Background: There is a perception among ear, nose, and throat (ENT) surgeons that oral antibiotics are over-prescribed for acute otitis externa (AOE), and the potential for topical therapy as first-line treatment is not fully realized in primary care. We evaluated the prescription rate of topical and oral antibiotics for AOE in primary care and in patients referred to the ENT emergency clinic. A systematic review was performed by searching the MEDLINE, Embase, PubMed, and Google Scholar databases between January 1990 and October 2020. The quality of the evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) tool. The outcome measures were the rate of topical and oral antibiotic prescriptions for AOE by primary care practitioners and the rate of oral antibiotic prescriptions that were not indicated.Methods:Results: Seven studies met the inclusion criteria. The overall quality of evidence was moderate. The rate of topical antibiotic prescriptions was between 77% and 95%, and oral antibiotics varied between 6% and 30% in patients that were managed only in primary care. Patients that were referred to an ENT emergency clinic had initially been treated by primary care practitioners with topical antibiotics in 14%-60% of cases and oral antibiotics in 16%-17%. The most commonly prescribed oral antibiotics were Amoxicillin and Co-amoxiclav (amoxicillin/clavulanic acid). No study had comprehensively reviewed the indication for oral antibiotics.Conclusion: The rate of topical antibiotic prescriptions for AOE was high in primary care; however, the rate was frequently suboptimal in patients attending the ENT emergency clinic. Although the rate of oral antibiotic prescriptions was relatively low, the choice of antibiotic for empirical treatment frequently did not cover the typical bacteria in AOE. There is a need for improvement in primary care prescribing of topical therapy prior to referral to the ENT emergency clinic. Acute otitis externa (AOE) is a common problem for general practitioners (GPs)  and is oInappropriate systemic antibiotic prescriptions can give rise to antibiotic resistance, which is associated with difficult-to-treat infections and carries an increased risk of mortality . The UniThe UK National Institute for Health and Care Excellence (NICE) guidelines on antimicrobial prescribing , last upTreatment failure due to unnecessary use of oral antibiotics and a lack of topical therapy is common in our experience of reviewing patients with uncomplicated AOE that have been referred by their GPs to the ENT emergency clinic. This has several implications including undue pressure on the secondary care service, prolonged patient suffering, cost, potential adverse drug effects, and risk of antimicrobial resistance. We therefore evaluated the rate of oral and topical antibiotic prescriptions for uncomplicated AOE in primary care by performing a systematic review of the published literature.MethodsThis systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement standards . The revOutcome MeasuresThe primary outcome measures were the rates of topical, oral, or a combination of antibiotic prescriptions for uncomplicated acute otitis externa (AOE) in primary care. The secondary outcome measures included the choice of prescribed antibiotics and the rate of oral antibiotic prescriptions without a valid indication. Literature Search StrategyThe electronic databases of MEDLINE, Embase, PubMed, and Google Scholar were searched. The last search was run on October 25, 2020. The MEDLINE and Embase search terms were ‘ AND  AND (otitis externa).’ The Google Scholar search was ‘"otitis externa" + antibiotics|treatment|therapeutics|topical + "general practice"|"primary care"|"general practitioner"|"family practice" - media - chronic - fungal - viral - dermatitis - allergic - animal.’ The PubMed search was ‘((therapeutics) OR (treatment) OR (antibiotics) OR ) AND (otitis externa) AND  OR  OR (primary care) OR (family practice)).’ Related articles on PubMed, ‘cited by’ feature on Google Scholar, and article bibliographies were also used to identify articles. Pre-prints prior to peer review were also included via Authorea.Eligibility CriteriaInclusion criteria were publications between January 1990 and October 2020, English language, humans, all age groups, and patients with AOE. Exclusion criteria included hospital prescriptions as we were interested in only general practice prescribing patterns. Patient with atypical infections such as viral or fungal or underlying dermatoses or chronic conditions were excluded to avoid skewing the sample to difficult-to-treat cases.Study SelectionArticles were screened by titles and abstracts. Full texts of relevant articles were retrieved and independently assessed by two authors (ZM and RS). Quality assessment of studies was performed independently by both authors. Consultation was obtained from an independent third author (HB) for any discrepancies. Assessment of the Quality of EvidenceThe GRADE  framework  was usedResultsOur search strategy identified a total of 430 articles. This included results from Embase (n = 98), MEDLINE (n = 44), PubMed n = 116), Google Scholar (n = 162), and other sources (n = 10), as shown in the PRISMA flow chart in Figure 16, GooglTopical AntibioticsRowlands et al.  analyzedThree studies reviewed GP referrals to the ENT emergency clinic in three UK hospitals and examined primary care treatment of AOE. The topical antibiotic prescription rates were 14% , 26% 14, respectOral AntibioticsRowlands et al.  found thOf the hospital-based studies, Pabla et al.  found thCombination of Topical and Oral AntibioticsRowlands et al.  found thUnnecessary Oral Antibiotic PrescriptionsOnly one study by Trinidade et al.  had reviDiscussionSummary of Main FindingsTopical antibiotics: The rate of topical antibiotic prescriptions in primary care was 77%-95%. The rate of topical antibiotics prescribed by GPs for patients that were referred to the ENT emergency clinics varied widely from 14% to 50% and up to 60% after an educational intervention for GPs. The wide variation observed in patients attending the emergency clinics may be related to the local referral criteria for acceptance into the clinic, which often vary between ENT departments.Oral antibiotics: The prevalence of prescriptions for oral antibiotics as monotherapy was 6%-30% in patients treated in primary care. A narrower primary care prescription rate of 16%-17% was observed in patients attending the ENT emergency clinic. When oral antibiotics were prescribed, Amoxicillin and Co-amoxiclav (amoxicillin/clavulanic acid) were consistently chosen by GPs to treat otitis externa. The use of oral antibiotics as monotherapy may be an estimate of the rate of cases of otitis externa that were suboptimally managed as the inferred omission of topical antibiotics highlights a potential unawareness among prescribers that topical therapy is the mainstay of treatment. The Thailand study by Greer et al.  suggesteComparison With Existing LiteratureThis is a rare review to examine the prescribing pattern of primary care practitioners for AOE. We identified a number of survey studies of GPs’ self-perceived prescribing preference, which generally over-stated the use of topical prescription compared to our findings. Robertson and Bennett  conducteThe frequent use of Amoxicillin and Co-amoxiclav (amoxicillin/clavulanic acid) identified in our review was concerning as the causative bacteria in AOE are predominantly Pseudomonas aeruginosa and Staphylococcus aureus , and theQuality of the EvidenceIndirectness: The study by Rowlands et al.  had a laRisk of bias: The Thailand study  of primaImprecision: All the studies except the study by Rowlands et al.  were limInconsistency: A high degree of variation in the rates of topical and oral antibiotic prescriptions was found in the five UK-based studies ,11,13-15Overall GRADE assessment: Our findings on rate of oral and topical antibiotic prescriptions as well as choice of antibiotics were generally applicable to GPs in the United Kingdom and probably to other similarly developed countries, but several limitations impaired the overall quality of evidence resulting in a moderate rating. The quality of evidence in relation to the rate of unnecessary oral antibiotic prescriptions, which lacked a valid indication, was low and could not be reliably evaluated.Implications for PracticeThe ENT emergency clinic is an established component of most ENT units in the UK ,21. RefeTierney et al.  conducteFurther ResearchThe current literature lacks studies that stratify AOE into complicated and uncomplicated cases, and therefore we were unable to determine the proportion of oral antibiotic prescriptions that lacked a valid indication. Hence, the current body of evidence is insufficient to estimate the rate of unnecessary oral antibiotic prescriptions in AOE. Due to the retrospective nature of the studies, we cannot be certain whether the low rate of primary care prescriptions for topical therapy observed in patients that were referred to the ENT emergency clinic was due to undocumented patient factors, such as occlusion of the canal with debris, or simply suboptimal primary care treatment. There is a need for well-designed prospective studies to address these problems. One study  demonstrTopical antibiotics were predominantly prescribed for AOE in primary care considerably more often than oral antibiotics. However only a relatively small proportion of patients had received topical therapy in primary care prior to referral to the ENT emergency clinic. Insufficient evidence was available to determine the proportion of oral antibiotics prescribed by GPs that lacked a clinical indication. There was good evidence to indicate that GPs frequently prescribed an inappropriate oral antibiotic choice, such as Amoxicillin or Co-amoxiclav (amoxicillin/clavulanic acid), despite inefficacy of these antibiotics to the common bacteria in AOE.This study draws attention to deficiencies in primary care initial management of AOE and the need for ENT doctors to reserve ENT emergency clinic hospital appointments for those patients that have been initiated on appropriate treatment in primary care. Educational initiatives should be directed to address these deficiencies.


Provision of provider-specific outpatient antibiotic prescribing data has resulted in significant decreases in antibiotic use. We describe the development of reports of inpatient antibiotic prescribing by hospitalists attending on acute medical wards in VA medical facilities. We created algorithms for determining the attending physician responsible for patient days present (DP), by considering changes of service  and transfers between services or physicians. Each antibiotic dose was assigned to a single attending, ward location, and service according to denominator assignment. Antibiotic use was grouped into Centers for Disease Control and Prevention drug categories and expressed as antibiotic days of therapy (DOT) per 1000 DP. Data were obtained from the VA Corporate Data Warehouse. Algorithms were iteratively refined based on reviews of medical records from three VA medical centers and applied to acute care patients at a single site for 2018-2020.In 2018-2020, 294 attendings oversaw acute inpatient care for >= 14 DP. 129 attendings with >= 300 DP oversaw 88.0% of all patient care and prescribed 87.6% of all antibiotics , 90.1% of broad-spectrum therapy for hospital-onset infections  and 88.3% of resistant Gram-positive therapy  in inpatient wards. The distribution of antibiotic use for acute care ward patients amongst these 129 staff is shown in the following figure.We developed algorithms to attribute antibiotic therapy to inpatient attendings that can be broadly applied in facilities with electronic medical records. As with outpatient prescribing, we found large variation across inpatient attendings in overall antibiotic use and broad-spectrum antibiotic use. In future work, we will obtain provider feedback of report usability and interpretability and assess whether distribution of these reports allows antibiotic stewards to favorably influence provider prescribing practices.Matthew B. Goetz, MD, Nothing to disclose Arjun Srinivasan, MD, Nothing to disclose


The AIDS epidemic among young students is serious, and effective preventive interventions are urgently needed. Game-based intervention has become an innovative way to change healthy behaviors, and we have developed an AIDS educational game called AIDS Fighter · Health Defense.In this study, we tested the effect of AIDS Fighter · Health Defense on young students in improving AIDS-related knowledge, stigma, and attitude related to high-risk behaviors in Southwest China.P≤.05.A randomized controlled trial was conducted from September 14 to 27, 2020. In total, 96 students from 2 classes in a middle school were selected by stratified cluster sampling in Luzhou City, Southwest China. The students were randomly divided into the intervention group  and the control group . The intervention group played the AIDS educational game AIDS Fighter · Health Defense; the control group learned AIDS-related knowledge through independent learning on the QQ chat group. An AIDS-related knowledge questionnaire, a stigma scale, and an attitude questionnaire on AIDS-related high-risk behaviors were used to measure the effect of the AIDS educational game via face-to-face interviews. The user experience of the game was assessed using the Educational Game User Experience Evaluation Scale. The difference was statistically significant at t=4.282 and P<.001. The stigma scores of the 2 groups were 2.44 (SD 0.57) and 2.48 (SD 0.47), with t=0.373 and P=0.71. The positive rate  of attitudes of high-risk AIDS behaviors of the 2 groups were 82.00 (SD 23.44) and 79.62 (SD 17.94), with t=0.555 and P=0.58. The mean percentage of the game evaluation was 54.73% as excellent, 31.45% as good, 13.09% as medium, and 0.73% as poor.After the intervention, the AIDS knowledge awareness rate  of the intervention and control groups were 70.09 (SD 11.58) and 57.49 (SD 16.58), with AIDS Fighter · Health Defense could increase AIDS-related knowledge among young students, but the effect of the game in reducing AIDS-related stigma and improving the attitudes of high-risk AIDS behaviors was not seen. Long-term effects and large-scale studies are needed to assess the efficacy of game-based intervention.Chinese Clinical Trial Registry ChiCTR2000038230; https://trialsearch.who.int/Trial2.aspx?TrialID=ChiCTR2000038230 According to the Joint United Nations Programme on HIV/AIDS (UNAIDS) data, there were approximately 3.4 million HIV infections among young people aged 15-24 years worldwide and approximately 460,000 new HIV infections among young people in 2019 [Therefore, it is necessary to take effective measures to control the prevalence of AIDS among young students . StudiesWith the development of science and technology, AIDS prevention education has changed from using traditional methods to using modern ones ,10. AmonResearch on AIDS health education games started late, mainly aimed at adolescents, including HIV-infected adolescents, gay men and other high-risk groups, and healthy adolescents. The targets of education are to increase adolescents' adherence to antiviral therapy and pre-exposure prophylaxis (PrEP) -18, promAIDS health educational games in China are in their infancy, and with few existing studies, single game elements, incomplete game mechanisms, and a lack of effect evaluation studies, the actual educational effect is not clear. To solve these problems, we developed an AIDS educational game, mainly targeting education for HIV/AIDS knowledge, attitude, and behavior, and refusal of drug and alcohol abuse. The game has a variety of elements and mechanisms that are suitable for AIDS prevention education of adolescents in China.In this study, we tested the effectiveness of the AIDS educational game on preventing HIV among young students in Luzhou City, Southwest China. Here we report results from this study.The AIDS educational game is called AIDS Fighter · Health Defense. The story line is that HIV launches an attack on the human body and players need to control heroes to eliminate HIV. During the battle, players are repeatedly trained to take condoms and refuse dangerous sexual behaviors, avoid drugs to refuse intravenous drug use, avoid alcohol to refuse dangerous sex when drunk, obtain antiviral drugs for PrEP and postexposure prophylaxis (PEP) .The human body system is used as the level in the game. There are 7 levels in total. The difficulty of the game increases from low to high. The sequence of levels is (1) immune system, (2) blood system, (3) skin and mucosal system, (4) central nervous system, (5) respiratory system, (6) digestive system, and (7) genitourinary system.The game copywriting of each level corresponds to the human body system of the level, describing that the system is infected with HIV. The success or failure of the game has corresponding text prompts. If the game fails, it prompts HIV to invade the human body and shows what the result will be; if it succeeds, encouraging text appears to remind the player that they have successfully avoided HIV infection.AIDS Fighter · Health Defense has the following mechanisms and components: (1) a virus combat game, (2) goal setting to eliminate HIV, (3) questions to be answered to be resurrect in the game, (4) point ranking, and (5) recognition and rewards. The game includes 5 functional modules:Game module: There are 7 levels involving 7 systems of the human body affected by AIDS.Quiz-and-Answer module: It provides a chance to the player to resurrect by answering questions on AIDS-related knowledge.Knowledge Corner module: It contains educational articles and videos on AIDS.Point-ranking module: Points are awarded according to the behavior and clearance situation during the game and the learning in the Knowledge Corner module, and the points are ranked.Data Management module: The educational information in the Knowledge Corner module can be edited, and in-game data collection, integration, classification, and application can be realized.The gameplay and screenshots are shown in A randomized controlled trial was conducted, in which 2 classes were selected from a middle school in Luzhou City using stratified cluster sampling. Third-party staff randomly allocated the 2 classes to the intervention group and the control group by tossing a coin.We had the following hypotheses (H):H1: AIDS Fighter · Health Defense can increase the awareness of AIDS-related knowledge among young students.H2: AIDS Fighter · Health Defense can reduce AIDS-related stigma among young students.H3: AIDS Fighter · Health Defense can improve the attitude of AIDS-related high-risk behaviors among young students.The study was approved by the ethics committee of the Affiliated Hospital of Southwest Medical University, China.The participants of the study were first-grade students of a secondary vocational school, and the location was Luzhou City, Southwest China. The eligibility criteria for participation were as follows: young students aged 15-24 years, informed consent and voluntary participation in this study (<16 years old required the consent of the guardian), and ability to access the internet. The exclusion criteria were as follows: The participant or guardian refused to provide consent to participate in the study, the participant did not complete the questionnaire survey, and the participant had used similar games before.The intervention and control groups received the corresponding intervention from September 14 to 27, 2020.The intervention group played AIDS Fighter · Health Defense through WeChat . Participants were asked to play the game and study the AIDS-related knowledge in the Knowledge Corner module and were required to earn at least 20 points per day. The details of the participants' use of the game can be checked through the game’s data management system.Participants in the control group were added to the QQ chat group . The same educational resources as the Knowledge Corner module in AIDS Fighter · Health Defense were uploaded to the QQ group. Participants were asked to learn the knowledge by themselves.The primary outcomes were AIDS-related knowledge, stigma, and attitude before and 14 days after intervention.AIDS-related knowledge was assessed through a self-made questionnaire with a total of 45 items, including the following 6 dimensions: basic knowledge of AIDS, knowledge of AIDS prevention, knowledge of AIDS testing, knowledge of AIDS treatment, knowledge of AIDS PrEP, and knowledge of AIDS-related laws and regulations.AIDS-related stigma was assessed through the Chinese version of the Zelaya HIV/AIDS Stigma Scale  with 24 AIDS-related attitude was assessed through a questionnaire with 8 items with the choice of “Yes” or “No” in Chinese. Five experts were invited to verify the content validity of these questionnaires, and the item-level content validity index (I-CVI) and scale-level CVI (S-CVI) were both 1.00.The secondary outcome was the user's experience of the game in the intervention group. It was assessed through the Educational Game User Experience Evaluation Scale with 22 items in Chinese. After playing the game, the user selects one of 4 options  to evaluate each indicator according to their actual experience.X̅ (SD), the two-tailed t test was performed to compare the groups, and difference-in-difference analysis was used to accurately evaluate the change in the intervention group. The difference was statistically significant when P≤.05. The data analysts were blinded to the allocation.The classification data were statistically described by percentage, the qualitative data were compared using the chi-square test, the statistical description of the quantitative data was given using by The 96 students included were aged from 16 to 19 years. There were no significant demographic differences between the 2 groups .Before the intervention, there was no statistically significant difference in the AIDS knowledge awareness rate, stigma scores, and positive rates of attitude of high-risk IDS behaviors between the 2 groups .t=4.282, P<.001). The stigma scores of the 2 groups were not statistically significant . The positive rates of attitude of high-risk AIDS behaviors in the 2 groups were not statistically significant ; see After the intervention, the awareness rate of AIDS-related knowledge in the intervention group was higher than that in the control group . The difference in the AIDS stigma score was not statistically significant  after the intervention. The difference in the positive rate of attitude of high-risk AIDS behaviors was also not statistically significant  after the intervention. After the intervention in the control group, the AIDS knowledge awareness rate, the stigma score, and the positive rate of attitude of high-risk AIDS behaviors were not statistically significant, but the positive rate of “Will you use condoms when you have sex with your lover?” dropped from 93.00 (SD 25.00) to 70.00 (SD 46.50), with t=2.955 and P=.004; see After the intervention, the AIDS knowledge awareness rate of the intervention group was higher than that before the intervention (P=.004), but the difference in the knowledge of AIDS testing and AIDS treatment was not significant. The mean differences in stigma scores and positive rates of attitude of high-risk AIDS behaviors were not statistically significant (The mean differences between the intervention and control groups before the intervention (baseline differences) were not statistically significant. After the intervention, the AIDS knowledge awareness rate of the intervention group was higher than that of the control group, and the difference-in-difference of the two groups was significant . Due to the low awareness of AIDS-related laws and regulations in the public [After the intervention group played the AIDS Fighter · Health Defense game, the awareness rate of AIDS knowledge in all dimensions was higher than that before the intervention. Of these dimensions, the awareness rate of AIDS-related laws and regulations increased the most (e public , patiente public . We founThere was no significant difference in the awareness rate of AIDS knowledge in the control group after the intervention, which implies that the effect of self-learning via the internet to improve AIDS-related knowledge of young students is poor. Under the background of exam-oriented education represented by China, young students have a strong learning ability to master the key points of learning quickly and effectively before the exam. Therefore, if an examination or assessment to test the learning effect could be added to the self-learning of AIDS health education for young students, it may increase the self-learning effect for them and improve their AIDS-related knowledge.This study found that after the intervention with AIDS Fighter · Health Defense, the AIDS-related stigma of young students showed a downward trend, although the results were not statistically significant. This may be because the formation and change of an individual’s cognition of or attitude toward something is a complex process that takes a long time , while tt=2.955 and P=.004. This result suggests that acquiring AIDS-related knowledge through online self-learning is not only less effective in education but may also make young students more open to sexual attitudes and more likely to indulge in risky sexual behaviors. We found that after the intervention with AIDS Fighter · Health Defense, the positive rate of attitudes of high-risk AIDS behaviors of young students increased. Therefore, game-based AIDS education has the potential to become an intervention method to improve the attitudes of high-risk AIDS behaviors and AIDS Fighter · Health Defense could become an effective and large-scale intervention tool.Reducing high-risk AIDS behaviors is one of the effective ways to prevent AIDS , and oneThe results of game experience suggest that young students have positive feedback for AIDS Fighter · Health Defense, believing that the game probably has high aesthetics and usability and is educational and playful, which can achieve or exceed the needs of learners. However, there are problems, such as insufficient stability of the game, insufficient novelty of the game elements, and insufficient appeal of the game plot. This reminds us that we should strengthen the combination of education and entertainment in AIDS game education and increase the appeal of educational games on the premise of ensuring the effect of AIDS education.This study found that AIDS Fighter · Health Defense can improve the AIDS-related knowledge among young students, but the effect of the game in reducing AIDS-related stigma and improving the attitudes of high-risk AIDS behaviors was not observed. This might be due to the small sample size and short intervention time; the results of AIDS-related stigma and attitudes of high-risk behaviors were not statistically significant. Therefore, large-scale, continuous, and multicenter research is needed to assess the efficacy of game-based intervention.


Microbial identification & antibiotic susceptibility testing is an important investigation in clinical microbiology laboratory. In many centres in India the report has only the isolate and antibiotics tested. The additional comments if added give guidance to the clinicians to utilize the results. Pre-analytical issues of adequate & relevant clinical history, appropriate sampling techniques, timely transport & storage, history of antibiotic usage along with post analytical issues of recommended line of antibiotic therapy and infection control practices are better addressed with this practice.This was a prospective qualitative study from the period of January 2017-March 2021 where in the standard operating protocol of Clinical Microbiology was reviewed and appropriate comments were included in the Laboratory Information System once the isolate was identified using VITEK 2, automated ID/AST instrument and interfaced. The Clinical Microbiologist would then review the comments upon discussion with the clinicians and then authorize reports. The reports included sample & isolate specific details , recommended antibiotic therapy and infection control related comments. This was based on standard international and national guidelines .There was a gradual improvement in completion of request forms with clinical history, sample site and antibiotic history being mentioned. This was assessed through periodic audits conducted every quarter from 36% in March 2017 to 95% in March 2021. Clinical communication with the microbiology laboratory also showed improvement with documentation. Feedback from clinicians was also taken on the utility of these comments, (87/120)72.5% of the clinicians found them useful(Grade 5). (32/120) 26 %(Grade 3) of the clinicians had concerns about the turnaround time and requested for provisional reports.Interpretative comments in reports act as a bridge between clinical microbiology, infectious diseases and infection control. They help us to choose the correct antibiotics or sometimes no antibiotics when the situation demands it. With all the recent advancements, the clinico-microbiological utility of culture reports is the need of the hour.All Authors: No reported disclosures


As highlighted earlier this year in the Lancet, this problem is already affecting millions of lives in all regions of the world. In this systematic analysis of the global burden of AMR, the Antimicrobial Resistance Collaborators estimated that a median of 1.27 million deaths in 2019 were directly attributable to AMR; a figure that is comparable with deaths from HIV and malaria combined.For the past 2 years, reporting on the COVID-19 pandemic has overshadowed another major health challenge that is threatening to undo a century of progress in medicine. Antimicrobial resistance (AMR)–the ability of bacteria, viruses, fungi, and parasites to resist drugs that are designed to kill them–would not only prevent us from treating specific infectious diseases, but would also affect our ability to do many medical procedures, such as chemotherapy or organ transplantations. The origins of AMR are multifactorial, with one of the largest causes being misuse and overuse of antimicrobials in humans, in animals , and in environmental scenarios. Inadequate measures for infection prevention, and insufficient adherence to treatments, are also key drivers of this problem. This explains that only a One Health approach , as proposed by WHO, the Food & Agriculture Organization, and the World Organization of Animal Health, can succeed in preserving the efficacy of present and future drugs. Although policy makers, industry leaders, funding agencies, and health-care workers have a role in this fight, biomedical researchers can support them by filling knowledge gaps or proposing new therapeutics and diagnostic tools.The Lancet journals showed how research can help to identify the optimal selection, dose, and duration of the existing antimicrobial treatments to achieve the best clinical outcomes for patients, while avoiding increasing risk of drug resistance. The ARTIC PC trial reported in The Lancet in October showed that amoxicillin, an antibiotic commonly prescribed for children with uncomplicated lower respiratory tract infections is, overall, unlikely to be effective and should not be prescribed unless pneumonia is suspected. Once such evidence-based guidelines are defined, political action, in the form of antimicrobial stewardship interventions, are needed to encourage their adoption. For example, in the Netherlands, although guidelines recommend that adults who are hospitalised with moderately severe community acquired pneumonia in non-intensive care unit wards be treated with narrow-spectrum antibiotics, broad-spectrum antibiotics are still frequently used instead. The CAP-PACT study group reported in the Lancet Infectious Diseases the impact of an antimicrobial stewardship intervention trialled in 12 Dutch hospitals. Through clinician education, prospective audits, feedback on antibiotic use, and engagement of opinion leaders, broad-spectrum antibiotic use was safely reduced in patients who partook in the study. However, this type of intervention might not be sufficient on its own to curtail AMR, as suggested by a study done by Shirin Aliabadi in England on the effects of the NHS Quality Premium stewardship programme. Although this intervention, which was based on financial incentives, successfully helped to reduce broad-spectrum antibiotic usage, it simply attenuated the incidence of Escherichia coli bacteraemia resistance over a limited period of time. To understand this unhindered spread of AMR, Shirin Aliabadi and colleagues encouraged the community to further investigate the resistome (the genes driving resistance) by asking about their distribution, how they are introduced into the population, and how they are transmitted. In addition, a study of these genes involved in antibiotic-resistance could be used to design prescription recommendations, as shown by Stefano Leo and Vladimir Lazarevic and their colleagues in eBioMedicine. The authors found that, in patients treated for Gram-negative bacteraemia, shortening the duration of treatment (a common recommendation in antibiotic stewardship programmes) did not result in a decreased abundance of antibiotic-resistance genes.Recent studies published in in a preclinical proof-of-concept study published in eBioMedicine Katja Becker and colleagues showed that apramycin could also efficiently treat complicated urinary tract infection and acute pyelonephritis. Because they also observed lower nephrotoxicity compared with the current treatment, gentamicin, apramycin could offer a wider therapeutic window than current treatment.Besides evaluating the use of existing treatments, biomedical researchers are also developing novel therapeutics. For example, apramycin has been proposed as an improved aminoglycoside antibiotic with superior in vitro activity against a range of highly drug-resistant Gram-negative pathogens, as well as greater efficacy in preclinical pneumonia models. Apramycin is currently undergoing clinical trials as a candidate to treat systemic Gram-negative infections. Moreover, that The Lancet's call to widen the mission of the Global Fund to Fight AIDS, Tuberculosis and Malaria and to include AMR will be heard and will provide new funding opportunities for researchers. As a direct result of these technical and economic challenges, the thinness of the clinical pipeline has been observed every year since 2017 by WHO and the Pew Charitable Trusts. In 2017, to guide research, WHO also released a list of 12 antibiotic-resistant pathogens that should be considered a priority to tackle. An updated analysis of the clinical pipeline, published in Antimicrobial Agents and Chemotherapy this January confirmed that, despite progress, more action is needed: 76 antibacterial agents are currently in clinical development  and 41 of them are targeted WHO priority pathogens. However, only 19 of these antibacterial agents have new pharmacophores, and four of these use new modes of actions compared with marketed drugs. These numbers pale in comparison with the more than 1300 treatments under development to tackle cancer. A reason to stay optimistic is the innovative potential observed in the preclinical pipeline. In their review published in Nature Reviews Microbiology in 2019, Ursula Theuretzbacher and colleagues found that, as of May, 2019, 407 antibacterial projects were underway, with almost half of the projects on direct-acting small molecules, and the remainder being non-traditional approaches . 135 projects involving direct-acting antibiotics represent novel approaches: antimicrobial peptides, natural products, or LpxC inhibitors that target new ribosomal binding sites, the membrane and cell wall, transcription and translation, gene interference, or metabolism. Another positive point is that most of these preclinical research programmes focus on Gram-negative pathogens, targeting the priority pathogens listed by WHO. However, more work and, crucially, funding are needed for these to be translated into effective therapies.Even though such studies are promising, we cannot rely on only new antibiotics to stop antibiotic resistance. The discovery of new drugs is technically challenging, and there is still not a sustainable economic model to fund the research and development of these new agents. We hope In the December issue of eBioMedicine, Jari Nuutila and colleagues presented an improved version of their previous flow cytometric methods, with a single-tube setup, which allowed easy and efficient detection of bacterial infections within 30 min. Retrospectively, they estimated that, in their cohort, 38% of antibiotic prescriptions were unnecessary and could have been avoided with the proposed screening test. Another tool was presented in January by Arjun Baghela and colleagues. Using bioinformatics to analyse gene expression profiles of patients in emergency rooms for sepsis, they identified signatures reflecting specific sepsis endotypes that could be used for personalised medicine. These profiles could be observed at admission in the emergency room, before any other diagnosis, representing an opportunity to reduce the use of broad-spectrum antibiotics that are currently administered as a first step to all patients.To fight infections, diagnostic tools are as important as therapeutics. A prompt and accurate diagnosis will help health-care providers to select the most appropriate drug and administer it as early as possible. Diagnostic techniques will also detect resistant germs when they emerge so that an alternative treatment, if available, can be proposed. In addition, the results of these tests constitute important information that can be used to shape public health responses . A potential diagnostic tool to discriminate bacterial from viral infections is the flow cytometric determination of host receptors on the surface of blood leukocytes. The existing tools are effective but are often time consuming, costly, or too complex to be done at the point of care. the US Centers for Disease Control and Prevention in their Antibiotic resistance threats report: to improve knowledge of the microbiome , improve understanding of AMR in the environment, develop strategies to prevent the spread of resistance, and to develop analytical tools to measure the efficiency of these strategies. eBioMedicine, as part of The Lancet Discovery Science, will continue offering a platform to publish and discuss essential, early evidence on these topics to guide the fight against the spread of AMR.In addition to the assessment of strategies to improve antibiotic stewardship and the development of novel therapeutics and of reliable diagnostics at point-of-care as shown above, biomedical research should also be used to fill the innovation gaps outlined by


Concrete age is the time since the moment water is added to the cement, and the age of concrete comprehensively reflects the physical properties of the concrete when curing under standard conditions. For concrete under nonstandard conditions, its physical properties are directly related to both its age and temperature history. The equivalent age of concrete is the time at which concrete under nonstandard conditions reaches the same state as concrete under standard conditions. Most equivalent methods, such as the Nurse-Saul function and the Arrhenius function, are based on a maturity index. However, the accuracy of these methods breaks down when the curing temperature range is wide. In this paper, the electrical resistivity of concrete is used as the index to determine the equivalent age of concrete. This method is based on the assumption that concrete with the same mixture proportions has the same electrical resistivity when the maturity of the concrete is the same, regardless of the curing history. The proposed method is advantageous because it can be performed in real time and is nondestructive. To constantly measure the electrical resistivity of concrete, an automatic data acquisition system is developed to monitor the electrical resistivity of concrete and reduce the error caused by polarization as much as possible. Then, a model for predicting the electrical resistivity of concrete under different curing temperatures is proposed to conveniently calculate the equivalent coefficient. Finally, the results calculated by the proposed equivalent method are compared with those of the standard method (Nurse-Saul equation), and the results of the proposed model are found to be more reasonable. The mechanical performance of concrete is an important factor that affects the progress of engineering, the safety of buildings, and the state of service4. Generally, concrete age is used to comprehensively reflect the physical and mechanical properties of concrete curing under standard conditions. For concrete curing under nonstandard conditions, the equivalent age is used to evaluate the state of the concrete. Concretes with the same composition will have the same strength when they have the same equivalent age, even with different curing histories. Identifying concrete equivalent age is a convenient way to determine the state of concrete6. For standard curing conditions , the concrete equivalent age equals its actual age. However, under natural conditions, the concrete curing environment differs considerably from the standard curing environment7. Therefore, obtaining the equivalent age through an age equivalent method is often necessary.Concrete is widely used in civil buildings and water conservation projects because of its good mechanical performance9. The obvious disadvantage of this method is that the number of test blocks that need to be reserved should be as large as possible because the compressive test experiment is a nonrepeatable fracturing experiment, and the test data points are relatively discrete; furthermore, the performance of a test block cannot represent the performance of the building structure11. The indirect equivalent methods establish a correlation between concrete age and the physical quantities of concrete, such as the elastic modulus and rebounding value. After measuring the relevant physical quantity, the equivalent age of the concrete can be calculated in accordance with the standard relation curve, which is obtained under standardized curing conditions. Indirect testing methods include the pull-out test15, rebound16, ultrasonic17, ultrasound–rebound synthesis19, and maturity methods24. The indexes used in the indirect test methods differ, but the equivalent concrete age can be obtained through conversion. The principle is that macroscopic physical properties are determined by the internal materials and pore structure of the concrete. However, existing indirect testing methods still demonstrate shortcomings in terms of the test time, scope, and accuracy. For example, the pull-out test method can be used when the concrete has a minimum strength, and the rebound method can only accurately measure changes in the surface most 10–15 mm of the concrete26. On the basis of the principle of indirect methods, this paper presents a method for obtaining the equivalent age of concrete via electrical resistivity.Concrete age equivalent methods can typically be classified into three types: direct, semi direct and indirect methods. The direct methods mainly involve taking cores of the structure to test the compressive strength to obtain the equivalent age. However, for many critical structural parts, drilling is not allowed. The semi direct methods mainly involve measuring the strength of samples cured under the same conditions as the structure; thus, the structure has the same age as the reserved samples28. The electrical conductivity of concrete is related not only to its composition but also to its pore solution content, temperature and age31. Electrical resistivity is the opposite of electrical conductivity32. The resistivity variation range of ordinary concrete is generally between 10 and 1012 Ω m34. Whittington et al.36 and Sun et al.37 reported that concrete conduction can be divided into ionic, electronic, and hole conduction. Concrete electrical resistivity has been widely used in many areas. In the early 1930s, Petin and Gajsinivitch38 studied the hydration process of cement by measuring the conductivity of concrete to establish the correlation between concrete resistivity and cement hydration. Concrete resistivity has also been used in chloride ion permeability detection39, damage detection41, and oxygen diffusion42. The resistivity of concrete is determined by the material characteristics and pore structure of concrete44. In theory, the electrical resistivity of concrete should be the same for concrete with the same composition and structure but different curing histories.Concrete is generally believed to be a poor conductor or insulator of electricity, but in reality, this property is not absoluteThis study proposes an equivalent method for determining concrete age by using concrete resistivity. First, the standard evolution curve of concrete electrical resistivity is obtained under standard curing conditions. Then, the electrical resistivity of concrete is tested under nonstandard curing conditions, and a model for predicting the electrical resistivity of concrete is presented. Finally, the equivalent method based on electrical resistivity is presented and compared with the maturity method. Through the comparison, the proposed equivalent method can quickly determine the actual concrete age in real time and is more reasonable than the standard method.48. In accordance with the purpose and requirements of this test, the direct current (DC) diode method with two electrodes is selected to measure the electrical resistivity of concrete.The testing methods for concrete resistivity are mainly divided into two-, four-, and no-electrode methodsTo obtain the electrical resistivity of concrete, an automatic concrete resistivity acquisition system is designed. The system can test the electrical resistivity of concrete quickly, accurately and in real time and consists of a data acquisition device, automatic control system and temperature control system.The data acquisition device is an intelligent resistivity meter that can automatically adjust the test range of resistance to ensure the accuracy of the result. The meter communicates with a computer, and the frequency of data collection can be programmed. The measured data can be stored in the computer, and specific indicators of the device are shown in Table 50. Despite this condition, the resistance values of the concrete in both directions are relatively stable. Therefore, the average of the resistance values in two directions in the concrete is used to represent the overall resistivity. This usage requires the test system to automatically implement reverse measurements. In this test, multiple relay modules are used to control the opening and closing of acquisition lines for the automatic switching of the resistance test direction. The working principle is shown in Fig. The automatic control system is used to reduce the effect of polarization caused by the DC test. According to previous research, during concrete testing, concrete exhibits the polarization phenomenon, which leads to a negative resistance value in one directionForward resistance of sample collection arises when relay 1, port 3 is closed; reverse resistance of sample collection emerges when relay 2, port 4 is closed. In the PC terminal, relay port opening and closing can be achieved through program control via automatic reverse acquisition by the resistance meter. Although the resistance in both directions was tested, the polarization of the concrete could not be eliminated. Therefore, a resistor box with a large resistance is connected in series to the circuit, thereby preventing the measurement of a negative resistance value by the intelligent resistivity meter. By adopting certain technical measures, the problem of concrete polarization caused by the two-electrode method can be eliminated as much as possible. The temperature control system is mainly used to control the concrete temperature during curing and to keep the curing temperature constant.The sample size in the test is 100 × 100 × 400 mm. The measuring electrode is composed of an aluminum plate with a size of 100 × 100 × 3 mm, in which boreholes are evenly drilled to increase the contact area between the concrete and the electrode Fig. . MeasuriThe evaluation of concrete resistance with time under different curing temperatures is measured in this test. When designing the test scheme, the following factors should be the same: the water-cement ratio, the proportion of sand, the sample size, the curing humidity, and the vibratory compactness of the concrete. Only the curing temperature and the curing time are changed. Considering that the temperature of the concrete service environment is generally between 20 and 50 °C, the curing temperatures are set to 20 °C, 25 °C, 30 °C, 35 °C, 40 °C, 45 °C, and 50 °C. GDS-408 constant temperature and humidity control box is used to control the test temperature. Because the volume of the sample is relatively small, the increase in temperature because of hydration can be ignored.51.The electrical resistivity of concrete changes continuously as concrete hydrates. The evaluation of the concrete electrical resistivity under standard curing conditions  is tested first. Additionally, we also test the compressive strength of concrete under standard curing conditions. The resistivity growth curve and the compressive strength curve are shown in Fig. 33 studied the hydration of cement by using the resistivity method, and they divided hydration into three stages: dissolution, induced formation, and setting and hardening. The variation pattern of concrete resistivity in this study is consistent with that reported by Wei et al.33.Figure 52. Generally, the higher the electrical resistivity of concrete is, the higher the compressive strength is. The reason for this correlation is that both the compressive strength and the electrical resistivity of concrete reflect the state of the concrete. The relationship between electrical resistivity and compressive strength is shown in Fig. It can be found that the compressive strength of concrete has a correlation with the electrical resistivity of the concrete under standard curing conditionsAccording to the test scheme, the electrical resistivity of concrete under different curing temperatures was tested. Considering the large amount of data collected in the experiment, data at fixed time intervals are extracted for processing without affecting the regularity of concrete resistivity change. The main experimental results are discussed below Fig. .Figure 6The concrete resistivity data at different curing temperatures are compared in Fig. As an anonymous reviewer mentioned, this phenomenon can be explained from the perspective of ionic mobility inside the concrete pores. The reason why early age concrete can conduct electricity is that there are many mobile ions in its voids. The increase of temperature will accelerate the movement of ions in the solution, thus showing stronger conductivity. But on the other hand, the temperature increase will accelerate the hydration reaction of concrete, making the connectivity between the pores of concrete become worse, and the ion cannot complete the movement from one electrode to the other electrode, thus increasing the resistivity of concrete. Therefore, the change caused by the increase of temperature is two aspects. On the one hand, it is conducive to enhance the conductivity of concrete, and on the other hand, it is not conducive to the increase of concrete conductivity. Therefore, the resistivity of concrete shows different laws in different temperature ranges.The use of concrete resistivity for determining the equivalent concrete age is derived from the traditional method that uses a maturity index to obtain the equivalent age of concrete. Whether concrete resistivity or another index is used, the equivalent age of concrete is determined by the concrete’s internal materials, pore structure, and other microstructures. Therefore, in the proposed equivalent method, the resistivity of concrete can be used as an equivalent index.54, the upper and lower bounds of concrete resistivity are obtained when the solid and gas–liquid mixture are in series or parallel. Therefore, the resistivity of concrete can be expressed as follows:Concrete can be composed of a solid skeleton and a gas–liquid mixture filling the pores of the solid skeleton. The resistivity of concrete is affected by that of the solid skeleton, that of the gas–liquid mixture, and the proportion of the two substances. According to the Wiener bounds theoryAccording to comprehensive Eqs.  and 2),,2), the The electrical resistivity of air is larger than that of water or solids, and the ratio of water or solids to air can be neglected, such as ore, Eq.  can be eAccording to the test results, the resistivity of concrete shows a logarithmic relationship with time, and the relationship with temperature can be expressed by cubic function. In addition, the curing time should be corrected by temperature. Therefore, the resistivity of solid phase can be expressed as a function of temperature and a function of age after temperature correction. Considering that the electrical resistivity of concrete is relatively stable when the concrete age is 90 days, the resistivity of the solid fraction changes with time and can be expressed based on the electrical resistivity of concrete at 90 days:T and time The parameter The parameter entclass1pt{minimaAnalysis of Fig. To verify the prediction capability of the proposed resistivity model for concrete at different temperatures and curing times, the calculated results of the proposed resistivity model are compared with the measured results. The comparison is shown in Fig. As shown in Fig. For concrete with the same age under different curing conditions, the equivalent age of the concrete can be obtained by the equivalent coefficient. The equivalent coefficient can be calculated by the concrete electrical resistivity model. For example, given that the curing temperatures of the two samples are 30 °C and 20 °C and the age of concrete is 5 days, the corresponding resistivity is For the 5-day concrete at 30 °C, the modified electrical resistivity of the concrete is 55. The national standard provides the following formula for calculating the equivalent concrete age during quality inspection:The environmental temperature may be constant or variable in the process of increasing concrete strength. The reference temperature in the equivalent age model is the standard curing temperature of 20 °C. Age equivalent results are compared with those of the accepted equivalent method in the specifications for hydraulic concrete construction (DL/T5144-2015), which was developed based on the Nurse-Saul equationTo obtain the equivalent age, the temperature under the constant-temperature curing conditions is set to 30 °C, and the curing time is set to 12 days. The results of equivalent age obtained from the national standard and those in accordance with the equivalent age calculated from the resistivity model are drawn on the same coordinate plane, and the results are shown in Fig. As shown in Fig. The concrete equivalent age calculated by the proposed method increases rapidly in the early stage of hydration. Then, the growth rate becomes progressively slower, but the overall trend is still a gradual increase. This phenomenon can be explained by the rapid reaction rate of concrete in the initial stage of mixing, and the physical properties of various aspects, such as the strength, also increase rapidly. Therefore, the growth rate of the equivalent age is high in the early stage. As the cement solidifies and hardens, the amount of cement clinker involved in the reaction decreases. In addition, many cement hydration products are generated, resulting in some cement clinker being “isolated”. Therefore, the overall reaction rate shows a gradual trend; at this time, the growth rate of concrete age is slow. Analysis of the reaction rate of the concrete shows that the phase growth process and the increasing electrical resistivity process are consistent with the hydration reaction rate of coagulation. The physical properties of concrete are closely related to the degree of hydration of the reactants. Therefore, the equivalent age of concrete based on the proposed resistivity model is reasonable, as this model can consider the effects of the reaction rate. The effective curing time of concrete in this study is 0–12 days due to limitations in testing time and conditions. During this period, the growth rate of the concrete age initially increases and then decreases.Under variable-temperature curing conditions, the temperature changes continuously. When obtaining the equivalent concrete age, the midpoint of each temperature curve section is taken as the curing temperature, and the curing temperature is considered to be a constant value. For spacing, temperature projection increases gradually by 1 °C. The temperature history during curing is shown in Table The concrete resistivity growth curve under the variable-temperature curing conditions is shown in Fig. A comparison of the equivalent age results calculated by the electrical resistivity model and the equivalent results obtained by the standard method, Nurse-Saul and Arrhenius equation is shown in Fig. As shown in Fig. A concrete equivalent age method based on concrete electrical resistivity is proposed. The method is implemented by measuring concrete resistivity and modifying the effect of temperature using the resistivity development curve under standard curing conditions. To achieve the equivalent concrete age, this study has designed an experimental test system that automatically measures concrete resistivity, establishes a resistivity model based on Winner bounds, solves the parameters in the proposed resistivity model, and applies the model to concrete age equivalence. The experimental test system is developed based on the two-electrode method, and the two directions of the concrete electrical resistivity are measured to calculate the average value of the concrete to eliminate the effects of the polarization phenomenon as much as possible.For the equivalence of the concrete age under different temperatures, the equivalent coefficient can be obtained by the electrical resistivity model. It should be noted that the parameters of the electrical resistivity model are only suitable for the concrete used in this paper. The parameters should be recalculated for concretes with different compositions. Using the proposed resistivity model, the equivalent age of concrete is achieved under the variable-temperature curing conditions. By solving the parameters in the proposed resistivity model, the functional relationship between resistivity and curing time and temperature is established. The temperature of concrete resistivity is modified, and the equivalent age is obtained in accordance with resistivity data under standard curing conditions. Compared with standard method, Nurse-Saul method and Arrhenius equation, it is found that the proposed model has strong applicability to constant temperature and variable temperature curing conditions, and can fully consider the nonlinearity of concrete age growth. Concrete resistivity itself can reflect the change of concrete activation energy to a certain extent. Therefore, the equivalent age obtained by resistivity equivalence is relatively closer to the actual situation and more flexible, especially for early age concrete.The proposed method has good feasibility and can be used to monitor the development of concrete age quickly and in real time, and because of the relationship between temperature and concrete resistivity, the development process of equivalent concrete age under complex temperature changes can be considered. The proposed method has better adaptability and higher accuracy in determining the equivalent concrete age than the standard method under variable-temperature curing conditions. In addition, the proposed method is nondestructive and can be repeated many times on one sample, especially under complex temperature change conditions. However, it should be noted that the concrete used in this paper is actually cement mortar without coarse aggregate, because the concrete with coarse aggregate has poor electrode contact and non-uniformity, which cannot solved present. In the future, we will conduct further research on concrete samples.


Umbrella sampling along a one-dimensional order parameter in combination with Hamiltonian replica exchange was employed to calculate the binding free energy of five guest molecules with known affinity to cucurbit[8]uril. A simple empirical approach correcting for the overestimation of the affinity by the GAFF force field was proposed and subsequently applied to the seven guest molecules of the “Drugs of Abuse” SAMPL8 challenge. Compared to the uncorrected binding free energies, the systematic error decreased but quantitative agreement with experiment was only reached for a few compounds. From a retrospective analysis a weak point of the correction term was identified.The online version of this article contains supplementary material available 10.1007/s10822-021-00439-w. Among the many possible methodological variants to compute binding free energies for host-guest systems within a rigorous thermodynamic framework , umbrellCoordinates of host and guest molecules see Fig.  for the Due to slight rounding errors in the calculated values, the resulting excess charge had to be distributed among the different atoms in a weighted manner, which was done using the Python community package ParmEd . These mThe mol2 file of CB7 was obtained from the Amber tutorials website . The addAlternative partial charges for the guest molecules were calculated with the DDEC6 approach . The effFor the given concentration of sodium phosphate buffer of 20 mM [equation  using anequation , resultiequation , the lowequation , 25. TheAvailable pz-axis of the simulation box alongside with a translational restraint  method –41 and cIf a free energy offset between the two flat bulk water regions of the free energy profiles was present, it was found to be relatively small  were trained on data generated for previous rounds of the challenge [From the results of previous SAMPL-challenges  and fromhallenge . While thallenge . Therefoapproach , comprisFor the set of five training molecules the contribution of the first term to the total correction in Eq.  was 97.6An initial assessment of force field and methodology to calculate binding free energies was attempted based on experimental data from the literature regarding the hydration free energy of G1 as well as on binding free energies of G1, G2, G5, G6 and G7 to CB7. Subsequently, the binding free energies of guests GT1 to GT5 to CB8 was calculated and used to parametrize an empirical correction model that was then applied to the SAMPL8 set of guest molecules.R is the universal gas constant, T is the temperature, TM, respectively [For the neutral form of G1 (methamphetamine) a hydration free energy of relation 5\documento 38 Pa , a rangeectively . For theBinding constants for some guest molecules to CB7 were measured by direct ectively . The binFor the more bulky guest molecules these sampling issues became more severe such that the simulated binding free energies are likely contaminated by insufficient sampling. The results are reported in Table In contrast to CB7, no significant sampling problems at the cavity entrance were observed for the CB8 host. The free-energy profiles of the five training guest molecules are shown in the Supplementary Information . In some cases, e.g. GT1, some offset was observed between the two bulk regions. However, compared to the profile well depth this effect is of minor importance.Fig. Free-energy profiles of the seven challenge guest molecules are shown in the Supplementary Information . Fig. ring Eq.  were traIf the correction model according to Eq.  is re-evBased on previous rounds of the SAMPL challenge in which the GAFF force field overestimated binding affinities to the CB8 host , quantitElectronic supplementary material 1 (PDF 189 kb)Below is the link to the electronic supplementary material.


Para lá chegar, obrigatoriamente passo por uma região de concentração de usuários de drogas chamada de cracolândia. Nesses momentos encontro de perto os importantes efeitos sociais e danosos da drogadição na saúde de seus usuários. No entanto, agora me deparo de um modo diferente através deste artigo “Heroin and Electrocardiography- Effect of Heroin on Electrocardigraphy parameters”1 deixam claro a pequena quantidade de informações sobre o assunto. Pesquisa no Pubmed mostra referência de 1980 intitulada “ECG examinations 115 heroin addicts”2 sem acesso ao seu conteúdo. Muito pouco encontramos desde então sobre este tema. Como explicar esse pouco interesse científico nesse interim sabendo que a drogadição cresce em números alarmantes. Fica aqui o primeiro questionamento: Pouco interesse dos pesquisadores nessa área? Pouca destinação de fomento financeiro para esta área? Dificuldades logísticas de pesquisas nesse campo? Desinteresse por esse grupo social?Os autores de “Heroin and Electrocardiography- Effect of Heroin on Electrocardigraphy parameters”World Drug Report, publicação daUnited Nations Office on Drugs and Crime (UNODC) revelam que cerca de 35 milhões de pessoas tiveram alguma desordem em decorrência do uso de drogas sendo que apenas 1 em cada sete recebeu tratamento.A magnitude dos números é impactante, dados de 2019 da4 No entanto, agressão miocárdica e arritmias podem ocorrer e estarem subdiagnosticadas.6A dependência leva ao uso desenfreado com riscos de consequências letais. No caso da heroína a mortalidade gira em torno de 1% a 3% dos usuários, sendo mais frequentemente relatada como consequência de depressão respiratória.1mostram a ocorrência de alteração na repolarização ventricular dos usuários de heroína, mais precisamente diminuição do intervalo QT e QTc além da medida Tpe. Estas alterações foram encontradas nos eletrocardiogramas (ECGs) realizados em até 12 h após uso da heroína, tempo de ação de seu metabolito ativo a 6-acetilmorfina. Estas alterações encontradas poderiam sinalizar a predisposição de eventos arrítmicos nesse grupo levando a originar ações diagnósticas e terapêuticas voltadas aos distúrbios do ritmo e seus riscos.Os autores de “Heroin and Electrocardiography- Effect of Heroin on Electrocardigraphy parameters”1conseguiram isolar as ações exclusivas da heroína em parâmetros eletrocardiográficos da repolarização ventricular ao incluir no estudo pacientes em tratamento da drogadição que estavam utilizando a buprenorphine que é um opioide agonista parcial sem ações que interfiram no ECG. Com isso puderam comparar o ECG de 16 pacientes em uso de heroína antes e após a parada do seu uso e encontrar como consequência o aumento do QT e QTc com o afastamento da drogadição. Vale ressaltar que foram apenas 16 de 66 pacientes que finalizaram a proposta terapêutica para a drogadição de heroína, ou seja 24,24% mostrando a baixa adesão a esta terapia.Como a dependência a heroína é muito elevada e sua abstinência insuportável, o objetivo terapêutico sempre foi a troca de opioides procurando um menor dano. Com isso a metadona foi utilizada para contrabalançar os efeitos danosos da heroína. Isto fez com que o uso associado impedisse de conhecermos as ações cardíacas exclusivas da heroína. Também é relevante salientar que o uso mais frequente não é o inalatório e sim o endovenoso, que frequentemente está associado a adulterantes de ação cardiovascular, motivo pelo qual as ações cardíacas exclusivas da heroína eram desconhecidas em grande parte até agora. Os autores de “Heroin and Electrocardiography- Effect of Heroin on Electrocardigraphy parameters”1 agregaram conhecimento a este tema com elegância deixando claro que novos estudos necessitam ser feitos.Os autores de “Heroin and Electrocardiography- Effect of Heroin on Electrocardigraphy parameters”7 Quanto a Beethoven, nós continuamos ouvindo sua música até hoje.No campo da música erudita este ano comemoramos o marco de 250 anos do nascimento de Ludwig Van Beethoven, compositor da Sinfonia Eroica apresentada ao mundo em 1804, sendo que a partir de 1895 a “droga heroica” compartilhou o mesmo nome, que foi dado por Heinrich Dreser, pesquisador da empresa farmacêutica Friedrich Bayer & Co, fazendo com que o nome comercial adotado por esta droga quando lançada no mercado em 1898 fosse Heroína, até ser proibida em 1924. 1that adds an incremental knowledge in the medical literature about heroin cardiac effects and searches for signals of when this occurs.As a Classical Music lover, I go to the São Paulo Concert Hall frequently. On my way to get there it’s necessary to drive through an area with high density of addicts on streets, known as Crackland. In that moment I get to see closely the important negative social effects and damage of addiction in its users. Now I meet this issue in a different way, reading the paper: “Heroin and Electrocardiography- Effect of Heroin on Electrocardiography parameters”1make it clear that there is little scientific information published in this field. Research in the PubMed shows a 1980 reference called “ECG examinations 115 heroin addicts”2with no access to the abstract or the full-text contents. Very little was found about this specific topic since then. How can this be explained considering addiction has since then increased in alarming scale? Is there lack of interest by researchers in this area? Are there little financial resources for researchers? Logistical difficulties for studies in this field? Lack of interest in this social group?The authors of “Heroin and Electrocardiography- Effect of Heroin on Electrocardiography parameters”The magnitude of the numbers is striking. Data from the “World Drug Report” published in 2019 by “The United Nations Office on Drugs and Crime (UNODC) reveals that 35 million people had some kind of disorder as a consequence of substance abuse and only one person in each seven received treatment.4although myocardial injury and arrhythmia can occur and may probably be underdiagnosed.6Addiction leads to rampant use with risk of death. In the case of heroin, the risk of death is about 1-3% among the addicts and it is most frequently related to respiratory depression1show an occurrence of abnormalities in the ventricular repolarization of heroin users, specifically decreased QT and QTc interval plus Tpe measure. These abnormalities were found in electrocardiograms performed in up to 12 hours after the use of heroin, the time of action of its active metabolit 6-acethilmorphine. These electrocardiograms abnormalities can be signalizing the predisposition to arrhythmic events in this group leading to therapeutic actions concerning to the rhythm disorders and the specific risks.The authors of “Heroin and Electrocardiography- Effect of Heroin on Electrocardiography parameters”1succeeded in isolating the heroin exclusive actions in ventricular repolarization electrocardiographic parameters by including in the study patients under treatment for addiction who were using buprenorphine, that is a partial agonist opioid that doesn’t change the parameters of repolarization in the electrocardiogram. In this manner, they could compare the electrocardiogram of 16 patients in the use of heroin before and after they stopped the drug and they were able to find an increase of duration of QT and QTc after discontinuing the addiction. It is important to say that only 16 from 66  patients followed the therapy until the end, showing the low adherence to the treatment.As the heroin dependence is high and its abstinence is unbearable, the therapeutic choice has always been the replacement by other less damaging opioids. In this way, methadone has been used as a substitute with less harmful effects than heroin. This fact has made it difficult to differentiate cardiac effects caused exclusively by heroin. It is also important to mention that the most frequent way of heroin use is intravenous and that many times it is mixed with adulterants which have cardiac effects. There are therefore multiple reasons why the exclusive cardiac actions of heroin were mostly unknown until now. The authors of “Heroin and Electrocardiography- Effect of Heroin on Electrocardiography parameters”1have given us, in an elegant way, a new contribution for the knowledge in this area and they have made it clear that other studies will be necessary to clarify this issue completely.The authors of “Heroin and Electrocardiography- Effect of Heroin on Electrocardiography parameters”7when it was finally prohibited. And about Beethoven, we still keep on listening to his music until today.In the field of Classical Music, this year we are celebrating 250 years of Ludwig Van Beethoven’s birthday. He composed the famous “Eroica Symphony“ in 1804. In 1895, a German researcher named Heinrich Dreser working for the pharmaceutic industry Friedrich Bayer & Co became interested in the potential therapeutic benefits of the diacetylmorphine and called it the “heroic drug”. In 1898, the drug was launched in the market and it was called Heroin. This commercial name was adopted until 1924


The paper reports the results of a comparative analysis of the experimental shear capacity obtained from the tests of reinforced concrete beams with various static schemes, loading modes and programs, and the shear capacity calculated using selected models. Single-span and two-span reinforced concrete beams under monotonic and cyclic loads were considered in the analysis. The computational models were selected based on their application to engineering practice, i.e., the approaches implemented in the European and US provisions. Due to the changing strength characteristics of concrete, the analysis was also focused on concrete contribution in the shear capacity of reinforced concrete beams in the cracked phase and on the angle of inclination of diagonal struts. During the laboratory tests, a modern ARAMIS digital image correlation (DIC) system was used for tracking the formation and development of diagonal cracks. The issue of the load-bearing capacity of reinforced concrete (RC) beams in the support zone, though extensively studied for years, still lacks proper understanding . The proSolving the shear problem theoretically seems virtually impossible, hence the need for calculation models that can describe, as precisely as possible, the behavior of the support zones of RC beams under load. Theoretical and experimental studies show  that shAdvances in the use of RC structures, bold realizations of engineering and monumental structures, and their mass scale push engineers and researchers to find savings in the consumption of concrete and steel. As a result, concrete and steel technology is improving ,6,7. TarThis work aims to present a comparative analysis of the shear capacity of RC beams with various static schemes and loading modes and programs obtained experimentally and computationally from selected models. It is important to note here that both the static scheme and the beam reinforcement were designed to ensure shear failure. The results obtained were the basis for determining the experimental shear capacity of the beams. Comparative analysis was based on numerical models chosen to fit different theoretical assumptions.The analysis uses test results for single-span and double-span reinforced concrete beams loaded to failure in a monotonic and cyclic manner. The computational models were selected in the context of their application to engineering practice, including the approaches implemented in the European and US provisions. Due to the changing strength characteristics of structural concrete, the analysis was designed to include the concrete contribution in the shear capacity of cracked RC beams. The adopted testing program for single span simply supported beams and those with two spans under monotonic and variable loads was assumed to allow establishing the element that would be a high-credibility numerical model verification pattern. During the laboratory loading tests, a modern ARAMIS digital image correlation (DIC) system was used to allow continuous tracking of displacements and crack  formation and development.yk = 500 MPa and class C. The designed concrete class was used for the production of reinforced concrete bridge members. The composition of the developed mixture was provided by an automatic concrete batching plant. The tested beams differed in length, cross-sectional dimensions, reinforcement structure, loading program and static scheme. The list of elements with the adopted symbols is presented in The tests were conducted on 11 RC beams loaded to shear failure. The beams were made from concrete in a prefabrication plant to the designed class C40/50 and steel B500SP with a characteristic yield strength fThe cross-sections of the longitudinal and shear reinforcement used in the tested elements, along with the calculated reinforcement ratio, are summarized in 1 and compression reinforcement d2, the effective depth of the section d and the lever arm of internal forces z.The average reinforcement ratio given in w).In the subsequent analyses, for a given type of beam reinforcement structure, averaged results of the reinforcement ratio were used. Due to different stirrup spacing on individual sections of the beam, the shear reinforcement ratio  was deteIn line with the adopted static test scheme, two types of supports, point and wide, were used, as shown in Two static schemes were implemented for testing, as shown in The two-span beam static scheme was adopted for two elements denoted as B3C-1 and 2. The load consisted of three concentrated forces applied from three actuators, S2, S3 and S4, arranged along the length of the beam as shown in Beams S2C-1 and 2 were loaded with two forces acting simultaneously within the given ranges. Beams B3C-1 and 2 were loaded with three forces d; two onIn addition to actuators enabling the implementation of the loading program, measuring equipment was used, which included the HBM measuring set and the DIC system (ARAMIS) ,11. The Five displacement sensors with a measuring range of 0.05 m were used for testing the single-span beams and ten sensors for testing the two-span beams. The sensors were placed at the beam midspan, under the force application points, and at a distance of ~0.25 m from the axis of the supports. Beam deflections measured with the HBM measuring set were used to verify the deformation results obtained from the optical measuring system. The deflections read from the sensors to an accuracy of 0.01 mm had the same values. The DIC system (ARAMIS) is used for non-contact, three-dimensional measurements of the surface deformation located within the measurement field range. It performs analyses and calculations and documents strains, allowing a graphical representation of results in a color scale. The calculations use a series of photos from two digital cameras. The strain of the pattern put on the side surface of the tested element is identified. The first photo in the series is taken as a photo of the component before loading and serves as the point of reference. After taking all the photos, the program compares them by assigning small square or rectangular planes, called facets, to the tested surface, and finds these facets in subsequent photos. Owing to the preparation of the tested surface, each facet has one and unique structure of black points. The system program compares the displacements of characteristic points (centers of facets). The device uses two-image photogrammetry for measurements . This alfor elements S2M and S2C, two tripods of the optical system allowed testing two beam support surfaces by creating overlapping measurement fields with dimensions 0.30 m × 1.40 m a,for BL-02M elements, due to loading with one concentrated force, the measurement field covered the support zone at the actuator with dimensions of 0.45 m × 1.70 m and 0.45 m × 1.80 m b,c,for double-span elements B3C, two tripods of the optical system were used to cover the measurement areas of the support zone loaded with two forces and with one force, thus creating two measurement fields with dimensions of 0.30 m × 1.40 m each d. The suConsidering the dimensions of the tested elements and the force distribution, the following measurement fields were adopted:The class of concrete and its strength characteristics were determined through axial compression tests  of concrcmCUBE obtained from the tests of concrete cubes, and fcm—average values of cylindrical strength of concrete estimated from the tests on cubic samples. Other values given in ckCUBE, the characteristic value of the strength of concrete on cylindrical samples—fck and the average value of axial tensile strength fctm.The strength of the steel reinforcing bars used in the beams was determined through the axial tensile test of shear and longitudinal reinforcement samples . The reim of the reinforcing bars used as the longitudinal and shear reinforcement in individual beams. The table also shows the automatically obtained results of the elasticity modulus—Es and the calculated characteristic values of the yield strength of the longitudinal reinforcement—fyk and shear reinforcement fywk.Due to the high repeatability of the results obtained for a given diameter and between diameters, the same steel parameters were adopted . The strb—width of the element, z—lever arm Analysis of the shear capacity of reinforced concrete beams was primarily focused on the obtained load levels at which the element failed. Based on these levels, the values of the cross-sectional forces were determined, i.e., the shear force V and the bending moment M, given in The calculated failure shear stresses in the beams under monotonic and cyclic loading are shown in Examples of strain maps of the element’s side surface superimposed on reinforcement drawings are shown in On the deformation maps corresponding to the measurement fields, which after completion of the test are assumed with the DIC (ARAMIS), the strains are marked using a color scale. The blue color marks the base area on which no strains are recorded yet. When they appear, the color of a given area becomes brighter, then changes to green and up to red, which indicates significant strains. In The development of built environments across the world has pushed forward R&D in concrete technology in the search for material saving opportunities and new methods for dimensioning reinforced concrete elements. Over the years of research, several shear capacity computational models have been developed to describe the behavior of the support zone under load. Formulated at the beginning of the 20th century by Mörsch ,16, EuroAnother approach to shear capacity of reinforced concrete elements is the ultimate failure state theory. It assumes that at the time of failure, the diagonal crack separates the beam into two parts connected by concrete in the non-cracked compression zone and by the reinforcement cut by that diagonal crack in the cracked zone. In this approach, the ultimate limit state of the concrete compression zone in the area above the so-called major diagonal crack is controversial because the strain in this area of concrete is determined by the combined effect of the moment and shear force. The precursor of this approach was M. S. Boriszański, who in 1937 began his research on the shear strength of reinforced concrete beams under the supervision of prof. A. A. Gwozdiew. The results of their analyses were published in . Their mStudies related to the behavior of the support zone in reinforced concrete elements are still carried out in many research centers with improved apparatus and computational capabilities. Results of these studies have extended the existing body of knowledge and to the development of new theories and methods, such as the Modified Compression Field Theory  used in Other, less known shear design approaches found in the literature include the shear zone model ,36, dimeDue to the multitude of theoretical models for the support zone of reinforced concrete elements, only those that were or are the basis for standard regulations used in engineering practice were used for this analysis, with the concrete contribution in the shear load capacity of beams taken into account. These were primarily the models based on the ultimate state of failure (concrete contribution) , a trussAdditionally, the analysis included models whose assumptions have been used in the provisions of American standards of 2014 and 2019  and the Boriszański failure model ,30,Mӧrsch truss model acc. to Kupfer–Rüsch  (PN-B-03Mӧrsch truss model acc. to Kupfer–Rüsch (PN-EN-1992-1:2008) ,Mӧrsch truss model acc. to Kupfer–Rüsch (DIN 1045-1:2008) ,models acc. to Model Code 2010; approximations 1, 2 and 3, ,models acc. to ACI-318-14; approaches 1, 2, 3, 4 (ACI-318-14) ,Bentz and Collins model—detailed method (B.C.-DT) ,Cladera, Mari, Bairan, Oller and Ribas model (CMBOR) ,Forsch, Yu, Cusatis and Bazant model (FYCB.) .Analysis of shear capacity of reinforced concrete beams should also account for the static scheme because statically indeterminate structural elements under variable loads dominate in building structures. Therefore, the beams loaded in a low-cycle manner were selected and subjected to additional extended analysis. After rejecting the models according to which the shear stresses are much lower and exceed  the expeA similar comparison in terms of the θ effect on shear stresses is shown in Boriszański model ,30,Model Code 2010 approximation 3 [Hong-Gun Park, Kyoung-Kyu Choi ,Bentz and Collins—simplified method ,Cladera, Mari, Bairan, Oller and Ribas ,Forsch, Yu, Cusatis and Bazant .Considering that some models include the concrete contribution term in shear capacity determination and some ignore its effect, the further analysis focused on the concrete contribution as provided by selected models. It is important because, depending on the calculation model, the values of the concrete shear capacity vary significantly. The models in which concrete contribution after cracking is included in shear capacity are:Mӧrsch truss model acc. to PN-EN-1992-1-1:2008 ,Model Code 2010 approximation 2 ,the shear reinforcement is assumed to carry all shear stresses. As the estimated concrete shear capacity is exceeded in:It is worth noting that among the models showing the greatest correspondence between the calculated and experimental shear capacity, there are those in which both shear reinforcement contribution and concrete contribution are included. It seems that the greatest differences between the calculated and experimental shear capacity are obtained using the truss-based models . Shear cFrom the figures above, it follows that the concrete contribution calculated with the procedures proposed in ACI-318-14 W3  in the eDevelopments in concrete and steel technology have enhanced the strength and ductility of these materials, the loading program, static scheme, and the dimensions of the beam cross-section affect the experimental shear capacity of the reinforced concrete beam support zone,as demonstrated, statically indeterminate elements show lower shear capacity than statically determinate elements under cyclic and monotonic loads,based on the results in shear capacity estimated from the model based on the state of failure according to Boriszański (BOR) ,30 exceevalues of shear capacity calculated from the modified truss model largely depend on the angle θ  and are much lower than the values obtained experimentally,the measured angle of the diagonal crack varies from the value calculated from the adopted models, in which the estimation method is given—the ctg θ value used in some models does not result from the inclination angle θ of the compressed concrete diagonals and can be used as an effective parameter for adjusting the shear design values to fit the experimental results ,the shear capacity of the RC beam support zone depends on the shear strength provided by the shear reinforcement and concrete (e.g., interlocking effect—MC2010 , dowel aThe principal findings from the performed laboratory tests and comparative analyses are as follows:verification of calculation models, including numerical models, should be based on test results for statically indeterminate beams under cyclic loading;the highest agreement between the experimental and calculated shear capacity was obtained from the models that are independent of angle θ;the value of ctg θ can serve as a parameter adjusting calculated shear capacity to real values;the support zone capacity calculations for the entire loading process and after cracking should take into account the capacities of both transverse reinforcement and concrete.The findings above lead to the following conclusions concerning the shear capacity of the support zone in reinforced concrete beams:The comparative analysis conclusions were based on the tests of beams made of the same concrete class and steel type. The concrete had higher strength than the designed grade C40/50, and the ultimate strains exceeded 3.5 ‰ . The steThe planned program of further shear tests of beams includes tests to supplement the material gap, i.e., tests of cyclically loaded double-span beams made of concrete class C30/37 and reinforcing steel class B, as well as high-strength concretes of approx. 90 MPa. Considering the importance of the fire resistance of reinforced concrete structures, tests should also be carried out for beam behavior at high temperatures, which has a significant impact on the adhesion of steel to concrete . However