Background: Suspected early-onset sepsis (EOS) is the main reason for antibiotic therapy at the start of life. Prolonged antibiotic therapy for culture-negative sepsis is often reported. Antibiotic stewardship is mandatory due to the potential negative effects of unnecessary antibiotics. Procalcitonin (PCT)-guided therapy is one possible strategy with published evidence to shorten antibiotic therapy. The aim of this study is to analyze the feasibility and the performance of the published PCT-algorithm in the clinical setting without study support.Methods: This is a retrospective, population-based study regarding duration of antibiotic therapy for suspected EOS in Central Switzerland between 2014 and 2018. All neonates >34 0/7 weeks of gestational age started on antibiotic therapy for suspected EOS within the first 3 calendar days of life were included. The Procalcitonin-guided algorithm according to the NeoPInS study was used as strategy to determine duration of antibiotic therapy.Results: In a population-based cohort of 35,642 life born neonates, the duration of antibiotic therapy of 879 neonates (2.5% of the cohort) treated for suspected EOS was 4 calendar days . We observed a statistically significant reduction from 4  to 3 calendar days  from 2014 to 2018. Duration of antibiotic therapy was independent of gestational age (late-preterm vs. term neonates), of the presence of risk factors or clinical signs, but dependent on the presence of abnormal laboratory measurements (C-reactive protein > 10 mg/l or leukocytopenia <5 Giga/l) before start of antibiotic therapy (p < 0.01).Conclusions: PCT-guided therapy using the NeoPInS algorithm is feasible and may lead to reduced duration of antibiotic therapy for suspected EOS as reported in the original study. We observed a learning curve to the new algorithm which may be explained as change process. The use of biomarker to guide duration of antibiotic therapy for suspected EOS may have unintended consequences with prolongation of antibiotic therapy in some cases. Internationally, length of exposure to antibiotics at the beginning of life for suspected neonatal early-onset sepsis (EOS) varies significantly , 2. ManyBiomarker-guided therapy is one published approach reducing prolonged antibiotic therapy. The recently published NeoPInS study showed that duration of antibiotic therapy started for suspected EOS in late preterm and term neonates could be reduced with the use of a Procalcitonin (PCT)-guided algorithm . DuratioAt the Lucerne Children's Hospital, the PCT-guided decision-making algorithm for suspected neonatal EOS according to NeoPInS was introduced as standard of care in 2014. In this retrospective, population-based study we aim to analyze the impact of the implementation of PCT-guidance regarding duration of empirical antibiotic therapy for suspected EOS in late-preterm and term neonates of the area of central Switzerland from 2014 to 2018 and to show reproducibility of the results of the original study.This is a retrospective, population-based study in neonates regarding duration of antibiotic therapy for suspected EOS in Central Switzerland between 2014 and 2018 treated at Lucerne Children's Hospital. The study was approved by the regional Swiss ethical committee, which gave consent to collect individual data of all late preterm and term neonates started on antibiotic therapy within the first 3 days of life at the Children's Hospital of Lucerne between January 1st, 2014 and December 31th, 2018.All neonates >34 0/7 weeks of gestational age (GA) started on antibiotic therapy for suspected EOS within the first 3 days after delivery (birth = day 1) at Lucerne Children's Hospital between January 1st, 2014 until December 31th, 2018.Neonates started on antibiotic therapy for antibiotic prophylaxis  were excluded.The primary outcome is defined as duration of antibiotic therapy started for suspected EOS within the first 3 days of life, calculated annually and for 2014–2018. Secondary outcomes were duration of antibiotic therapy depending on GA (preterm infants 34 0/7–36 6/7 weeks of GA vs. term infants more than 36 6/7 weeks of GA), and on the presence of risk factors, and/or clinical signs, and/or laboratory signs possibly related to EOS. Therefore, the primary outcome is measured as change over time after the implementation of the NeoPInS algorithm with testing for possible confounding factors (secondary outcomes).n = 9) or in delivery houses (n = 2). The standard care of neonates within the first few days of life is taken by the head of the obstetric departments of the different hospitals together with liaison pediatricians. All hospitals and delivery houses are part of a network for neonatal care of Central Switzerland. Lucerne Children's Hospital is the only neonatal center of this network and responsible for neonatal transports within the area and special care for all neonates, including intermediate and intensive care. Neonatal antibiotic treatment in Central Switzerland is only performed in our hospital.Lucerne Children's Hospital is a tertiary neonatal center and the only Children's hospital in Central Switzerland serving a population of ~806,000 people . Within that area, birth rates are on average around 7,000 deliveries annually. Deliveries  are provided on the same campus as the Children's Hospital is located, in different regional hospitals : Screening-based approach for GBS was in place in all hospitals requiring a vaginal and perianal GBS-swab (detecting method: PCR) after 35 weeks of gestation. In unknown or positive GBS-status antibiotics are given immediately after rupture of membrane or latest 4 h before delivery.Strategy regarding start of antibiotic therapy: The Swiss guideline recommend to start antibiotic treatment (aminoglycoside combined with amoxicillin intravenously) for neonates with clinical signs possibly related to EOS . At absewww.nest-net.org], antibiotics were stopped 24 h after start. If PCT values were above the reference range, antibiotics were continued for at least 48 h. Continuation of antibiotic therapy after 48 h was dependent on culture results, clinical course, and C-reactive protein (CRP). In cases with high risk for culture negative sepsis antibiotics were continued for 5–7 days. Continuation of antibiotic therapy despite normal PCT values and negative cultures was possible and according to the assessment of the treating physician. The algorithm is available in the original study publication and at our research website www.nest-net.org . Duration of antibiotics given are defined by calendar days. Every day with at least one dose of antibiotics given is counted. Risk factors for EOS were defined accordingly to the Swiss guidelines regarding management for suspected EOS: (i) Maternal group B streptococci (GBS) colonization  (ii) prolonged rupture of membranes >18 h, (iii) chorioamnionitis  . ClinicaAll neonates admitted to the children's Hospital of Lucerne within the first 3 days of life were identified through the electronic encoding data base of the hospital. Within that list, all neonates born in central Switzerland of at least 34 0/7 weeks of gestational age receiving empirical antibiotics for suspected early onset sepsis were identified by review of the electronical discharge letter. Risk factors, clinical signs, laboratory values, duration of antibiotic therapy and results of blood cultures and cerebro-spinal fluid cultures were manually collected from the electronical data set for all neonates fulfilling the inclusion criteria. The culture positive neonates were cross-checked with the electronical data base of positive cultures of the microbiology department. The number of deliveries within the catchment area were collected from each obstetric department as well as from the two delivery houses.Descriptive data is presented as median and interquartiles  for continuous variables and as frequency (%) for categorical variables. Demographics and characteristics of patient groups were compared by using Fisher's exact test for categorical variables. Continuous variables were analyzed by Cuzick's non-parametric test for trend (a Wilcoxon-type test for trend), as well as by the Kruskal-Wallis test . Multiplp < 0.001 according to Cuzick's non-parametric test for trend), as well as for the proportion of infants started on antibiotic therapy . The proportion of hospitalized infants started on antibiotic therapy remained unchanged between 44 and 46% (p = 0.629).The cohort contained 35,642 neonates of at least 34 0/7 weeks of gestational age, born from January 1, 2014 to December 31, 2018 in Central Switzerland. Admitted to the Children's Hospital of Lucerne within the first 3 days of life were 1988 neonates (5.6%) and 876 (2.5%) were started on antibiotic therapy due to suspected EOS . There wMost neonates  started on antibiotics had clinical signs possibly related to EOS, whereas 385 (44.0%) had risk factors for EOS and 230 (26.3%) had laboratory abnormalities at start of antibiotic therapy . Risk fap < 0.001), as well as by the Kruskal-Wallis test (p < 0.001). In the multiple regression analysis, duration of antibiotic therapy was not depending on gestational age (late-preterm vs. term neonates) and clinical signs , but on the presence of abnormal laboratory measurements (C-reactive protein > 10 mg/l or leukocytopenia <5 Giga/l) before start of antibiotic therapy (p < 0.001) and the calendar year of birth (p < 0.001) . Analyses of annual duration of antibiotic therapy showed a reduction from 4  to 3 calendar days  from 2014 to 2018 . The tre< 0.001) . FurtherOur retrospective, population-based study over 5 years showed an overall duration of antibiotic therapy started for suspected EOS of 4 calendar days (IQR 2–5). Interestingly, there was a continuous reduction from 2014 to 2018 from 4 calendar days in 2014 (IQR 3–6) to 3 in 2018 (IQR 2–4). Abnormal biomarker measurements (leukocytopenia below 5 g/l and/or CRP >10 mg/l) at time of suspicion of EOS independently has led to a longer duration of antibiotic therapy. In this era of globally increasing antibiotic resistance rates, the World Health Organization has highlighted the urgent need for enhanced antimicrobial stewardship programs. In addition, the importance of the individual microbiome and the development at the beginning of life makes antibiotic stewardship to a mandatory task for every physician caring for neonates.Overall, 2.5% of our population in central Switzerland between 2014 and 2018 were treated with antibiotics due to suspected EOS within the first 3 days of life. This is comparable to other recently published population-based studies in Norway and the rate achieved by using the sepsis calculator , 17. A rThere are not many studies published reporting duration of antibiotic therapy for suspected EOS in population-based cohorts. Comparing our results of duration of antibiotic therapy for suspected EOS with the literature, we conclude that the PCT-guided algorithm of NeoPInS may shorten antibiotic therapy overall. Fjalstad reported a duration of overall 6 days  for term neonates with culture-negative EOS and 4 days  for “rule-out” sepsis situations in a population-based cohort of 3,964 neonates treated with antibiotics for suspected EOS . DretvicThe observed continuous reduction of duration of antibiotic therapy from 2014 to 2018 may be reasoned as learning curve to PCT guidance. Whereas, our center was part of the NeoPInS study, junior physicians and even consultants were not really familiar with the use of the algorithm due to regular rotations of the staff. Implementation of a new management algorithm means always a change. Not all staff members are convinced from the beginning and it takes time to adapt and to trust a new management strategy. Recent studies have shown that compliance with neonatal antimicrobial stewardship programs are not easy to obtain –23. On tImportant to note, biomarker guidance may not have only beneficial effects. Abnormal biomarker measurements at the time of the first dose of antibiotics has led to a prolonged duration of antibiotic therapy. Even more, the effect of abnormal biomarker measurements showed the highest odds ratio for prolonged duration of antibiotic therapy in the multiple regression analysis. This shows the challenge of the use of biomarkerfor guidance of therapy: The heuristics of the human brain regarding decision making is potentially biased and works often in a dichotomized way . If a meThe main weaknesses of our study are 2-fold: First, the low rate of culture proven EOS hinders us to make any conclusion regarding the safety of the NeoPInS approach in our study. Nevertheless, together with the original NeoPInS study, the data base is getting stronger showing that there are no missed sepsis cases and no sepsis-related mortality. Secondly, due to the implementation of the NeoPInS algorithm as the new standard for care, we did not have a control group. Therefore, it is not possible to make any judgment regarding the impact of the new strategy compared to the situation without algorithm. The significant trend of annual shortening of the duration of antibiotic treatment from 2014 to 2018 is a hint that there is a benefit through the new strategy, whereas we really do not know what had the biggest impact. The strengths of the study are the population-based cohort with an unchanged protocol and unchanged guidelines regarding management for suspected EOS within the 5-year time-frame.We conclude, that PCT-guided therapy using the NeoPInS algorithm is feasible and may lead to reduced duration of antibiotic therapy for suspected EOS as reported in the original NeoPInS study. We observed a learning curve to the new algorithm which may be explained as change process. The use of biomarker to guide duration of antibiotic therapy for suspected EOS may have unintended consequences with prolongation of antibiotic therapy in some cases. Further studies analyzing an educational intervention and the impact of the newly launched NeoPInS app are potential next steps in the ongoing endeavor to improve antibiotic stewardship at the beginning of life.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethikkommission Nordwest und Zentralschweiz EKNZ. Written informed consent from the participants' legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.JZ-J, MS, and DL: study concept and design which was approved by all authors, supervision and monitoring data entry, and checking database for accuracy. JZ-J, MS, and CB: data collection. DL: statistical analysis. JZ-J, MS, DL, MB, and MH: analysis and interpretation of data. All authors read, critically revised and approved the manuscript, approved the final version, and agree to be accountable for all aspects of the work.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.


To reconstruct locomotor behaviors of fossil hominins and understand the evolution of bipedal locomotion in the human lineage, it is important to clarify the functional morphology of the talar trochlea in humans and extant great apes. Therefore, the present study aimed to investigate the interspecific-differencesof the talar trochlear morphology among humans, chimpanzees, gorillas, and orangutans by means of cone frustum approximation to calculate an apical angle and geometric morphometrics for detailed variability in the shape of the talar trochlea. The apical angles in gorillas and orangutans were significantly greater than those in humans and chimpanzees, but no statistical difference was observed between humans and chimpanzees, indicating that the apical angle did not necessarily correspond with the degree of arboreality in hominoids. The geometric morphometrics revealed clear interspecific differences in the trochlear morphology, but no clear association between the morphological characteristics of the trochlea and locomotor behavior was observed. The morphology of the trochlea may not be a distinct skeletal correlate of locomotor behavior, possibly because the morphology is determined not only by locomotor behavior, but also by other factors such as phylogeny and body size. Clarifying the pattern of the morphological variations of the talar trochlea in humans and non-human great apes and how it possibly corresponds to the differences in their locomotor behavior is therefore of particular importance in reconstructing locomotor behaviors of fossil hominins and understanding the evolution of bipedal locomotion in the human lineage5.Reconstructing the locomotor behaviors of early hominids from their fossilized skeletal remains is vital to clarify the origin and evolution of human obligatory bipedal locomotion. Among all the skeletal elements, the human talus, or ankle bone, is known to be highly specialized to adapt to bipedal locomotion in the course of human evolution, as the foot most directly interacts with the ground or tree substrates during locomotion. Specifically, the morphology of the talar trochlea imposes the axis of rotation and the range of motion of the foot with respect to the tibia2. Owing to the conical shape of the trochlea, the axis of rotation of the foot with respect to the tibia is considered to be inclined medially so that the anterior foot is naturally abducted and inverted during ankle dorsiflexion, and vice versa during plantarflexion1. In great apes, the apex angle of the conical trochlea was reportedly much larger than that of humans2, indicating that such natural concomitant abduction and inversion of the ankle joint due to dorsiflexion is larger in great apes3. Larger abduction and inversion of the foot during ankle dorsiflexion allows the plantar surface of the feet to be placed parallel to the arboreal substrate (tree trunk) for firm gripping6. Therefore, the larger apex angle of the cone-shaped trochlea in great apes is considered an adaptation to vertical climbing and arboreal locomotion3.It has been suggested that the articular surface of the talar trochlea in humans is shaped like the surface of the frustum of a cone with the apex oriented medially (but not like the surface of a cylinder), as the radius of curvature of the medial side of the trochlea is smaller than the lateral side7. The talar angle is defined as the angle on the coronal plane formed by a line representing the superior surface of the talar trochlea and a line connecting the inferior-most points of the tibial and fibular facets that reportedly approximates the axis of rotation of the ankle joint3. However, the surface of the cone frustum and the axis of rotation of the ankle joint are essentially three-dimensional (3D), and the apical angle cannot necessarily be estimated two-dimensionally in the coronal plane. Therefore, the talar angle may have underestimated or overestimated the true apical angle. If the articular surface of the talar trochlea was three-dimensionally fitted by the surface of the frustum of a cone, the true apical angle of the trochlear surface could be quantified and compared, possibly providing useful morphological correlates of talocrural mobility and locomotor behavior. However, no studies have attempted to mathematically approximate the talar trochlea by a conical surface to three-dimensionally quantify the apex angle of the cone frustum, although the trochlea surface has been previously approximated by a plane9, cylinder9, and paraboloids10 for morphological analyses of the articular surface. Inman1 carried out the only study to measure the apex angle of human tali by physically placing a metal rod through the hole of the ankle axis and metal wires on the trochlear surface such that they intersected with the rod; however, it was not an elaborate approximation of a surface by minimizing the sum of the squared distances between a set of points comprising the talar trochlea and the surface of the cone.Previous studies have quantified the talar angle  to estimate the apex angle of the talar trochlea to infer the axis of rotation of the ankle joint and the degree of arboreality14. However, these studies compared the overall talar morphology but did not analyze the detailed trochlear morphology. Sorrentino et al.5 has recently analyzed detailed morphological variations of all the talar articular surfaces including that of the trochlea using geometric morphometrics and demonstrated that the humans possessed mediolaterally wider, flatter, and more squared talar trochlea than chimpanzees and gorillas. However, the study did not investigate the apical angle of the talar trochlea. In addition, the orangutan tali were not included in their analysis since the aim was to identify the overall morphological affinity of the fossil tali in the tali of humans and African great apes, but not to extract possible morphological correspondence between trochlear morphology and locomotor behavior.The present study aimed to investigate the apical angle of the talar trochlea of human and great ape tali by means of cone frustum approximation. Specifically, we investigated whether the talar trochlea can be approximated by the cone surface, and if there was a possible correspondence between the apex angle and differences in locomotor behavior and the degree of arboreality among humans and great apes. In addition, since the cone frustum is a simple approximation of the talar trochlea, we also conducted a geometric morphometric analysis of the trochlear morphology, namely the medial and lateral rims and the central groove of the trochlea, to extract possible correlates of talocrural shape and locomotor behavior. Previous studies investigated the morphological variations of the talus among humans and great apesPan troglodytes troglodytes, 5 P. troglodytes schweinfurthii, 4 P. troglodytes verus, and 1 P. troglodytes hybrid), 20 gorillas (18 Gorilla gorilla gorilla and 2 G. beringei beringei), and 20 orangutans (19 Pongo pygmaeus and 1 Pongo abelii) were used for the analysis. Human specimens were collected at the University Museum, University of Tokyo. Wild specimens of 10 chimpanzees, 10 gorillas and 14 orangutans were obtained from MorphoSource . Specimens of seven chimpanzees, five gorillas, and four orangutans were captive cadaver feet donated to the Primate Research Institute, Kyoto University from zoos in Japan. Three dry bone specimens of chimpanzees were of wild individuals from the Mahale Mountain National Park, Tanzania. Five dry bone specimens of gorillas were of captive specimens housed at the National Museum of Nature and Science, Japan. Two dry bone specimens of orangutans were collected at the Laboratory of Physical Anthropology, Kyoto University. Tali from seven Japanese macaques (Macaca fuscata) were also included in this analysis as an outgroup. They were captive dry bone specimens housed at the Laboratory of Physical Anthropology, Kyoto University, except for one cadaver specimen studied in Ogihara et al.15. All samples were adult and free of obvious pathology. All tali were segmented from the CT scans, and bone models of the tali were generated in Mimics 22.0 . The left tali were mirrored and analyzed as right-sided specimens. Pixel size and slice interval of the CT scans were 0.16 mm for humans, ≤ 1.0 mm for chimpanzees, gorillas and orangutans, and ≤ 0.2 mm for Japanese macaques.Computed tomography (CT) scans of tali from 20 humans, 20 chimpanzees  .7, each talus was placed in a 3D space so that the plantar edge of the calcaneal facet and the inferior aspect of the talar head were on the same plane, and the medial and lateral malleolar facets were in the same coronal plane3. The angle between the line connecting the superior-most points on the medial and lateral trochlear rims and the line connecting the inferior-most points on the articular surfaces of the medial and lateral malleoli in the coronal plane was measured as the talar angle  of shape variations among specimens.The medial and lateral rims and the central groove of the trochlea were approximated by a fifth-order Bezier curve using custom-made softwareted Fig. , and theP-value set at P < 0.005 (0.05/10), was used if tests for normality or homogeneity of variance failed. Normality and homogeneity of variance were tested using the Shapiro–Wilk test and the Bartlett’s test, respectively. To test for significant difference between the apical and talar angles in each species a paired t-test was performed. The correlation between these angles was analyzed using Spearman’s rank correlation coefficient. The statistical significance level was set at P-value < 0.05. Data processing and analyses were implemented in the open source R software, version 3.5.223 using the R package “geomorph”.The apical angle of the cone and the PC scores were compared among species using analysis of variance (ANOVA). If ANOVA was significant, a post-hoc Tukey’s HSD test was performed. The Kruskal–Wallis test with a post-hoc Wilcoxon rank-sum test for multiple comparisons, followed by Bonferroni correction with the adjusted t-test or Wilcoxon rank-sum test.Both wild and captive specimens were included in the present study. To investigate the possible differences in the trochlea morphology between wild and captive specimens of the same species, we tested if the mean PC scores were statistically different between wild and captive specimens in chimpanzees, gorillas and orangutans using two-tailed The cone frustum surfaces that approximated the trochlear articular surfaces of each representative human, chimpanzee, gorilla, orangutan, and macaque tali, along with the calculated apical angles, are presented in Fig. x2 = 36.7, P < 0.0001). The apical angle of gorillas was found to be significantly larger than that of humans (P < 0.0001) and chimpanzees (P < 0.0001). The apical angle of orangutans was also significantly larger than that of humans (P = 0.0002) and chimpanzees (P < 0.0001). In addition, the apical angle of Japanese macaques was significantly larger than that of humans (P = 0.0003) and chimpanzees (P = 0.0007). However, no statistical difference was detected between the apical angles of humans and chimpanzees.Figure 7. However, the apical angles were significantly smaller than the talar angles in humans (P = 0.04) and chimpanzees (P = 0.01) while those in gorillas and Japanese macaques were significantly larger than the talar angles  , but the correlation coefficient was not large (R = 0.379), indicating that the talar angle did not clearly correspond with the apical angle.Figure The results of the geometric morphometric analysis of the trochleae are presented in Fig. x2 = 57.4, P < 0.0001), PC2 , PC3 , PC4 , and PC5 . The pattern of shape variations in Fig. ANOVA and the Kruskal–Wallis test identified significant differences in the trochlea shape among species for PC1  conventionally used to estimate the apical angles of the cones7 . Geometrically, the talar angle should be half of the apical angle because the cone apex is at the intersection between the line passing through the supratalar surface and the talocrural rotational axis corresponding to the cone axis, and the talar angle is the angle between the two lines on the coronal plane. However, this geometrical relationship was not clearly observed in our study , but not that of chimpanzees (P = 0.149). These findings suggest that the talar angle may not be as different as once thought between humans and chimpanzees. Humans engage in habitual bipedalism. Gorillas engage in knuckle-walking and are regarded as the most terrestrial of the great apes, although western lowland gorillas are known to climb on trees for feeding to some extent26. Chimpanzees also engage in knuckle-walking and travel between feeding trees mainly on the ground27, but they frequently engage in vertical climbing and suspensory locomotion as well29. Orangutans are fundamentally quadrumanous climbers in the rain forest canopy, and they seldom walk on the ground32. Therefore, there is a distinctive difference in the degree of arboreality among species. However, the present study suggested that the apical  angle is not clearly associated with the degree of arboreality in humans and great apes.The present study demonstrated statistically significant interspecific differences in the apical angle. The apical angles of the humans and chimpanzees were significantly smaller than those of gorillas and orangutans, but no statistical difference was detected between humans and chimpanzees, as well as between gorillas and orangutans Fig. . This re34. It was also found that chimpanzees and gorillas possessed more trapezoidal trochleae than humans  trochleae did not exhibit such a feature, but the trochlea was more rectangular than those of the other species, possibly to adapt to increased contact force during plantarflexion, particularly in the late stance phase of human walking36. The gorilla trochlea differed from that of the other four species in having a less-curved posteromedial trochlea, more medially projected medial malleolar extension onto the talar neck, and deeper central groove. The former two features may be related to the reduced range of the talocrural joint in gorillas to accommodate their large body mass38. The enhanced central groove provides increased stability of the talocrural joint in the mediolateral direction. The orangutan trochlea is unique in having a wider posterior margin of the trochlea and a more dorsally turned anteromedial and posterolateral trochlear surface, indicating that the trochlear surface is relatively flatter. The functional significance of this morphological feature is obscure, but it might be related to the fact that the orangutan foot functions as a suspensory supporting organ for hook-like digital gripping without involvement of the hallux, although in the chimpanzee and gorillas, the foot may be adapted to hallux-assisted power gripping39. However, to make further inferences about the form-function relationship of the talar trochlea, data on actual foot use in African great apes and orangutans during terrestrial and arboreal locomotion are lacking and should be investigated in future studies.Our geometric morphometric analysis clearly extracted and visualized interspecific differences in the shape of the talar trochlea among humans and great apes, which were not clearly observed in the comparisons of the apical and talar angles. Chimpanzees, along with macaques, possessed a longer and highly curved talar trochlea Fig. A. The loans Fig. A as repo3, but the apical angle of the trochlea was not substantially different between humans and chimpanzees (Fig. 5 indicating that the morphology of the hominin trochlea is not unequivocally linked to locomotor behavior. Therefore, caution needs to be exercised in assessing the morphological affinities of fossil hominid tali to reconstruct their locomotor behavior.The present study demonstrated that the talar trochlea was clearly different in shape between humans and great apes. However, the present study also found that the talar shape was not clearly associated with the differences in locomotor behavior and the degree of arboreality among the species. For example, the apical or talar angle of the trochlea is believed to be correlated with the degree of foot inversion facilitating vertical climbing by positioning the foot sole against the tree substrateees Fig. . In addiees Fig. A demonst40 and fibula41, which are also important determinants of the mobility of the talocrural joint.The present study has some limitations. First, the apical angle of the cone may be affected by the manual extraction of the trochlear surface. However, we defined the extracted region as objectively as possible; hence, this effect was confirmed to be relatively minor. Second, the present study included both wild and captive specimens in non-human species. However, we confirmed that the use of captive specimens has only minor effect on our results . Third, In conclusion, we demonstrated that the trochlea of the talus can be approximated by a conical surface in humans and great apes. However, it was found that the calculated apical angle did not clearly correspond to the degree of arboreality. Our detailed trochlear shape analysis using geometric morphometrics successfully extracted interspecific differences in the morphology of the trochlea; however, no clear association was observed between the morphology and locomotor behavior. The morphology of the talar trochlea may not be a distinct skeletal correlate of locomotor behavior.Supplementary Information.


We consider a class of functions defined on metric spaces which generalizes the concept of piecewise Lipschitz continuous functions on an interval or on polyhedral structures. The study of such functions requires the investigation of their exception sets where the Lipschitz property fails. The newly introduced notion of permeability describes sets which are natural exceptions for Lipschitz continuity in a well-defined sense. One of the main results states that continuous functions which are intrinsically Lipschitz continuous outside a permeable set are Lipschitz continuous on the whole domain with respect to the intrinsic metric. We provide examples of permeable sets in  I that have a certain property  when restricted to a subset I. The complement exception set for the function’s property. A particularly common example here is the case of a finite exception set I into several parts or pieces, hence leading to the notions of piecewise continuous, differentiable, etc. functions. The property which will be of our interest is the one of Lipschitz continuity and our work is motivated by the desire to generalize the notion of ‘piecewise Lipschitz continuity’ to the multidimensional case. Consider the following definition:Exception sets for the regularity of a function are encountered when considering functions piecewise Lipschitz continuous if there exist finitely many points A function With this definition, the following result is easily proven :f is Lipschitz continuous.Let piecewise linear (pl) or piecewise differentiable (pdiff) functions, see e.g., , so we can writeK is large enough to guarantee that for every interval j the functions g is contained in a single Step 3 Write L, we have for every finite collection of paths UVK big enough to ensure k with the type . Now we k with the paths the line segments from Summing up, we get for the length of Denote by Let Then every continuous function This follows immediately from Corollary x and y of length smaller than 2 which has a finite intersection with Consider the topologist’s sine:The following example shows that one cannot simply dispense with the assumption that the exception set is topologically closed.C is the topological closure of the setRecall that the classical Cantor set By extruding We conclude this section with more examples of permeable sets. First note that we can somewhat relax the requirement that a Lipschitz manifold be a closed subset of transversal intersection:The conclusion of Theorem intersect transversally in open sets a linear subspaces such that Let intersect transversally iff they intersect transversally in every We say top- or lip-submanifold, one has to replace In the cases of a lip-submanifolds differs only in the construction of the paths lip-submanifolds. Similar arguments yield that a topologically closed lip-submanifold with boundary is permeable.The proof of Theorem As unions of affine hyperplanes exhibit transversal intersections, they are permeable. Hence piecewise Lipschitz functions in the sense of Definition Let B on some probability space top-submanifold (with boundary), but not a lip-submanifoldP to g, which is Hölder continuous with exponent smaller g). See also the related questions in [The motivation for this example comes from the standard result from probability theory that almost every path of an m 1.5 in . It statm 1.2 in  states t


Self-sensing concrete (SSC) has been vastly studied for its possibility to provide a cost-effective solution for structural health monitoring of concrete structures, rendering it very attractive in real-life applications. In this review paper, comprehensive information about the components of self-sensing concrete, dispersion methods and mix design, as well as the recent progress in the field of self-sensing concrete, has been provided. The information and recent research findings about self-sensing materials for smart composites, their properties, measurement of self-sensing signal and the behavior of self-sensing concrete under different loading conditions are included. Factors influencing the electrical resistance of self-sensitive concrete such as dry-wet cycle, ice formation and freeze thaw cycle and current frequency, etc., which were not covered by previous review papers on self-sensing concrete, are discussed in detail. Finally, major emphasis is placed on the application of self-sensing technology in existing and new structures. Concrete is the second most widely used material, with around 30 million tons consumed annually. It finds its application in pavements, buildings, nuclear power plants and dams,  etc. DifThe introduction of self-sensing concrete could help to sense and monitor concrete structures, thus allowing the improvement of safety, durability, serviceability and reliability. Intrinsic self-sensing concrete (ISSC) consists of incorporating functional fillers such as carbon black (CB), carbon fibers (CF), graphite powder (GP), carbon nanomaterials and others into conventional concrete, thus improving mechanical properties and providing the ability to monitor damage and stress/strain . DiffereOverall, the properties of SSC are influenced by many factors and initial conditions such as material selection, particularly the matrix material, functional filler, dispersion material and further dispersion processes. An important step in the preparation procedure is the mix design, which includes the selection of the optimal concentration of functional fillers that differs according to the material. Hence, the final SSC design is different and highly dependent on the properties of the fillers. Similarly, the methods and materials used to monitor the sensing abilities of concrete differ and are mainly selected based on the preferences of the researchers. In studies related to the application of SSC, the final results vary according to the loading conditions and depend on the factors affecting its electrical resistivity. In addition, the conductive mechanism in concrete changes depending on the type of load, which affects the concentration of the functional filler in certain areas. By improving the properties of SSC, the real-life application of it has a promising potential in various fields, which can be demonstrated by practical experiments carried out by researchers.In this review paper, a comprehensive approach to the use of self-sensitive concrete starting from material selection to its application is described using existing literature and research. It is novel in the sense that it includes an up-to-date detailed description of the experimental investigations performed in the area of SSC. The details of the factors influencing its sensing properties such as dry-wet cycle, ice formation and freeze thaw cycle and current frequency, etc., which were not covered by previous review papers on SSC, are incorporated. Finally, this review paper aims at providing readers extensive up-to-date information about the potential application of self-sensing technology. The review paper starts with providing information about the components of SSC, dispersion methods and mix design. The details about the measurement of self-sensing signal and the conductive mechanism of SSC with and without external loading are provided in Self-sensing function of the concrete is obtained from the piezoresistive effect of functional fillers, which are dispersed in the matrix phase and form a conductive network. Therefore, when concrete is subjected to some force, the network alters, and it results in a change in electrical resistance. Overall, the self-sensing concrete has a very complex structure, and for a detailed description of the basic concepts, the next section focuses on matrix material, functional filler, dispersion methods, mix preparation and design.The composition of SSC includes matrix material, functional filler and dispersion material. Here, the matrix material is usually represented as conventional concrete, and it could be made of cement, mortar and paste . The maiSelf-sensing concrete mainly achieves its properties because of the inclusion of conductive functional fillers such as carbon black (CB), short and continuous carbon fibers (CF), steel slag (SS), nickel powder (NP), magnetic fly ash (MFA), graphite powder (GP) and carbon nanomaterials functional fillers such as carbon nanotubes (CNT) and carbon nanofiber (CNF) . Some hyElectrical conductivity plays an essential part in SSC characteristics. According to Heilig , this paDifferent methods could be used for the proper dispersion of fibers and can be divided into physical and chemical methods. The physical methods include processes such as sonication, ball milling and mechanical stirring . AlessanChemical methods for dispersion include surfactants and mineral admixtures . AccordiNevertheless, two methods, including chemical and physical, could be applied at the same time. In the experimental study conducted by Faghih  to dispeThe mix preparation design for self-sensing concrete follows a similar protocol as in the case of conventional concrete design except for the addition of filler in self-sensing concrete. Due to high surface area of the filler, the workability of the concrete mix could be affected, and the chemicals that are used as dispersant materials could influence the mechanical properties of SSC at the same time. The addition of a specific percentage of filler in the mix should be carefully selected to achieve the desired results. For instance, it was found that the increase in CNF from 0.25% to 1.0% volume fraction of the concrete resulted in the decrease in electrical resistance by nearly half of the initial value . CompareIn general, there are three types of dispersion processes regarding the addition of functional fillers, and they are classified as the first admixing method, synchronous admixing method and latter admixing method . Mostly,There are many factors, such as reactance, electrical resistance, dielectric constant, impedance and capacitance, for determining the sensitivity of the concrete . HoweverThe research conducted by Wen and Chung  comparedThe authors Wen and Chung  performeThe influence of DC and AC electrical circuits on self-sensing concrete containing conductive particles should also be mentioned. The use of DC has been shown to be economically viable and useful for laboratory applications to characterize cement composites . It shouFunctional fillers inside of SSC behave differently during loading and non-loading conditions. Different concentrations of filler materials in SSC could be divided into various zones that have different electrical resistivity.The concentration of functional fillers inside of the concrete matrix influences the change of electrical resistivity. The relationship between them is demonstrated in Zone A is called the insulation zone, and it is characterized by a low concentration of fillers and large spacing between them. The large distance between fillers results in the problematic formation of the conductive path, which creates difficulties for the electron’s movement and causes lower conductivity of SSC. In this region, the ionic conduction prevails in the concrete matrix .Zone B, which is the percolation zone, contains an increasing concentration of the fillers in the concrete matrix, thus providing smaller spacing for fillers and creating a better conductive path. Due to easier electronic transition, the conductivity of the sensing concrete increases. In the percolation zone below the percolation threshold, different types of conductions dominate, such as contacting conduction, tunneling conduction and ionic conduction. After the concentration of fillers surpasses the percolation threshold, the tunneling conduction and direct contact between functional fillers prevail in conductivity .Zone C is a conductive zone that is described as a zone with a high concentration of the functional fillers, which mostly has total contact with each other; thus, the prevailing conduction in this region is the direct contact between fillers .During the loading condition, the electrical resistivity of SSC changes, and this is caused due to the change of several factors: intrinsic resistance, bonding between concrete matrix and fillers, contact between fillers, tunneling distance and capacitance ,46,47,48The mentioned factors could work together and have an impact on the sensing properties of concrete. In the insulation zone (Zone A), the conductivity of the concrete is very low, and it is difficult to create the conductive pathway there. Therefore, the self-sensing response in this zone is weak or completely absent during loading conditions due to high electrical resistivity. In the inchoate of zone B, the factors such as change of capacitance, intrinsic resistance of fillers and the change of bonding between concrete matrix and functional fillers mainly prevail. Near the percolation threshold zone, the main influencing factor is the variation of tunneling distance, while the dominant factors are the change of contact between fillers, tunneling distance between fillers and intrinsic resistance of fillers at the end of zone. The sensitivity of the concrete is good in this zone due to many factors that affect the sensing properties .In the conductive zone, C, the leading factors are the change of contact between fillers and the change of intrinsic resistance due to the dense packing of the fillers and their close contact. Consequently, in the composites, the change in sensitivity is hard to achieve, and low initial electrical resistivity also prevails here. As a result, in the formation of SSC, the percolation threshold is an important parameter because it represents the balance between low functional fillers concentration, high sensitivity and low electrical resistivity, thus helping to find an optimum design of the concrete . The relationship between change in electrical resistivity and external force can characterize the sensing behavior of concrete. Additionally, the stress sensitivity coefficients, amplitude of change in electrical resistance and force sensitivity coefficients are other factors that can describe such an important parameter as concrete sensitivity. Overall, the main concept of self-sensing is that concrete can demonstrate different sensing behaviors at various loading types, such as compression, tension and flexure, and it can be affected by many factors that have an impact on the electrical resistivity of the composites, which is described further.Different behavior of SSC can be observed at various loading types . During During the loading stage, when the sample is subjected to repeated compression, the electrical resistivity pression . The reaversible . The excOne of the most common loads to which concrete structures are subjected to is an impact load. During impact loading, During the monotonic tension, the electrical resistivity  created . HoweverWhen the sample is subjected to the repeated tension, the electrical resistivity increases with loading, but the electrical resistivity decreases during the unloading phase. The behavior of the change in the mplitude . In partTension and the compression parts of SSC work in the opposite way when the beam is subjected to the load at the center , as can According to the research study conducted by Wang et al. , the eleElectrical resistivity can be influenced by many factors, including the external forces, components of the concrete, technology used and different environmental conditions  4]. The. The4]. The concentration of the fillers in the composite affects the distribution and also a formation of the conductive network; hence, it is one of the most important parameters that influence the properties of SSC . The depThe geometrical shape of fillers, including parameters such as structure, size and surface characteristics, also impacts the sensing properties of the concrete as it affects the conductive network. For instance, long carbon fibers can create a more continuous network, thus providing lower resistivity of cement composite but can negatively influence the workability and uniform distribution of fibers.Chiarello and Zinno  evaluateHan et al.  evaluateThe change in the temperature results in the expansion or contraction of the concrete, thus impacting the distance between functional fillers, which in turn, influence the conductive network. Few researchers have evaluated the effect of temperature on the sensing behavior and the electrical resistivity of SSC. McCarter et al.  investigThe propagation of cracks in cement composites can be limited by a high loading rate, which can also suppress plastic deformation . This coHan et al.  evaluateMoisture content also influences the electrical resistance of sensing concrete. Very few researchers have evaluated the influence of moisture within SSC. Maier  investigIt is known that generally, in the dry state, conduction by electrons is dominant, while the ionic conduction is more significant than electronic conduction in the wet state due to the presence of ions inside of the water. Wen and Chung  investigThe ice formation and the freeze-thaw cycle can affect the electric conductivity and electrical resistivity, which in turn degrade the properties of SSC. For instance, Cai and Liu  evaluateThe influence of the freeze-thaw cycle on cement mortar was studied in detail by Cao and Chung , who comThe current frequency, which is used to measure changes before and after different loading conditions, is another factor that has an influence on the self-sensing properties of the concrete. Demirel et al.  analyzedApart from the factors discussed above, some other factors include corrosive environment and duration of loading, etc. ,52,71, wThere are many research studies conducted with functional fillers in SSC. The following section focuses on the research conducted on self-sensing materials used for smart composites, which are listed in Carbon fibers that are implemented in the concrete could be divided into several types. The majority of the carbon fiber market uses polyacrylonitrile (PAN) carbon fibers, the next priority is given to pitch carbon fibers and lastly to rayon carbon fiber textiles . The impShort fibers are mainly used in concrete to increase the flexural toughness and strength and, at the same time, to decrease drying shrinkage ,81. SimiSeveral researchers evaluated the performance of carbon fibers including Wen and Chung , who speWang et al.  evaluateThe results of fractional change in resistance with a load applied monotonically on this RC beam are presented in The authors also compared the cyclic flexural loading effect on the electrical resistance for the first and last five cycles, the results of which are presented in Carbon fibers dispersed in a cement-based material can have great potential for fatigue damage monitoring in different concrete structures. Based on the literature reviewed above ,72 and tCFRP are polymer matrix composite materials mainly reinforced by carbon fibers. CFRP are classified as thermosets such as epoxy and polyester; and thermoplastics such as nylon that are manufactured by open and closed mold processes as well as with the pultrusion method. Different carbon hybrid composites and other fibers such as glass and aramid are designed for strength and sensing efficiency improvement . The disOverall, polymer composites are anisotropic materials and exhibit piezoresistivity under various loading types. For instance, the unidirectional CF reinforced composites with epoxy were found to sense their strain along the fiber direction. These continuous carbon fiber composites have highly desirable qualities such as high strength, material toughness, fatigue endurance, lightweight, resistance to abrasion, corrosion and chemical attack . HoweverOne of the most commonly used hybrid composites is the carbon fiber-glass fiber (CF–GF) hybrid composites. The glass tows contribute as a reinforcement platform, while carbon fibers provide piezoresistivity, thus serving as the sensory agent . From FiFor electrical measurements, electrical contacts were installed at each end of the carbon rod through connection with copper electrodes. An abrupt increase in electrical resistance was observed in the specimen with CF during the monotonic tensile test. The reason for a sudden increment is the breakage of carbon fibers, which can be treated as an emergency or alarm signal. The particular value of a load before the alarm signal can be designed by using a variation of the proportion of glass and carbon fibers . If the Nevertheless, the major limitation of hybrid CF–GF hybrid composites is their failure during early stage damage disclosure . AccordiThe yarns intertwining process is the main principle of braided composite rods. Polyester fibers are introduced for the braided structure while the glass fiber and the carbon fibers are combined for the core reinforcement development, thus producing BCRs . The maiAdditionally, there was a study conducted by Feng and Ou  that incAccording to Finally, the study concluded that, with SCFRP fabric installment, the increase in bearing capability was observed, and the decrease in energy values was detected with the development of cracks in the beam. This suggests that the integration of SCFRP into concrete-based material has strength improving capabilities as well as an ability to monitor the development of damage in the concrete elements. Therefore, it can be inferred that CFRP has a promising future as the self-sensing technology for the health monitoring and strengthening of the buildings. Continuous PAN-based carbon fibers were also developed for the strain and damage detection of the buildings . The intThe experiment conducted by the research group used three different beam models without strengthening, with CFRP strengthening and with textile sensor strengthening. The data obtained in the calibrating test in beams showed the relationship of change of strain under external loading conditions, as presented in The total strength of the beam with strengthening was improved compared to the beam without strengthening, as evidenced by a significant increase in the force that caused the first cracks on the specimen. Similarly, it was observed that the small strain of the strengthened specimens caused an increase in the relative electrical resistance, which is explained by the misalignment of axial carbon fibers under load that resulted in decreasing numbers of connection points between fibers at different loading conditions, as previously mentioned. Therefore, the influence of the strengthening fabrics made with continuous carbon fibers could be used as self-sensors to improve the strength by increasing the loading capacity of concrete structure and also to perform the health monitoring by deformation detection that was caused by external loads . Overall, it can be said that the carbon fibers, including short and continuous, can considerably improve the bearing capacity of the elements made of concrete and additionally can provide the ability for the reinforced concrete to monitor health conditions by self-sensing properties.The development in the field of nanotechnology resulted in the implementation of carbon nanomaterials such as CNFs and CNT in self-sensing composite materials. CNTs are the most studied nanofillers in the literature that consists of graphene layers connected into a cylindrical shape, while CNF contains graphene layers in the shape of cones, plates or cups . Both caIn a study conducted by Alessandro et al. , the autFrom test results, it was observed that CNTs and CBs demonstrated a polarization effect, which can be entirely eliminated after 20 min of charge without any external load. Additionally, it was indicated that the sensitivity of GNPs compared to other types of carbon fibers was the most uncertain and inaccurate and showed the worst results . TherefThe addition of CNF in the cement matrix has been reported to provide a good self-sensing result. Recently, Galao et al.  evaluateThe strain monitoring ability of CNF was studied by a lot of authors, including ,32,35,90Apart from conventional carbon fibers, the self-sensing properties of other types of nanomaterials, such as hybrid composite rods, have also been investigated. The research study conducted by Nanni et al.  developeAnother relatively new hybrid nanocarbon materials engineered cement-based sensors (HNCSs) was proposed by Ding et al. . The autIt can be observed that three types of measuring sensors react almost simultaneously when the force was applied to the sample with only a little difference in the variation of impact intensities. From the graph of response-decaying curves of all three sensors that is shown in Overall, self-sensing hybrid composites have been developing for self-monitoring purpose, and a lot of recent research studies demonstrated high sensitivity during applied loads with such fillers. For example, Azhari and Banthis  evaluateThe conductivity of SSC can be improved by increasing the amount of the dispersed fibers; however, the role of their size and the distribution in the cement-based material should also be considered due to the ability to limit sensing performance. The conductive network, which is an essential factor for damage sensitivity, could be blocked by the poor dispersion of the fibers. One of the most practical ways to avoid high cost and impact on the workability of the concrete due to the increasing concentration of dispersed fibers is a uniform distribution of those fibers inside of cement-based material. One of the novel methods for dispersing the fibers was introduced by Gupta et al. , who sugThe CNT-based thin films were applied on the surface of the fine (sand) and coarse aggregates before the concrete casting. Thin films were made according to the research study of Mortensen . FirstlyDuring the fabrication process, Type I/II cement was used with a 0.42–0.44 w/c ratio together with SPL. The obtained fine aggregate from crushed granite was sieved by using a minimum size of 0.149 mm. A large coarse aggregate of river rock with a size of 19 mm was used. In order to achieve uniform coating, fine aggregates were sprayed six times, while coarse aggregates were sprayed three times together with manual mixing in order to prevent uncoated aggregate appearance. The cylinder and beam shaped specimens were cured for 28 days. Overall, four dif-ferent types of samples were made for the experiment, including control samples without coating, aggregate-coated, sand-coated and both sand and aggregated coated. The speci-mens were tested for compressive and flexural strengths. Detailed results are presented in Tables 1 and 2 of Reference .According to test results, the lowest value for compressive strength was observed for the aggregate-coated sample and was found to be 6500 psi. Similarly, the values of sand-coated and both sand and aggregate-coated specimens were 6860 and 7580 psi. Hence, it can be said that the implementation of the MWNT-based thin films can save the mechanical properties of the untreated sample and even can improve it, as it can be observed from the specimen with both sand and aggregate-coated. The only disadvantage of coating is that the mechanical properties of coarse aggregates could be deteriorated due to the smoother surface formation that, in turn, would decrease the bonding effectiveness with the cement matrix. Nevertheless, it was found that the design guidelines were meet (4400 psi) by the samples.From flexural testing, it was found that the aggregate-coated strength value (950 psi) was close to the control sample (953 psi). The difference in the modulus of rupture be-tween the control and the sand-coated sample was 6%, while a 14% difference was ob-tained from both sand and aggregate coated specimens.Additionally, by using an electrical impedance tomography (EIT), three types of concrete plates  were tested for damage detection. The first sample for testing was pristine concrete (control), where six copper mesh electrodes were located on each side of the plate. During the experiment, the damage was caused by three holes that were drilled inside of the concrete plate. According to the test results , the chA similar test procedure was performed for the second sample of aggregates coated plate with MWNT-latex thin films . From tThe results for the last samples of sand-coated and both sand and aggregate-coated showed a clear image of EIT resistivity during the drilling process . The auSimilarly, Nasibulin et al.  suggesteThe first step is to perform a synthesis of CNT and CNF on the surface of cement and clinker particles, and the fluidized bed reactor was introduced for this purpose. After that, in order to find the concentration of grown CNT and CNF, samples were analyzed using thermogravimetric analysis. The final composite material, which is a hardened cement paste, can be formed after the hydration process. In order to investigate the compressive, flexural strengths and the electrical resistance, beams with dimensions of 60 mm × 10 mm × 10 mm were prepared and cured in aqueous condition for 7, 14 and 28 days. The researchers found that the utilization of cement particles as a catalyst results in compressive strength of the obtained cement paste value equal to more than two times the plain cement. Moreover, the electrical conductivity after water curing increased almost up to 40 times than the plain specimen. The research group also performed the testing of mechanical properties of mortar beams with dimensions of 40 mm × 40 mm × 160 mm that contained different concentrations of CNF in order to find the optimum amount of the CNF. Overall, two new methods, including uniform dispersion of CNTs on top of the aggregate surface and the growth of carbon nanomaterials directly on the concrete matrix, were introduced. During the spraying of CNTs, the results showed that all of the specimens exceeded minimum design requirements for concrete; moreover, samples made of sand-coated and both sand and coarse aggregate-coated concrete showed higher compressive strength compared to the control specimen. The test for damage detection showed that the sand-coated and both sand and coarse aggregate-coated samples demonstrated localized resistivity results due to good propagation of current through the material. Similarly, the novel approach for synthesizing CNT/CNF on the surface of matrix particles demonstrated promising results in terms of compressive strength improvement as well as a high increase in electrical conductivity of the specimen. Therefore, these methods, i.e., spraying MWNT-latex thin films on top of the aggregates and growing CNT or CNF directly on the cement matrix, should be considered as one of the alternative methods for dispersion; however, more research studies should be conducted on different types of procedures adopted for nanomaterial distribution.Various researchers tried to implement SSC in real-life applications. There is a new method of monitoring masonry buildings by using the concept of SSC in the development of smart bricks. During the manufacturing process, special functional fillers are installed into the bricks that can be used as strain sensors, as shown in Another promising application of the concept of self-sensing technology is traffic detection and weight in motion. Shi and Chung  providedPotential usage of the hybrid glass/carbon textile-reinforced concrete (TRC) element was demonstrated by Goldfeld et al. . AccordiThe implementation of self-sensing sensors could be used to monitor the corrosion process inside concrete elements. Lu  tracked Removing the ice and snow from the pavement is traditionally performed by applying deicing salts and mechanical removal. However, the implementation of carbon fiber-based electrically conductive concrete (ECON) could help to create the heated pavement systems (HPS) as an alternative method to common methods. Sassani et al.  investigOne of the most common usages of SSC is for structural health monitoring. By comparing and analyzing the results from self-sensing abilities, it is possible to choose the best type as well as the optimal dosage of fillers. In one of the studies conducted by Feng and Ou , a self-Overall, there are a lot of fields that could use SSC technology in daily life. This paper provides an overview of SSC, which is an integration of electrically conductive filler material within cementitious materials. The self-sensing characteristics allow the composite to respond to stress/strain changes as well as to damage. Some of the benefits of using SSC include high sensitivity, the same lifespan as in concrete, good mechanical properties, easy installation and continuous monitoring.Properties of SSC provide an ability to detect tiny cracks before they start to become significant, which is crucial in different civil infrastructure maintenance such as high-rise buildings, dams, pipelines, nuclear power plants, highways and bridges. However, there are various factors that affect the general characteristics and properties of SSC, such as functional filler concentration, moisture, geometric shape of functional filler, temperature and loading rate, etc.; hence, it is recommended to monitor and to control them in order to obtain accurate data and the desired concrete characteristics. It is also apparent that the researchers used different types of metrics, such as relative resistance, resistivity and conductivity to measure changes in the behavior of self-sensing concrete. While resistance can be easily measured with equipment, resistivity and conductivity require composite dimensions to obtain values. According to most studies, when reinforcement is presented in concrete, the electric current field is distorted, resulting in inaccuracy of resistivity measurements. Therefore, it is suggested that further research studies should include information that states considerations of relative to this factor.In terms of functional fillers, there are many functional filler materials that were investigated and that could be incorporated into cement composites such as carbon nanotubes, carbon nanofibers, graphene oxide, carbon black, steel slag, nickel and graphite powder, magnetic fly ash and so on. The main aim of the research study regarding functional fillers was to find cheap and, at the same time, effective materials since it is the priciest component of SSC. Parameters such as dispersion method and mix preparation design should be considered in order to achieve the desired properties of concrete because they play a key role in improving electrical properties. Uniform dispersion of composites allows eliminating disadvantages such as a decrease in strength and poor sensing properties during agglomeration, providing the possibility to reduce the amount of filler and, thus, rendering the cost of SSC less expensive. Therefore, a reasonable selection of dispersion methods, including relatively new ones such as spraying, should be considered during the selection procedure in order to improve the uniformity of the mix. Although SSC has not been used in practical projects and its commercial applications are still very limited, there is a potential possibility to apply this technology in fields such as leakage detection, corrosion process monitoring, traffic monitoring and so on. Practical tests carried out on self-sensing materials, including carbon fibers, carbon nanomaterials and other carbon-based fillers, have been extensively described in detail and proven that this technology can be practically implemented in real-life projects. Despite differences in the obtained results from various experiments, the stress/strain change responses, as well as damage detection, are always clearly exhibited, demonstrating the potential of SSC in an application for structure health monitoring, weight in motion and traffic detection, etc. Overall, the most used materials that were optimal in different areas of application are sensors made with dispersed fillers and embedded cement-based piezoelectric sensors. However, in order to practically apply SSC in different structures and areas, additional research studies with a focus in creating universal standards in construction are suggested.


One of the biggest challenges in facilitating the installation of concrete is the development of fibre-reinforced concrete. Although nowadays fibre reinforced concrete is relatively common, it is still necessary to deepen in the study on its behaviour, especially regarding its fatigue behaviour. This paper proposes a new methodology to analyse the bending fatigue behaviour of notched test specimens. From these tests, it was possible to verify that, despite carrying out the tests with load control, the presence of fibres extends the fatigue life of the concrete after cracking. This effect is of great importance since during the extra lifetime with the cracked concrete, the damage to the concrete will be evident and the corresponding maintenance measures can be carried out. Regarding the analysis of the results, in addition to obtaining a traditional S-N curve, two new criteria have been applied, namely energy and notch growth. From these two new approaches, it was possible to determine critical energy values that can be used as predictive indicators of the collapse of the element. Moreover, from the notch growth analysis, it was possible to determine crack growth rate as a function of the stress conditions for the concrete and the specific geometry. From the comparison among the results obtained from the different tests, a limit cracking index of 0.05 mm can be defined. Three d3 were tested. All the fatigue-tested specimens were cured in a humidity chamber under controlled conditions (20 ± 2 °C and 95 ± 5% humidity).The fatigue tests were performed at 90 days, using the Staircase method ,47. TwelTo prepare the specimens for the test, a crack was made, based on the standard EN 14651:2007 . The craTo measure the CMOD a COD extensometer was used. Two metal pieces were fixed to the two sides of the crack, in the centre of it, and an extensometer was fitted, taking the specimens to breakage and recording the Load-COD data.The specimen was placed on a cylinder of 30 mm diameter, on the opposite side to the cracked face. On the cracked face, two cylinders were place at a 500 mm separation, with the same dimensions as the first one. The test assembly of the specimen can be seen in σ = stress; F = load applied; L = distance between the two lower cylinders; b = specimen width; h = distance from the base to the beginning of the notch.Fatigue testing begins by loading the specimen to the medium load level at a speed of 0.5 MPa/s. When this mean load value has been reached, sinusoidal loads are applied between the maximum and minimum load values indicated in During all the fatigue tests, the testing time, load, actuator displacement (ACT) and COD aperture of two cycles of every 100 were registered during the whole test. To analyse these data, and due to the waveform, a regression to a sinusoidal wave was done by mean of a one degree Fourier regression, see Equation (3), which was transformed into Equation (4) by means of Equation (5) . This onIn addition to analysing the effect of the cycle concatenation on the mean value and amplitude, the effect on the area of the loop generated by drawing the COD opening versus the load was also analysed. Two different types of area were analysed, on the one hand, the area representing the energy provided The total energy (stored + dissipated) represents the energy provided to the system to produce the deflection of the specimen. This total energy is divided into two types of energy, stored energy, and dissipated energy. The dissipated energy is the energy released by the specimen during the cycle. On the other hand, the stored energy is the energy that the material return/restore cycle by cycle.During the analysis of the data, it was found that in all cases there were two clearly differentiated behavioural zones, before and after the cracking of the concrete. Another additional parameter was analysed during the fatigue tests, the COD opening velocity. This velocity was obtained as the derivative of the COD opening as a function of time. This curve has a U shape, see The average compressive strength at 28 days is 50 MPa. In R,3, COD = 2.5 mm). The average of these values is fR,3 = 6.27 MPa. In The cycles to cracking of the specimens fit very well with an S-N curve. On the other hand, the number of cycles until specimen breakage does not fit so well. This is because, after cracking of the concrete, the fibres are the ones that manage the fatigue process. For this reason, the orientation and number of fibres holding the crack will define the behaviour of the concrete. This result is in agreement with the results obtained by Jose Rios and Héctor Cifuentes , who conThe fatigue life after cracking is very variable and does not seem to follow a clear trend. In all cases where component failure is reached, the presence of fibres has increased the life of the component to some extent. This does not have to happen because it is a concrete with fibres, since, the tests generally done on concrete with fibres are carried out under machine displacement control, while in this case they were done under load control.The additional cycles provided by the presence of fibres, although generally not many, make the difference between having a fragile break. A fragile break means no apparent signs that the break will occur and having clear signals that the break is nearby. This, in a real situation, will enable measures to be taken after breakage becomes evident.F to a minimum of −F. Each of these two loads will have a different impact on the damage caused to the concrete. The constant applied load will accumulate creep damage, while in the case of cyclic loading, it will accumulate fatigue damage. As the specimen is subjected to a fatigue test based on the application of sinusoidal loads, the specimen is simultaneously subjected to two types of load. On the one hand, a constant load equivalent to the average value of the wave applied and, on the other hand, a sinusoidal load ranging from a maximum load It can be seen that Increasing the stress range value increases the growth rate of the maximum opening value, the average value, and the amplitude. Based on the analysis of the evolution of the growth of the notches throughout the test, it could be deduced that, in the case that the stress range is small, the evolution of the opening is practically that of the medium level. In the case of a test with high tensional range values, the values of crack opening amplitude and the mean value of it can become similar.In From An S-N curve of the material was obtained before it was cracked. Once the concrete has cracked, the quantity and orientation of the fibres is so important in the response of the concrete to cyclic loads that it leads to extremely heterogeneous behaviour.The presence of fibres was proven to increases the fatigue life of concrete, even in tests carried out under load control. This provides a time between the concrete breakage and the structural breakage, which can be used to take appropriate corrective measures.A critical crack opening was detected after which concrete cracking occurs, which could be used as an indicator the premature failure of the specimen.A critical energy value was observed that indicates that the test specimen will break, so it could be used as a parameter to determine the remaining life of the concrete. However, it should be noted that since it is an energy parameter, it is specific to each geometry.It was verified that the mechanism producing failure of the concrete is caused by microcracks inherent to concrete in the notch beginning to grow due to the loads applied. The velocity of growth of the cracks depends on the range of stress applied in the test, a correlation existing between them. However, geometry probably also has an influence.The following conclusions can be drawn from the work:There are not many research on the fatigue behavior of fiber reinforced. However, the importance that this material may have soon, thanks to its better performance and savings in execution, necessary to investigate on it. Hence the importance of the results presented and the obtained results, opening the door to a new type of analysis regarding behaviour of concrete under bending fatigue. Although it is important to emphasize that this study has to be complemented with future studies in which not only different specimen geometries are analysed, but also different notch sizes.


We showed previously that the α7 nicotinic acetylcholine receptor antagonist, methyllycaconitine, specifically attenuated morphine-primed reinstatement of conditioned place preference in rodents and this effect was mediated in the ventral hippocampus.The purpose of this study was to evaluate α7 nicotinic acetylcholine receptor antagonism in reinstatement of the conditioned place preference for the more widely abused opioid, heroin, and to compare the effect of α7 nicotinic acetylcholine receptor blockade on reinstatement of heroin-seeking and heroin self-administration in an intravenous self-administration model of addictive behaviour.Rats were trained to acquire heroin conditioned place preference or heroin self-administration; both followed by extinction of responding. Methyllycaconitine or saline was given prior to reinstatement of drug-primed conditioned place preference, or drug-prime plus cue-induced reinstatement of intravenous self-administration, using two protocols: without delivery of heroin in response to lever pressing to model heroin-seeking, or with heroin self-administration, using fixed and progressive ratio reward schedules, to model relapse.Methyllycaconitine had no effect on acquisition of heroin conditioned place preference or lever-pressing for food rewards. Methyllycaconitine blocked reinstatement of heroin-primed conditioned place preference. Methyllycaconitine did not prevent drug-prime plus cue-induced reinstatement of heroin-seeking, reinstatement of heroin self-administration, or diminish the reinforcing effect of heroin.The α7 nicotinic acetylcholine receptor antagonist, methyllycaconitine, prevented reinstatement of the opioid conditioned place preference, consistent with a role for α7 nicotinic acetylcholine receptors in the retrieval of associative memories of drug liking. The lack of effect of methyllycaconitine in heroin-dependent rats in two intravenous self-administration models suggests that α7 nicotinic acetylcholine receptors do not play a role in later stages of heroin abuse. Drug addiction is defined as a chronic relapsing disorder . ParticuRelapse not only sustains the addiction cycle  but alsoOpioids induce strong neuroadaptations associated with the key characteristics of dependence, including tolerance, withdrawal and contextual and emotional associations that contribute to compulsive use, cravings and relapse .A compleCholinergic inputs to the reward circuitry, from the basal forebrain and pedunculopontine and laterodorsal tegmental nuclei, are associated with arousal, attention, learning and reward. Of particular interest are nicotinic acetylcholine receptors (nAChRs) that not only mediate actions of endogenous acetylcholine but also the effects of exogenous nicotine, and are responsible for sustaining tobacco addiction . nAChRs 3H-AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor binding in the ventral hippocampus, and MLA infused directly into this brain area  abolished morphine-primed reinstatement of CPP  provides a representative model of volitional drug taking in psychologically dependent animals and was used in two configurations to model reinstatement of drug-seeking (craving) and reinstatement of drug self-administration (abuse). We observed different effects of α7 nAChR inhibition by MLA in these models: drug seeking in heroin-primed CPP was abolished by MLA, whereas reinstatement of drug seeking or drug self-administration was unaffected by MLA.All experiments were approved by the UK Home Office and performed in accordance with the UK Animals (Scientific Procedures) Act of 1986 and conformed to the Animals Research: Reporting In Vivo Experiments (ARRIVE) guidelines . All aniad libitum. All experiments were conducted during the light phase, between 08:00–18:00 under dim white light (approximately 15 lux light intensity).Male Wistar rats  were housed in groups of four in a controlled environment . Food and water were available ad libitum. All training and experimental sessions were conducted during the light phase.Male Sprague Dawley rats  were single-housed in the same room as the operant chambers in a controlled environment , with unlimited access to water. Rats had a daily socialisation session in a large arena to mitigate against social isolation stress. Rats were placed on a 90% food restriction regimen except during the first week of habituation, 24 h pre-surgery and 48 h post-surgery, during which time food was available Although different strains were used in the two behavioural paradigms based on local precedent, Wistar rats perform well in heroin self-administration , and SprHeroin hydrochloride was purchased from MacFarlan Smith, Edinburgh, UK; MLA was purchased from Abcam, Cambridge, UK. MLA was dissolved in sterile saline (0.9% w/v) and injected subcutaneously (s.c.) at a volume of 1 mL/kg. Control animals received the same volume of vehicle injections  s.c. Heroin was dissolved in saline (0.9% w/v). Heroin and saline for intravenous (i.v.) infusion were filter-sterilised through a 0.22 µm filter and were administered at 0.5 mL/kg.CPP was carried out as previously described  in threeRats underwent two drug-free habituation trials (1 × 15 min session/day for 2 consecutive days) to detect any innate preference for either compartment. Animals were then pseudo-randomly assigned to treatment groups so that mean baseline preferences were close to zero . Heroin n = 12) acquired heroin CPP as above and underwent a second post-conditioning preference text; 3 days later, animals received either MLA  or saline (n = 4) 20 min before an additional 15-minute post-conditioning preference test.Animals (n = 48), as described previously (n = 12 per treatment group). Three days later, for the reinstatement of heroin CPP, animals received a priming dose of heroin (1 mg/kg s.c.) prior to preference testing. This priming dose of heroin was previously shown to induce reinstatement of CPP in rats  was giv in rats , therefoAnimals were excluded from statistical analysis if extinction training failed to meet criterion (less than 70% of time spent in the previously drug-paired compartment) – 11 of 48 rats; or if a statistical outlier (Grubb’s outlier test) – one animal was excluded.t-test.The effect of MLA on the acquisition and reinstatement of heroin CPP was analysed by two-way analysis of variance (ANOVA) with Bonferroni post-hoc analysis. The effect of MLA on the expression of heroin CPP was analysed by Student’s IVSA was carried out essentially as previously described . All expn = 26) were trained to lever-press for food pellets  on a fixed ratio (FR) 1 schedule. Training sessions lasted for 1 h or until a rat had received 50 food pellet rewards. Once rats had acquired lever-pressing on the FR1 schedule, the response requirement was increased to FR2, then FR3 and the left lever was assigned as the active lever. Thereafter, only responses on the left lever resulted in the delivery of a reward. Operant responding was deemed stable under the FR3 schedule when the rats earned ⩾45 food pellets within 1 h over four consecutive sessions. All rats acquired FR3 lever-pressing.After 1 week of habituation, rats (n = 6 rats) or MLA  20 min prior to the test session. They were subsequently placed in the operant chambers to lever-press for food pellets on a FR3 schedule for the maximum allotted time of 1 h or until the maximum 50 pellets were dispensed.Twelve of the 26 rats were randomly allocated to either a saline or MLA pre-treatment group in an experiment to assess the effect of MLA on lever-pressing for food rewards on a FR3 reward schedule (2 and 5% CO2) and implanted with chronic indwelling i.v. silicone catheters into the right jugular vein, as described by After food training and the lever-pressing experiment were completed, rats were anaesthetised by isoflurane (2.5–2.75% in 95% ORats were trained to self-administer heroin (starting with 50 µg/kg/injection) in daily two-hour sessions starting on a FR3 schedule. Sessions were initiated by a non-contingent infusion of heroin and simultaneous presentation of a stimulus cue light and a 2.9 kHz tone cue set at 65 dB. The house light was illuminated and the left lever was active. The drug was delivered in a volume of 0.5 mL/kg over a period of 4–5 s depending on the weight of the rat; with a 30-second time-out after each drug infusion, during which time the house light remained on and lever-pressing had no programmed consequences. When rats had approximately eight FR3 sessions, the response requirement was increased to FR5. The final heroin acquisition dose of 15 µg/kg/inj and the FR5 schedule of drug reinforcement were selected based on previous studies using heroin and other opioid reinforcers . Rats weAfter the completion of the heroin self-administration training, rats were subjected to extinction sessions. In daily sessions, heroin-maintained lever responding was extinguished by substituting heroin with saline (0.5 mL/kg/inj) and withholding the tone and light cues. Responses on the active lever on the FR5 schedule (30 s timeout) resulted in the delivery of saline. At least five extinction sessions were given after heroin training.n = 7) or MLA .After completion of the extinction phase, rats were divided into two groups in a pseudo-random manner based on similar levels of active lever-press responding during the acquisition and extinction of heroin self-administration : 171 ± 27 active lever-presses during acquisition and 18 ± 6 at extinction; Group 2 (MLA): 172 ± 22 active lever-presses during acquisition and 21 ± 3 at extinction). Twenty minutes prior to the reinstatement session, rats were administered either saline  delivered through the indwelling catheter, immediately before the test session. The session was initiated by non-contingent presentation of the tone and light cues. Upon the correct number of active lever-presses (FR5), rats received saline infusions paired with the tone and light cues, with a 30 s timeout, where active lever-presses had no programmed responses. The test session lasted 2 h or until the maximum of 20 injections was achieved. The test session took place once daily on four consecutive days.After a second saline extinction phase (two sessions), the reinstatement of heroin self-administration was initiated by the non-contingent presentation of a heroin infusion (15 µg/kg i.v.) and simultaneous presentation of the tone and light cues. Throughout the test session, responses on the active lever on the FR5 schedule resulted in the delivery of heroin (15 µg/kg/inj) paired with the presentation of the tone and light cues. The test session lasted 2 h or until a maximum of 20 injections was achieved. Each rat underwent between 4–6 sessions (once per day), to stabilise responding and the results presented are the mean of the last three sessions.When stable responding was again achieved on the FR5 schedule, the break-point for responding was determined in a single four-hour progressive ratio (PR) session using a logarithmic PR schedule ; Table 1Operant responding was deemed stable under the FR3 schedule when the rats earned ⩾45 food pellets within 1h over four consecutive sessions.Positive reinforcement criterion was a mean ⩾12 inj/session over three consecutive sessions. Eight rats did not meet this criterion and were excluded from the study.The criterion for extinction for individual rats was defined as when the mean number of active lever-presses over the last three sessions was ⩽30% of the group mean for heroin acquisition.t-test. This mixed model is appropriate for analysing repeated measures data. The PR breakpoint results were square root transformed and analysed by unpaired t-test.All variables analysed in the heroin IVSA experiments were found to be positively skewed, so a square root transformation was found to be appropriate, to assume normal distribution and equal variance. For acquisition and reinstatement of heroin self-administration and saline extinction, the data used in the analysis were means of the last three sessions. Results from experiments investigating the reinstatement of heroin-seeking were taken from single sessions. Data were square root transformed and analysed by a mixed linear model with treatment as a fixed factor and animal as a random factor (where treatment is a combination of the self-administration test session and the subcutaneous treatment). Comparisons to saline extinction (same subcutaneous treatment) and to subcutaneous saline (same self-administration test session) were by the multiple In agreement with previous studies see , heroin F = 0.03, p = 0.86) but a significant effect of test  = 10.62, p = 0.002). Post-hoc analyses showed significant heroin CPP in both treatment groups .Administration of MLA prior to heroin conditioning had no effect on the acquisition of heroin CPP: both control and MLA-treated rats readily acquired heroin CPP . There wp = 0.032, n = 12; paired Student’s t-test). On day 12, MLA had no effect on the expression of CPP .To examine the effect of α7 nAChR inhibition on the expression of heroin CPP, 12 rats underwent heroin conditioning and were subsequently tested for any preference for the drug-paired chamber ; eight of these animals then underwent a subsequent test, carried out 3 days later, with saline or MLA given 20 min prior to that test  = 3.7, p = 0.013). Post-hoc analyses showed no preference in the saline control group for either compartment . Indeed the preference scores after heroin-primed reinstatement were substantially higher than after conditioning, an observation previously seen for morphine-primed CPP (p < 0.001). MLA had no effect on locomotor activity during reinstatement, compared with saline (data not shown). The priming dose of heroin significantly reduced total distance moved (and this was reflected in a reduced number of transitions between compartments). This decrease in distance moved was abolished in animals pre-treated with MLA.MLA was then tested on the reinstatement of heroin CPP: rats acquired heroin CPP which was then extinguished by repeated saline administration associated with both CPP compartments. MLA or saline was administered 20 min prior to a priming dose of heroin  or saline. Rats were tested for preference in the CPP apparatus immediately after the administration of the priming dose of heroin. There was a significant effect of treatment during reinstatement  or active lever-presses/min .All rats readily acquired lever-pressing for food rewards. Pre-treatment with MLA  20 min before the test session had no effect on lever-pressing for food . There wp = 0.6), showing a lack of effect of MLA on the reinstatement of heroin-seeking. Reinstatement of heroin-seeking was repeated over three further daily sessions, and in each session, MLA was without effect (data not shown).After the acquisition of heroin self-administration with drug-paired cues and extinction of operant responding on saline without drug-paired cues, both saline and MLA-treated groups of rats readily reinstated heroin-seeking when challenged with heroin priming + the presentation of the drug-paired tone + light cues . There wFollowing acquisition and extinction of heroin self-administration, the control group of rats that were pre-treated with saline readily reinstated heroin self-administration . Pre-tret-test, p = 0.2), or the number of infusions self-administered by the rats .The effect of MLA (4 mg/kg s.c.) on the relative reinforcing efficacy of heroin was examined in a single PR session . There wThis study corroborates and extends previous findings that MLA attenuates morphine-primed reinstatement of CPP in mice and rats . Here weTo aid the interpretation of the findings from this study, As the name states, CPP is a model of ‘drug liking’. An unconditioned stimulus, e.g. heroin, is paired with a conditioned stimulus (compartment) to form a conditioned response . SubjectIn contrast, MLA had no effect on any component of heroin self-administration measured. As illustrated in As seen in this study and in No previous studies have investigated the role of α7 nAChRs in opiate drug-seeking, whereas there is a limited literature for other psychoactive substances. MLA, at comparable doses to that used in the present study, was reported to reduce several behavioural and neurochemical responses to δ-9-tetrahydrocannabinol, including IVSA , in contWe previously hypothesised that in CPP, α7 nAChRs play a specific role in the retrieval of drug-associated memories, triggered by cue or drug-prime, that are important in relapse behaviour . This viIn this study we have identified that the role of α7 nAChRs in the retrieval of drug-associated memories occurs in the initial phase of drug liking before repeated self-exposure to the reinforcing effect of the µ-opioid receptor agonist produces a state of psychological dependence in the animals, suggesting that α7 nAChR antagonists are unlikely to be a viable approach to the treatment of opiate abuse or dependence. The combined findings from the CPP and self-administration models are consistent in showing that blockade of α7 nAChRs does not influence the reinforcing effect of µ-opioid receptor agonists or the development of psychological dependence. The results indicate that the effects of α7 nAChR antagonists on the reinstatement of drug-seeking and relapse into drug abuse are dependent on the point in the drug abuse cascade that is selected for investigation and the trigger(s) used to reinstate drug-seeking.