–T cycles. The porosity of ITZ is much higher than that of mortar, and this is one of the main factors that result in the difference of mechanical properties between ITZ and mortar38. Subsequently, with the increase of F–T cycles, the number of micropores increases gradually, micropores converge and extend to larger pores gradually. The thickness of the weak band increases to 50 μm after 1500 F–T cycles rapidly 32, especially for concrete. In the study, Mori–Tanaka scheme is employed to estimate the effective modulus of elasticity of concrete subjected to F–T cycles. According to the scheme, the macroscopic strain E and the macroscopic stress of a representative elementary volume V could be determined by Eqs. ,,41. For Through localization, the macroscopic strain and local strain could be obtained from Eq. . The Ther, the homogenized stiffness tensor C0, fr, and Ar are the stiffness tensor of the matrix, the volume fraction, and the 4th-order localization tensor of each inclusion, respectively.If the representative elementary volume contains inclusions from Eq.  ~ (7).9\The upscaling scheme is applied in four steps according to the order of magnitude in size of the elementary heterogeneity. The calculated results at each homogenization step of the multi-scale model are summarized in Tables 44. Subsequently, in this research, the variation tendency of dynamic modulus of elasticity and the predicted modulus of elasticity under F–T cycles were compared. Figure 45. The number of micorpores in mortar increases rapidly, and the aperture size also expands after 700 F–T cycles. Therefore, it could be concluded that the mechanical properties deterioration of concrete is mainly attributed to the deterioration of mechanical properties (such as modulus and hardness) of microscopic components, and the increase and propagation of micropores especially for micropores in ITZ.The modulus of elasticity of concrete without F–T cycle measured from uniaxial loading test was 23.44 GPa while the calculated result by homogenization scheme was 20.2 GPa with the corresponding errors 13.2%. This calculated result is in agreement with the experimental value. Therefore, the modulus of elasticity of concrete at macroscale could be calculated using the homogenization scheme presented in this study. Due to the limited test conditions the modulus of elasticity of samples after F–T conditions were not conducted. The dynamic modulus of elasticity was higher than calculated modulus of elasticity; however, the dynamic modulus of elasticity has a linear correlation with modulus of elasticity1. The indentation modulus and hardness of the main compositions in mortar (such as C-S–H and CH) both gradually decreases with the increase of F–T cycles, with the greatest reduction approximate 38% after 1500 F–T cycles. However, the more noteworthy is that the indentation modulus and hardness of the main compositions in interfacial transition zone (ITZ), show a more obvious decreasing tendency with the greatest reduction approximate 50%.2. The volume fraction of miacropores in both mortar and ITZ increases as the F–T cycles increase. In addition, the micropores gradually converge and connect to form larger diameter pores with the porosity reaching 47.25% and 59.52% respectively under 1500 F–T cycles. The thickness of ITZ increased from 25 to 50 μm rapidly after 1500 F–T cycles.3. Based on nanoindentation results, the effective modulus of elasticity under different F–T cycles are analyzed through Mori–Tanaka scheme. The calculated results correspond well with the test results and the variation tendency of dynamic modulus of elasticity.In this paper, the micromechanical properties deterioration of concrete after 0, 300, 500, 700, 900, and 1500 F–T cycles were investigated by means of nanoindentation technique and XRD. The following conclusions could be drawn:. It provided a helpful basis for finding effective measures of improving the F–T durability of concrete in engineering.The mechanical properties deterioration of concrete under F–T cycle is mainly attributed to the decrease of mechanical properties of microscopic components, and the increase and propagation of micropores especially for micropores in ITZ


To observe the effect of metformin (MET) monotherapy versus MET plus liraglutide (LIRA) on gonadal and metabolic profiles in overweight patients with polycystic ovary syndrome (PCOS).Sixty overweight patients with PCOS were recruited from January 2021 to January 2022 in Shengjing Hospital of China Medical University and were randomly assigned to the MET or combination (COM) group to receive 12 weeks of MET monotherapy or MET plus LIRA therapy. Anthropometric measurements, menstrual cycle changes, gonadal profiles, and oral glucose tolerance tests (OGTT) were conducted at baseline and after the 12-week treatment.Fifty-two subjects completed the trial while eight were lost during the follow-up. Both MET and COM improved menstrual cycles, anthropometric parameters, and glucose metabolism after the 12-week treatment; however, there was no statistical difference between the two groups. MET plus LIRA therapy improved hyperandrogenemia, including TT , SHBG (sex hormone binding globulin) and FAI (free androgen index), whereas MET monotherapy only improved SHBG and FAI when compared with baseline. Furthermore, both MET monotherapy and MET plus LIRA therapy improved E2 (estradiol) while only MET plus LIRA therapy improved LH (luteinizing hormone), FSH (follicle stimulating hormone) and Prog (progesterone) more effectively than baseline. Additionally, MET plus LIRA therapy may improve TT, SHBG, FAI, LH and Prog more effectively than MET monotherapy; however, there were no significant differences on E2, FSH and LH/FSH between the two groups.In overweight patients with PCOS, both MET monotherapy and MET plus LIRA therapy improved glucose metabolism and relieved insulin resistance (IR). Additionally, MET plus LIRA therapy was more effective than MET monotherapy in improving reproductive abnormalities and hyperandrogenemia, potentially by modulating the hypothalamic-pituitary-ovarian axis. Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disease characterized by ovulatory dysfunction and hyperandrogenemia (HA), affecting 5–15% women of reproductive age  with a wMetformin (MET) is a biguanide insulin sensitizer which may reduce hepatic glucose production, stimulate insulin-mediated glucose uptake in the liver and skeletal muscle, and reduce gluconeogenic substrate utilization . MET is We recruited 60 patients aged 18 to 40 years, who were diagnosed with PCOS in the outpatient department of Endocrinology, Shengjing Hospital of China Medical University from January 2021 to January 2022. All patients were informed about the study purpose, and signed written informed consent prior to participation. This study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Shengjing Hospital of China Medical University (registration number: 2020PS624K). The study was registered on Clinical Trials.gov .2; (3) age between 18 and 40 years; (4) no medication that affects insulin sensitivity or ovarian function within the first three months of the trial; (5) use barrier contraception.The inclusion criteria for the subjects were as follows: (1) meet the Rotterdam diagnostic criteria of PCOS phenotype B with hyperandrogenism and ovulatory dysfunction ; (2) bod2); (5) thyroid dysfunction; (6) history of cancer; (7) active infection; (8) weekly alcohol intake > 100 g; (9) pregnancy and breastfeeding; (10) 17-hydroxyprogesterone level > 2 ng/mL .The exclusion criteria for the subjects were as follows: (1) allergy to GLP-1 RAs or MET; (2) severe cardiovascular disease; (3) abnormal liver function test results  levels 2.5 times higher than the upper limit of the normal range); (4) renal insufficiency  height, weight, and age; (2) menstrual cycle; and (3) medical history. Eligible patients were assigned to the MET group or MET plus LIRA (COM) group through simple randomization at a 1:1 ratio using computer-generated codes. Patients in MET and COM group were administered MET 1000 mg BID p.o. or LIRA 1.2 mg QD s.c. plus MET 1000 mg BID p.o. for 12 consecutive weeks, respectively. Over the 12-week treatment course, all patients received the same diet and physical exercise. All subjects returned to the hospital for clinical, metabolic, and laboratory evaluations at baseline, the 4itiation Figure 1th week and the 12th week after treatment, trained personnel obtained anthropometric data, including height, weight, and abdominal girth (AG) for all patients using standardized protocols. The height and weight of each subject wearing light clothes were measured to the nearest 0.1 cm and 0.1 kg, respectively. BMI was calculated as weight (kg) divided by the square of height (m). AG was measured to an accuracy of 0.1 cm by placing a tape measure around the body at the level of the navel. Women with a BMI above 24 kg/m2 were classified as overweight.At baseline, the 4During the 12-week treatment period, patients were asked to use barrier contraception only. Menstrual cycle changes were recorded. Menstrual cycle disorders included oligomenorrhea and amenorrhea. Oligomenorrhea referred to patients with less than six menstrual periods within 12 months while amenorrhea referred to patients who have stopped menstruating for more than 6 months. Each bleeding counts as one menstrual cycle. Menstrual cycle recovery was defined as the recurrence of regular menstrual cycles in patients.th week after treatment, the subjects fasted for 8–12 h overnight. We collected fasting venous blood to determine fasting glucose (FG) and fasting insulin (FINS). Subsequently, we performed a 75 g oral glucose tolerance test (OGTT) and collected venous blood at 0 h, 1 h and 2 h to determine the blood glucose and insulin concentrations. The homeostasis model assessment-insulin resistance (HOMA-IR) score was calculated to evaluate IR. HOMA-IR score = FINS (mU/L) × FG (mmol/L)/22.5. The approximate trapezoidal method was used to estimate the area under the curve of glucose  and the area under the curve of insulin . As all patients had irregular menstrual periods at enrollment, gonadal profiles were measured when venous blood samples were collected into BD Vacutainer Tubes  at baseline, the 4th and the 12th week. We did not perform progestin-induced menstrual bleeding to evaluate the hormones at the follicular phase of the menstrual cycle. The samples were centrifuged at 3600 rpm and 4°C for 10 min. The serum and plasma were aliquoted and stored at –80°C before estimating serum total testosterone (TT), LH, FSH, progesterone (Prog), estradiol (E2), and SHBG levels. LH/FSH = LH (mIU/mL)/FSH (mIU/mL). Free androgen index (FAI) = TT (nmol/L)/SHBG (nmol/L) × 100. The standard glucose oxidase method was used to determine plasma glucose levels using Abbott CI16200. Radio-immunological assay was used to detect insulin, chemiluminescent immunoassay was used to detect LH, FSH, Prog, E2 and SHBG, while TT was measured by electro-chemiluminescent immunoassay using Beckman Coulter Unicel DXI800. Pre- and post-intervention samples from all subjects were analyzed in the same run, and all samples were measured in the same laboratory using standard laboratory techniques.At baseline and the 12P-values on both sides <0.05 was 22 per group. The final sample size was 52. The Anderson–Darling method was used to test the normality of continuous data. Continuous data were presented as mean ± standard deviation (SD)  or median and interquartile range . Pre- and post-treatment effects in each group were analyzed using ANOVA or paired t-test  or paired Wilcoxon test  if appropriate. Effects between groups at the same time point were analyzed using unpaired t-test  or rank test  if appropriate. Categorical variables were expressed as frequencies or percentages and compared using the chi-square test. All P-values were two-tailed, and P < 0.05 was considered statistically significant. All data analyses were performed using GraphPad Prism 8.0.1  and SPSS 23.0 .The sample size was calculated using the average difference formula, assuming that the minimum average difference between the treatment groups was 20%, and the average SE (standard error) was 2.2%. The sample size required for a statistical power of 0.80 and th week (four in the MET group and one in the COM group). Mild gastrointestinal side effects, such as nausea, heartburn, vomiting, and diarrhea, occurred in both groups during the first two weeks of treatment with a higher proportion of these adverse reactions in the COM group. Two participants had one episode of hypoglycemia, while one participant in the COM group developed a rash at the injection site. Most adverse reactions were mild and spontaneously resolved after 2 weeks of treatment. No participants dropped out owing to drug intolerance in both groups with the final compliance 83.3% in the MET group and 90% in the COM group. All 52 subjects underwent anthropometric measurements, menstruation monitoring, and gonadal profiles detection at baseline, the 4th and the 12th week; however, only 38 subjects (16 in the MET group and 22 in the COM group) underwent OGTT tests at baseline and the 12th week  at baseline.Sixty participants were randomly allocated to receive MET 1000 mg BID p.o. monotherapy (MET group) or MET 1000 mg BID p.o. plus LIRA 1.2 mg QD s.c. therapy (COM group). For all patients receiving MET, the dose began at 500 mg BID and gradually reached the target dose of 1000 mg BID after 1 week. For all patients receiving LIRA, the dose began at 0.6 mg QD and gradually reached the target dose of 1.2 mg QD after 1 week. Only 52 participants (25 in the MET group and 27 in the COM group) completed the 12-week follow-up; three participants conceived (one in the MET group and two in the COM group), and five participants could not be contacted at the end of the 122th week Figure 1The characteristics of the subjects at baseline are presented in P < 0.05) and 77.78% (21/27) in the COM group (P < 0.01). After the 12-week treatment, the recovery rate of menstrual cycle was 88.00% (22/25) in the MET group (P < 0.01) and 92.59% (25/27) in the COM group (P < 0.01). There was no difference between the two groups  in the MET group (o groups Table 2.P < 0.01) and the COM group (P < 0.01). After the 4-week and 12-week treatment, BMI was significantly decreased when compared with baseline in both the MET group (P < 0.01) and the COM group (P < 0.01). AG was also significantly decreased when compared with baseline after the 4-week and 12-week treatment in both the MET group (P < 0.01) and the COM group (P < 0.01). There was no significant difference between the two groups in improving body weight, BMI, and AG  and the COM group (P < 0.01). There was no significant difference between the two groups in improving FG, FINS, and HOMA-IR  and COM group (P < 0.01) (P < 0.01) while it was higher than baseline after both the 4-week and the 12-week treatment in the COM group (P < 0.01) (P < 0.01) and the COM group (P < 0.01) (P < 0.01), FSH (P < 0.01), Prog (P < 0.01), and TT (P < 0.01) improved significantly only in the COM group (P < 0.05) was observed only in the COM group  ng/mL vs. 1.08 (0.52–10.61) ng/mL, P = 0.020], TT , SHBG , and FAI  were significantly improved, and more improvement was observed in the COM group. There was no significant difference between the two groups in improving E2, FSH and LH/FSH (E2 increased when compared with baseline in both the MET group ( < 0.01) Table 2.This study was the first randomized controlled trial designed to compare the effect of MET monotherapy versus MET plus LIRA therapy mainly focusing on gonadal profiles in overweight patients with PCOS. Our results demonstrated that both MET monotherapy and MET plus LIRA therapy improved E2, SHBG and FAI, whereas only MET plus LIRA therapy improved LH, FSH, Prog and TT more effectively than baseline. Additionally, MET plus LIRA therapy was more effective than MET monotherapy in improving serum LH, Prog, TT, SHBG, and FAI levels after the 12-week treatment. We also found that both MET plus LIRA therapy and MET monotherapy improved menstrual cycles, anthropometric parameters, and glucose metabolism with no significant differences between the two groups.Approximately 98% of women with PCOS experienced menstrual disorders and infertility . Sever e2 and −4.2 ± 3.4 vs −2.2 ± 6.2 cm) within 12 weeks  ng/mL vs. 1.08 (0.52–10.61) ng/mL, P = 0.020] after 12 weeks of treatment, indicating the recovery of local hyperandrogenic state and ovulatory function of PCOS ovaries.HA is the most common hormonal change in PCOS, and women with PCOS typically present elevated serum levels of multiple androgens . Chen etP = 0.032], serum SHBG levels , and FAI  when compared with those in the MET group, indicating that MET plus LIRA therapy may be more effective than MET monotherapy in improving HA in overweight patients with PCOS.Women with PCOS typically have low serum SHBG levels owing to IR and obesity, thus resulting in high levels of bioavailable active free testosterone (FT), leading to higher rates of menstrual disorders, ovarian cysts, hypo-ovulation, infertility, and hirsutism. Therefore, both the decreased circulating insulin and improved IR status can cause the increase of serum SHBG levels, leading to the decreased serum FT levels, thereby improving outcomes in patients with PCOS . Nylande2 following a 24-week low-ketogenic diet. Preliminary studies have reported significant improvements in body weight, free testosterone, LH/FSH ratio, and FINS .Thanks to Editage for assisting with language editing services.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.


Using an admixed organic corrosion inhibitor is one of the most efficient strategies to enhance the corrosion resistance and durability of reinforced concrete. However, traditional admixed organic corrosion inhibitors only increase the corrosion resistance of the embedded reinforcing steel, and the optimization effect on the pore structure and the impermeability of concrete is very limited. In this study, in order to evaluate the corrosion-inhibition effect of a novel hydrophobic functional organic corrosion inhibitor, the adsorption behavior of a hydrophobic functional organic corrosion inhibitor and its related effect on the electrochemical behavior of the reinforcing steel was investigated. In addition, this paper further discusses the effect of a hydrophobic functional organic corrosion inhibitor on pore structure and hydrophobic properties, as well as the impermeability of concrete. The results indicated that the hydrophobic functional organic corrosion inhibitor was effectively adsorbed on the surface of the steel bar, and the higher adsorption content was relevant to the higher inhibitor dosage. On one hand, the hydrophobic functional organic corrosion inhibitor exhibited both a pore-blocking effect and a hydrophobic effect on concrete, leading to a refined pore structure and reduced capillary water absorption amount; on the other hand, the hydrophobic functional organic corrosion inhibitor exhibited an excellent corrosion-inhibition effect on the reinforcement embedded in the concrete, presenting an inhibition efficiency higher than 90% with a concentration of 4 wt.%. Reinforced concrete is the most widely used civil engineering material in marine environments. However, due to its porous microstructure, aggressive chlorides exhibiting small ionic radii and high chemical activity in seawater can transport through the concrete and reach the surface of reinforcing steel, thereby destroying passive film and inducing the localized corrosion of the reinforcement ,2,3. The2 and chlorides, increasing the critical chloride concentration for corrosion initiation and reducing the corrosion damage rate of the reinforcement [Among different corrosion protection strategies, admixed organic corrosion inhibitors are regarded as an effective way to enhance the corrosion resistance of reinforced concrete ,6,7. Comorcement ,9,12. Baorcement  and Wellorcement  illustraorcement  found th2, which was significantly smaller than the control specimen (20 μA/cm2); the inhibition efficiency was about 90%. It was reported [The high inhibition efficiency of various admixed organic corrosion inhibitors has been widely reported in the literature. Shen et al.  investigreported  that aftreported  found thp) of the reference sample was about 50.3 kΩ·cm2, and Rp increased to 77.1, 131.5, 192.4 and 213.6 kΩ·cm2 with 0.2, 0.4, 0.6 and 0.8 wt.% inhibitor in SPS, respectively. However, it is essential to clarify the influence of the hydrophobic functional organic corrosion inhibitor on the micro/macro properties of the concrete matrix and the corrosion performance of the reinforcement embedded in the concrete. To this end, the present study aims to evaluate the inhibition effect of the novel hydrophobic functional organic corrosion inhibitor on reinforced concrete. On one hand, the influence of the hydrophobic functional organic corrosion inhibitor on the micro/macro properties of concrete was investigated, including contact angle, pore structure and the water absorption behavior of concrete. On the other hand, the electrochemical behavior of the reinforcing steel embedded in concrete was characterized by OCP, electrochemical impedance spectroscopy (EIS) and potentio-dynamic polarization (PD).Based on the above literature review, it can be found that the interaction between the traditional admixed organic corrosion inhibitor and reinforcement and its corrosion-inhibition behavior has been strongly emphasized in previous studies. However, the influence of the traditional admixed organic corrosion inhibitor on the concrete matrix was less reported, especially regarding pore structure and the impermeability of concrete. This study belongs to a research project about the design and preparation of novel hydrophobic functional organic corrosion inhibitors for the corrosion protection of reinforced concrete serving in extremely harsh marine environments. The proposed organic corrosion inhibitor, on one hand, can strongly adsorb on the reinforcement surface and subsequently improve the corrosion resistance of the reinforcement; on the other hand, it can reduce the porosity and increase the hydrophobicity of concrete, halting chloride transport in the concrete matrix. The previous study  indicate− in concrete pore solution, releasing both a multisite adsorption group and a hydrophobic group. The released hydrophobic group can react with Ca2+ in concrete pore solution to form a hydrophobic film on pore walls, leading to the reduced porosity and increased hydrophobicity of concrete. In this way, chloride penetration in concrete is halted. Furthermore, the released multisite adsorption groups are efficiently adsorbed and generate a protection film on the steel surface, halting the adsorption of aggressive ions and enhancing the corrosion resistance of the reinforcing steel.The hydrophobic functional organic corrosion inhibitor  used in this study mainly consisted of glycosidic ketone, which was esterized and amidated from polyhydroxy amino organic molecules. As a result, the prepared hydrophobic functional organic corrosion inhibitor processes both hydrophobic groups and multisite adsorption groups, as shown in 2, NaOH, KOH and NaCl) were analytically pure.The cement used in this study was P.O. 42.5 ordinary Portland cement; its chemical compositions and particle size distribution are shown in 2 + 0.06 mol/L NaOH + 0.180 mol/L KOH; pH of the prepared SPS is 12.7.According to the literature , the rec2. The concentration of hydrophobic functional organic corrosion inhibitor in both cement paste and concrete was 0 wt.% (reference), 1 wt.%, 2 wt.% and 4 wt.% per dry cement weight, respectively. The curing conditions for the cement paste, concrete and reinforced concrete samples were 20 °C and 95% RH.In this study, the effect of hydrophobic functional organic corrosion inhibitor on the pore structure of the cement paste was evaluated with mercury intrusion porosimetry (MIP). MIP is widely adopted for investigating the porosity and pore size distribution of cement-based materials, i.e., cement paste, mortar and concrete. Many factors affect the accuracy of MIP results, mainly including sampling, sample conditioning, pressure application rate, maximum applied intrusion pressure, used contact angle and the surface tension of mercury. In addition, the expansion of sample cells under pressure, differential mercury compression, sample compression and the hydrostatic head of mercury also affect the accuracy of the MIP results. The parameter used for MIP tests in this study is consistent with the reported studies to guarantee the accuracy of the derived results. After curing for 28 days, the cement paste sample was crushed into small pieces  and immersed in ethanol for 7 days to stop hydration; the sample was then dried at 40 °C in a vacuum-drying chamber for 14 days before the MIP tests. The pore structure of the cement paste sample was analyzed with Auto Pore 9500 IV (micromeritics).Based on the MIP results, the pore diameter can be calculated based on the applied pressure using the Washburn equation :D = −4γcThe contact angle is used to evaluate the affinity between the solid surface and the liquid it is contacting: a smaller contact angle represents better surface wettability. A contact angle greater than 90° corresponds to a solid surface which is not wettable with the liquid. Otherwise, a contact angle less than 90° corresponds to a surface presenting good wettability with the formation of a larger solid–liquid interface.The contact angle was determined for both the cement paste and the concrete samples containing the hydrophobic functional organic corrosion inhibitor with different concentrations. The measuring range of the used contact angle instrument was from 1° to 180° with a resolution of 0.01°. At 28 days’ curing age, the contact angles at at least 10 different locations were measured after natural drying; the aggregates were carefully avoided when measuring the contact angle of concrete samples. There were 3 replicates for each specimen.2); w0 is the initial sample weight before water absorption (g); wt is the sample weight after water absorption at a specific time interval (g); and A is the exposed surface area of the cement paste or concrete sample (m2).The effect of the hydrophobic functional organic corrosion inhibitor on the capillary water absorption of both the cement paste and the concrete was evaluated according to the ASTM-C1585 standard. The advantage of the capillary water absorption test is that this measurement is quite easy to be conducted in a laboratory using the gravimetric technique. The shortcomings of the capillary water absorption test can be described as follows: first, the penetration depth and distribution of water molecules are unable to be obtained via this method. Furthermore, the influence of gravity on the capillary absorption coefficient should also be considered in long-term experiments. After curing for 28 days, the cement paste and concrete samples were dried at 40 °C until they reached a constant weight in the vacuum-drying chamber. The specimen weight was measured at an interval of 24 h until the fully dried state was achieved (about 7 days), i.e., the weight loss of the sample within 24 h was lower than 0.02 %. Afterwards, the other 5 surfaces were isolated with epoxy and only one surface was exposed to water the during capillary water absorption measurement to ensure one-way water transport . The top−2·h−1/2) and t is the absorption time (h).Subsequently, the capillary water absorption coefficient of the cement or concrete sample can be calculated as follows:2 was immersed in the above relevant SPS. At the immersion age of 7, 14 and 28 days, the TOC of the collected top SPS was measured. Based on the difference in the TOC of the SPS before and after adsorption, the adsorption amount of the hydrophobic functional organic corrosion inhibitor on the carbon steel surface of the SPS was calculated.In this study, the adsorption amount of the hydrophobic functional organic corrosion inhibitor on the surface of HPB235 carbon steel in SPS was evaluated using total organic carbon amount (TOC). The initial TOC of the SPS containing the hydrophobic functional organic corrosion inhibitor with different concentrations  was determined using a total organic carbon analyzer . Afterwards, HPB235 carbon steel with the dimensions of 40 mm × 40 mm × 5 mm and a working surface area of 28.660 cm−2 Hz–10−5 Hz at 10 mV. PD measurement was conducted in −200 mV–1000 mV (vs. OCP) with 0.5 mV·s−1.After 28 days of curing, reinforced concrete samples were half-immersed in 3.5 wt.% NaCl solution. The influence of the hydrophobic functional organic corrosion inhibitor on the electrochemical behavior of the reinforced concrete was evaluated using OCP, EIS and PD measurements at different immersion time intervals . The used equipment was Metrohm Autolab-Potentionstat PGSAT 302N, and a three-electrode set-up containing a reference electrode , a working electrode (reinforcement electrode) and a counter electrode (Ti mesh) was used for electrochemical measurements at 25 °C ± 1 °C. EIS measurements were conducted in 10The total porosity and pore size distribution of the cement paste with different dosages of the hydrophobic functional corrosion inhibitor at 28 days of curing are presented in The pore volumes and the different pore size ranges for the cement paste samples at 28 d of curing are summarized in Compared to the cement paste, the effect of the hydrophobic functional corrosion inhibitor on the contact angle was less pronounced for the concrete sample, as shown in −2 after 48 h of immersion. In the presence of the hydrophobic functional corrosion inhibitor, the capillary water absorption amount in the cement paste was significantly reduced; the lower capillary water absorption amount was relevant to the larger dosage of the hydrophobic functional corrosion inhibitor in the cement paste. After 48 h of immersion, the capillary water absorption amounts of cement paste were 5.81, 4.81 and 3.94 kg·m−2 with the inhibitor dosages of 1, 2 and 4 wt.%, which were reduced by 24.3%, 37.3% and 48.6% compared to the reference sample. The capillary water absorption amounts of concrete were all smaller compared to cement paste. However, a similar trend was also observed for the concrete samples , the capillary water absorption coefficients (k) for cement paste and concrete with different dosages of hydrophobic functional corrosion inhibitor were calculated, as presented in 2) in the SPS with 4 wt.% hydrophobic functional organic corrosion inhibitor after 7 d of immersion, which was already 90% of the adsorption amount after 28 d of immersion in the same solution (303.35 mg(L·cm2)). Furthermore, the larger adsorption amount was relevant to the larger initial content of hydrophobic functional organic corrosion inhibitor in SPS. After 28 d of immersion, the adsorption amount was 109.11, 149.43 and 303.35 mg(L·cm2) for the samples immersed in SPS with 1, 2 and 4 wt.% hydrophobic functional organic corrosion inhibitor, respectively. The results indicated that effective adsorption was relevant to the hydrophobic functional organic corrosion inhibitor on the carbon steel surface; the adsorbed corrosion inhibitor might increase the corrosion resistance of reinforced concrete, which was confirmed by the electrochemical measurements, as described in detail further below.The OCP of the reinforcement in the concrete immersed in 3.5 wt.% NaCl solution is presented in 2 and the reinforcement, normally the reinforcement embedded in concrete with a low internal humidity exhibits a more positive OCP [Due to the difficult contact between Otive OCP . In the tive OCP  that thes(RctQdl), embedded in s is concrete resistance, including electrolyte resistance; Rct is the charge transfer resistance of the embedded reinforcement; and Qdl represents the characteristic of the electrical double layer. A constant phase element (CPE) was used to represent the heterogeneity at the reinforcement/concrete interface [ct and Qdl of the reinforcement embedded in the concrete are summarized in ct of all samples increased during the first 56 d of immersion; after 72 d of immersion, the Rct of the reinforcing steel was slightly reduced. At each immersion age, the Rct of the reinforcement embedded in concrete admixed with the hydrophobic functional organic corrosion inhibitor was one order of magnitude higher than the reference sample; correspondingly, the Qdl of the reinforcement embedded in the concrete admixed with the hydrophobic functional organic corrosion inhibitor was lower than the reference sample. Furthermore, the higher Rct of the embedded reinforcement was relevant to the specimen with a higher dosage of the hydrophobic functional organic corrosion inhibitor. For example, at 56 d of immersion, the Rct values of the reinforcement embedded in concrete with 1, 2 and 4 wt.% hydrophobic functional organic corrosion inhibitor were 6.071, 8.310 and 25.578 kΩ/cm2, which were significantly higher than the Rct values of the reference sample (0.330 kΩ/cm2). The above experimental results indicate that the hydrophobic functional organic corrosion inhibitor effectively improved the corrosion resistance of the reinforced concrete.In this study, a Randles circuit  was one order of magnitude lower than the reference sample (in the range of 1.29 × 10−6−3.47 × 10−6 A/cm2). The significantly reduced corrosion current density was consistent with the increased Rct of the reinforcement derived from the EIS results in Based on the experimental results in this study, the hydrophobic functional organic corrosion inhibitor significantly altered the performance of the concrete and embedded reinforcement. For the concrete, the pronounced pore refinement was relevant to the specimen in the presence of the hydrophobic functional organic corrosion inhibitor, as evidenced by the reduced total porosity and content of large pores . FurtherIn this study, the corrosion performance of reinforced concrete in the presence of a novel hydrophobic functional organic corrosion inhibitor was evaluated. The hydrophobic functional organic corrosion inhibitor reduced the total porosity and amount of large pores, leading to a refined pore structure in the cement paste. Furthermore, the capillary water absorption amount of the cement-based materials was significantly reduced due to the reduced porosity and enhanced hydrophobic properties of the cement-based materials due to the hydrophobic functional organic corrosion inhibitor.The embedded reinforcement exhibited more positive open-circuit potential and a higher corrosion resistance in concrete admixed with the hydrophobic functional organic corrosion inhibitor due to the halted water and chloride transport process and, subsequently, the lower internal humidity of the concrete. Furthermore, the hydrophobic functional organic corrosion inhibitor was effectively adsorbed on the reinforcing steel surface, improving the corrosion resistance of the embedded reinforcement. The better corrosion-inhibition effect was relevant to the higher dosage of corrosion inhibitor in concrete. Therefore, the novel hydrophobic functional organic corrosion inhibitor exhibited very high inhibition efficiency, and can be potentially used for the efficient corrosion protection of reinforced concrete in severe marine environments.


The characterizations, drug release, in vivo biodistribution, and pharmacokinetics of the micelles were analyzed. The treatment efficacy of the dual-drug loaded micelles was evaluated in a subcutaneous colon cancer mice model. Sor is a common molecular target agent that can inhibit the mitogen-activated protein kinase (MAPK) pathway to treat solid tumors. Met can also regulate the MAPK pathway and inhibit the expression of the phosphorylated extracellular signal-regulated kinase (p-ERK). Moreover, both Sor and Met play important roles in cell cycle arrest. The integration of these two drugs aims to achieve synergistic effects against colon cancer. The micelles can be targeted to cancer cells and possess longer blood circulation time. The two agents can be released rapidly in the tumor sites. The in vivo study showed that the micelles can prevent tumor progression by inhibiting the expressions of p-ERK and cyclin D1. This study indicated that the Sor/Met-loaded micelles are suitable for CRC treatment.Colorectal cancer (CRC) is a common clinical disease with a poor prognosis and a high recurrence rate. Chemotherapy is important to inhibit the post-surgical recurrence of CRC patients. But many limitations restrict the further application of chemotherapy. In this study, sorafenib (Sor) and metformin (Met) co-loaded poly(ethylene glycol)-block-poly(L-glutamic acid- Colorectal cancer (CRC) threatens people's health seriously worldwide. Despite the advanced development in CRC diagnosis and surgical intervention, tumor recurrence tends to happen in lots of patients . SystemaNanotechnology, an emerging science, has promoted the development of pharmacy . The nanSorafenib (Sor) can decrease the phosphorylated extracellular signal-regulated kinase (p-ERK) levels and block the mitogen-activated protein kinase (MAPK) pathway to inhibit tumor progression , 15. Theco-L-phenylalanine) [mPEG-b-P(Glu-co-Phe)] micelles were prepared, followed by the encapsulation of Sor and Met. Herein, the copolymers can be self-assembled, and different components of the copolymer possess different functions to deliver Sor and Met. The PEG shell mainly provides the protective effects for the loading agents. Glutamic acid units assist in electrostatic interaction between the glutamic acid carboxyl group and the Met amino group. Sor is hydrophobic and can be loaded into the nanocarrier by physical embedding. Phenylalanine units increase the hydrophobic/aromatic interaction within the inner core of micelles  micelles (NSM) showed a better synergistic effect against colon cancer compared with free Sor and Met treatment. In this study, poly(ethylene glycol)-block-poly(L-glutamic acid-micelles . The chaco-Phe) and mPEG-b-P(Glu-co-Phe) copolymers, preparation of mPEG-b-P(Glu-co-Phe)/Sor/Met micelles, characterizations of copolymers, NSM stability, in vitro drug release, cytotoxicity assays, and cellular uptakes are shown in the The materials, synthesis of mPEG-b-P. BALB/c mice  and Sprague-Dawley rats  were used and bought from Jilin University.4 mL−1) into the right flanks of BALB/c mice. When the tumors were about 300 mm3, the animals were divided into three groups with six animals in each group, i.e., normal saline (control), free Sor and Met (SM), and NSM at Sor dose of 10 mg kg−1 and Met dose of 40 mg kg−1. Then, 100 μL normal saline, SM solution, or NSM solution was applied through the tail vein five times every 3 days.The subcutaneous animal model was established by injecting CT26 cells . NSM or SM solutions (2 mL) with equivalent Sor dose of 20 mg kg−1 and Met dose of 80 mg kg−1 were injected via tail vein. Blood samples were collected at different time points. The Sor and Met concentrations were analyzed with the HLPC method.Sprague-Dawley rats were divided into NSM and SM groups (The largest diameter (L) and smallest diameter (S) of tumors were measured every day, and the tumor volume was calculated with Equation .After 14 days post-treatment, all the mice were euthanized. The tumor growth rate (TGR) was calculated by the ratio of the tumor volume at 14 days post-treatment and the tumor volume before treatment. Blood samples were collected and the levels of ALT, AST, CK-MB, BUN, and D-Lac were analyzed by the ELISA method. The tumor weight of each sample was recorded.The tumor tissues and other major organs were stained with hematoxylin and eosin (H&E). The immunohistochemical assays were also applied to evaluate ERK, p-ERK, and cyclin D1 levels in tumor tissues. The positive cells were stained brown-yellow, and the relative positive area was analyzed by Image J .t-test were used. P < 0.05 indicated statistically significant, and P < 0.01 and P < 0.001 indicated highly statistically significant.One-way ANOVA and Student's b-P(Glu-co-Phe) copolymers  copolymers self-assembled in aqueous solutions and entrap Sor and Met within micelles. The electrostatic interactions between the drugs and polymers would benefit the release of drugs. The electrostatic interactions will be damaged in the acidic environment within tumor tissues, thus resulting in drug-releasing  and control group (P < 0.001), demonstrating that NSM possesses stronger cell proliferation inhibition efficiency than SM. However, NSM did not show severe cytotoxicity to normal human intestinal mucosa endothelial cells HIEC. The viability of HIEC cells was all above 85% and there was no significant difference in cell viability among all groups . However, there is no significant difference in the cellular uptake of Met between the two groups at 4 h. There is no difference in the Sor cellular uptake at 6 h between SM and NSM groups. The cellular uptake of Met is higher in the NSM group than that in the SM group at 6 h (*P < 0.05). This may be because free SM and NSM may have different cellular uptake methods, and mPEG-b-P(Glu-co-Phe) may increase the ability of Sor and Met to enter the cell. The cellular uptakes of Met and Sor in the NSM group are all above 90% at 6 h. The high cellular uptakes of Sor and Met could benefit the synergistic chemotherapeutic effects against CRC.Efficient cellular uptakes of drugs can increase antitumor activity. The cellular uptakes of Sor  and Met The biodistributions of Met and Sor in different tissues were detected with the HPLC method in this study.The amounts of Met and Sor were at higher levels in the tissues at 6 h post-injection than that at 12-h post-injection. There were more Met and Sor accumulated in the NSM groups than in the SM group. Met and Sor are mainly located in liver and tumor tissues in the subcutaneous colon cancer mice model . At 12-hb-P(Glu-co-Phe) micelles decreased due to the increased stability of polymeric micelles and sustained drug delivery possibly.Plasma pharmacokinetics of Met and Sor in SM and NSM are evaluated with HPLC post-intravenous administration . The Metin vivo antitumor efficiency, and the tumor weights are also recorded. The tumor weight is the least in the NSM group, and the difference is significant between SM and NSM groups (P < 0.001) (P < 0.05) and Control group (P < 0.01). As shown in P < 0.05). The general body conditions of animals are good after NSM treatment due to small toxicity. The results demonstrated that NSM possessed higher tumor inhibition efficiency over SM treatment. This is because of the increased accumulation of NSM and the fast release of Met and Sor from the micelles within the tumor tissues possibly.The subcutaneous colon cancer mice model was performed to evaluate the anticancer efficiency of NSM. After the sacrifice of mice, the tumors are carefully resected to further assess the < 0.001) . Consist< 0.001) . There iBiochemical analyses were applied to evaluate the general conditions of major organs. Besides, the toxicity of Met was evaluated by testing D-Lac levels, which were inclined to induce lactic acidosis .P < 0.05)  .The biological values of ALT, AST, CK-MB, BUN, and D-Lac are first tested in this study. The results do not reveal apparent damage in normal organs. H&E analysis of major organs is performed to analyze the security of NSM further. In the control group, the H&E staining of organs shows the normal histological structure . No obviThe ERK, p-ERK, and cyclin D1 levels were analyzed to reveal the anticancer mechanism of NSM.The MAPK/ERK pathway is one of the key pathways for solid tumor development. The inhibition of the MAPK/ERK pathway could not phosphorylate ERK, reducing the proliferation of tumor cells , 32. ImmCyclin D1 is one of the most important regulators of the cell cycle . The uprThe above results demonstrate that NSM mainly performs its tumor inhibition efficiency through downregulating the expressions of p-ERK and cyclin D1, thus inhibiting the MAPK/ERK pathway and influencing the cell cycle. As a result, the proliferation of tumors can be prevented.b-P(Glu-co-Phe) copolymer-based drug delivery system was developed. Sor and Met were loaded in the mPEG-b-P(Glu-co-Phe) micelles to achieve the chemotherapeutic effect. NSM can be targeted to cancer cells and release Sor and Met rapidly within tumors. A subcutaneous colon cancer mice model was developed to assess the anticancer efficacy of NSM. NSM can inhibit tumor proliferation through the synergistic effect of Sor and Met on blocking the MAPK/ERK pathway and arresting the cell cycle of colon cancer cells. All these results demonstrated the superiority of Sor/Met loaded-mPEG-b-P(Glu-co-Phe) micelles in the treatment of CRC.In this study, an mPEG-The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The animal study was reviewed and approved by the Experimental Center of Jilin University.XZ wrote the manuscript. LC, GX, and HH performed the study. HH analyzed the data. TL and HZ revised the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


In the outpatient management of severe wasting, routine antibiotic therapy is recommended for all children upon admission regardless of whether clinical signs of infection are present. Indicated antibiotic therapy, where antibiotics are provided only upon presentation of clinical signs of infection, may be considered for its potential to allow for more prudent antibiotic use and greater program coverage, reducing the risk of antibiotic resistance as well as costs and logistical burdens associated with treatment. We therefore conducted a cost-effectiveness analysis to measure the effects of indicated antibiotic therapy compared to routine antibiotic therapy in terms of incremental cost-per-life-year saved in Niger.We used a cohort model to conduct a cost-effectiveness analysis from a healthcare system perspective to project and weigh the lifetime discounted costs and effects of indicated antibiotic therapy compared to routine antibiotic therapy in the treatment of uncomplicated severe wasting in children in Niger. We calculated incremental cost-effectiveness ratios (ICERs) in terms of treatment-related healthcare costs per discounted life-years saved (LYS), and conducted program coverage scenario and sensitivity analyses to assess model uncertainty.The ICER for indicated antibiotic therapy compared to routine antibiotic therapy was $8.5/LYS, which is under the cost-effectiveness threshold for Niger. The probability of the indicated strategy being optimal was 76.1% when program coverage was equal to coverage associated with routine therapy but was 100% likely to be optimal in probabilistic sensitivity analysis scenarios where indicated program coverage improved 5 percentage points.Indicated antibiotic therapy likely represents a cost-effective strategy, particularly if indicated treatment can result in expanded coverage. With the risk of increasing antibiotic resistance worldwide, antibiotic stewardship and simplified treatment protocols for severe wasting using indicated antibiotic therapy may represent good value for money in some low risk populations.The online version contains supplementary material available at 10.1186/s12962-022-00374-z. Antibiotic resistance can cause infections that can be difficult and costly to treat and is a problem of growing concern . AntibioSevere wasting affects at least 14 million children under 5 years of age and contributes to more than half a million deaths each year , 3. In tIn 2014, we conducted a randomized, placebo-controlled trial among severely wasted children in Niger to assess the effect of indicated vs. routine antibiotic therapy on nutritional recovery . Indicated antibiotic therapy, where treatment was provided upon presentation with clinical signs of infection, was evaluated given its potential to allow for more prudent antibiotic use that could also reduce costs and logistical burdens associated with treatment. We found routine antibiotic therapy did not impact the likelihood of sustained nutritional recovery  or the risk of transfer to inpatient care up to 12 weeks, compared to indicated antibiotic therapy  [Global guidance on routine antibiotic therapy in the treatment of severe wasting should weigh both individual and public health risks and benefits, including the emergence of antibiotic resistance, possible individual side effects and cost and logistical considerations that enable scaling up within national nutritional programs. The optimal strategy would be associated with the best clinical outcome at the lowest price with the least selective pressure for antibiotic resistance. Assessing the cost-effectiveness of antibiotic therapy in the treatment of severe wasting aims to explore whether routine antibiotic treatment makes a sufficient contribution to health to justify its costs. To broaden the available evidence to inform use of routine antibiotics among malnourished children, we specifically conducted a cost-effectiveness analysis to measure the effects of indicated antibiotic therapy compared to routine antibiotic therapy in terms of incremental cost-per-life-year saved in Niger and formally evaluate the impact of program costs and increased coverage scenarios not captured in the trial but are nonetheless influential for decision-making.We developed a computer-based simulation model to estimate life expectancy and intervention-related costs of indicated vs. routine antibiotic therapy in the treatment of uncomplicated severe wasting in children in Niger. We compared the tradeoff between lifetime discounted health effects, quantified using life years saved (LYS), and treatment-related healthcare costs using incremental cost-effectiveness analysis from a healthcare system perspective. The simulation model discounted health effects and costs using an annual rate of 3.5%. An overview of our methodology is shown in Fig. Our model was structured for three time periods to match our data sources: 1) admission for outpatient severe wasting treatment to 12 weeks; (2) 12 weeks to 1 year; and (3) 1 year until death. The model population was determined by the proportion of children under 5 years of age  and the  admissioMortality risks were considered separately for the three time periods of the model  were based on whether or not the child experienced a second episode of severe wasting after recovery from the index case . The risk of relapse was assumed to be 10.5% –52 were  and a haIntervention costs considered all treatment-related healthcare expenditures from admission to 1 year, including inpatient care associated with transfer or non-response during treatment and relapse up to 1 year. Unit costs for expenditure within four major cost categories of treatment  were estimated using a micro-costing analysis of the treatment of severe wasting in Niger . MarginaWe used conventional incremental cost-effectiveness analysis methods to calculate an incremental cost-effectiveness ratio (ICER) for indicated antibiotic therapy compared to routine antibiotic therapy. Incremental effectiveness was defined using LYS as the difference in projected discounted life expectancy between the indicated versus routine antibiotic strategies. We used the per capita Gross Domestic Product (GDP) for Niger ($378 ) as our We limited the analytical time horizon to the 12-week trial period in sensitivity analysis. We further varied all model inputs through upper and lower bounds in one-way sensitivity analyses and performed a probabilistic sensitivity analysis by drawing 1000 model input parameters from the probability distributions shown in Table From a population size of 100,000, 20,430 individuals were estimated to be under 5 years of age, with 7764 total cases of severe wasting expected over a 12-month period. For this cohort of children with severe wasting, the model projected 395,043 undiscounted life years, 147,385 discounted life years, and $1,862,478 in treatment costs ($239.80 per child treated) with routine antibiotic therapy. The same results were 395,480 undiscounted life years, 147,552 discounted life years, and $1,863,897 in treatment costs ($240.10 per child treated) with indicated antibiotic therapy. The ICER (using discounted LYS) for indicated antibiotic therapy was $8.5/LYS compared to the routine antibiotic therapy . HoweveOne limitation of our analysis was that we modeled linear cost increases as coverage increased, although it is quite possible that costs increase non-linearly as program coverage is expanded to remote areas. Though data was lacking to define a non-linear cost-coverage function over the range of program coverage levels, our two-way sensitivity analyses showed that indicated antibiotic therapy was cost effective for any reasonable cost function. The threshold where indicated antibiotic therapy would no longer be cost effective (where Fig. Outpatient management for severe wasting has been adopted in over 70 countries  and all The present analysis used unique trial-based data and cohort models to examine life expectancy and treatment-related costs with extensive scenario and sensitivity analyses and adds new evidence to inform global guidance and practice on the use of routine antibiotics in treatment of severe wasting. While routine antibiotic therapy may provide clinical benefit in high risk populations, indicated antibiotic therapy represented a cost-effective strategy, particularly with program coverage expansion of 5 more percentage points. This information provides support for indicated antibiotic therapy in some settings, although future research on whether the indicated strategy could result in increased program coverage and the shape of the cost function from coverage expansions is warranted.Additional file 1: Figure S1. Schematic for modelled risk of mortality over time by treatment outcome.Additional file 2: Table S1. Costs of therapeutic food and medical supplies per child-outcome. Table S2. Costs of personnel, infrastructure and logistical support per fixed cost category. Table S3. One-way sensitivity analysis results. Table S4. Probabilistic sensitivity analysis results with varying levels of coverage for the routine and indicated treatment strategies.


Host–guest complexes, also known as inclusion complexes, are supramolecular structures ,2 composThe hosts have a cavity that allows them to behave as main host receptors with high affinity and selectivity for guest molecules. Macrocycles are generally used as host molecules . These molecules include cryptands , crown eIn the literature, there are multiple examples of the applicability of these supramolecular systems in numerous fields of science and technology, such as functional materials, catalysts, electronic devices, sensors, and in the pharmaceutical or food industries ,24,25,26In this Special Issue, entitled “Host–Guest Complexes”, structural aspects of the formation and stability of these complexes, as well as their characterization and aspects related to their technological applications, are addressed. Galmés et al.  addresseLikewise, corresponding results have been presented with the modification and/or improvement of physicochemical characteristics of substances associated with the use of inclusion complexes. This takes advantage of synergistic effects ,32 for iIn this Special Issue, findings in the field of biotechnology are also presented by García-Pérez et al. , such asIn short, the set of contributions that make up this Special Issue show that host–guest complexes constitute an interesting family of chemical structures whose study is an integral part of innovative current scientific research in the field of supramolecular chemistry. This is due to both the scientific interest they arouse and the multiple and varied applications in the field of new technologies in a large number of industrial sectors.