John Rex talks to Gary Humphreys about the challenges faced in developing and bringing to market new antibiotics. Q: Despite increasing concern about antibiotic resistance, very few new antibiotics are emerging from the R&D pipeline. What is holding back their development?Klebsiella pneumoniae and Escherichiacoli, some strains of which have become resistant to all or nearly all available antibiotics. It’s estimated that bacterial drug resistance kills around 1.3 million people every year directly, and contributes to the deaths of another 5 million. To tackle that problem, we need antibiotics that work differently, and we are not currently developing them. The various reviews done of compounds in the R&D pipeline suggest that many are modifications of existing drug classes, and will not be sufficient to address antimicrobial resistance.A: Well first, it’s probably worth stating why that matters. Over time, and as a result of adaptation driven by natural selection, certain microorganisms have become resistant to the antibiotics that previously either killed them or prevented them from reproducing. This includes As to why the pipeline is so thin, it comes down to the fact that the antibiotic business is not profitable under normal market conditions. It takes 10–15 years and sometimes longer to develop a new antibiotic at a total cost that exceeds 1 billion US dollars (US$) when you include inevitable failures. If you are lucky enough to arrive at a safe and effective product, you then find that there is a limit to the sales you can achieve because clinicians are going to use it as sparingly as possible. And rightly so: the more an antibiotic is used, the more quickly microorganisms develop resistance to it. This is different to every other class of drug, which may get replaced by better drugs, but don’t themselves lose their therapeutic power. Add to this all your other costs, such as the need to manufacture fresh stock on a regular basis, and you’re struggling. The best current estimate is that it costs around US$ 350 million to complete post-approval work and manufacture the compound during its first 10 years on the market, which means you need to generate US$ 35 million a year just to break even on a cash-flow basis. So, bottom line, because companies struggle to recover their costs, let alone make a profit, they have tended to drop out of the market.“Innovation is not the problem; the market model is the problem.”In the 1980s there were something like 18 multinational companies committed to antibiotic research. Today, there are only a handful. The space left by those companies has been filled by smaller biotech companies, which today account for around 80% of the investigational antibiotics that have the potential to become tomorrow’s big weapons in the fight against antibiotic resistance. Unfortunately, most of those companies are struggling financially, and there are plenty of examples of small companies that have come up with promising new drugs and pushed through all the clinical trial and regulatory challenges, only to go bust after they have launched their product.Q: Can you give some examples?Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus. So, all in all, an interesting drug. It was approved for medical use in the USA in August 2019 and in the European Union in July 2020. Nabriva launched the drug as Xenleta, but couldn’t generate enough sales, and announced that it was winding down its business in January of this year. Other examples include the antibiotic firms Melinta Therapeutics, Aradigm and Achaogen, which all declared bankruptcy in 2019. So, it can be argued that innovation is not the problem; the market model is the problem.A: A recent example is Nabriva Therapeutics, which spun off from Sandoz’s antibiotic research and development (R&D) operations and discovered a drug called lefamulin in 2006. The drug can be taken by mouth or injection, and is used to treat adults with community-acquired bacterial pneumonia. Around a million people are hospitalized with that disease in the USA each year, some 50 000 of whom die, and there are of course many more cases worldwide. So, it had the potential to be a useful, impactful drug, and in clinical trials was shown to be comparable in clinical outcomes to moxifloxacin, a widely used antibiotic. Moreover, lefamulin was shown to have in vitro activity against other pathogens including Q: How can we address this?A: We need to look at the way we assign value to antibiotics, getting past the notion that value has to be a function of use. I find that a helpful way to get this idea across is to compare antibiotics to fire extinguishers. The analogy isn’t perfect since fires do not become resistant to extinguishers, but there are some interesting points of comparison. Like fires, infectious disease outbreaks occur abruptly and spread rapidly. Like fire extinguishers, antibiotics appear to have zero value until an outbreak occurs, at which point, like fire extinguishers, they become enormously valuable. I’d also add that, like fire extinguishers, antibiotics don’t just appear in the home: they have to be developed, manufactured, maintained and properly used.It is often pointed out that the high casualty rate of the 1918 influenza pandemic wasn’t due to the virus itself, but rather to the lack of antibiotics to treat pulmonary infections. A similar case can be made for the coronavirus 2019 (COVID-19) pandemic: for lack of a good fire extinguisher, the world caught fire. The beta coronaviruses that cause upper respiratory illness have been known for 20 years. If someone had developed a drug that was effective in treating such illnesses, we could have nipped the outbreaks in the bud, saved millions of lives, and avoided the shutdown of the global economy. Nobody developed that drug because there was no market for it. And if a company had developed it, the company would have made some money when the pandemic arrived, but the real value of what they had saved the global economy would not have been recognized. We need to get our heads around the idea that something we don’t use often nevertheless has significant value, and indeed question the notion of use itself. If I asked you if you used a fire extinguisher today, you’d probably say, “No.” But I’d have to disagree: just by having one on the wall, you are using it.Q: How do you get people to pay to develop something they may never use?A: In the same way people pay for insurance: in instalments. This approach has been debated for some time, and the consensus view is that we need some form of subscription, whereby the beneficiaries of the product – let’s say a government on behalf of its population – makes regular payments to companies that successfully develop a needed new antibiotic. By doing this you effectively delink the companies’ revenue stream from sales of their products. They no longer need a regular stream of sales, relying instead on the subscription, which acts as a ‘pull incentive’. This approach is also great for antibiotic stewardship, since the company no longer needs use-based sales to stay in business. Of course, you have to come up with criteria for picking the antibiotics purchased in this way. Some countries are now considering the introduction of such subscription schemes, led by the United Kingdom, where the National Health Service has agreed to pay Pfizer and Shionogi a fixed fee of £10 million (US$ 12.5 million) a year for ten years for two antibiotics. As a pilot, the United Kingdom’s initiative offers a first opportunity to see a delinked pull incentive at work and can serve to inspire other initiatives.“For lack of a good fire extinguisher, the world caught fire.”Q: But is US$ 12 million enough to incentivize R&D, given the costs you cited?A: You have to look at that amount in the broader context. Numerous studies, including a recent one by the United States Government Accountability Office, suggest that providing a global total of US$ 1– US$ 4 billion over a 10-year period after approval by regulatory authorities is sufficient. The best current estimate to date is from work by Kevin Outterson, and suggests around US$ 3.1 billion for an effective, fully delinked subscription. If other major economies contributed amounts similar to the United Kingdom on a proportionate basis, for example as a percentage of gross domestic product, the economics of new antibiotic development would become similar to those in the development of new cancer therapies.th United States Congress. The act is a bipartisan piece of legislation aimed at incentivizing innovative drug development, targeting the most threatening infections and supporting appropriate use of antibiotics. Drafted over two years ago, it has now been thoroughly debated and there is growing pressure to get it passed this year. If it does pass, it will be a game-changer in the antibiotic innovation space. Meanwhile, the Canadian government is putting together a report on pull incentives; Japan has announced its first steps towards introducing pull incentives; and the European Commission has very recently proposed that pull incentives be implemented using transferable data exclusivity vouchers as a bridge to by-country delinked procurement models. It is very exciting to see such a wide range of approaches to the problem – there’s obviously a strong recognition that something has to be done about AMR!Encouragingly, all of the G7 countries are seriously considering pull incentives. In the USA, the PASTEUR  Act was recently introduced into the 118Q: Are you optimistic that all this discussion will feed through into implementation?A: I am. You have to remember that 10 years ago we did not have much activity at this level. There were significant initiatives like the Infectious Diseases Society of America’s “Bad Bugs, No Drugs!” and “10×20” initiatives, but momentum has really been gathering since 2016, not just with new initiatives such as the Global Antibiotic Research & Development Partnership which was set up by WHO and the Drugs for Neglected Disease initiative that year, but with increased prioritization by global political leaders. The 2016 United Nations General Assembly (UNGA) on antimicrobial resistance is the clearest expression of this priority. The topic will be on the UNGA agenda again in 2024, with a focus on committing to new targets and practical steps to address the problem. What could be more practical than developing and installing the fire extinguishers we need to tackle the next outbreak? And the time to start making them is now!


Antibiotics account for over 10% of the overall drug expense of the National Health System in Italy in 2021. Their use in children is of particular interest on one side, because acute infections are very common in children, while they build their immunologic library of competence; on the other side, although many acute infections are expected and turn out to be of viral origin, caregivers will often ask the family doctor or primary care attending to reassure them by prescribing antibiotic treatment, although it may often be unnecessary. The inappropriate prescription of antibiotics in children may likely be a source not only of undue economic burden for the public health system but also of increasing development of antimicrobial resistance (AMR). Based on those issues, the inappropriate use of antibiotics in children should be avoided to reduce the risks of unnecessary toxicity, increase in health costs, lifelong effects, and selection of resistant organisms causing undue deaths. Antimicrobial stewardship (AMS) describes a coherent set of actions that ensure an optimal use of antimicrobials to improve patient outcomes while limiting the risk of adverse events including AMR. The aim of this paper is to spread some concept of good use of antibiotics for pediatricians or every other physician involved in the choice to prescribe, or not, antibiotics in children. Several actions could be of help in this process, including the following: (1) identify patients with high probability of bacterial infection; (2) collect samples for culture study before starting antibiotic treatment if invasive bacterial infection is suspected; (3) select the appropriate antibiotic molecule based on local resistance and narrow spectrum for the suspected pathogen(s); avoid multi-antibiotic association; prescribe correct dosage; (4) choose the best route of administration  and the best schedule of administration for every prescription ; (5) schedule clinical and laboratory re-evaluation with the aim to consider therapeutic de-escalation; (6) stop antibiotic administration as soon as possible, avoiding the application of “antibiotic course”. Antibiotics account for over 10% of the overall drug expense of the National Health System in Italy in 2021 [During the first decades following their discovery, antibiotics were regarded as an everlasting weapon, which favored their overuse. In the meanwhile, some microorganisms were on their way to progressively develop tools and skills to evade the effect of antibiotics, thus jeopardizing our ability to treat infectious diseases expected to be potentially or likely curable. As a result, the worldwide spread of the use of antibiotics increased the selective pressure on the global microbial population, thus inducing a significant increase in antimicrobial resistance (AMR) .Among other warnings on antibiotic overuse in pediatric patients, who have a longer follow up, there are also reported increases in the prevalence of asthma , allergiBased on the above, pediatricians should keep in mind that the use of antibiotics should always be driven by precise principles and information. Antimicrobial stewardship (AMS) describes a coherent set of actions that ensure an optimal use of antimicrobials to improve patient outcomes while limiting the risk of adverse events including AMR. The introduction of AMS programs in hospitals is part of most national action plans to mitigate AMR, yet the optimal components and actions of such a program remain undetermined.AMR happens when germs such as bacteria, virus and fungi develop the ability to defeat the drugs designed to kill them. AMR is a naturally occurring process. However, any increase in AMR is driven by a combination of germs exposed to antibiotics and the spread of their resistance mechanisms. Mechanisms may be different, from modifying the drug target to eliminating drugs from the microbial cell before they can reach their target ,8. The fWidespread exposure to antibiotics eliminates susceptible strains and selects resistant ones. Selective pressure will act without distinction both on pathogens that were the intended target of antibiotic therapy, but also on other microorganisms that colonize the host , and natural elements  . TherapeAs a result of AMR spread, any patient who received antibiotics could afterwards be affected by resistant infection, but the local and global diffusion of resistant germs is not less important for the community. In fact, the inappropriate use of antibiotics (as listed above) is a driving factor to exert selective pressure on microbial populations, which results in resistant strains selection ,14: indeOn the basis of the statistical models used by “Antimicrobial Resistance Collaborators”, there were an estimated 4.95 million deaths associated with bacterial AMR in 2019, including 1.27 million deaths attributable to bacterial AMR .Another important aspect is the economic effect, which includes direct and indirect cost. The direct cost of illness includes cost of hospitalization and medication. The indirect cost of illness comprises the present and future costs to society from morbidity, disability, premature death, and in particular the reduced effective labor supply (due to the lower productivity and deaths of workers) .The World Bank Group published a report presenting different scenarios, estimating the effect of AMR on the global economy: in the optimistic scenario, with the lower effect of AMR, the global economic output is projected to be 1.0% lower by 2030 and 1.1% lower by 2050 than in the standard World Bank long-term projection for the global economy that excludes AMR .The global action plan on antimicrobial resistance by the World Health Organization (WHO)  outlinesOn one side, health care providers’ perception and attitude regarding AMR is often disregarded ; otherwiThe aim of this paper is to focus the non-specialist reader’s attention on evaluations and behaviors which build up, in a single word, a more appropriate use of antibiotics.Antimicrobial stewardship (ABS) involves optimizing antibiotic use while using cost-effective interventions to minimize antibiotic resistance . The ABSGenerally, ABS programs include a multidisciplinary institutional team that organizes surveillance on antimicrobial prescription, optimizes prescription process , creates regular infectious diseases team consultation, and takes care of educational programs on appropriate antibiotic use. ABS programs have been more often run in adult patient settings. The specificity of pediatric patients, made of lower total numbers, but also their spreading from primary care to the ICU ,22,23, cOverall, the major goal of an ABS program is the education of pediatricians so that awareness of the antimicrobial stewardship’s principles are shared with physicians in the hospital and outside it, so that all of them may become proactive in refining an antimicrobial prescription.The first step is to avoid unnecessary treatments. Some simple questions may help physicians: is antibiotic therapy mandatory for that patient, at that time and for his clinical condition? Might it be a viral infection? May a wait-and-re-evaluate approach be appropriate for that patient before starting treatment?In a patient in good condition, with a short-lasting history of mild symptom, a wait and re-evaluate (after 24–48 h) approach is widely acceptable. Spontaneous improvement often occurs suggesting the benign course of the infection, especially for upper respiratory tract infections. Re-evaluation and delay to start antibiotic therapy is often a useful strategy to avoid unnecessary treatments. Caregivers may play a key role in deciding to delay prescription: if caregivers are attentive and receptive, delay can be easier and safe, sharing with parents the opportunity for clinical re-evaluation in case of worsening. Sometimes, parents/caregivers may be non-compliant for a wait-and-see strategy: they will claim an immediate start of antibiotic therapy, thus inducing the physician to prescribe an antibiotic therapy which appears likely unnecessary, given the likely viral origin of the infection. Caregivers’ education will be pivotal: it is much better if they are already informed on the difference between viral and bacterial infections, the lack of advantage, and the risk of disadvantage  if antibiotic prescription is inappropriate. The time spent to educate patients and caregivers will result in saved antibiotic doses, avoidance of side effects and reduced risk of AMR.Prescribing antibiotics in patients with suspected or proved viral infection in a good clinical condition, with the aim of preventing bacterial over-infection, should always be avoided, since it would have the sole effect of modifying the commensal flora ,14 and lBacterial infection may certainly occur as a complication of surgery. However, is “preventive” administration, i.e., antibiotic prophylaxis, useful for this patient? It may be certainly useful but only in very limited situations: clean  or clean contaminated surgery. In fact, consequences of bacterial infection in this surgery can lead to life-threatening complications. Neutropenic patients may deserve prophylactic antibiotic, while the role of prophylaxis in dental maneuvers in cardiopathic patients or in malformations of the urinary tract has been greatly reappraised.Bacterial isolates from culture of blood, urine, cerebrospinal fluid or secretions are of the greatest importance to identify the pathogen, explore its pattern of sensitivity/resistance and thus optimize the antibiotic prescription for a possible or documented invasive bacterial infection .Especially in hospital settings, physicians should collect laboratory information  likely of interest to modulate antibiotic therapy over the coming days and should not forget to accumulate data on bacterial isolates to build local data on bacterial epidemiology.-Previous microbiological isolates from the same patient, if available;-Local data on antimicrobial resistance, whether information is available;-To choose the antibiotic with the narrowest antimicrobial spectrum (the range of microorganisms an antimicrobic agent can kill or inhibit), related to the patient clinical condition;-Avoid multi-agent prescription, i.e., two or more molecules at the same time; when multiple therapies are necessary, avoid possible overlapping of antibacterial spectra ;-Prescribe the appropriate dosage, paying attention that the antibiotic is not under dosed. Administration of suboptimal dosage, with the aim of reducing the risk of side effects, is not a good choice, since what is really reduced is only the probability to be effective. For example, prescription of amoxicillin is often underdosed, with dosage inferior to 60 mg/kg/die ,28,29;-Choose the most appropriate way of administration: parenteral administration should be the first choice in septic patients, especially if with hemodynamic instability, or in case of difficult oral administration . In every other situation, oral administration could be the first choice given its non-inferiority in many infectious diseases, such as hospitalized children with severe not complicated pneumonia ,30, boneOnce biologic samples have been collected and basal evaluation is complete, antibiotic therapy can start. To choose initial, empiric antibiotic therapy, some specific issues may be of support:Furthermore, intravenous administration should be avoided if not strictly necessary because of the non-molecule-specific risk of adverse effects such as phlebitis, local and vascular infection, excess fluid administration and patient discomfort ,38,39,40Escherichia coli and Klebsiella pneumonia and vancomycin resistance in Enterococcus faecium increased during 2016–2020. High rates of resistance to third-generation cephalosporins and carbapenems in Klebsiella pneumoniae, of carbapenem-resistant Acinetobacter species and Pseudomonas aeruginosa in several countries in the European Region are of concern [National and international surveillance on antimicrobial resistance have been developed in the last few decades. About 85% of countries/areas in the WHO European Region have an AMR national/area action plan. The European Centre for Disease Prevention and Control (ECDC) and the WHO Regional Office for Europe published a joint report on AMR data from invasive isolates in Europe . The rep concern . An up-to-date knowledge of local AMR data is one of the most important resources to limit the use of broad-spectrum antimicrobials, especially when a narrower spectrum molecule has comparable effectiveness ,42.The Access group includes first and second-choice antibiotics to treat the most common conditions with the best therapeutic value, minimizing the potential to induce resistance. Frequently for these antibiotics, oral administration is possible .The Watch group includes a selection of antibiotic molecules that should be used for specific and limited infections either as a first or second-choice agent. Their prescription is generally the target of antimicrobial stewardship programs for their higher potential to induce AMR.The Reserve group should be regarded as the final resource against multi-resistant bacteria when all previous antibiotic treatments have already failed. They are intended only for hospital use, and their prescription is usually under strict control, single-patient oriented, and better with specialist consultation.The World Health Organization (WHO) has implemented, in the context of a global project to combat AMR  , a classSome basic knowledge of pharmacokinetic characteristics of different classes of antibiotics is important to decide the best schedule of administration (dosage and number of daily doses) of an antibiotic.Beta-lactam antibiotics  are frequently prescribed in children. The pharmacokinetic/pharmacodynamic (PK/PD) target for antimicrobial success is the fraction of time that the unbound drug concentration at the infection site is above the MIC (T > MIC) for every specific pathogen .An optimal administration of time-dependent antibiotics  should try to reach a stable plasma concentration above the MIC for all times of antibiotic treatment. If intravenous administration is started, the ideal schedule, currently under evaluation for many parenteral molecules  provides a loading dose to reach the effective concentration above the MIC, which is followed by continuous infusion to ensure T > MIC is maintained as long as possible ,45 Figu. If antiOn the other hand, the effectiveness of concentration-dependent drugs is determined by the maximum concentration reached in a single point of the kinetic curve. The reference variables are the maximum concentration (Cmax) that is reached beyond the MIC (Cmax/MIC) and the area under the curve (AUC) that is above the MIC (AUC/MIC). The higher the values reached by these two variables, the greater the antibacterial effect .The antibiotic administration must be questioned daily to confirm the need to prolong treatment.The concept of “antibiotic course”—i.e., administration for a predetermined time, to be completed regardless of patient clinical response and improvement—is obsolete ,47. ContEarly switch from parenteral to oral administration is recommended—even after 48 h—when the patients show a significant clinical improvement  and the inflammation markers  show a favorable trend. An early switch should be recommended toward a non-inferior oral treatment, also to reduce adverse effect, such as phlebitis, local and vascular infection, excess fluid administration and patient discomfort . Switch The re-evaluation of antibiotic treatment is mandatory as soon as an antibiogram is available: checking the susceptibility of the isolated microorganism to currently administered antibiotic(s) is necessary but not sufficient. The antibiotic administered should have the narrowest spectrum available for the isolated pathogen. Thus, when microbiological data become available, antibiotic treatment should be modified with a target therapy, ideally with a molecule active only against the isolated microorganism.The use of broad-spectrum molecules should be limited to ensure patient safety: an inappropriately extended use of broad-spectrum antibiotics results in interference with commensal microorganisms and the selection of resistant strains. These microorganisms could then be responsible for severe and difficult to treat infections .Therefore, the concept of therapeutic de-escalation could be summarized as follows: as soon as the patient has clinically improved and/or new microbiological information becomes available, antibiotic treatment must be re-evaluated and possibly modified to use the minimum number of antibiotics, possibly just one, with the narrowest spectrum and consider parenteral to oral switch.Many clinical trials have been conducted, and many are underway with the aim to define the standard antibiotic treatment duration for different infectious diseases, including urinary tract infections ,49, pneuSeveral studies confirm that patients well-appearing with uncomplicated pneumonia should be treated for no longer than 5 days , althougInappropriate or “too early” start of antibiotic therapy even in a clinical picture suggesting a viral infection;Post-operative prophylaxis not indicated or continued beyond 24 h.Lack of microbiological analysis supporting antibiotic treatment;Non-optimal antibiotic selection: starting with a broad-spectrum antibiotic when another with narrower spectrum  could be used;Suboptimal dosage and administration schedule for the considered infectious disease; parenteral administration even if oral route is feasible and equally effective;No therapeutic de-escalation, i.e., no modification of broad-spectrum therapy with a narrow-spectrum one;Duration of antibiotic therapy based on a pre-established “antibiotic course”.Antimicrobial prescriptions are frequent for children during the first years of life because of the frequent occurrence of febrile episodes. Yet, special attention should be paid also according to the implication that such prescription may have not only for the individual child  but also for the community. An excessive use of antibiotics facilitates an increase in AMR. Based on the above, starting an antibiotic therapy, apparently a frequent and low-intensity action, should instead be regarded as an occasion for the physician to implement quality in the daily work. Many critical issues can lead to a non-optimal use of antibiotics. An assessment list for prescribing antibiotics  should kIn conclusion, antibiotic prescription is a complex medical act, which requires a careful and thoughtful evaluation. Every physician should choose the best antibiotic for “that” patient, best route of administration, and time when antibiotic therapy can be discontinued; the initial decision should be reassessed upon the availability of new clinical or microbiological information. All these elements must be considered not only for the well-being of the single patient but also for the well-being of future individuals who might not benefit any more from a resource that, until now, has been viewed as granted and unlimited.


There have been substantial advances in our understanding of many aspects of strigolactone regulation of branching since the discovery of strigolactones as phytohormones. These include further insights into the network of phytohormones and other signals that regulate branching, as well as deep insights into strigolactone biosynthesis, metabolism, transport, perception and downstream signaling. In this review, we provide an update on recent advances in our understanding of how the strigolactone pathway co-ordinately and dynamically regulates bud outgrowth and pose some important outstanding questions that are yet to be resolved. Axillary buds are located in the axils of leaves and consist of an axillary meristem protected by surrounding leaf primordia and young leaves. Throughout the life of a plant, the fate of each axillary bud is highly regulated. Whether a bud remains inhibited or develops into a branch/tiller depends on intricate signaling networks that integrate environmental and genetic factors. The differential regulation of the fate of these axillary buds contributes to the amazing plasticity observed in plant shoot architectures, even in genetically identical plants. Understanding this regulation and the genetic control of shoot branching is crucial as bud outgrowth is an important agronomic trait that contributes to the overall shoot architecture of a plant and is a potential target for yield optimization in diverse food, ornamental and forestry crops .in planta, including bud outgrowth, plant height, senescence, adventitious and lateral root growth and root hair development  are the most recently identified of a number of phytohormones that affect shoot branching . SLs areelopment . It is lr plants  The functional significance of the diversity of SLs found within and among plant species is only starting to be elucidated e.g. . SLs canPetunia hybrida (petunia), Pisum sativum (pea), Arabidopsis thaliana (arabidopsis) and Oryza sativa (rice) carotene , which tcarotene . Interesn planta   results in plants with an increased branching or tillering phenotype . As discMuch of the structural diversity in SLs is due to rearrangement and decoration of the CL scaffold by various combinations of cytochrome P450 enzymes ] and CYP711A subfamily homologs in many other species  Lotus japonicus CL is converted to 18-hydroxy CLA (18-OH-CLA) via CLA by CYP711A9 and 18-OH-CLA is converted to 5-deoxystrigol by CYP722C, encoded by the gene 5-DEOXYSTRIGOL DEFECTIVE (DSD) (Solanum lycopersicum (tomato) and Vigna unguiculata (cowpea), CLA is converted to orobanchol (via intermediates) by CYP722C (Gossypium arboreum (cotton), CYP722C converts CLA to 5-deoxystrigol via 18-OH-CLA VE (DSD) , 2020b.  CYP722C . In cont8-OH-CLA .Other enzymes are involved in the canonical SL biosynthesis pathway, including a sulfotransferase that, as discussed later, determines the stereochemistry of SLs produced  in planta. Although exogenous treatment of canonical SLs 5-deoxystrigol, 4-deoxyorobanchol, orobanchol or solanacol (and others) can inhibit bud outgrowth , a sulfotransferase LOW GERMINATION STIMULANT1 (LGS1) functions together with a 2-oxoglutarate-dependent dioxygenase (2OGDD) to determine the dominant SL molecular structure in the root exudate possible . It is treceptor .clamt loss-of-function mutants have moderately increased branching along with an accumulation of CLA and reduced MeCLA ed MeCLA . This sudundancy .lbo mutants (Zea mays) and sorghum LBO homologs that can perform the same reaction in protein assays opens the pathway to reverse genetics approaches antities  antities . Due to n planta . Becauselbo mutant in arabidopsis has an increased branching phenotype, albeit one which is weaker than other mutants in the core SL biosynthesis pathway (LBO impacts tillering in Panicum virgatum L. (switchgrass)  . It is clbo clamt double mutant plants in arabidopsis and the intermediate branching phenotypes of the lbo and clamt single mutants compared to the wild type and mutants in the core SL biosynthesis pathway  mutant did not exhibit an increased branching phenotype despite reduced zealactone in the root exudate  allele  exudate . By cont) allele . Togethe) allele .L. japonicus, another 2OGDD enzyme is encoded by the gene LOTUSLACTONE DEFECTIVE (LLD), from a clade that is phylogenetically close to LBO. LLD is required for the synthesis of the non-canonical SL, lotuslactone  and epi-5-deoxystrigol (in rice) to be at the limit of detection   functions ctively)  and orobctively) . Howeverin planta is conserved across species or if there is diversity in the structure of the bioactive hormone across species, such as exists for gibberellin berellin .CLAMT and LBO, which are currently the last known enzymatic steps in the production of the SL shoot branching inhibitor, are both strongly expressed at the node, suggesting that the production of the shoot branching hormone occurs local to the axillary bud , including specifically at the node and in the bud  is genes . Future is genes .D27, CCD7, CCD8 and LBO  in L. japonicus aponicus .trans-β-carotene can also impact SL production. For example, a chloroplast-localized ζ-carotene isomerase (Z-ISO) catalyzes the isomerization of 9,15,9ʹ-tri-cis-ζ-carotene to form 9,9ʹ-di-cis-ζ-carotene, an intermediate upstream of all-trans-β-carotene, the precursor to both SL and abscisic acid (ABA) biosynthesis pathways (tillering20 mutants that have impaired Z-ISO exhibit reduced ABA (measured in shoot bases and roots), reduced SL  and an increased tillering phenotype that can be restored by exogenous application of SL or ABA  clade  clade . However5) clade .AtCXE15 (AtCXE15 promoter suggest that AtCXE15 is expressed in multiple parts of the plant including shoot vasculature and the region of axillary buds (AtCXE15 and its homologs in Nicotiana tobacum (tobacco) is regulated by SL, auxin and various environmental factors (The recent discovery of carboxylesterases (CXEs) that hydrolyze SLs is an exciting advance and opens possibilities for dynamic and localized management of SLs and shoot branching phenotypes  AtCXE15 . In addiary buds . The exp factors , suggestin vitro studies show CXE15 can hydrolyze diverse SLs including canonical SLs 5-deoxystrigol and orobanchol and the non-canonical SL MeCLA  enzymes (The identity (or identities) of the mobile form(s) of SLs and their precursors are not fully clear. Mutant  enzymes , this su enzymes ; the mobmax1 mutant shoots by grafting to wild-type rootstocks s mobile . Importas mobile .lbo scions, an observation which would normally be interpreted as indicating that the product of LBO, 1ʹ-OH-MeCLA or other hydroxylated structures yet to be identified  mutant scions , is an ATP-binding cassette (ABC) subtype G (ABCG) transporter that has a polar and asymmetric localization and was demonstrated to function as a cellular exporter of SL in petunia . In addiaf axils . This islary bud , but explary bud . Petuniat scions . Insteadt scions .Medicago truncatula that is thought to be required for normal exudation of SL from the root into the rhizosphere supports a role for this family of proteins in SL transport across plant species . Future research needs to determine if the transport of SLs in shoot tissue by PDR1 is conserved across species and if (and how) SL is transported into axillary buds. In addition, the substrate specificity of PDR1 needs to be determined. Moreover, the mode of long-distance SL (and/or precursor) transport remains to be discovered.in planta can elicit equivalent or varied signaling responses.The SL receptor, DAD2/DWARF14 (D14), is an α/β-hydrolase that signals and deactivates the hormone by hydrolytic degradation . The prein planta remains to be determined, although the hydrolytic activity of D14 in in vitro enzymatic studies and in mutants that have lost receptor activity but retain hydrolase activity would suggest that it might  and its orthologs SUPPRESSOR OF MAX2 1-LIKE6, 7 and 8   am genes . This neAs a further part of the mechanism of SL homeostasis, SL signaling induces the ubiquitination and degradation of the SL receptor, D14 . One modA potentially important cross talk between the SL and gibberellin pathways  has receTB1/FINE CULM1/BRANCHED1 (BRC1), which encodes a TB1, CYCLOIDEA, PCF (TCP) transcription factor that is predominantly expressed in axillary buds and represses their outgrowth (HOMEOBOX PROTEIN 21 (HB21), HB40 and HB53], which then, together with BRC1, enhance the expression of 9-CIS-EPOXICAROTENOID DIOXIGENASE 3 (NCED3), which in turn leads to local accumulation of ABA utgrowth  and manyutgrowth . One sucn of ABA  n of ABA . This ben of ABA .HB40 is observed under normal light conditions  BRC1-dependent, SL induction of nditions ; (II) ABbidopsis ; (III) Abidopsis ; (IV) trbidopsis  and (V) r number .hb21 hb40 hb53 triple mutant compared to the wild type might indicate that it is unlikely that ABA is a major target of the SL pathway, this could be a result of BRC1 regulating NCED3 expression independent of HB21, HB40 and HB53 and HB53 . For exaCKX9 in rice and the elevated bud cytokinin observed in the d53 gain-of-function mutant shoot base  and metabolism (in pea and rice)  oot base . Furtheroot base .max4 SL-deficient mutant that more frequently merge with stem vascular bundles and less frequently merge with leaf trace compared to those of wild-type plants e plants .Activation of auxin export from buds does not seem to be an initial trigger for bud outgrowth and instead is a complementary mechanism for SLs to modulate ongoing branch growth  BRC1 and cytokinin ignaling  ignaling . Anotherignaling . It is signaling . HoweverSMXL7/D53 transcripts in buds . Interestingly, recent studies reveal that the circadian clock regulates tillering via transcriptional regulation of SL biosynthesis, response and signaling . Hormonepression . Future Where do SL perception and signaling occur for the regulation of bud outgrowth? Shoot localization studies indicate that D14, MAX2 and D53/SMXL6,7,8 are all vascular localized . HoweverIntriguingly, the D14 protein is present in phloem sap , consistin planta functions. This is because it is likely that further enzymes that are required specifically for the synthesis of the branching hormone, but not root and rhizosphere canonical SLs, will be identified. These enzymes, such as CLAMT and LBO, are exciting targets to specifically manipulate bud outgrowth without as many effects on other aspects of development. While current research points to 1ʹ-OH-MeCLA (or other hydroxylated structures yet to be identified; Arguably, the main outstanding question here is the structural identity of the endogenous SL shoot branching hormone. This is clearly hampered by the instability of SLs and the difficulty in synthesizing them. As discussed, recent detailed enzymatic studies combined with mutant phenotypic analyses are ruling out specific SL molecular structures. Ultimately, the breakthrough identification of the shoot branching hormone structure and the characterization of the enzymatic reactions in its synthesis will present exciting opportunities to specifically manipulate shoot branching in crops to optimize yield without disruption to rhizosphere functions of SLs or, potentially, other important lbo mutant shoots as effectively as for other SL biosynthesis mutant shoots, perhaps due to a limited ability of CLA to enter the axillary bud to be further converted to the unknown bioactive SL branching inhibitor (One intriguing possibility for LBO function relates to the relative membrane permeability of CLA and MeCLA (nhibitor .Continued research is required for the purpose of the structurally diverse SLs, canonical and non-canonical, both within and between plant species. Tightly controlled enzymatic regulation may enable spatial and temporal regulation of SL types and different SL-regulated processes, with the production of particular SL structures targeted to required localities. As such, the roles of canonical SLs beyond the rhizosphere and of specific non-canonical SLs such as lotuslactone  that areFinally, it is becoming clear that the SL pathway is an important integrator of nutritional and metabolic signals . This sh


Antibiotic stewardship (AS) programs have become a priority for health authorities to reduce the number of infections by super-resistant microorganisms. The need for these initiatives to minimize the inadequate use of antimicrobials is essential, and the election of the antibiotic in the emergency department usually impacts the choice of treatment if the patients need hospital admission, becoming an opportunity for antibiotic stewardship. In the pediatric population, broad-spectrum antibiotics are more likely to be overprescribed without any evidence-based management, and most of the publications have focused on the prescription of antibiotics in ambulatory settings. Antibiotic stewardship efforts in pediatric emergency departments in Latin American settings are limited. The lack of literature on AS programs in the pediatric emergency departments in Latin America (LA) limits the information available. The aim of this review was to give a regional perspective on how pediatric emergency departments in LA are working towards antimicrobial stewardship. Initiation of empiric antibiotics in a pediatric emergency department is high, especially in ambulatory settings, with variations between low/middle-income and high-income countries . EffortsAs antibiotic use continues to increase worldwide, the need for antimicrobial stewardship (AS) programs to minimize inadequate use is essential, and many countries have incorporated this initiative into the emergency departments (ED) ,4,5. IncThe practice of choosing the optimal dosing, duration of therapy, and route of administration of the different antimicrobials is what is defined as AS. The aim of this program is to decrease antibiotic resistance, eradicate the unneeded use of antimicrobials, and reduce health costs, alongside improving outcomes for patients . GeneralIn Latin America, most countries fall into the category of Low Middle-Income Countries (LMIC), and the components established in hospital AS programs in high-income countries are usually absent, such as antimicrobials committees, infrastructure, monitoring of local antibiotic resistance, and implementation of efficient interventions . The aimThe systematic review was done according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . We searThe selection of the articles included was based on the review of the abstracts and relevant studies. The search and selection of articles were performed in an independent way by the two authors (AYC and GNZ). Any disagreement was resolved by consensus. Refer to We include for review studies or papers performed on emergency departments, the pediatric population, and Latin America (LA). The studies included were peer-reviewed. If we found a lack of specific publications, as mentioned before, we decided to revise studies focusing on AS programs in LA in general, and on the other hand, papers from pediatric emergency departments outside LA. We limited the search to publications written in English or Spanish. The selected studies were reviewed to identify all relevant papers to be included in our final analysis.The data extraction was performed by the two authors (AYC and GNZ) and included information about AS, activities related to AS, and reports of the use of antibiotic protocols in emergency departments in the region.We included in the review a total of 66 studies after excluding 182 papers from the screening. To give the regional perspective of AS in LA, the information will be divided into three sections: AS in pediatric emergency departments, AS in LA with a focus on the pediatric population, and EDs. In LA and especially in the Eds, the use of antibiotics, as well as many other medications, is determined by a complexity of factors that include knowledge of and attitudes towards antimicrobials, the health system, and socio-demographic, cultural, and regulatory factors that will make physicians decide which drug to prescribe. Refer to In the pediatric population, the application of AS programs demonstrated less antimicrobial utilization, fewer prescription mistakes, fewer adverse events, and decreased health costs with improved clinical outcomes . Most ofAS in the pediatric population is based on the policies of a multidisciplinary committee, including the Infectious Diseases Society of America, the Pediatric Infectious Disease Society, and the Society for Healthcare Epidemiology of America . This coMost of the literature findings regarding AS program implementation are from high-income countries, with the majority, according to Dona et al., in the US (52.2%), followed by Europe (24.7%), Asia (17.7%) and Argentina/Canada (5.4%) .The development of guidelines by pediatric infectious disease authorities in different continents has helped in the implementation and spreading of AS programs that can be well-adjusted to each country and health institution ,32. The In pediatrics, it is common that different clinical pathways are developed to focus on specific infections like community-acquired pneumonia , bone inThe decision on prescribing an antibiotic to a pediatric patient in an emergency department usually is not an easy one. During the COVID-19 pandemic, reports of high prescriptions of antibiotics in Latin America were 24.3% for patients with COVID-19 or multisystem inflammatory syndrome, with more use of antibiotics related to patients who needed oxygen support, mechanical ventilation, and had acute distress respiratory syndrome .The election of the antibiotic in the ED usually impacts the choice of treatment if the patients need hospital admission, becoming an opportunity for AS from day 1 of hospital stay when patients need initiation of antimicrobial treatment . Some faPathways to introduce AS programs in pediatric EDs are crucial and should accompany the inclusion of ED personnel in AS hospital committees, communicating and spreading the best practices concerning the use of antibiotics, implementation of rapid diagnostic tests, and integration of electronic health records that can support clinical decisions . In a stThe decision of when the physicians prescribe an antibiotic in an emergency department is critical, and it usually takes place after talking to the patient’s caregivers, after reviewing the case with a specialist, and after the result of an ancillary test like an imaging study. Some publications have focused on the importance of the clinical decision protocols for AS programs that will help in supporting the physician’s decisions about treatments at different moments of practice .The inclusion of pediatric emergency departments in the fight to decrease antibiotic resistance is challenging, especially because of the limited time to make complex diagnoses, overcrowding, lack of follow-up for ambulatory patients, variety of experience and training in ED providers, and difficulties in differentiating the microorganism-causing infections in children, which make them prone to receiving excessive antibiotics ,42. NeveThe ED is one of the most important departments where the AS programs can be implemented as they are the site of prescription of the first doses of antibiotics in hospitals and of a large number of antibiotics for patients discharged directly to their homes or other healthcare centers . ImplemeThe implementation of an AS program can vary in different contexts, including reasons for prescription and AS program interventions that require an adaptation according to health personnel and economic resources. In many countries in LA, there is a poor laboratory infrastructure and support for an AS program; however, this is not in itself a reason to delay the implementation a program . The AS As refer in Although the guidelines for the implementation of AS programs recognize that the ED is the preferred site for these programs, participation is still low. A multidisciplinary AS team or individual should be appointed and should undertake functions to successfully deliver and implement the interventions in the ED . It is iBefore the implementation of AS programs in a pediatric emergency department in LMICs, some requirements are important, such as the availability of diagnostic testing, the possibility of educational activities for the health personnel, the improvement of how the drugs are distributed, and a reinforcement of the infrastructure and follow-up for all patients who need initiation of antibiotic treatment .The strategies to implement an AS program that could work in a pediatric emergency department are the preauthorization of specific antimicrobials before they are prescribed, a prospective audit and feedback which engages the provider after an antibiotic is prescribed , and thePreauthorization is a strategy to improve antibiotic use by requiring clinicians to get approval for certain antibiotics before they are prescribed. This intervention has been associated with a significant reduction in the use of the restricted agents and the associated costs. Outcome studies with preauthorization have proved to decrease antibiotic use and antibiotic resistance. Other studies have demonstrated no adverse effects for patients. However, preauthorization requires the real-time availability of the person providing approval . In someThe cost-effectiveness of AS programs in an LA needs to be determined with a multidisciplinary approach that involves economic evaluations, impact on the community setting, and measures that can accurately not only determine drug costs but also diagnostic costs. The reliable cost-effective implementation of these programs should help the physician in the decision-making and enable the correct distribution of resources in places with limited finances .Lastly, other strategies are focused to increase the appropriate use of oral antibiotics for initial therapy and the timely transition of patients from an IV to oral antibiotics whenever possible. Passive educational activities, such as lectures or informational pamphlets, should be used to complement other stewardship activities .Reports of AS programs and activities in the pediatric population in LA are scarce, and most of the publications related to antibiotic stewardship programs come from the adult population ,31,50,51In April 2023, a survey was performed on pediatric emergency physicians (PEM) or pediatricians from the Pediatric Emergency Medicine Society (Sociedad Latino Americana de Emergencias Pediátricas—SLEPE) working in the emergency departments of pediatric hospitals in different countries in Latin America. The survey was sent to 52 physicians from different hospitals in LA and had a return rate of 31 (59%), with surveys from Argentina, Brazil, Bolivia, Chile, Colombia, Costa Rica, the Dominican Republic, Guatemala, Mexico, Paraguay, Perú, and Uruguay. Most of the hospitals (85%) were tertiary-care academic hospitals. Of the total hospitals, 61.2% of them have activities related to the Antibiotic Stewardship Program in their institution, but only 35% of them include the emergency department. Seventy-five percent of the physicians who answered the survey mentioned that in their departments, they have protocols for different diseases that require antibiotics, like urinary tract infections, community-acquired pneumonia, and skin infections. Regarding the members of the committee in charge of AS programs, all included an infectious disease physician and a smaller proportion of epidemiologists (52.6%), pediatricians (31.5%), microbiologists (26.3%), and pharmacists (26.3%). This varied from hospital to hospital. Hospitals where no AS programs exist were in Guatemala, Bolivia, México, and Chile. All the information gathered from the survey regarding the experience of AS programs or activities related to pediatric Latin-American hospitals is not published in peer-reviewed journals, according to the physicians.  regarding the use of antibiotics for patients that needed hospital admission, the administration of antimicrobials was more frequent in intensive care units, emergency departments, and medicine wards, with more than half of the patients having treatment for community-acquired infections. Around 11.5% of the use of antibiotics was related to healthcare-associated infections . AdherenThe prevalence of purchasing antibiotics without a prescription has been described to be around 13%, and in 60% of the cases, the pharmacists in some reports were the ones who recommended antibiotics for acute upper respiratory tract infections ,26. AccoIn a survey done by Muñoz et al. for physicians from ten LA hospitals, 40.7% did not have an AS program implemented, with 51.9% not having access to electronic health care records, technology tools, or training support; one-third did not bring any guidance of antibiotic treatment according to local susceptibility .According to Hegewisch-Taylor et al., by 2020, only 18 countries in LA have reported their experience with AS initiatives, with countries like Argentina, Colombia, Mexico, and Brazil having the majority of the publications in this area, more specifically in higher-level care hospitals in urban areas ; this miThe problem in our region, apart from the lack of resources and infrastructure to implement AS programs, is the limited first-line antibiotic treatment for different diseases in some countries, poor regulation of the use of antibiotics, the access to antimicrobials , and the high cost of broad-spectrum antibiotics ,55.The Pan American Health Organization (PAHO) reported an increase in antibiotic resistance in LA . They reThe Pediatric Emergency Medicine (PEM) subspecialty in LA is relatively new, with many countries opening training programs all over the region. Since 2010, the subspecialty has been recognized by local institutions, giving importance not only to the subspecialty but also the ED in children’s or mixed hospitals taking care of the pediatric population . The latIn the pediatric population, most of the publications have focused on the prescription of antibiotics in ambulatory settings. Ecker et al. reported that between 86–96% of the health personnel in ambulatory care will prescribe an antibiotic for children under five years of age for dysenteric diarrhea, pneumonia, and pharyngitis ,18. In aA paper by Schiffiano et al. reports a follow-up for a group of children in Peru who spent a prolonged time on antibiotics for common diseases, exceeding the recommended duration. On average, these children had spent 4.3% of their first 5 years of life on antibiotics with medical personnel as the main prescribers . In specThe introduction and implementation of AS programs in hospitals in LA have decreased the use of a broad spectrum of antibiotics by up to 20%, improved the use of resources, and introduced better surveillance for multi-resistant bacteria ,21. In aLittle is known about the implementation of specific programs in AS in the pediatric emergency department. Nevertheless, in some countries (such as Costa Rica and Colombia), the surveillance data for clinically important agents are promoted by governmental institutions that make notifications mandatory in all health centers, including the emergency departments. These surveillance programs also promote the rational use of antimicrobials and help to generate recommendations that reduce the threat of antimicrobial resistance ,61.Important efforts have been made in countries in LA, focusing on intensive care units where the higher use of antibiotics is overwhelming. Most of the AS efforts are focused on these areas . AccordiThis review had some limitations. Information related to antibiotic stewardship programs in the pediatric emergency departments in Latin America is limited, and most of these programs focus on specific diseases antibiotic management rather than a description of activities to reduce the antibiotic resistance to microorganisms in these settings. The strength of the review is that it gives a general perspective of the literature published so far concerning the pediatric population in the Latin American region and gives recommendations on how to implement an AS program that could be easy to adapt for every hospital in the region.The lack of literature published on AS programs in the pediatric emergency departments in LA limits the information available. Efforts should be made to develop AS programs in these settings or incorporate the pediatric ED in an already established program. This is critical to control the multi-resistant pathogens in our region. Despite many antibiotic prescriptions being written every day by providers from the ED, AS efforts in pediatric EDs in Latin American settings are limited. Although most of the literature agrees that implementation of AS in the ED setting is feasible and necessary, support from national authorities is needed for our region to improve practices in antibiotic prescribing. Lastly, promoting research in this area with the publication of the results of these programs will help to understand the current situation and actual practices in our region and incorporate better practices in the pediatric emergency departments.


This study reports the viability of developing geopolymer concrete using a laboratory-synthesised silica fume (SF)-derived SS solution in combination with NaOH at a molarity of 10M as an alternative binary alkali-alkaline activator to Ground Granulated Blast Furnace slag (GGBS). The use of SF in the development of geoolymer activators will pave the way for the quality usage of other high-silica content by-products from nature, industry, and agriculture. In the currently reported proof of concept, four geopolymer concrete batches were produced using different alkaline activator/precursor-A/P ratios (0.5 and 0.9) and SS to NaOH-SS/SH volume ratios (0.8/1.2 and 1.2/0.8), to establish the impact on the engineering performance. Two controls were adopted for ordinary and geopolymer concrete mixes. The engineering performance was assessed using slump and compaction index (CI) tests, while the Unconfined Compressive Strength (UCS) and tensile splitting (TS) tests were measured at different curing ages in accordance with their appropriate standards. The results indicated a reduction in slump values as the A/P ratio decreased, while the CI values showed a reversal of the identified trend in slump. Consequently, mix GC2 attained the highest UCS strength gain (62.6 MPa), displaying the superiority of the alkali activation and polymerisation process over the CSH gel. Furthermore, the impact of A/P variation on the UCS was more pronounced than SS/SH due to its vital contribution to the overall geopolymerisation process. Commercial sodium hydroxide (NaOH) and sodium silicate (SS) have remained two of the leading alkaline activators widely used in producing geopolymer concrete, despite some identified negatives regarding their availability and additional CO It is the most used artificial material in existence and is composed of Portland cement, aggregate, sand, and water in a specified mix proportion , with ceoduction . As suchoduction ,5,6,7.2 emissions and energy consumption [2xSiO2+X, such as sodium metasilicate—Na2SiO3, sodium orthosilicate—Na4SiO4, and sodium pyrosilicate—Na6Si2O7. These compounds are generally colourless, transparent solids or white powders that are soluble in water in various amounts to form alkaline solutions [Geopolymers are inorganic alumino-silicate polymers with a three-dimensional network, which are obtained by the reaction of rich aluminosilicate materials, such as metakaolin, fly ash, Ground Granulated Blast Furnace slag (GGBS), etc., with a highly alkaline aqueous solution ,8. This sumption . Based osumption ,11,12,13sumption , SS is aolutions .2 content and molarity (M)—defined as the molar ratio between SiO2 and Na2O [SS is the most important type of silicate due to its availability and low-cost silica source, resulting in its wide use in various industrial applications such as deflocculates, emulsifiers, adhesives, detergents, and sealants . Firstlyand Na2O . Secondland Na2O . Shilar and Na2O  reviewedSilica fume (SF) is a by-product from the ferrosilicon industry with tiny particle sizes and is mostly used as filler. Consequently, it comprises a high percentage of amorphous silicon dioxide, rendering it a highly reactive pozzolanic material . Using SAlthough the choice of using commercially produced SS has been well received, there has not been a perfect evaluation of the effectiveness of a laboratory-synthesised SS that can be developed and used to develop geopolymer concrete on a construction site at normal atmospheric conditions (20 ± 2 °C). This hinders the practical application and promotion of geopolymer concrete since the production of NaOH and SS is commercially controlled under very strict industrial and atmospheric conditions that are not applicable on a construction site. Raza and Zhong  also reiOnce the concept of a viable, strong, and durable geopolymer formulation is proven using SF in a laboratory-synthesised activator, it is hoped that this will be a step in widening scope by enthusing the use of other high-silica content waste and by-product materials from nature, industry, and/or agriculture in a similar manner. For example, high-silica content shales and slates and industrial and agricultural waste materials such as ashes from furnaces and the growing of coffee, palm oil, sugarcane, and rice, among others, would be used in a more valorised form. Their current bulk usage in cementitious systems would gradually change, as these ashes would now be used in more valuable, smaller dosages as activators rather than as target bulk materials in cementation. In addition, there is also the diversification of the routes towards geopolymer cementation, which is still in the early stages of exploration for wider industrial use. Therefore, the proof of concept reported in the current work is seen from these perspectives.2) and the decomposition of calcite (CaCO3).The potential performance of a developed system is best understood through detailed characterisation of the material components. The current study utilised ordinary Portland Cement (CEM-II/ B-V 32.5R), Ground Granulated Blast-furnace Slag (GGBS), silica fume (SF), sodium hydroxide (NaOH), and aggregates. OPC was supplied and manufactured by Lafarge Cement UK in accordance with BS EN 197-1:2011 . Table 12) of 97.1%. It was manufactured in Norway by Elkem Silicon Materials and supplied under the trading name of Elkem Undensified Microsilica 971 by Tarmac Cement and Lime Company, Buxton Lime and Powders, Derbyshire, Derby, UK. The TG/DTG analysis revealed that the silica fume showed a negligible weight loss as the temperature increased to 1000 °C, accounting for a maximum mass loss of 1.9%. This mass loss is represented in the DTG curve by a straight line with a very light peak in the range of 400–800 °C, which could be due to the decomposition of the impurity in this product. The commercial NaOH used was in the form of white pellets with a molecular weight of 40 g/mol and a pH value of 14, and was obtained from Fisher Scientific Ltd., Loughborough, Leicestershire, UK. It was employed to produce a NaOH solution with a molarity of 10M. This obtained solution was then used as an activator to dissolve silica fume and produce a SS solution with a SiO2/Na2O molar ratio of about 2.GGBS was used as an aluminosilicate precursor material in this study and was manufactured in accordance with BS EN 15167-1:2006  by CivilThe coarse aggregate used was of two grades (20 mm and 10 mm) and one type of fine aggregate. The coarse aggregates were limestone aggregates, whereas the fine aggregate was natural river sand dredged from the Bristol Channel. Both coarse and fine aggregates were supplied by a local quarry through a local supplier, in accordance with the requirements of BS EN 12620:2002+A1:2008 . Figure Two different approaches were investigated to design the concrete formulations assessed in this study . FirstlyFor completeness and proper analysis, the study adopted two controls (C and GC0) for both ordinary and geopolymer concrete mixes. The ordinary concrete mix (C) was formulated using OPC at a water/binder ratio of 0.55, while GC0 was designed by activating GGBS with a binary activator blend of SS and SH solution at an AP mass ratio of 0.7 and a SS/SH volume ratio of 1/1. As for the other four geopolymer batches (GC1–GC4), they were developed using different A/P ratios (0.5 and 0.9) and SS/SH volume ratios (0.8/1.2 and 1.2/0.8). This was to establish the independent effect of these two variables (A/P and SS/SH volume ratios) on the performance of geopolymer concrete. Likewise, in all these geopolymer concrete batches, the total binder content (precursor + activator) was set equal to the mass of cement in the control plain mix, while the water content added was set to be 1.5 L to achieve a minimum slump value of 50 mm for the case of GC0.2/Na2O molar ratio of 2 and the purity of SF used in the current study (97.1 % SiO2) were considered.The alkali-alkaline activator used in geopolymer formulations was a mixture of SH and silica fume-derived SS solution in three different SH/SS volume proportions . This binary blended activator was used due to the lower cost and availability of sodium-based activators compared to potassium-based activators . The SH 3 and 1.59 g/mL3, respectively, after 24 h. In addition, the viscosity of both solutions was determined as 25 ± 2 cSt for SH and 745 ± 5 cSt for SS, using a Fungi Lab Digital Rotational Viscometer Premium Series at a speed of 100 RPM for a total period of 1.5 min.The SH and SS solution was prepared and stored in a sealed container at an ambient temperature of 20 ± 2 °C for 24 h prior to its subsequent use as an activator for the aluminosilicate precursor. This was carried out to achieve chemical equilibrium of the exothermic reaction of SH and to complete the dissolution of silica fume particles. This is an important step, as the exothermicity of the activator can accelerate the geopolymerisation process, thus adversely impacting the properties of geopolymer concrete in its fresh state ,26. The A mixing regime was initially employed to prepare the geopolymer concrete. Firstly, the mass of dry ingredients  was precisely weighed in accordance with the proportions in The consistency of the fresh concrete was measured using the slump (S) and Compaction Index test (CI) according to BS EN 12350-2:2019  and BS EIn the control OPC system, the binder/water ratio was set at 0.55, implying 4 L of water was needed for 7.3 kg of cement . As prevThe impact of A/P ratios observed in GC0, GC1, and GC2 mixes showed that the slump value decreased as the A/P ratio decreased, while the compatibility degree indicated a reversal of the identified trend in slump. This implied that reducing the activator (liquid) and increasing GGBS content induced a reduced consistency of geopolymer, which is analogous to the effect of the water/cement ratio on the consistency of OPC concrete  and in lRegarding the increase in the sodium silicate to sodium hydroxide (SS/SH) ratio, observation showed that the slump decreased as the SS increased, indicating the negative effect of SS on the consistency of concrete. According to Gomaa et al.  and ProvThe display of strength gain by the OPC (Control 1) mix was due to the initial hydration of the cement components with water to produce cementing gels (C-S-H) necessary for strength gain. In contrast, the trend of strength increase in the geopolymer concrete was due to a polymerisation process that involves the chemical reaction of aluminosilicate minerals (GGBS) under alkaline conditions (SS/SH solution), resulting in a three-dimensional amorphous aluminosilicate matrix that exhibits strength corresponding to or superior to the OPC concrete ,8. MoreoThe effect of the A/P ratio observed in GC0, GC1, and GC2 mixes showed that the UCS value of the geopolymer concretes increased gradually as the A/P ratio decreased. This implies that the A/P has a similar role to that observed in the impacts of water/cement ratio variation on the UCS performance of OPC concrete . Hence, 2O/Na2O and reducing the alkalinity (pH) value of the system. Therefore, the polymerisation process is hindered by promoting the increase of poorly polymerised reaction products. After that, the geopolymerisation process is impacted by initiating a reduced setting time and subsequent polycondensation (hardening) process [In contrast to the reduction in UCS trend observed with an increase in the A/P ratio, observation showed an increase in consistency achieved by GC1 a,b for e process . However process . During  process . The tra process , lowerin process , and ult2 and water to form a composition of white carbonate salt known as efflorescence [Similar to OPC-based concrete, geopolymer concrete is a porous product; hence, alkaline compounds can be mobile through the pore network. Thus, the migration of liquid could act as an avenue for ion leaching and become a source of ion transportation from the pore solution to the external surface of the geopolymer concrete . Thereafrescence . Figure 2+ ions to the surface and the reaction of such migrated ions with the atmosphere [+ and OH− ions from the pore solution to the outer surface and the final reaction with atmospheric CO2 and water [Moreover, the mechanism of efflorescence formation in geopolymer concrete systems differs from that of OPC-based systems. In OPC-based systems, the efflorescence occurs due to the migration of soluble Camosphere . In contnd water ,9. In prnd water .Generally, the effect of the SS/SH ratio observed in geopolymer mix GC0, GC3, and GC4 mixes showed that the UCS value of the geopolymer concretes increased gradually as the SS solution increased at all curing ages. As evidenced in TS in concrete is essential for investigating the behaviour of the formulated geopolymer concrete mixes to shear, steel anchorage, crack development, and other applications in hardened concrete . Figure The outcomes from the current study suggest the viability of developing a geopolymer concrete using a laboratory-synthesised silica fume-derived sodium silicate solution in combination with NaOH as an alternative binary alkali-alkaline activator to GGBS, thereby leading to sustainability improvements in construction. Therefore, the following conclusions can be drawn:The impact of A/P ratio variations in the geopolymer mix GC0, GC1, and GC2 in terms of consistency indicated a reduction in slump values as the A/P ratio decreased from 0.5 to 0.9, while the compatibility degree showed a reversal of the identified trend in slump. Moreover, the variation in the SS/SH ratio (SS increase) at a fixed A/P ratio of 0.7 negatively impacted the consistency of the developed geopolymer concrete (slump reduction) due to the high viscosity of the SS solution;The formulated geopolymer concrete mixes (GC0–GC4) achieved higher UCS at all curing ages than the OPC (Control 1) mix, with mix GC2 attaining the highest UCS value of 62.6 MPa, thereby displaying the superiority of the alkali activation and polymerisation process over the CSH gel formation in ordinary concrete production;The effect of the A/P ratio observed in GC0, GC1, and GC2 mixes in terms of strength showed a UCS value increase at all curing ages  for every reduction in the A/P ratio. Therefore, in contrast to the decrease in UCS trend observed with an increase in the A/P ratio, efflorescence, which impacts the aesthetics of the concrete application, is likely to develop on the geopolymer concrete due to the excess alkaline compound in the concrete system;In terms of SS/SH variations, the UCS gain is minimal compared with the A/P ratio variations. This suggests that the A/P ratio has a more pronounced impact on strength gain, which is attributed to the geopolymerisation process;Depending on the concrete design strength or construction applications, a 0.5–0.7 A/P ratio with a SS/SH ratio of 1:1 or a slight SS increase of not more than 2% is advised.Although a laboratory-synthesised SF-derived geopolymer product was successful in this research, certain criteria should be considered in large-scale production on a construction site. As such, for properly storing activators and precursor materials under the required conditions, only machine mixing or ready-mix concrete should be employed because it replicates the mixing regime in the laboratory, and bath mixing operators must have adequate knowledge of geopolymer concrete.


In Greece, 49.4% of the participants were female, and in Turkey, this figure was 62.4%. The Greek respondents reported that obtaining antibiotics without a prescription was easier (52.6% reported “easy or very easy”) than the Turkish (35.6% reported “easy or very easy”) respondents did. This study reveals that Greek citizens were more educated and knowledgeable about antibiotics (58.5% of Greeks and 44.2% of Turks identified antibiotics correctly), their effects (20.9% of Greeks and 26.3% of Turks agreed with wrong statements about antibiotics) and the risks of antibiotic resistance, compared to those from Turkey. On the other hand, the Greek respondents were more prone to use leftover antibiotics or to give them to someone else later (p < 0.001). The findings of this study indicate that Greece and Turkey, both countries with high rates of antibiotic usage, exhibit distinct variations in their knowledge, attitudes, and perceptions concerning antibiotic use and antibiotic resistance. Effective countermeasures such as public campaigns should be targeted according to the population and those areas of knowledge, attitudes and behaviours in which the main shortcomings lie.Antimicrobial resistance is one of the largest threats to public health worldwide. As the inappropriate use of antibiotics is one of the leading causes of antibiotic resistance, it is important to have an understanding of the public’s knowledge, attitudes and behaviours towards antibiotics and antimicrobial resistance. The present study investigated the knowledge, attitudes and behaviours towards antibiotics among the public living in Greece and Turkey using an online cross-sectional survey, with social media advertising  and snowball sampling. In total, 709 individuals completed the survey (Greece  Antimicrobial resistance (AMR) is a substantial cause of morbidity and mortality across the globe. In 2019, AMR led to the deaths of at least 1.27 million people and was associated with nearly five million deaths worldwide . MoreoveThe unnecessary and inappropriate use of antibiotics is the main factor underlying the development of AMR . TherefoIn Turkey, several studies have investigated the attitudes, knowledge and behaviours towards antibiotics ,12,13,14A study of 1057 Bursa residents found that many believed antibiotics could be used to treat bacterial infections (58.3%), viral infections (75.5%), as well as coughs, colds and the flu (60.4%) . In addin = 322) found that 64.3% of the participants reported self-medicating with antibiotics, with a cold and fever being the leading reasons for self-medicating [n = 1044), they found that 63.7% of the participants had used antibiotics in the last 12 months, and 19.4% indicated that they stopped taking antibiotics when their symptoms improved [A study in Ankara (dicating . The majn = 412) knowledge, attitudes and behaviours towards antibiotic use in children with upper respiratory tract infections (URTIs) [Although Greece remains one of the largest consumers of antibiotics, there have been surprisingly few studies investigating the attitudes, knowledge and behaviours about antibiotics in the last decade. However, during the COVID-19 pandemic, researchers investigated parental ( (URTIs) . AlthougSimilarly, the majority of parents (85%) were aware that COVID-19 originated from a viral source, but approximately half of them (49.8%) were unsure about the necessity of antibiotics in its treatment. Furthermore, the study revealed that all demographic characteristics, except for gender, exhibited a noteworthy impact on parents’ knowledge, attitudes and practices concerning antibiotic use for upper respiratory tract infections (URTIs) and COVID-19.The current study examined the knowledge, attitudes and practices related to antibiotics within the general public of Turkey and Greece. The study used a cross-sectional survey, Facebook advertising and snowball sampling to obtain samples from the general public of both countries. These findings hold the potential to steer future interventions aimed at enhancing awareness and curbing unnecessary antibiotic usage in both nations.Sample size estimation using G*Power 3.1 application  indicated that the minimum sample size for sample comparisons was 184. The sample sizes were 309 for Greece and 400 for Turkey. The inclusion criteria for participants were age ≥ 18 and being a resident in Greece or Turkey. Since the questionnaire was presented in Turkish in Turkey and in Greek in Greece, only individuals with knowledge of these languages could participate. The questionnaire included a question about mother tongue: all Greek participants reported their mother tongue being Greek and all Turkish participants reported their mother tongue being Turkish.The questionnaires were translated into the local languages using native speakers of English and the local languages. These were then back translated using a second native speaker of both languages.The design of the study followed the protocol proposed in the Checklist for Reporting Results of Internet E-Surveys (CHERRIES) with minor adjustments for the study. To collect data, an online questionnaire was administered through Google Forms, and recruitment was carried out using advertising on social media platforms, such as Facebook, as well as employing snowball sampling techniques. In addition to social media advertising, friends, family members and colleagues were emailed and asked to forward the questionnaire link to people in their network. Participants were all provided with comprehensive information about the study’s background, objectives, voluntary participation, as well as an assurance of anonymity and data confidentiality. All participants provided informed consent before engaging in the study, and the research protocol received approval from the Social Science Ethics Research Board (SSERB) at the University of Nicosia .The questionnaire comprised six sections. t-tests, Chi-square tests and Mann–Whitney U tests were employed. A significance level of p < 0.05 was used to determine statistical significance.The study utilized IBM SPSS Statistics for Windows, version 25 , to conduct all analyses. To compare the knowledge, attitudes, and practices of participants from the two countries, independent samples p < 0.001) and had a higher proportion of females, more married individuals and a higher level of education compared to the Greek sample. Additionally, participants were questioned about their smoking habits, physical fitness, general health and whether they had a health professional background. There were no significant differences between the two countries with regards to the proportion that had a health professional background, smoking status and whether they reported themselves to be in good health. However, more people in the Greek sample considered themselves to be fit.The data comprise responses from 309 participants from Greece  and 400 participants from Turkey . The sample characteristics are displayed in p < 0.001).Participants were then asked about their recent experiences with antibiotics . More thp < 0.001) and amoxicillin as antibiotics . There were more Turkish individuals (12.8%) than Greek individuals (6.8%) who thought ibuprofen was an antibiotic and more Greek citizens (10.1%) thought paracetamol was an antibiotic than did Turkish citizens (6.8%). In summary, the country comparisons (Mann–Whitney statistics) show there were significant intercountry differences for all but penicillin. In general, Greeks seemed to be better at recognizing antibiotics than Turks. Without the knowledge of which pharmaceuticals are antibiotics and which are not, patients cannot be expected to use the medications as prescribed.Participants were also asked whether they were able to recognise which medications were antibiotics . Table 3p < 0.001). Greek respondents acknowledged, more often than Turkish respondents, that a person could be a “carrier” of resistant bacteria without getting ill. In addition, 16.9% of Greeks and 17.8% of Turks thought that resistance could spread from one person to another. Greek respondents agreed more than Turkish respondents with the statement that the more we use antibiotics in society, the higher the risk of resistance developing (p < 0.001). In general, Greek individuals were more knowledgeable about antibiotic resistance than Turkish individuals.Participants were asked questions about the development of antibiotic resistance  = −1.43, p = 0.154. Overall, the two countries did not seem to greatly differ in their attitudes to antibiotics.The assessment of attitudes towards antibiotic use was conducted through ten statements, with responses recorded on a five-point Likert scale, which ranged from “strongly disagree” (1) to “strongly agree” (5). The unnecessary use and overuse of antibiotics are the most important causes of antibiotic resistance in the community, which is mainly driven by the lack of knowledge and awareness regarding antibiotic use and the development of antimicrobial resistance. In the current study, the knowledge, attitudes and behaviours regarding antibiotic use and antibiotic resistance were investigated in two OECD countries with very high antimicrobial consumption and resistance rates, Turkey and Greece, in order to identify problematic attitudes, beliefs and behaviours and to guide future interventions to improve awareness and to reduce the misuse of antibiotics in both countries.As reported in the OECD Health Policy Studies of 2018, antimicrobial resistance (AMR) rates have shown a persistent increase across all OECD countries from 2005 to 2015. The highest rates of AMR, approximately 35% in Turkey, Korea and Greece, were seven times higher than the lowest rates observed among OECD member countries. The projections made by the OECD suggest that AMR will continue to rise in OECD countries, placing a significant burden on the population’s health and on healthcare budgets. In response to this concerning trend, Turkey has implemented two main antimicrobial stewardship programs (ASPs), which were established by the Ministry of Health (MoH). The first ASP targeted hospitals, while the second focused on the community. The MoH initiated the second ASP, a 4-year National Action Plan for Rational Drug Use 2014–2017), after the World Health Organization (WHO) expressed concerns about the exceptionally high outpatient use of antibiotics. This community-level initiative aimed to raise public awareness of prudent antibiotic use, leading to public campaigns to discourage inappropriate antibiotic use. In 2015, over-the-counter (OTC) sales of antibiotics were prohibited . These efforts yielded positive results, reducing first-line prescription rates from 35% to 25% and dropping antimicrobial consumption of J01 class antibiotics  nationwide from 42.2 DID to 35.25 DID between 2011 and 2017. However, despite these improvements, antibiotic resistance remains a significant issue in Turkey. Likewise, Greece demonstrates a significant level of antibiotic consumption, ranking among the highest in Europe for both hospitals and the community, according to the European Centre for Disease Prevention and Control (ECDC) antimicrobial consumption database (ESAC-Net) [, after tBased on the findings from the 2018 OECD Health Policy Studies, antimicrobial resistance (AMR) rates have exhibited a consistent and alarming rise in all OECD countries from 2005 to 2015. Notably, Turkey, Korea and Greece recorded the highest rates of antimicrobial resistance, reaching approximately 35%, which were seven times higher than the lowest rates observed among other member countries. These results indicate an urgent need to address the growing issue of AMR in OECD nations, as projected by the OECD, which predicts a continual increase in AMR rates, posing substantial challenges to population health and healthcare budgets [In the current study, citizens of Turkey and Greece were investigated in terms of their experiences with antibiotics. In both communities, previous antibiotic use during the past year was over 40%. However, the vast majority of the citizens indicated that they followed doctor’s orders on antibiotic use and did not request antibiotics if they were not necessary. In terms of accessibility, 15.6% of the participants in Greece stated that it was difficult or extremely difficult to obtain antibiotics without a prescription, while this rate was much higher (40.6%) in Turkey. These results suggest a tighter control of OTC sales of antibiotics in Turkey compared to Greece. Self-medication has been previously reported in similar studies in both urban and rural areas in Greece, which showed the major source being the acquisition from pharmacies without prescription and the use of left-over antibiotics at home or, to a lesser extent, from friends/relatives ,20,21. IFor antibiotic stewardship to be effective at the community level, citizens must firstly have knowledge about drugs, as well as being able to recognize the types and classes of drugs they use. The results obtained in our study showed that the recognition scores in the community were higher for amoxicillin and tetracycline in Greece compared to those in Turkey. Importantly, more Turkish respondents thought that ibuprofen (12.8%) was an antibiotic, compared to Greek respondents (6.8%). Overall, the Greek citizens were found to be more knowledgeable about drug classes and were better able to recognize drugs than the Turkish respondents were. In a study performed on patients attending a hospital in the Marmara region of Turkey, the authors found that the recognition scores for antibiotics were even lower than those found in the current study. They found that 22% and 17% of the participants thought paracetamol and ibuprofen were antibiotics, respectively . Among oPublic awareness of antibiotic resistance is a critical step in the prevention of AMR, which is a major threat to the clinical efficacy of antimicrobial medication. In the current study, most participants in both Turkey (80.7%) and Greece (77.6%) were aware that bacteria can become resistant to antibiotics. The vast majority of individuals from both communities were also aware of the risks of unnecessary antibiotic use  and the need to fully complete a course of antibiotics . A recent public survey of knowledge and attitudes regarding antibiotic use in the capital city Ankara (Turkey) found that while 67.5% of the participants were aware of the term antibiotic resistance, 17.1% of them could not link antibiotic use to the development of resistance . A separTurkey and Greece represent two countries that have been under the radar for antibiotic consumption and resistance rates, and ASPs have been implemented in both countries in an effort to curb the AMR problem. The findings of the current study indicate that the general public in Greece has a better recognition of antimicrobial drugs, knowledge of antibiotics and antibiotic resistance in comparison to that in Turkey, yet no differences were observed in terms of the attitudes towards antibiotic use. A multifaceted regional campaign in Greece, promoting prudent use of antibiotics, was found to lead to a rationalization in the choice of antimicrobials in both the general public and primary care physicians, but there was no reduction in the total antimicrobial consumption . InterveTo the best of our knowledge, this is the first study to compare the KAP of citizens in Greece and Turkey, which have the leading antibiotic consumption and resistance rates in the Europe region. This study revealed important information on the knowledge gaps and problematic attitudes in both countries. However, the present study also has several limitations, the first of which is the relatively low number of participants from both countries. A second limitation could be that the majority of the participants in both communities had higher degrees, and whether participants were living in residential or rural areas was not measured. In addition, the samples were selected using social media advertising and snowball sampling, and so are not likely to be representative of the general populations of the two countries.Continued interventions targeting the general population in both countries, such as public health education campaigns, are needed to encourage appropriate antibiotics use in the community. A stricter control of OTC sales of antibiotics through the enforcement of existing laws, particularly in rural areas, is also needed in both countries. Strategies such as the retention of prescriptions for antibiotics by pharmacies, government inspections and engaging pharmacists in the design of interventions should be considered. An integrated health strategy in both Turkey and Greece may help to reduce the uncontrolled antibiotic use, not only for human use but in all sectors involved.


However, there is currently a lack of a specialized platform to collect microbial SL gene pairs. Therefore, we designed a synthetic interaction database for microbial genetics that collects 13,313 SL and 2,994 Synthetic Rescue (SR) gene pairs that are reported in the literature, as well as 86,981 putative SL pairs got through homologous transfer method in 281 bacterial genomes. Our database website provides multiple functions such as search, browse, visualization, and Blast. Based on the SL interaction data in the S. cerevisiae, we review the issue of duplications’ essentiality and observed that the duplicated genes and singletons have a similar ratio of being essential when we consider both individual and SL. The Microbial Synthetic Lethal and Rescue Database (Mslar) is expected to be a useful reference resource for researchers interested in the SL and SR genes of microorganisms. Mslar is open freely to everyone and available on the web at http://guolab.whu.edu.cn/Mslar/.Synthetic lethality (SL) occurs when mutations in two genes together lead to cell or organism death, while a single mutation in either gene does not have a significant impact. This concept can also be extended to three or more genes for SL. Computational and experimental methods have been developed to predict and verify SL gene pairs, especially for  Escherichia coli as a reference set to calculate potential SL interactions among more than 2,700 bacteria, among which 281 have homologous SL gene pairs verified in E. coli.Research on SL interaction could provide novel drug targets and help construct a minimal genome. There have been many studies using metabolic models of different microbial systems or experimental array screen to study SL interactions. Here we developed a database to collect SL gene pairs of microorganisms, while also including SR gene pairs. Studies have transferred SL gene pairs onto other species through lineal homology, and also found that there are SL interactions. Based on this principle, we also used  Synthetic lethality (SR) is a genetic phenomenon where the combination of two mutations leads to cell death or inability to survive, while each mutation on its own does not have a significant impact . SynthetEscherichia coli, as well as eukaryotes, such as yeast, fruit flies, nematodes, and so on [SL interactions have been studied in prokaryotes, such as model organisms nd so on –9. The snd so on –13.Escherichia coli because it is an extremely important model organism with a widely available single-gene deletion collection (Keio) [E. coli model iAF1260 [et al. studied the SL interaction of Escherichia coli growing under nutritional stress [et al. crossed 53 shape-perturbing genes that expressed outer membrane or plasma membrane proteins with Keio to construct 1.7 million double deletion mutants, such that 1,373 SL interactions were screened out [S. cerevisiae, constructing more than 23 million double mutants, from which about 550,000 negative interactions and 350,000 positive interactions were identified [et al. identified more than 2,000 SR pairs of double deletion mutants through an alternative network-based strategy to force cells to bypass the functions affected by the defective genes or compensate for the lost function to restore biological function [Escherichia coli SL, there have also been corresponding studies on Bacillus subtilis, Candida albicans, Streptococcus agalactiae, and other microorganisms [Screening and discovery of SL interactions relied on mutation screening , nowadayn (Keio) . Costas  iAF1260 . Eric D.l stress , using 8ened out . In 2016function . In addirganisms –26. BaseOur database website provides multiple functionalities, including ‘Search’, ‘Browse’, ‘Visualization’, and ‘Blast’ options. All of the SL and SR data in the database can be downloaded directly. The statistics page displays summary information in detail as well as the reference literature. The help page introduces the functionalities of our database.Enter the gene name in the search box on the home page of the database website to search whether the gene has interaction data in our database. By default, the program will query for SL interactions from all the data we have collected. You can select the strain and interaction type to search. If the result returns, a table will be displayed on the left , and a sBy default, the Browse page displays SL and SR data collected from literature by us . You canS. cerevisiae and E. coli account for a large proportion, which is because E. coli and the yeast, as the most critical model organisms, have been extensively studied by various researchers, including the study of SL effects. Among the 8,831 gene pairs of SL interactions in yeast collected by us, 2,997 genes were involved. And the highest number of genes having pairwise interactions with the same gene is 132, that is to say, this gene had SL interactions with a total of 132 genes. The 86,981 putative SL of 281 strains obtained by the homologous transfer method can also be viewed on the browse page.Our database contains 13,313 SL interactions and 2,994 SR interactions. The interaction gene pairs of Submit at least two FASTA nucleotide sequences on the Blast page . Then, shttps://www.slkg.net/) provides an integrated platform that queries drug repositioning for tumor-specific therapy based on the concepts of synthetic lethality (SL) and synthetic dosage lethality (SDL). SynLethDB (https://synlethdb.sist.shanghaitech.edu.cn/) is a synthetic lethality database that aims to help cancer research by discovering selective and sensitive anti-cancer drug targets.There are already SL related databases, but these mostly focus on cancer synthetic lethality genes. SLKG .Based on the complete list of synthetic gene pairs in S. cerevisiae. There are a total of 1110 essential genes and 9225 synthetic lethal pairs in S. cerevisiae. On the other hand, this species has 1152 duplicates [Secondly, duplicated genes have been observed to be less essential than single genes according to the ratios of being essential in these two types of genes. In 2003, Gu and his colleagues observed that the proportion of essential genes (PE) among duplicates is much lower than among singletons in yeast . Howeverplicates ,34 and tBy searching the keyword "synthetic lethality" in the NCBI PubMed database, we obtained hundreds of publications about SL. After reading abstracts, we screened out literature related to microbial SL gene, and then carefully read more than 20 pieces of literature to find the data we need. The data were obtained by the text mining method. We then screened out the data we were interested in according to the methods and reference indexes provided by the literature. Most of the SL genes in our database belong to Saccharomyces cerevisiae and Escherichia coli, which is also because these two are the most critical model microbes of eukaryotic and prokaryotic. After obtaining the SL data, we downloaded and processed the gene annotation information of corresponding microorganisms from genome data websites (GenBank and SGD). And added this data to our database to provide more complete data information. In the SL data items collected by us, original important information and PMID are saved, so that users can view the detailed information of SL gene pairs and explore the research methods of SL in literature. The data we collected are shown in https://d3js.org/) was applied to realize the visual node interactive Graph of gene interaction. We also used PHP for database access and Python for data processing. All major browsers support access to our database website.After consistently handling the original data, we used MySQL to build the database. And we designed the responsive website in combination with HTML, CSS, JavaScript, and Vue. The force-directed Graph of D3.js Click here for additional data file.