A low adherence to recommendations on antibiotic prophylaxis has been reported worldwide. Since 2009, cesarean sections have been performed under user fee exemption in Benin with a free kit containing the required supplies and antibiotics for prophylaxis. Despite the kit, the level of antibiotic prophylaxis achievement remains low. We conducted a convergent parallel design study in 2017 using a self-administered questionnaire and interviews to assess the knowledge and explore the beliefs of healthcare professionals regarding antibiotic prophylaxis in three hospitals. Of the 35 participants, 33 filled out the questionnaire. Based on the five conventional criteria of antibiotic prophylaxis, the mean level of knowledge was 3.3 out of 5, and only 15.2% scored 5 out of 5. From the verbatim of 19 interviewees, determinants such as suboptimal patient status health, low confidence in antibiotics, some disagreement with the policy, inappropriate infrastructures and limited financial resources in hospitals, poor management of the policy in the central level, and patient refusal to buy antibiotics can explain poor practices. Because of the dysfunction at these levels, the patient becomes the major determinant of adequate antibiotic prophylaxis. Policymakers have to consider these determinants for improving antibiotic prophylaxis in a way that ensures patient safety and reduces the incidence of antimicrobial resistance. In 2021, new research from the World Health Organization reported that the cesarean section (CS) rate was more than one in five (21%) of all childbirths globally. In developing countries, a rate of 8% of women gave birth by CS, with 5% in sub-Saharan Africa . HoweverIn the absence of universal health insurance coverage, the fear of medical, social, and financial implications of childbirth by CS decreases its affordability in developing countries . To reacA total of 35 healthcare professionals agreed to take part in the survey. The assessment of the HcPs’ knowledge was based on data from 33 participants who completed the self-administered questionnaire. The response rate was 94.3% (33/35). Males represented 51.5% (17/33) of all participants; 60.6% (20/33) were nurse anesthetists; and the others  were physicians . The median age and professional seniority were, respectively, 39.6 years old (range 23–57 years old) and 7.8 years (range = 1–22 years). The respondents’ demographic characteristics are displayed in From the data collected in the three hospitals, the indication and the timing of the antibiotic prophylaxis were the criteria that had the best scores: 90.1% and 97.0%, respectively. On the contrary, 69.7%, 48.5%, and 51.5% of the HcPs did not provide good responses to the choice of molecule, dose, or duration of administration of antibiotic prophylaxis, respectively. Only 5 medical doctors out of the 33 participants (15.2%) provided a good response to the five conventional criteria (scored 5/5). The mean level of knowledge was 3.3 out of 5. A total of 25 HcPs (75.8%) scored at least three out of five. The HcPs with certain seniority (more than 10 years) indicated the antibiotics of the kit as those recommended. The younger HcPs often indicated broad-spectrum antibiotics. The participants stated that they had not attended training on antibiotic prophylaxis since they started working, and all of them declared that antibiotic prophylaxis practice has to be improved in their hospital. The levels of the response of the HcPs on the five conventional criteria for antibiotic prophylaxis are represented in For the three less-known criteria, we calculated the scores of the responses for each socio-professional category, with the results displayed in The interviews were conducted over two months and included 19 healthcare professionals  from the 33 respondents of the previous sample within the three hospitals. The study population ranged from 23 to 57 years in age. Ten face-to-face interviews and two focus groups of three and five participants, composed exclusively of nurse anesthetists, were conducted. All participating medical doctors preferred face-to-face interviews (not focus groups). The discussions lasted approximately 20–45 min for the individual interviews, and 36–50 min for the focus groups. Apart from the field notes of one of the interviewees, no field notes were taken for the recorded interviews. The obstetricians in one of the three hospitals did not give us the opportunity to conduct interviews with them. Data collection was stopped when we did not have other volunteer participants in the study period.Within the data emerging from the verbatim retranscription, five main determinants subdivided into 17 codes were inductively identified to influence antibiotic prophylaxis achievement in hospitals: patient health determinants, hospital-related determinants, healthcare professionals’ individual determinants, central organizational and structural determinants (policy management), and patient behavior determinants In the opinion of the HcPs, patients’ health determinants may influence antibiotic prophylaxis practices in terms of their personal hygiene, medical history, and occurrence of complications after a cesarean section. They also thought that the fact that some patients may already be contaminated with resistant germs has to be considered.When we asked about the reasons that can lead to the choice of antibiotic for prophylaxis, one of the obstetricians, referring to patients’ hygiene and other required hygiene conditions, answered as follows:“But for me, it is above all the patients who do not wash themselves properly- the hygiene of the skin on which we are going to work on. The absence of shower before patients enter in the operating room. The conditions that must be met before the patients enters the operating room are not met.”On the contrary, a nurse anesthetist argued that patient contraindications  to the antibiotics in the kit (ampicillin and gentamicin) and the type of CS (emergency vs. planned) can impact HcPs’ attitudes toward antibiotic prophylaxis practices.“Now, there are some women for whom we do not use gentamicin. But if the woman is not allergic to ampicillin, we will use both.”“We systematically administer 2 g of ampicillin and 160 mg of gentamicin if the woman has no history of hypertension.”In sum, it appears that the perception of safety is key to the choice of antibiotic prophylaxis in terms of the molecule, dose, and duration.Organization and conditions of care in the hospitals were frequently described as influencing antibiotic prophylaxis practices. Inadequate or inconstant hospital infrastructures with potential consequences for hygiene could influence the achievement of the antibiotic prophylaxis criteria. Then, in the Benin work context, the lack of important tools or an aseptic environment and improper operating rooms were mentioned as reasons for using different antibiotic prophylaxis practices than those recommended. Again, the perceived infectious risk related to contamination of the environment and the global safety of the patient drove the HcPs’ behavior.“Yes, the working conditions. To start, the climatic conditions make it impossible to do things differently. And then the surgical units are also substandard—you couldn’t say that the unit is systematically sterile.”The capacity of the hospitals to provide the recommended antibiotics plays an important role in the quality of antibiotic prophylaxis practices. Limited financial and logistical resources induced variable and/or incomplete composition of the CS kit in some hospitals. An interviewee mentioned that the antibiotic provided in the kit is the cheapest, and this choice was made for the form.“But that’s what’s cheaper, that’s why they put that in the kit to free themselves.”Others suggested that more resources have to be provided to hospitals, since limited resources can lead to an improper antibiotic in the kit, in turn, resulting in improper practice.“We must also think about providing public hospitals with resources. Maybe it’s because they don’t have the financial means that they do pretty much.”Regardless of the knowledge of the HcPs on antibiotic prophylaxis or their point of view on the kit, they tended to use what they had available. From the analysis of our data, we understood that, if the contents of the kit provided by the hospital are in line with the recommendations, they will respect the guidance, despite a lack of knowledge or a conflicting point of view on antibiotic prophylaxis. If the antibiotics become available too late, the timing of prophylaxis will not be respected, even when HcPs’ knowledge of correct timing is good.® (ciprofloxacin) in the box, you use it; if at another time, there isn’t any, you don’t use anything at all.”“Yes, actually, at a given moment, you use what you have, and that’s it. If you see some CiploxDisagreement between specialists, preference for departmental habits over central recommendations, and inactive stewardship policies have led to a lack of consensus in the hospitals, which might lead to different practices within the same hospital.“It’s here, in reanimation, that our doctors said, ‘No more ampicillin here.’ The antibiotic you should use is co-amoxiclav (amoxicillin + clavulanic acid); at least that’s what we use. That’s not a hospital consensus.”Communication issues at several levels were linked to the lack of consensus and, more generally, to the use of improper antibiotic prophylaxis:With hierarchy: HcPs reported that administrative managers did not share the CS kit information with all parties concerned, or they shared it with a delay, so the practices in the hospitals did not conform to central recommendations.“But apparently it was the hospital managers who have left to some workshops; but they didn’t give us any feedback.”Between specialists: Anesthetists and obstetricians working in the same department had different ideas on antibiotic prophylaxis, and did not make decisions or discuss them together to produce a consensual rule.“The gynecologists hold staff meetings every day, and we are invited to the Monday staff meeting. I think the communication methods need to be reviewed because when we say, ‘That’s what needs to be done,’ they come along and do things their way.”Between colleagues: Practitioners in the same field and in the same hospital had divergent opinions on practices of antibiotic prophylaxis for CSs.“That’s why I don’t agree completely with my colleague, because she’s not aware of what is in the kit and she hasn’t been curious enough to ask.”Across the patient pathway: Taking care of patients is not a global concept. Oral or written information about patients (patient records) are rare or not considered from one department to another. Each department works unilaterally, driving confusion, omissions, and lowering standards in antibiotic prophylaxis practices.“The thing is that here we don’t get any more information about the patients. I don’t know whether there are infections afterwards because we don’t know anything about what happens after day one.”The interviewees highlighted the low activity of the stewardship policy in their hospitals. They then expressed a veritable need of evidence-based medicine and data to improve their practices. They stated that relevant feedback about the biological tests performed and continuous training on antibiotic use are important to improve antibiotic prophylaxis practices.“No, not that I know; but if there is a structure like that in place and it was never obvious to them before that they should look at how antibiotic prophylaxis is carried out on women, there is something wrong.”The HcPs’ views on the cesarean kit, related to their knowledge about antibiotic prophylaxis and their perception of freedom of practice, influence their practices. The HcPs expressed variable confidence in the kit as far as efficacy is concerned. Knowledge about antibiotic prophylaxis, such as the antimicrobial spectrum required, could help them to understand this.On the one hand, some healthcare professionals perceived the advantages of having a proper antibiotic prophylaxis policy to save money for patients, avoid antimicrobial resistance, and standardize quality practices.“Respecting that protocol, which, in my opinion, is good and it avoids patients having to make unnecessary expenditures, could even lessen resistance.”school of thought” concept.The HcPs appreciated when the contents of the kit allowed antibiotic prophylaxis to be practiced in line with their ““We do what we have seen others do. You cannot just decide to use a third-generation cephalosporin, for example. That’s not in line with what is done.”On the other hand, some of the HcPs preferred an alternative protocol (antibiotic choice) for antibiotic prophylaxis. The HcPs in certain hospitals had more confidence in their personal experiences.“No, we draw up our own protocol based on what we have experienced in the service.”Despite their preference for alternative protocols, some practitioners resigned themselves to using the kit.“But none of those molecules are available here in Benin. So, we are resigned to that.”An interviewee pointed out the overuse of antibiotics in some interventions as follows:“Sometimes, we exaggerate in the antibiotic prophylaxis here. Me, I often have trouble when we want to do clean intervention (for example the planned hernia intervention), and we put Ceftriaxone for prophylaxis.”Leadership in antibiotic prophylaxis decisions also had an impact on the practices. Some of the HcPs considered the kit as a landmark.“Antibiotic prophylaxis is based on what’s in the kit. We use the antibiotics that are available in the kit.”Other interviewees stated that the doctor’s decision is the landmark, and that the other members of the team should abide by it. He or she is free to change what they want to use in their practice, and the doctor is not under any influence.“In the end, the surgeon (doctor) decides on the antibiotic, which we continue after the surgical unit until the time comes to stop and replace it with oral administration.”“After the intervention, it is the gynecologist who defines whether we should continue the prophylaxis or not and marks it in the post-operative protocol.”Some of the HcPs feel obliged to follow the kit protocol despite their own opinion, whereas others continue to consider what they were taught in their training.“Except that the ampicillin, we use there, I don’t really agree with that. Even if we can go to ceftriaxone, it will be good”“Because what I was taught about antibiotic prophylaxis when I was in training is that you have to start low and then go up”The organization and structure of the CS fee exemption policy in Benin were a matter of controversy. Some disagreements on central policy management were reported in all of the hospitals included in our study. In addition to the perceived inefficacy of the kit, the negative point of view of the HcPs on the national policy might influence the implementation of standardized antibiotic prophylaxis.“Their kit is useless; when it comes to antibiotic prophylaxis, it’s worthless.”A lack of communication or consensus between policymakers and practitioners emerged in the verbatim transcripts. The practitioners felt uninvolved in the policy formulation and were hesitant.“In my opinion, there was no consultation of local healthcare workers about this business of fees exemption in cesarean. It’s a political matter. We were very hesitant at first because the basis for it is not clear.”Low approval of the antibiotics selected in the kit by the central authority, and the absence of monitoring of the utilization of the kit were expressed by the interviewees.“We have available to us a prepacked kit that includes an antibiotic that is not indicated for prophylaxis.”The interviewees commonly described patient behavior as a central determinant of the poor achievement of antibiotic prophylaxis practice. The HcPs bemoaned the fact that patients do not bring any antibiotics, do not buy the prescribed quantity of antibiotics, or do not bring them on time. Limited resources for patients (lack of money) to buy antibiotics  was frequently mentioned. Patients also frequently misunderstood the retroactive reimbursement for the CS procedure, and, therefore, refused the additional fees for the antibiotic prescription when CSs are supposed to be exempt of user fees. Thus, we can hypothesize that patients’ behaviors can influence all of the conventional criteria for antibiotic prophylaxis practices.“Let me tell you that for some time now, most can no longer manage to pay. They say, ‘we can’t buy it,” and we say, ‘go and buy whatever you can.’ Sometimes some of them come back with two bottles, others with one bottle.”Our study assessed the level of knowledge and explored the beliefs of healthcare professionals on antibiotic prophylaxis in CSs in the context of the user fees exemption policy in three hospitals in Benin. The rate of response of the participants to the survey of knowledge according to the five conventional criteria of antibiotic prophylaxis was approximately 94.3%, which is higher than the 84.8% reported in a Saudi study in 2013 , and theFirst of all, concerning the choice of antibiotic, the HcPs expressed their disagreement according to the antibiotics selected in the kit, and the CS fee exemption policy in general. Some physicians did not consider the kit safe enough; thus, they were more confident in their own abilities, and preferred to use broad-spectrum antibiotics  to avoid the impact of antimicrobial resistance and wound contamination in their patients. In this way, such practices can lead to a vicious cycle of antimicrobial consumption and resistance, as described in a Hungarian study . MoreoveSecond, according to the statements of the interviewees, an improper dose of antibiotic prophylaxis is due to the patients’ behaviors in terms of refusal to buy antibiotics or buying incomplete doses. Curiously, the HcPs’ level of knowledge was also low for this criterion. Thus, we think that the HcPs were less aware of good practices of antibiotic prophylaxis; otherwise, they could coach the patients to provide the correct dose of antibiotics for prophylaxis. Therefore, we can hypothesize that there is a relationship between the level of knowledge and practices. However, in another study, a dissonance was found wherein participants could correctly identify the appropriate use of antibiotics, and yet fail to apply them in practice . AdherenThird, improper duration can be explained by the fact that the HcPs fear the occurrence of infection after a CS because of the inadequate hospital environment, the patient’s hygiene, and the lack of an evidence-based protocol. In a study performed in Thailand in 2003, an obstetrician argued that post-operative infections affect his reputation, so he tends to overuse antibiotic prophylaxis . In factIn sum, from the analysis of the five determinants, we understand that improper practices can be explained by various reasons at different levels, such as a poor level of knowledge among healthcare professionals on antibiotic prophylaxis and a lack of confidence in the antibiotics in the kit, or the unavailability of infrastructure and financial resources for the adequate achievement of antibiotic prophylaxis and the non-conforming implementation of the policy at the hospital level. At the central level, we found that poor management of the policy, in terms of a lack of communication with local HcPs to ensure their adherence to the policy and to consider their opinions on the choice of antibiotics, contributed to the dysfunctions. It results that the failure of the organization of the policy at these three levels often shifts the responsibility of adequate antibiotic prophylaxis to the patient (or their parents). Even if patients are important members of the healthcare team and participate more in healthcare decision-making , they arThis mixed-methods study is the first to assess the level of knowledge and beliefs on antibiotic prophylaxis in CSs in Benin. The survey, combined with qualitative data, helped to understand the link between knowledge and beliefs on the one hand, and their effects on antibiotic prophylaxis practices on the other hand.This study has some limitations. First, the sample of the survey was small. This was due to the challenge we faced to enroll participants in the study, mostly because we opted to administer the question only on the day we reached the hospital, and to collect the filled questionnaires within a short deadline. Second, all of the included healthcare professionals were from hospitals located in the southern part of the country; thus, they are not entirely representative of the whole country. It will be interesting to perform a large study including other hospitals and more healthcare professionals. Third, in the qualitative study, we did not reach saturation, because some HcPs did not accept being interviewed. However, we think our findings could contribute to improvements, since they have helped to understand that the poor achievement of antibiotic prophylaxis practices according to the five conventional criteria is due to the low level of knowledge and poor management of the policy.This mixed-methods study encompassed quantitative and qualitative data to assess the level of knowledge and explore beliefs on antibiotic prophylaxis practices in hospitals. After a survey, some interviews were conducted with healthcare professionals. From August to October 2017, through a convergent parallel design study , we collThe HcPs who were in the obstetric ward at the time we reached the hospital were informed about the purpose of the study, and the self-administered questionnaire, adapted from those used in a similar study in Burkina Faso , was givThe face-to-face interviews and focus groups were performed in the three hospitals using a semi-structured guide. The HcPs concerned by antibiotic prophylaxis practices in each hospital  were recruited based on convenience sampling. Depending on the availability of the HcPs, focus groups or face-to-face interviews were organized by physical contact at the sites (wards). The meetings were conducted by the principal investigator of the study , who was trained to perform qualitative research. She met the HcPs previously during the observational study conducted in 2016 [Quantitative data were analyzed using IBM Corp . Descriptive statistics presented continuous variables using medians, and categorical variables were presented as numbers and percentages. The filled questionnaires were scored on a basis of five points considering the five conventional criteria. One point was attributed to each conventional criterion with a good response, and 0 points for a wrong response. The score of each health professional was calculated by summing the points obtained for the five criteria. Each HcP’s knowledge was scored as x/5 . The mean level of knowledge was calculated by pooling the scores of all participants and dividing the sum by 33. Since the five conventional criteria are essential for the quality of antibiotic prophylaxis, we applied the “all-or-none” law to categorize the level of knowledge of the HcPs. Thus, the level was considered as good when the score was 5/5. Any other score below 5/5 was considered as poor.In addition, we asked an open question about practice improvement and demographic characteristics . The completed questionnaires were picked up on the day of the survey or a few days later, according to the HcPs’ availability. All of the collected data were anonymously registered.All of the collected data were transcribed verbatim in Word software. Each file was named using the words “interview or focus group + the name of the hospital.”Data analysis was performed by two pharmacists from different countries, including the main investigator. Both were aware of the Benin context, and the main investigator was from Benin. The analysis was performed using inductive content analysis methods—specifically, a “manifest analysis,” in which we stood on “what the interviewees have been said” without straying from our research questions. The analysis comprised approximately five steps, described following a process drawn by Bengtsson . One addCesarean sections can be a life-saving intervention, and antibiotic prophylaxis is an uncontestable parameter to ensure the quality of life and health of patients. Unfortunately, its criteria are insufficiently known by the HcPs in Benin. The lack of confidence in the kit’s antibiotics, the absence of consensus between healthcare professionals, and their disagreement with the national policy were noticed in the hospitals included in our study. This results in failure in the implementation of the policy, and imposes additional fees for patients, despite the user fee exemption for cesarean sections. The healthcare professionals recognized that their practices were not optimal, and attested that they required an operational antibiotics stewardship policy in their hospitals in order to improve said practices. Several determinants involving all actors, implemented on all levels of the healthcare system in Benin, could help to address the challenges of good practices in order to decrease the occurrence of antimicrobial resistance and ensure women’s safety.


Background: Antibiotics are not recommended but are often prescribed for upper respiratory-tract infections (URIs). Prescribers cite patient expectation as a driver of inappropriate antibiotic prescribing; prior literature has demonstrated higher satisfaction scores in patients who receive antibiotics compared to those who do not. We assessed whether veteran satisfaction at URI visits was associated with antibiotic receipt or with reported expectation for antibiotics. Methods: We surveyed veterans with documented URI encounters in the Veterans’ Affairs Tennessee Valley Healthcare System between January 1, 2018, and December 31, 2019. Patients not evaluated in person, with documented dementia, or who died prior to the study start date were excluded. Veterans were asked to recall their URI visit and to complete the Patient Safety Questionnaire (PSQ)-18 (Rand Corporation) and questions assessing antibiotic expectations. The PSQ-18, an 18-item survey that assesses patient satisfaction, uses a 5-point Likert scale , yielding a composite score of 18–90. Higher scores represent more satisfaction with care. Demographic and visit-specific information were extracted via chart review. We used multivariable linear regression to assess differences in composite PSQ-18 satisfaction scores between those who did and did not receive an antibiotic, adjusted for patient and visit characteristics, and to assess differences in satisfaction scores for those who did and did not report expecting antibiotics, adjusted for antibiotic receipt. Results: We identified 1,435 patients seen for URI at 17 sites. After exclusions, 1,343 veterans were eligible for chart abstraction. After excluding 42 responders who responded after study close or returned blank surveys, the final analytic cohort included 432 (32.2%) of 1,343 responders; 225 (52.1%) received an antibiotic and 207 (47.9%) did not. Mean total satisfaction for veterans who received an antibiotic was 67.8  compared to 66.7  for those who did not (Figure Conclusions: Our findings suggest that prescribing an antibiotic is not associated with increased veteran satisfaction for URI visits but is associated with expecting an antibiotic. Future work will evaluate methods to change veteran antibiotic expectations.Funding: NoDisclosures: None


Controversy persists regarding optimal antibiotic regimes. We sought to evaluate current international antibiotics guidelines for total joint arthroplasty (TJA) of the hip and knee. (2) Methods: 42 arthroplasty societies across 6 continents were contacted and their published literature reviewed. (3) Results: 17 societies had guidelines; of which 11 recommended an antibiotic agent or antibiotic class ; 15 recommended antibiotic infusion within an hour of incision and 10 advised for post-operative doses . (4) Conclusions: Prophylactic antibiotic guidelines for TJA are often absent or heterogenous in their advice. Prophylactic systemic antibiotic therapy (PSAT) has been used to reduce the incidence of surgical site infections (SSIs) for decades. Prior to routine use in total joint arthroplasty (TJA), the rate of prosthetic joint infection (PJI) was as high as 5% . PJIs haThis study aims to investigate the practice of orthopaedic surgeons performing primary total hip arthroplasty (THA) and total knee arthroplasty (TKA) in the international community by surveying national orthopaedic, hip, knee and arthroplasty societies. The focus is on key variables: choice of antibiotic agent , timing of first dose (which influences when peak and trough tissue concentrations are achieved) and length of post-operative antibiotic course .Forty-two societies across six continents  were reviewed . FourteeTen (59%) guidelines suggested a first-generation cephalosporin such as cefazolin as first-line. One (5%) guideline recommended cloxacillin. The remainder  did not specify agents but suggested broad-spectrum intravenous antibiotics.Five of ten guidelines that propose second-line agents suggest vancomycin in cases of known allergy with the remaining five proposing clindamycin as second-line treatment. The Australian Orthopaedic Association (AOA) suggest teicoplanin as another alternative.The Australian, Philippine and Thai arthroplasty societies recommend vancomycin as the agent of choice when there is a “high risk for MRSA” defined as known to be infected or colonised with MRSA. The UK ‘Getting It Right First Time’ initiative (GRIFT) and the American Association of Hip and Knee Surgeons (AAHKS) advocate the use of “broad spectrum antibiotics” but do not specify agents.Fifteen (88%) guidelines are explicit about the requirement for antibiotics at induction. Six guidelines state administration timings and, of these, five suggest infusion no more than 60 min and one recommends a maximum time of 45 min before incision. The Philippine Arthroplasty Society recommends PSAT administration before tourniquet inflation for TKA.Of the ten guidelines that comment on length of post-operative length of PSAT, eight (80%) recommend no more than 24 h of cover. The New Zealand Orthopaedic Association state cover should be 24 to 36 h and the Japanese Orthopaedic Association recommend 48 h of cover.Our study showed a significant diversity of practice and in many cases a lack of guidance regarding prophylactic antibiotics. The difficulty in establishing such guidelines lies in differences in antibiotic strains over time , betweenThe majority of published guidelines suggest broad-spectrum intravenous antibiotics are used. In cases that provide more detailed guidelines (such as AAOS and SOS) there is a theme of ensuring that the most common organisms are covered: Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli and Proteus . First- In contrast, the SOF opts for cloxacillin due to its narrow spectrum active against the most common organisms associated with PJI and a low side effect profile . The relIn cases of beta-lactam allergy various strategies are proposed amongst guidelines. The SOF proposes it is safe to give cloxacillin if there is only a history of a limited rash and no itching . If therThe increasing incidence of PJIs involving resistant organisms such as methicillin-resistant Staphylococcus aureus (MRSA) has led some units to use agents that target these such as glycopeptides vancomycin and teicoplanin  instead Timing of PSAT infusion was the most consistent variable among guidelines with 83% stating antibiotics should be given less than 60 min before incision when cephalosporins are used. A systematic review and meta-analysis including 54,552 patients found an increased risk of infection if antibiotics were administered after incision or more than 120 min before incision . No diffThe majority of guidelines in our study recommend a maximum of 24 h of antibiotics postoperatively. This is in keeping with the 2013 International Consensus meeting on Periprosthetic Joint Infection . The onlThere is little evidence that PSAT beyond a single peri-operative dose reduces the incidence of SSIs. A systematic review and meta-analysis of 4 RCTs including 4036 TJAs by Thornely et al. found no significant difference between post-operative PSAT (16 h to 6 days) and single dose PSAT at induction although they assessed the quality of evidence to be very low . SimilarIn 2017 the Centers for Disease Control and Prevention (CDC) issued a recommendation that no further doses of antibiotics should be given after closure of the surgical wound . The AAOProlonged antibiotic prophylaxis beyond 24 h has been shown to be ineffective at reducing SSIs and may increase antimicrobial resistance ,41. A muWhen considering the antibiotic agent and duration, one should also consider the practicalities of ensuring correct administration. A study of adherence to peri-operative antibiotic guidelines in Canada showed only 32% of patients received their post-operative antibiotics as prescribed compared with 93% at the time of induction . This maGuidelines were only found for 40% of societies reviewed. There was a low response rate to email contact (43%) although this likely represents a true lack of guidelines as societies are less likely to reply giving negative confirmation. No guidelines were received or found for South America. Interestingly, a recent survey of TKA operative practice in Latin America had a high response rate of 83% and demonstrated a significant variation in practice compared to worldwide national registries which would suggest our finding of no guidance more likely to be genuine .This study focused on available guidance and may not reflect actual practice. The diversity of worldwide guidelines presented in this study provides surgeons and healthcare providers with a large scope to adjust PSAT regimes within available guidelines. This is particularly applicable where guidance is more vague such as in the UK where the BOA recommends “each surgical unit should have a locally agreed policy including advice from microbiologists” . SimilarHigh-income countries were deliberately targeted due to the paucity of arthroplasty surgery and literature in low-income countries . There iThe Enhancing transparency in reporting the synthesis of qualitative research (ENTREQ) statement was used for study and manuscript construction . BetweenFollowing review of websites for published guidelines those where no guidelines were present were contacted via direct email taken from the society website. They were asked to respond to a single question: ‘Do you have published guidelines on the use of prophylactic antibiotics during hip and/or knee replacement?’ With a follow up statement: ‘If yes, could you please provide them either as a link to your website or attached in a reply to this email, or if no, do you follow any other society or international guidelines?’ Where possible this question was also sent translated in the societies’ native language. A further follow-up email was sent on 14 September 2022 for those that did not initially respond. Guidelines were reviewed and data extracted by hand with reference to antibiotic agent, timing of administration, duration of antibiotics and alternative regimes. Multidisciplinary involvement in guideline construction was also noted where possible. Where guidelines were not in English they were translated by native speaking members of the authorship or translated with Google Translate .Orthopaedic and arthroplasty societies worldwide demonstrate a lack of guidance and or a disparate range of recommendations for PSAT in the context of TJA. Overall, a cephalosporin such as cefalozin is the favoured agent of choice, administered 15 to 60 min before incision. The majority of guidelines suggest 24 h of antibiotic cover but further study is required to clarify optimum cover.


The role of c-MET as member of the receptor tyrosine kinase superfamily in the signaling pathway of non-small cell lung cancer (NSCLC) has been extensively described , 2. MET 68Ga-EMP-100 is a novel PET ligand that addresses the tyrosine kinase c-MET and has already shown its applicability in patients with metastatic renal cell carcinoma [arcinoma .18F-FDG PET/CT for treatment monitoring purposes, where multiple pulmonary and hepatic metastases with high glucose consumption were noted . Moreover, the patient underwent 68Ga-EMP-100 PET/CT (6 days before 18F-FDG PET/CT) to further assess c-MET expression in these tumoral sites. Here, a highly heterogeneous c-MET expression was found with some lesions showing high c-MET expression, but also lesions with only slight or even barely any increased c-MET expression despite their high glucose consumption on 18F-FDG PET . Overall, elevated tumor metabolism was not necessarily accompanied by high c-MET expression.We present a case of a 56-year-old female former smoker with stage IV EGFR mutation-positive NSCLC  and concomitant MET exon 14 skipping mutation. After multiple pretreatments including radiochemotherapy and additional systemic therapies with afatinib, crizotinib, osimertinib, and cabozantinib, the patient underwent 68Ga-EMP-100 PET/CT for pre-therapeutic and non-invasive assessment of whole-body c-MET expression in NSCLC patients prior to c-MET targeting tyrosine kinase inhibitors such as cabozantinib [68Ga-EMP-100 PET/CT, and thus inform treatment priorities.This case illustrates the heterogeneity of tumor molecular biology in the stage IV setting, and the potential of zantinib , 5. Tiss


Under corrosive environments, concrete material properties can deteriorate significantly, which can seriously affect structural safety. Therefore, it has important engineering applications to improve the durability performance at a lower economic cost. This paper proposes a new, highly durable concrete using inexpensive construction materials such as basalt fiber, sodium methyl silicate, and inorganic aluminum salt waterproofing agent. With the massive application of sewage treatment projects, the problem of concrete durability degradation is becoming more and more serious. In this paper, five types of concrete are developed for the sewage environment, and the apparent morphology and fine structure of the specimens after corrosion in sewage were analyzed. The density, water absorption, and compressive strength were measured to investigate the deterioration pattern of concrete properties. It was found that ordinary concrete was subject to significant corrosion, generating large deposits of algae on the surface and accompanied by sanding. The new concrete showed superior corrosion resistance compared to conventional concrete. Among other factors, the inorganic aluminum salt waterproofing agent effect was the most prominent. The study found that the strength of ordinary concrete decreased by about 15% in the test environment, while the new concrete had a slight increase. Comprehensive evaluation showed that the combination of basalt fiber and inorganic aluminum salt waterproofing agent had the best effect. Its use is recommended. Concrete structures serving in harsh environments give rise to huge annual losses due to insufficient durability. With the development of the modern city, the demand for water treatment structure is strong. As a typical corrosive environment, sewage has caused serious corrosion to structures such as sewage tanks and pipelines, greatly shortening their service life and increasing maintenance costs, resulting in immeasurable economic losses. Therefore, it is urgent to improve the durability of concrete in sewage environment.2S and biological sulfuric acid corrosion [2S, biological sulfuric acid corrosion in sewage. Li [2S and relative humidity on concrete sewer corrosion. The results show that the corrosion rates in the gas phase and partially submerged concrete specimens are positively correlated with the concentration of H2S, and high relative humidity affects the specimens in the gas phase. Sun et al. [2S impairs the oxidation of sulfide in the pipe, making the concrete surface sulfide absorption decrease after the first increase. Min et al. [2S cavitation or sulfuric acid corrosion, the essence is acid corrosion; with an increase in corrosion time, there is a more pronounced decline in the strength of the concrete. The large amount of H2S produced by microorganisms in the sewage is the main reason for the degradation of concrete material properties.Domestic and foreign research has been conducted for a long time to explore the corrosion mechanism of sewage on concrete, both physicochemical corrosion ,2, and morrosion ,7. Scholwage. Li , Jiang [wage. Li  et al. sn et al. ,11 foundn et al.  studied n et al.  studied n et al. , Xiao [1n et al. ,16 et alMuch research has been carried out by scholars on how to improve the corrosion resistance of concrete materials; the coating method and the addition of highly durable materials are hot research directions. For concrete in a sewage environment, a surface coating of bacterial inhibitor will reduce the bacterial activity ; the bacZhou et al.  conducteIn this paper, we add various materials, such as water-soluble sodium silicate and inorganic water repellent, to basalt fiber to further enhance the performance of concrete against penetration. This forms a certain protective film inside the concrete to block the corrosion by harmful substances. This paper develops a new type of modified concrete by adding fiber and an anti-seepage agent. It has high mechanical properties and corrosion resistance, and excellent protective effect. This method is novel, practical, simple to operate, low cost, and has good application prospects. This paper describes a corrosion study carried out for this new concrete material, using an organic aqueous solution instead of sewage. The study measured the apparent change pattern after corrosion. The density, water absorption, and compressive strength of the material were also determined. At the same time, microscopic corrosion structure and composition analyses were performed. The results of this paper can provide a basis for the engineering application of this new concrete material.Cement: Qinling P · O42.5 ordinary Portland cement; aggregate: coarse aggregate has the particle size of 5 mm~16 mm continuous graded gravel; the fine aggregate is medium sand, and the fineness modulus is 2.6~2.8. Water reducer: polycarboxylic acid high-performance water reducer. Other materials: mineral powder, silica fume, titanium dioxide, alum, quartz sand, sodium methyl silicate, inorganic aluminum salt waterproofing agent, basalt fiber (fiber volume content 0.10%). The test block size is 100 mm × 100 mm × 100 mm; the specific material ratio is shown in The test block was immersed in artificially configured high-concentration organic water, and the high-concentration artificial sewage mix ratio is shown in The test will be of five different ratio test blocks immersed in organic water solution. Every 60 d, part of the test blocks is taken out, to observe the corrosion of the test blocks. The changes in the phenological phenomena of concrete with increasing corrosion cycles are shown in Compressive strength can reflect to a certain extent the concrete test block bearing capacity. The strength test was carried out on the test blocks by taking test blocks out every 60 d to observe the effect of corrosion solution on the bearing capacity of concrete with different ratios. The compressive strength test is based on the “Standard for Mechanical Properties Test Methods of General Concrete”, and three test blocks are taken from each group for compressive strength . The testing machine with displacement control was loaded at a rate of 0.45 mm/min and stopped loading when the specimens reached 75% of the maximum load-bearing capacity.The mechanical test of the compressive strength of the concrete after corrosion was carried out. It can be seen from Concrete pore structure changes after corrosion. 2 crystals were observed; both generated deep cracks, but the basalt fibers in C2 inhibited the development of cracks. Hexagonal plate-like Ca(OH)2 crystals can be observed in C3 and C4 test blocks, and their internal structures are relatively dense. It shows that adding sodium methyl silicate and inorganic aluminum salt waterproofing agents can effectively improve the corrosion resistance of concrete in a sewage environment. Fibers can also be observed crossing in C4, which are tightly connected to the structure. However, C5, double-doped with sodium methyl silicate and inorganic aluminum salt water repellent, has a slightly loose structure and ettringite formation. The production of calcium alumina in C1 and C2 indicates the intrusion of SO42− ions, causng a reaction with hydration products, while a large amount of Ca(OH)2 in C3 and C4 means that sodium methyl silicate and inorganic aluminum salt water repellent can both promote cement hydration and block the infiltration of harmful substances, ensuring that the corrosion resistance of the material is improved.The SEM microstructure of the concrete after 240 d of corrosion by organic aqueous solution is shown in 42− reacts with cement hydration products to form ettringite. Ettringite will produce expansion stress and damage the internal structure of concrete, which is also the main reason for concrete damage. Therefore, the compressive strength of C1 is the lowest. A small amount of ettringite was detected in C2, and the content of Ca(OH)2 decreased with the increase of corrosion, but it was still the main component. The diffraction peaks of C2S and C3S in C3 and C4 decreased significantly; the diffraction peak of Ca(OH)2 was very high, and ettringite was not detected. This shows that incorporating sodium methyl silicate and inorganic aluminum salt waterproofing agent is beneficial to cement hydration and effectively prevents the entry of SO42−. The diffraction peaks of C2S and C3S in C5 get lower and lower. It can be seen that the double mixing of sodium methyl silicate and inorganic aluminum salt waterproofing agent has a more apparent promoting effect on cement hydration. Still, a small amount of ettringite is produced. It is possible that the double-doped waterproofing agent has a weakened effect on their respective barrier effects and does not achieve the barrier effect of 1 + 1 > 2. The generation of ettringite will have a certain impact on the strength of concrete, which is consistent with the conclusion of the compressive strength values obtained.From Density and water absorption tests were conducted for each concrete mixing ratio after corrosion, and the results were as follows. The concrete density variation is shown in As shown in The cross-sectional comparison revealed that the compactness of C2 was better than that of C1, indicating that adding mineral admixtures can fill the pores in the concrete and make the concrete structure more compact than ordinary concrete. The fibers can inhibit the generation and development of cracks while improving the corrosion resistance of the concrete. The concrete densities in the C3, C4, and C5 mixes were consistently higher, and the water absorption rates were lower. Adding sodium methyl silicate and inorganic aluminum salt water repellent is beneficial to reduce internal defects, increase compactness, and improve concrete’s corrosion resistance.Tests were conducted to test the compressive strength of the concrete after corrosion, and the following results were obtained. The load-displacement curve of each mixing ratio test block is shown in The strength of concrete after corrosion is shown in To sum up, the plastic deformation ability is obviously improved by adding basalt fiber to concrete. Sodium methyl silicate and inorganic aluminum salt waterproofing agents can effectively improve concrete’s mechanical properties and corrosion resistance.2S by anaerobic sulfate-reducing bacteria (SRB). H2S is further combined with oxygen to form H2SO4. These acidic compounds are neutralized with concrete so that the pH value of the concrete surface is gradually reduced. When the pH value is close to 4, the acidophilic SOB (ASOB) bacteria (such as Acidithiobacillus ferrooxidans and Acidithiobacillus thiooxidans) begin to multiply in large quantities, which will produce concentrated biological sulfuric acid, further acidify the environment, and then form biological sulfuric acid corrosion, which is the main reason for the deterioration of concrete performance.The composition of the organic aqueous solution is complex, and concrete structures are easily eroded. The initial concrete surface is alkaline, and the solution contains sulfate ions, which are converted into H2 and later react with C-S-H gel to form gypsum, reducing the structural strength and increasing porosity. The gypsum will continue to react with hydrated calcium aluminate to create swelling ettringite, which will generate internal stress and eventually cause concrete cracking, as shown in Concrete contains many calcium compounds . Biosulfuric acid will initially react with Ca(OH)To lessen the deterioration of concrete performance, two kinds of waterproofing agents, sodium methyl silicate and inorganic aluminum salt, were added to prevent the penetration of harmful substances and protect concrete from corrosion. Sodium methyl silicate can form a layer of impermeable waterproof resin film on the surface of cement-based materials, as shown in Schematic diagram of the action model of sodium methyl silicate:Inorganic aluminum salt waterproofing agent action model schematic diagram:The following conclusions were mainly obtained by studying new basalt fiber concrete’s durability performance and corrosion mechanism under an organic water environment.(1)After organic water solution corrosion, there are a lot of black algae deposits and crystallization on the concrete surface, and there is a sanding phenomenon. The addition of sodium methyl silicate and inorganic aluminum salt water repellent led to an improvement in the concrete surface corrosion. The effect of adding inorganic aluminum salt waterproofing agent is more prominent.(2)Through microscopic analysis, it is found that there are many pores in ordinary concrete, and the pores of other mix ratios are significantly reduced. Among them, the test block with added inorganic aluminum salt waterproof agent is the most compact.(3)The compressive strength analysis shows that the addition of inorganic aluminum salt waterproofing agent can increase the strength of the material by about 12% and the strength retention rate by 15%. The combination of basalt fiber and inorganic aluminum salt waterproofing agent has the best effect. It is recommended to be used in preference to normal concrete.(4)3.The addition of an inorganic aluminum salt waterproofing agent significantly reduced corrosion and improved the durability of concrete materials in a sewage environment corrosion; the recommended dose of 6 kg/m(5)This new highly durable concrete protection mechanism relies on basalt fiber and inorganic aluminum salt waterproofing agent, the addition of which causes filling of the internal pores, increased density of concrete materials and reduced rate of penetration of harmful substances. Sodium methyl silicate and cement-based materials react to form a specific waterproof layer, blocking ion penetration; however, the inorganic aluminum salt waterproofing agent protection effect is more prominent.


Antibiotic overuse is high in patients hospitalized with coronavirus disease 2019 (COVID-19) despite a low documented prevalence of bacterial infections in many studies. In this study evaluating 65 COVID-19 patients in the intensive care unit, empiric broad-spectrum antibiotics were often overutilized with an inertia to de-escalate despite negative culture results. Broad-spectrum antibiotics (BSAs), such as piperacillin–tazobactam, are commonly prescribed for a mean duration of 5 to 7 days. However, antibiotics appear unlikely to improve outcomes in hospitalized COVID-19 patients. Antibiotic overuse in COVID-19 patients may be associated with unintended consequences including adverse events and the development of antimicrobial resistance. The purpose of this study was to examine outcomes and antibiotic use in ICU COVID-19 patients treated with an empiric antibiotic course compared to patients with documented bacterial infection and those whom antibiotics were stopped ≤72 hours given negative cultures.Nearly three-quarters of patients with coronavirus disease 2019 (COVID-19) receive antibiotics even though the prevalence of bacterial coinfections is low  result (the index regimen) and if blood and/or respiratory cultures were obtained ≤24 hours of antibiotic initiation. We applied the following exclusion criteria: death ≤72 hours of antibiotic initiation, antibiotics initiated prior to a positive SARS-CoV-2 result, transfer from an outside hospital, antibiotics initiated while in a non-ICU unit, or patient already on antibiotics for an alternate indication . Patients were still considered for inclusion if empiric antibiotics were ordered and then discontinued upon confirmation of SARS-CoV-2 infection, as long as they met the criteria above for the index regimen and culture obtainment. Prior antibiotic exposure was defined as receipt of intravenous antibiotics for ≥48 hours within the last 90 days. Multiple antibiotic courses following the index regimen were assessed but were not considered unique events. Eligible patients were categorized into 1 of 3 groups: (1) culture-negative, antibiotics discontinued ≤72 hours, (2) culture-negative, antibiotics continued >72 hours, or (3) culture-positive.Following institutional review board approval, patients were identified using electronic surveillance software and were followed until hospital discharge or in-hospital death. Electronic medical record review and Research Electronic Data Capture (REDCap) were used to collect and organize the following data: comorbidities with a high risk of progressing to severe COVID-19 illness (identified by study investigator during record review rather than ICD-10 code), supplemental oxygen requirement at antibiotic initiation, COVID-19-specific therapy, microbiological culture information, and antibiotic use. Secondary outcomes included time from antibiotic discontinuation until restart, in-hospital mortality, and time from antibiotic initiation to ICU discharge and hospital discharge or death. Adverse events were also assessed, including acute kidney injury, development of multidrug resistance, antibiotic-related rash, and Clostridioides difficile infection. Acute kidney injury as defined by the Acute Kidney Injury Network criteria was assessed following 24 hours of the initial regimen and up to 48 hours after discontinuation. Multidrug-resistant organisms included methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus, or Gram-negative bacteria resistant to 1 or more classes of antimicrobial agents per the Centers for Disease Control and Prevention definition.The primary outcome was clinical success, defined as being discharged alive or >2-point decrease in the World Health Organization Clinical Progression Scale score from day of antibiotic initiation to day 30.2 test or the Fisher exact test for nominal variables, the Kruskal-Wallis test for ordinal variables and time variables, and one-way analysis of variance for other interval variables. A 2-tailed P value of <.05 was considered statistically significant. No adjustments were made for multiple testing. All analyses were conducted using SAS Enterprise Guide version 7.1 software .The 3 groups were compared on baseline characteristics, antibiotic use, outcomes, and adverse events using the χDuring the 4-month study period, of 296 ICU COVID-19 patients screened, only 65 (22%) met inclusion criteria. The most common exclusions were antibiotic initiation prior to confirmed positive SARS-CoV-2 result (n = 84), no culture obtainment (n = 44), and non-ICU admission upon antibiotic initiation (n = 37). Of the 65 included patients, 23 (35%) had culture-positive infection; 32 (49%) were culture-negative and had antibiotics continued >72 hours; and 10 (15%) were culture-negative and had antibiotics discontinued ≤72 hours of initiation.Staphylococcus aureus (MSSA) isolated primarily from respiratory cultures in this group (Fig. Table oup Fig. . Median Outcomes of clinical success, in-hospital mortality, time to restart of antibiotics, and time to ICU and hospital discharge or death did not differ between the groups. Discontinuing antibiotics ≤72 hours if culture-negative did not impact clinical outcomes compared with groups treated with longer antibiotic courses with or without positive cultures. The highest rates of adverse events occurred among the 40.6% of patients who were culture-negative and had antibiotics continued >72 hours. However, these events did not reach statistical significance.Consistent with prior published literature, ICU COVID-19 patients were often treated with empiric BSAs despite low rates of corroborating culture-positive infections. The observed rate of 35% of COVID-19 patients with positive cultures in our study was higher than the rates described in other cohorts. However, in examining a variety of clinical outcomes, we identified no benefit for continuing antibiotics >72 hours in ICU COVID-19 patients with negative cultures. Instead, there was suggestion of harm with more adverse events in our cohort of patients treated >72 hours with negative cultures.Also consistent with prior data, BSAs with anti-MRSA and anti-pseudomonal activity were the most frequently prescribed despite low rates of cultures with these organisms. Given that MSSA accounted for nearly half the positive cultures in our study, opportunities for narrowing antibiotic regimens are evident. Antimicrobial stewardship efforts may also focus on ensuring appropriate treatment durations in this group based on the 10.5-day median duration observed for respiratory cultures.This study had several limitations. The study design was retrospective, we had a small sample size, and the study was conducted over a relatively short period prior to the emergence of new SARS-CoV-2 variants and the adjunctive use of tocilizumab or baricitinib. However, it was a multicenter study including multiple ICUs of both tertiary-level and rural community hospitals. It also represents real-world experience in treating ICU COVID-19 patients.In conclusion, significant opportunities exist to limit antibiotic exposure in ICU COVID-19 patients because empiric BSAs do not appear to be associated with benefit and may result in harm. When antibiotics are prescribed, spectrum of activity should be targeted at commonly identified pathogens. We observed high rates of anti-MRSA and anti-pseudomonal antibiotic use despite low rates of cultures with these pathogens.


Brittle matrix composites such as concrete are susceptible to damage in the form of cracks. Most of the current self-repair and self-healing techniques have repair limits on crack widths or high costs of an external stimulator, or have an unfavorable effect on the composite’s strength. This paper proposes a new concept of corrosion-induced intelligent fiber (CIF) and a new self-repairing system that uses the CIFs to close cracks in brittle matrix composites within a corrosive environment without external help, and without compromising the strength. The CIF comprises an inner core fiber and an outer corrodible coating that are in equilibrium, with the core fiber in tension and the corrodible coating in compression. The preparation steps and shape recovery mechanism of the CIF and the self-repair mechanism of the CIF composites are explained. Based on these concepts, this paper also describes several mechanical models built to predict the magnitude of pre-stress stored in the core fiber, and the maximum pre-stress released to the matrix composites, and the minimum length of the reliable anchor ends of CIF. The sample calculation results show that the recovery strain was 0.5% for the CIF with the steel core fiber and 12.7% for the CIF with the nylon core fiber; the maximum crack closing force provided by the CIF to concrete can be increased by increasing the amount of the CIFs in concrete and the initial tensile stress of the core fiber. This paper provides some suggestions for enhancing the self-repair capability of brittle composites in complex working environments. Brittle matrix composites such as ceramics, concrete, and brick are susceptible to cracking due to their low tensile strength, which can affect the overall mechanical performance and durability of the structures made of the composites ,2,3. Tra3 crystals that fill the capillaries and microcracks in the concrete. When the concrete is again cracked, the active molecules are reactivated and continue to react until the cracks are healed. However, this method has minimal effect on repairing cracks over 400 μm in width [2 that reacts with Ca2+ in the concrete to produce CaCO3 crystals that seal and repair cracks up to 500 μm wide [Concrete is one of the most widely used construction materials. It is well known that concrete has some ability to self-heal ; its micin width ,19,20.  and a new self-repairing system that uses the CIFs to close cracks in the brittle matrix composites within a corrosive environment without external help. The CIF can be prepared by coating the surface of the pre-tensioned core fiber with a corrosion-prone coating, then the CIFs can be embedded in the crack-prone parts of the brittle matrix composites. Once cracking occurs, the corrosive media in the environment penetrate through the cracks and trigger the shrinkage of the CIFs, which in turn releases the stored pre-stress to drive the cracks in the brittle matrix composites to close. Based on this concept, this paper also builds several mechanical models of the CIF and the self-repairing system to predict the magnitude of pre-stress stored in the core fiber, and the maximum pre-stress released to the brittle matrix composite, and the minimum length of the reliable anchor ends of CIF. This paper aims to provide the conceptual and theoretical development of the new CIF that can be efficient for closing cracks with a wide width range without external help, and without compromising strength, which has the potential to realize the intelligent functions of the brittle matrix composites in their feedback to external corrosion damage.σ0  by Al, thenfε = Δx1/l; substituting fε = σ0/fE into Equation (7), thenσ0 is much smaller than fE, thus,E1 = cVcE + fVfE is the composite elastic modulus, and cV + fV = 1.As shown in l see a; in thel see b, the tetage see c, the lesion see d, the coF stored in the core fiber isF is maximum, the pre-stress released to the matrix composite is maximum. To solve the maximum value of the axial force of the core fiber, the F is first derived to obtainF’ = 0, thencE = fE, the F is maximum, and fV = 0.5; when cE ≠ fE, for the equationcE > 0 and fE > 0, then a < 0 or a > 1, thus Δ = 4a2 – 4a > 0 and Equation (15) has two different real roots, which arefV < 1, it should be discarded, while the other real rootmaxF.Based on Equation (10), the axial force l’. When the CIF reserved with permanent anchor ends is added into the matrix composite, the pre-stress released to the matrix composite can be predicted when the shrinkage of CIF stops.The permanent anchor ends of CIF are the portion of the core fiber not coated with the corrodible coating, or the portion where the surface of the core fiber with corrodible coating is coated with the corrosion-resistant coating; the length of any permanent anchor end is defined as The CIF is unidirectionally and uniformly arranged in the matrix composite;The influence of the Poisson’s ratio on the magnitude of the axial stress is disregarded;The permanent anchor ends are tightly bonded with the matrix composite without slippage;The force influence of the corrosion product of the corrodible coating is disregarded.In order to simplify the calculation of interaction between the CIF and the brittle matrix composite, the following assumptions are made:The symbols used in this section are listed in E2 is the composite elastic modulus of the brittle matrix composite with the core fiber, and E2 = fVfE1/(1 – cV1) + mVmE/(1 – cV1), fV1 + cV1 = sV, and sV + mV = 1.After the cross-section of the corrodible coating is completely lost, the pre-stress released to the brittle matrix composite by the shrinkage of the core fiber is maximum. As the corrosion product does not participate in the force, the core fiber and the brittle matrix composite establish a final tensile–compressive equilibrium. According to Equation (9), it can be known that the pre-stress released to the matrix composite by the shrinkage of the core fiber isaT = τπdl′, and the drawing force of the CIF is aT = tT, the following is obtainedτ is the bonding stress between the CIF and the matrix composite at the interface, and when the composition and properties of the matrix composite and the CIF are known, τ can be determined; l’ is the anchor length (the length of one end) of the CIF in the brittle matrix composite, and d is the diameter of the cross-section of the anchor end.In order that the permanent anchor ends are reliable without slipping, a sufficient length is required. It is assumed that the bonding anchoring force of the permanent anchor end is Formula (19) is substituted into Equation (20) to obtainBased on the concept of CIF, the self-repair method of the CIF composites has obvious advantages. First, the CIF composites working in a corrosive environment are capable of self-repairing without external help and independent of temperature, so compared to the self-repair techniques using SMA or an electric field, the use of CIF in concrete can reduce the costs. Second, the larger the pre-stress stored in the core fiber, or the higher corrosion degree the corrodible coating encounters, the larger the crack closure force that can be released to the concrete, meaning a wider crack can be repaired; thus, compared to the self-healing or self-repair techniques using crystalline admixtures, microcapsules, or bacteria, the use of CIF in concrete can close cracks with a wider width range without compromising the strength of the concrete. Third, before the corrodible coating is corroded thoroughly, when the concrete is again cracked, the corrodible coating can continue to be corroded until the cracks are closed or the cross-section of the corrodible coating is completely lost. Fourth, the use of CIF in concrete can act as effective reinforcement both before and after corrosion.cE = fE, the maximum axial force stored in the core fiber (maxF) is obtained when the volume fraction of the core fiber in the CIF was 50%; if cE ≠ fE, the maxF is obtained when the volume fraction of the core fiber is determined according to Equation (17). Setting the amount of CIFs in concrete (sV) to be 4V%, and assuming that the CIF is unidirectionally and uniformly arranged in the concrete, then the pre-stress stored in the core fiber , and set the matrix composite to be concrete in a chloride environment. The material parameters of CIF and concrete are listed in sV) and the initial tensile stress of the core fiber (sV and From the above sample calculation, it can be shown that, after the iron coating of the CIF is lost due to chloride corrosion, the recovery strain of the core fiber is 0.5% for the steel fiber and 12.7% for the nylon fiber. That is, if the length of the CIF is 20 mm, the recovery strain can be 2.5 mm for the CIF with the nylon core fiber, which means, if the CIF concrete member is free of external force, the theoretical crack closure width can be up to 2.5 mm. It can also be seen from The application of CIF will benefit crack closure, increase rigidity, and improve the corrosion resistance of concrete. This paper only provides the conceptual and theoretical study of the CIF and CIF composites; many important issues remain for future study. First, the performance of the self-repairing system and the optimization of the composition and properties of the CIF need to be explained via finite element analysis. Second, the optimized CIF needs to be prepared in the laboratory and explored with a set of experiments that can show the self-repairing behavior of the CIF composite within a corrosive environment.This paper presents a new concept of CIF that comprises an inner corrosion-resistant core fiber and an outer corrodible coating that can be easily corroded by corrosive media in the environment. During preparation process, the inner core fiber is put into tension and the outer corrodible coating into compression, such that the CIF is in equilibrium. When the CIF is in contact with corrosive media, the outer corrodible coating is corroded, and the core fiber shrinks and displays shape recovery, which in turn releases the pre-tension stress in the core fiber. By far, shape memory fibers comprising core fibers coated with a corrosion-resistant compound/material are well known, but a shape memory fiber by coating a corrodible coating on a core fiber has not yet been reported.This paper also proposes a new self-repairing system that uses the CIFs to close cracks in brittle matrix composites within a corrosive environment. Once cracking occurs, the CIFs embedded in the matrix composite can be triggered to shrink by the corrosive media from the environment, which in turn releases the pre-stress stored in the core fiber and thereby applies a compressive force to the matrix composite that acts to close the cracks. By far, self-repair concrete comprising reinforcing fibers is well known, but not with a corrodible coating in equilibrium with the core fiber. Compared to the current self-repair or self-healing techniques for concrete, the use of CIF in concrete can cost less than using SMA or the electrochemical deposition method because it is independent of temperature and does not need external help. Furthermore, it can be more efficient for closing wider cracks than that provided by the crystalline admixtures, microcapsules, or bacteria methods, all of which have unfavorable effect on concrete strength. Additionally, the use of CIF in brittle matrix composite can act as effective reinforcement both before and after corrosion.Based on the concepts, this paper also builds several mechanical models to predict the magnitude of pre-stress stored in the core fiber, the maximum pre-stress released to the brittle matrix composite, and the minimum length of the reliable anchor ends of CIF. These aim to attain an optimum combination of the CIF and matrix composite to provide enough crack closing force. Based on a sample calculation, the recovery strain was 0.5% for CIF with a steel core fiber and 12.7% for CIF with a nylon core fiber. The maximum crack closing force provided by the CIF to concrete can be increased by increasing the amount of CIFs in concrete and the initial tensile stress of the core fiber.The presence of CIF can be helpful toward improving the crack resistance of concrete, especially the low-modulus polymer fiber concrete. It can help to reduce the probability of premature concrete cracking and improve the durability of the concrete structures in corrosive environments, including marine and underground environments. For the future work, many important issues related to the concepts need to be explored. First, the optimization of the composition and properties of the CIF needs to be found via finite element analysis before performing the time-consuming laboratory tests; second, the optimized CIF needs to be prepared in the laboratory; and third, a set of experiments should be conducted to explore the self-repairing behavior of the CIF composite within actual corrosive environments.


Furthermore, it is currently unclear how variable glycosylation and Fab arm exchange may influence the ability of IgG4 to activate complement. Here, we used well-defined, glyco-engineered monoclonal preparations of IgG4 and determined their ability to activate complement in a controlled system. We show that IgG4 can activate complement only at high antigen and antibody concentrations, via the classical pathway. Moreover, elevated or reduced Fc galactosylation enhanced or diminished complement activation, respectively, with no apparent contribution from the lectin pathway. Fab glycans slightly reduced complement activation. Lastly, we show that bispecific, monovalent IgG4 resulting from Fab arm exchange is a less potent activator of complement than monospecific IgG4. Taken together, these results imply that involvement of IgG4-mediated complement activation in pathology is possible but unlikely.Of the four human immunoglobulin G (IgG) subclasses, IgG4 is considered the least inflammatory, in part because it poorly activates the complement system. Regardless, in IgG4 related disease (IgG4-RD) and in autoimmune disorders with high levels of IgG4 autoantibodies, the presence of these antibodies has been linked to consumption and deposition of complement components. This apparent paradox suggests that conditions may exist, potentially reminiscent of  In contrast to IgG1 and IgG3, the most potent subclasses in activating complement ity CDC; –7. IgG4 ity CDC; , 8. It h binding .2R1, a secretory phospholipase A2 receptor, expressed on cells in the glomerular basement membrane of the kidney  and in several autoimmune disorders, such as pemphigus, autoimmune pancreatitis, and primary membranous nephropathy (pMN) –12. Oftee kidney . Althouge kidney , which iin vivo deposits, in which complement activation can be observed. Furthermore, IgG4 undergoes several post-translational modifications, such as glycosylation and Fab arm exchange, that have been implicated in complement activation, but not studied in detail for IgG4 despite the importance of these modifications to its function.This raises several questions that warrant further investigation. Even though IgG4 has been considered a poor activator of complement at best, there could be certain conditions, potentially reminiscent of Fab arm exchange is a unique aspect of IgG4 and refers to its ability to exchange half-molecules of one heavy chain-light chain pair with another IgG4 molecule –17. TherN-linked glycan site, asparagine (N) at the position 297, in both CH2 domains of the Fc region (N-linked glycans comprises N-acetylglucosamine (GlcNAc) and mannose residues with possible extensions of galactose, sialic acid, core fucose, and bisecting GlcNAc  or other ficolins and collectins  was added at least 4 h post transfection. The galactose-glycovariants were produced as described previously ] eviously . To prod® P 188 (Sigma-Aldrich), at 5% CO2, 37°C while shaking at 125 rpm.High mannose-glycovariants were produced using HEK293-6E cells with a MGAT1 knock-out (KO), which lack N-acetylglucosaminyl transferase I (GlcNAc-T I) , 39. The® protein G HP 1 mL column  and eluted with 0.1 M glycine pH 2.5 (Merck). The eluate was then dialyzed against 5 mM NaAc (pH 4.5). Antibody concentrations were determined by measuring A280 on a NanoDrop One spectrophotometer (ThermoFisher) and samples were stored at -20°C.Culture supernatant was harvested five or six days after transfection and filtered using a 0.2 nm Puradisc™ syringe filter . Antibodies were purified on a HiTrap2.2®), both in a ratio of 1:4 (anti-bt or anti-TNP to irrelevant clone). Fab arm exchange was induced by mild reduction with 10 and 0.5 mM L-glutathione  for IgG1 and IgG4 respectively, in presence of 0.1% w/v Kolliphor® P407 (BASF). Samples were incubated at 37°C for over 20 h, after which the reaction was stopped with 12 mM and 0.6 mM 2-iodoacetamide  for IgG1 and IgG4 respectively. IgG1 and IgG4 bispecific antibodies were made fresh for each experiment due to aggregation of the antibodies during storage. Bispecificity was confirmed for all clones.To be able to produce bispecific IgG1 antibodies, a mutation of K409R was introduced into the heavy chain of the IgG1 anti-bt clone, which allows for Fab arm exchange of IgG1 in a manner similar to IgG4. IgG1 K409R anti-bt was reacted with an in-house generated IgG1 K409R variant of adalimumab, and IgG4 anti-bt or anti-TNP with IgG4 natalizumab  for 1 h and the bands were visualized using a ChemiDoc™ Universal Hood III (Bio-Rad).To study the influence of glycosylation on the molecular weight of IgG1 and IgG4, a reduced SDS-PAGE was performed on a NuPAGE 4-12% Bis-Tris gel according to manufacturer’s protocol (Invitrogen). The gel was stained with InstantBlue2.42HPO4 . Nunc MaxiSorp™ flat-bottom plates (ThermoFisher) were coated with 5 µg/mL of biotinylated HSA (HSA-bt) or 10 µg/mL of TNPlated HSA (HSA-TNP) in PBS and incubated at 4°C overnight. IgG antibodies were serially diluted in PBS supplemented with 0.1% v/v Tween®-20 and 0.2% w/v gelatin (Merck) and incubated shaking at room temperature for at least 1 h. After washing, C3b deposition was allowed for 1 hour at RT by addition of 2.5% normal human serum  in veronal buffer , 1.8 mM sodium-barbital (Fagron), 0.146 M sodium chloride (Merck)) supplemented with 1 mM calcium chloride , 0.5 mM magnesium chloride  and 0.2% Tween-20 (VB+/+). For inhibition conditions, VB++ was supplemented with additional anti-C1q-85 , an Sanquin , 46) and Sanquin , 48;) or Sanquin .Alternatively, instead of the addition of serum dilution, IgG binding to the coat was measured using mouse-anti-IgG-horseradish peroxidase . Deposited C3b was detected with mouse anti-human C3-19-HRP  and bou2.52 and 0.5 mM MgCl2. Conditions with complement inhibitors were included as described above, but with four times higher concentrations. A positive control (100% lysis) was generated by adding 0.5% w/v saponin (Merck/Millipore) to RBCs and used to normalize the data. After incubation, 40 µL of buffer was added, plates were centrifuged at 1800 rpm for 2 min and 100 µL supernatant was transferred to MaxiSorp™ plates. The OD was measured as ΔOD(412 nm) – OD(690 nm). The percentage of cell lysis for each sample was calculated as follows: % Lysis = ODsample/mean OD100% * 100.The CDC assay to assess terminal pathway activation by the anti-bt IgG antibodies was performed as described earlier, with minor alterations . To biot2.6Kruskal-Wallis test with Dunn’s multiple comparisons test was performed for statistical comparison of the IgG4 glycovariants.33.1To study complement activation by IgG4, C3b deposition and CDC were determined in a recombinant antibody system with anti-hapten antigens which allowed for control of antigen density. Using recombinant anti-biotin antibodies with biotinylated HSA, we found that IgG1 activated complement efficiently in all conditions tested, in contrast to IgG4 which could only activate complement at high antigen densities (HSA-bt 120 and 240 µM) and high antibody concentrations . At the level of C3b deposition, differences between the IgG4 glycovariants were observed, with the HG variant steadily outperforming the NG and LG variants , as comp3.3We next investigate the possible role of the Fab glycans on complement activation as they are relatively abundant on IgG4 . Therefo3.4via MBL (via the classical pathway and moreover, that this activation is irrespective of glycosylation as all variants rely on C1q for activation. Moreover, we found that C1q could also bind to IgG4, although to a lesser extent than to IgG1 (via the classical pathway. As the alternative pathway requires higher serum concentrations to be studied, we also performed the experiment at 10% serum and allowed deposition at 37°C and we found similar results (Next, we investigated which pathway of the complement system was activated by these IgG4 glycovariants. C3b deposition and RBC lysis were performed in the presence of inhibitors of C1q, MBL, and FD, to determine the contribution of the classical pathway, lectin pathway and alternative pathway, respectively. Despite the suggestion that IgG4 might activate complement via MBL , we founTaken together, no role for the lectin pathway in IgG4 complement activation was found, which instead appears to mainly employ the classical pathway that was slightly enhanced by galactosylation on the level of C3b deposition.3.5in vivo. Through this Fab arm exchange process, monovalent-bispecific IgG4 antibodies with decreased avidity for their targets are generated (via ELISA, which was found to be reduced for both anti-biotin and anti-TNP bispecific IgG4 clones, but also for the bispecific anti-biotin IgG1 clone in comparison to their monospecific counterparts. The binding of the monospecific and bispecific IgG antibodies to either biotin (In our previous assays, only bivalent-monospecific antibodies were used, but IgG4 antibodies can recombine half-molecules with different antigen specificities enerated . We ther4IgG4 is generally considered a poor activator of complement, but at the same time has been linked to complement-induced fibrosis in IgG4-RD and IgG4 autoimmunity –12. Thisvia the lectin pathway (2R1-associated pMN can also occur in individuals with MBL deficiency (2R1 antibodies often co-occur with other subclasses as well (via the classical pathway. Lastly, variable domain glycosylation, known to be elevated in IgG4 (2R1 antibodies from pMN patients could be bound by MBL and the suggestion that the lectin route is mainly responsible for complement activation at affected tissues (Agalactosylated IgG has been shown to correlate with disease severity in several autoimmune diseases where complement contributes to pathology, including rheumatoid arthritis and systemic lupus erythematosus , 54. Aga pathway , 12. Howficiency  and IgG4 as well , 57. In  in IgG4 , diminis tissues . However tissues , whereasin vivo, for example within antibody deposits in IgG4-RD or pMN, remains to be investigated.It has been previously described that at high concentrations of both antibody and antigen, IgG4 could induce C3 and terminal pathway activation . We confvia antigen binding, IgG Fc tails can cluster together to form hexamers via weak Fc-Fc interactions, mediated in part by Fc glycans, to interact with the hexagonal C1 complex (Upon recruiting antibodies to a surface  complex , 62, 63. complex , 65. Des complex , 67. Reg complex . Similar complex , 61. Thivia the classical pathway. A slight impairment of complement activation by IgG4 was found in the presence of Fab glycans. IgG Fab glycosylation impacts antibody stability, half-life, binding characteristics, and immune complex formation (We also studied the effect of galactosylation on IgG4 complement activation, which has previously received little attention, as most of the research on Fc glycosylation has focused on IgG1. For IgG1 it has been shown that galactosylation enhances C1q binding and downstream CDC activity , 23, 52.ormation . It has ormation . Since Iin vivo situation. Here we show that bispecific IgG4 induces less C3b deposition than monospecific IgG4, which is particularly relevant for interpreting other studies on IgG4 complement activation that use monospecific antibody preparations. Interestingly, it has been previously shown that a monovalent IgG1 antibody outperformed its bivalent monospecific counterpart in CDC experiments (in vivo.Another important hallmark of IgG4 is its ability to undergo Fab arm exchange and form bispecific antibodies –16, whiceriments , 74. Howeriments , suggestin vivo Fab arm exchange. Currently IgG4 antibodies account for approximately 13% of all therapeutic monoclonal antibodies approved or in development (IgG4 is believed to have mainly neutralizing and anti-inflammatory functions due to limited complement fixation and crosslinking, therefore it has been exploited for the development of therapeutic antibodies that are intended to block their target, often including a stabilizing S228P mutation to minimize elopment . Two exaelopment , 77. Howvia the classical pathway. In addition, galactosylation has a subtle enhancing impact on the capacity of IgG4 antibodies to activate complement, whereas Fab arm exchange, a hallmark of IgG4, has the opposite effect. These findings imply that pathogenic role of IgG4 in diseases such as IgG4-RD or pMN via recruitment of the complement system is possible, but unlikely.In summary, we demonstrate that although IgG4 is a weak trigger for complement activation, it cannot be considered completely ‘complement-dead’, since it does activate complement, but only at high antigen densities and high antibody concentrations, and only The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.All authors contributed to the article and approved the submitted version. Designing research studies: NO, TD, TR, GV. Conducting experiments and data acquisition: NO, TD, MS, PO-H, JN, CK, MW. Analyzing data: NO, TD, MS, JC, TR. Writing the manuscript: NO, TD, TR.