By 2040, more than a quarter of the U.S. population will have diagnosed arthritic conditions. Adults with arthritis and other rheumatic conditions earn less than average yet have medical care expenditures that are over 12% of average household income. Adaptive aids can help arthritis patients continue to maintain independence and quality of life; however, their high costs limit accessibility for older people and the poor. One method used for consumer price reduction is distributed manufacturing with 3-D printers. In order to assess if such a method would be financially beneficial, this study evaluates the techno-economic viability of distributed manufacturing of adaptive aids for arthritis patients. Twenty freely accessible designs for 3-D printable adaptive aids were successfully fabricated on low-cost desktop 3-D printers and performed their functions adequately. The financial savings averaged >94% compared to commercially-available products. Overall, twenty adaptive aids were printed for US$20 of plastic; while on average, each adaptive aid would save over US$20. As printing a tiny subset of the adaptive aids needed by a single patient would recover the full capital and operational costs of a low-cost 3-D printer, it can be concluded that there is considerable potential for distributed manufacturing to assist arthritis patients. Arthritis is a common and disabling chronic condition consisting of joint pain and physical disability that has negative effects on the quality of life of patients ,2. In thArthritis has a substantial economic cost for Americans. Adults with arthritis and other rheumatic conditions incurred mean medical care expenditures of $6,978 in 2003  and Amerwww.makersmakingchange.com), an organization that connects people with disabilities that need assistive technologies (such as arthritis patients) with makers, was developed to design and fabricate assistive technologies. One way such an organization can scale laterally, and have their work help many that suffer from the same problem, is to distribute their technologies with open licenses so they can be utilized in distributed manufacturing [One method gaining favor for price reduction in consumer goods is distributed manufacturing of the goods with digital technologies such as 3-D printers ,14,15,16acturing ,39.In order to assess if such a method would be financially-viable for those with arthritis, this study evaluates the techno-economic viability of distributed manufacturing of adaptive aids for arthritis patients and specifically focuses on arthritis of the hands because the aids would be most likely to be able to be manufactured on a desktop 3-D printer. Twenty 3-D printable adaptive aids, which are provided to the global commons under free and open-source licenses, were fabricated on low-cost desktop 3-D printers in order to determine the distributed manufacturing costs. These products were tested for function and compared to those that offer similar functions on the U.S. market. These results are evaluated to determine the potential for distributed manufacturing to assist arthritis patients and conclusions are drawn.For this analysis to be widely applicable, it was critical that the materials were relevant and accessible to the average consumer with arthritis or those that would be helping them, i.e., Makers Making Change. The most common desktop 3-D printing polymer is polylactic acid (PLA) and was selected for this study. PLA is popular because the deformation of the material is well understood  and it dThe 3-D printers used for this study were delta-style RepRaps ,49, whicwww.myminifactory.com). MyMiniFactory was used because all of the designs have already been pre-screened to be 3-D printable by MyMiniFactory staff.They had freely available STL posted on an open-source 3-D printing design website MyMiniFactory . This allows for relatively straight-forward customization of the device for specific people needing the aid.They were licensed with an open-source compatible license or designer requests as defined by the Open Source Hardware Association .They were able to be printed on a consumer grade 3-D printer .They were able to be printed and used if manufactured from PLA .They possessed a functionally equivalent commercialized proprietary product or a clear application for arthritis patients.Twenty adaptive aids designed to help those with arthritis to accomplish a wide-array of routine ADLs were selected for inclusion in the study using the following six criteria:The selected open-source 3-D printable adaptive aids for arthritis patients are shown in For the adaptive aids selected in The economic inputs for distributed manufacturing are polymer feedstock, electricity and labor. The price of 1 kg of 1.75 mm diameter PLA filament is US$19.99  (or the m is the 3-D printed mass of the parts for the adaptive aid in grams and c the cost per gram is given above. As m is the primary determinant of the economics of the adaptive aids an experiment was run on 150 replicates of an ASTM Type IV tensile bar from thirty new (<2 months of experience) delta RepRap users each printing five samples with a random selection of slicing settings with 100% fill. The new users were chosen to simulate new arthritis patients with a small or no 3-D printing experience. The slicing settings changed print speed (nozzle speed over the print bed), layer height, and nozzle temperature in such a way as to obtain a visually acceptable 3-D print. These changes could be expected to be made by users even if they used recommended print settings that are more important for the mechanical integrity of the device such as fill percentage and shell thickness. This experiment was used to determine the potential error in the operating cost from Equation (1).With the assumptions that labor costs and electricity costs were excluded as detailed below, the operating cost (O) for the 3-D printer for a given adaptive aid was calculated as:aT) includes the cost of purchased components (p) :The total cost for a given adaptive aid manufactured using a distributed model  and warming up to printing temperature included, the 3-D printer uses about 0.06 kW/h or less than 1 penny per hour to operate. As the filament costs dwarfed the electricity costs they were neglected for simplicity. Lastly labor costs were also excluded from the financial analysis because fabricating an aid with a 3-D printer would fall under self-consumption . This assumption is valid for pre-designed arthritis aids  it would result in a cost of US$1.53, which is a 91.8% savings rather than 92.5%.http://www.openscad.org/) or FreeCAD (https://www.freecadweb.org/), both of which are natively parametric CAD packages allowing relatively easy customization for those with access to the raw source files. This was the case for all the designs selected because of criteria 2. In addition, customizer applications have been developed for OpenSCAD that enabled novices to customize products with no knowledge or experience with CAD because of a simple user interface [Similar to previous work that has shown substantial economic savings for 3-D printing high-end scientific tools ,80,81,82nterface . This maNinety-four percent savings are substantial enough for a person with arthritis to consider gaining access to a 3-D printer, whether purchasing and operating it themselves, using one at the local library, makerspace, fablab, or an online service . Thus, it should be clear that although the highest level of savings are for patients to print their own aids, those with arthritis can still get 3-D printed aids from any number of 3-D printing services including major retailers and shippers as well as local 3-D printing on demand services such as MakeXYZ. It should be pointed out that the markup for commercial online services could erode the savings shown here, but would depend on the service as well as provide a wider selection of materials  that may make for a more robust aid. It is clear that the savings per adaptive aid are high enough that margins could be maintained by also including labor costs although this would be highly variable depending on the community. All of the adaptive aids shown in Although some of the designs were developed by those with arthritis themselves, many of the arthritis aids available on the Internet were made by makers that know patients or by groups like Makers Making Change. It should be pointed out that the 20 case study adaptive aids used here are a tiny fraction of the aids of all kinds already available in the numerous 3-D printing free design repositories that now hold millions of designs of all manner of products . It shouThis was a preliminary investigation into the technical and economic potential for adaptive aids for arthritis patients that specifically focused on arthritis of the hands and thus could be significantly expanded in the future. First, designs for adaptive aids for other types of arthritis could be similarly evaluated. Second, an entire catalog of open-source 3-D printable equivalents for all commercial adaptive aids could be developed and then submitted to the same study as was done here. The economic analysis here assumed a similar lifetime for the 3-D printed products and the conventionally manufactured products. This assumption would need to be carefully analyzed and the products tested over long time periods to determine lifetimes to do full life cycle economic analysis. Many products like the light switch extender d, pen hoThe largest savings are generally seen for products that can be completely 3-D printed. Some of the examples shown here such as pen holder aid j, typingLastly, all economic analyses completed in this study focused on the U.S. market. It is likely that similar economic savings could be found for other regions of the world including Central and South America, Europe, Oceania, Asia, and Africa, but further work is needed to demonstrate this with the same detailed analysis. Many regions in the world  would have higher costs for imported items because of VAT or tariffs. This complicates the analysis because not only does the cost of the commercial adaptive aid change, but so does the cost of 3-D printing filament. Also, in many areas of the world with a less robust 3-D printer market, low-cost 3-D printing filament may not be as easily accessible. This lack of access can be offset with the use of recycled locally-manufactured filament , which wArthritis does not only take effect in elderly people above the age of 65, but also on otherwise healthy members of the younger generations. For example, Caroline Wozniacki, a professional tennis player, was diagnosed with rheumatoid arthritis at age 28, just a few weeks before the U.S. Open this year. Wozniacki spoke about how she is working with her diagnosis to overcome her hardships and work toward a goal of creating a positive mindset for herself . A studyThe largest potential savings for the arthritis patients are if they are able to manufacture the aids themselves. Although arthritis can impair the young, arthritis relevance increases with age and the geriatric population is the one that would benefit the most from this technological development. However, it remains unclear if older patients would have the appropriate technological knowledge to 3-D print their own aids. Future work is necessary to evaluate this along with the ability of all ages of arthritis patients to search for and identify open source 3-D-printable designs online. A study could be done to confirm that the time it takes arthritis patients from all age groups to search for the 3-D-printable design online is approximately equivalent to the time needed for shopping for the equivalent product online as it is for experienced 3-D printer users. This future clinical trial could consider a significant number of patients, grouped in different grades of arthritis conditions who are asked to determine the difficulty to print out the aids, degree of satisfaction, useful of the aid, support received, self-capability to find objects in a catalogue or online, run the 3-D printer and fabricate the object, as well as their subjective cost to effort value received.These readily 3-D printable objects can have a great effect on the community. For example, consider a person was leaving her apartment because her family came to pick her up. When she returns, she must figure out the best way of holding a small key and inserting it into the lock in the door. What if she had a Key Case m that alArthritic diseases cause significant morbidity, costing patients between $5,700 and $9,600 yearly . With anThe type of assistive aids required by an individual patient depends on which of the patient’s joints are affected by the arthritis, the severity of the patient’s arthritis, the frequency with which they need to accomplish a particular task, and the force needed to go through the patient’s joints to accomplish the task. Modifications for various tasks can be done by using an alternative tool , by retrofitting a patient’s home with accessible features (i.e., elevated toilet seats, grab bars in the bathroom, and 3-D printable aids such as door handles as opposed to door knobs  and autoDeploying 3-D printers in doctor’s offices, where musculoskeletal complaints account for 13% of all visits, would allow for physicians to suggest, prescribe, and print properly customized and sized aids for their patients at the point of care when the patient presents with a complaint. This is one method by which patients could be educated on their disease and have their needs addressed in a practical manner by their physician without the need for opioids or other pharmaceuticals. Future work is needed to determine if this would create an increase in visits as patients want to customize, replace or obtain additional copies of a 3-D printed aid. In addition, how to provide compensation for the staff time needed to provide this service would need to be determined. In a similar way, 3-D printers could be very effectively used in physical therapists’ and occupational therapists’ clinics as many patients presenting to these health care providers have specific functional requirements for which they are seeking solutions. While strengthening the patient’s muscles and improving their joints’ range of motion will provide benefit to the patient, so too will the use of specific functional aids which the therapist could prescribe and customize to the patient in clinic before printing and fitting the aid to the patient.Nursing homes and assisted living residences could also take advantage of having a 3-D printer on-site to be able to provide functional aids for their patients with physical limitations. Arthritis is a significant and underreported problem in nursing homes . PatientHospitals would also be able to offer their patients the benefit of 3-D printed assistive devices. Many patients present to hospital with new acute conditions, but also with undiagnosed chronic conditions as many of the elderly who live alone have either found a method of coping with their disabilities or simply avoid certain activities that they cannot accomplish independently. Upon evaluation in hospital, the opportunity arises to address some of these deficiencies and improve the patient’s level of function and activity. Arthritis is the most expensive condition treated in hospital by private health insurance in the U.S., and the second most expensive condition treated in U.S. hospitals overall in 2013 . HospitaThere is a gap found in surveys between actual assistive device usage and perception of personal benefit from assistive devices for ADLs in patients with disability . The reaAs the results of twenty freely accessible case-study designs show, adaptive aids for those that suffer from arthritis can be successfully fabricated on low-cost desktop 3-D printers and are technically proficient at performing their functions. On average, distributed manufacturing of these open-source adaptive devices resulted in financial savings greater than 94% compared to commercially-available products. Thus Medicare patients are able to 3-D print adaptive aids for less than their 20% copayments on prescribed DMEs. Remarkably, a single spool of polymer filament that retails for less than US$20 could print out all the aids investigated in this study and, on average, each adaptive aid would save the user over US$20. As printing a tiny subset of the available adaptive aid designs freely available on the internet or those needed by even a single patient would recover the full capital and operational costs of a low-cost 3-D printer, it can be concluded that there is considerable potential for distributed manufacturing to assist arthritis patients. This is perhaps most clear in nursing homes and hospitals where the capital costs for 3-D printers as well as the expertise to use them could be amortized over a large population of patients. As shown in this study, open access designs for arthritis aids are readily available and accessible. These designs help with a variety of tasks. With the advancements of open-source devices like those shown here, makers can help to alleviate some of the burden and pain that arthritis symptoms may cause. Policy makers as well as philanthropists should consider funding the open-source design of arthritis aids that have not already been developed. As arthritis is going to be an even more prevalent problem in the future, the application of distributed manufacturing represents a means to economically help society adapt to some of the increased costs associated with the disease.


Inappropriate antibiotic prescribing is a cause of antimicrobial resistance. Acute Respiratory Tract Infections (ARTI) are common diseases for those antibiotics are most likely prescribed in outpatient setting.To clarify factors associated with antibiotic prescribing for non-bacterial acute respiratory tract infections (NB-ARTI) and identify targets for reducing inappropriate prescribing for NB-ARTI in Japan.We conducted a retrospective, observational study using longitudinal claims data between April 2012 and June 2017. We assessed the rate of and factors associated with inappropriate antibiotic prescribing in outpatient settings for all NB-ARTI consultations included in the database.The mean monthly antibiotic prescribing rate per 100 NB-ARTI consultations during the study period was 31.65. The monthly antibiotic prescribing rate per 100 NB-ARTI consultations decreased by 19.2% from April 2012 to June 2017. Adolescents (13–18 years) and adults of working age (19–29 and 30–39 years) were more likely prescribed antibiotics compared with elderly patients ≥ 60 years . Outpatient clinics registered as internal medicine or ear, nose, and throat specialty were more likely to prescribe antibiotics than those of paediatric specialty or other specialties. Among health facility type, clinics without beds (aOR 2.123 [95%CI: 2.113–2.133]) and clinics with beds (aOR: 1.752 [95%CI: 1.7371–1.767]) prescribed significantly more antibiotics for NB-ARTI than outpatient departments inside general hospitals.Inappropriate antibiotic prescribing for NB-ARTI is common in Japan. Although the antibiotic prescribing rate has decreased, further interventions are required to promote antimicrobial stewardship (ASP). Education and awareness for adults and promotion of ASP among physicians in clinics without beds are key drivers to reduce inappropriate antibiotic prescribing in Japan. Inappropriate use of antimicrobials is one of the drivers of the emergence of antimicrobial resistance (AMR). The Japanese government published the National Action Plan on AMR (NAP) in 2016, in which promoting appropriate antimicrobial use is listed as one of the main strategies , suggestAcute respiratory tract infections (ARTI) are common diseases in primary care and many patients with ARTI symptoms are prescribed antibiotics despite the fact that the majority of these infections are caused by viruses. In the US, approximately 30% of antibiotic prescriptions in emergency departments and physicians’ office was reported to be unnecessary and 50% of antibiotic prescriptions for ARTI was deemed to be inappropriate . It was Several studies on antibiotic prescribing practice for ARTI in Japan have been reported thus far. A previous study using local claims data from 2005 showed that antibiotics were prescribed in 60% of ARTI consultations in the outpatient setting . YoshidaThis is a retrospective observational study using administrative claims data from April 2012 to June 2017 obtained from JMDC Inc. . The JMDC database contains anonymous claims data of 5.8 million (as of June 2018) corporate employees covered by the employees’ health insurance plans and their family members aged younger than 75 years, that roughly represents 5% of Japanese population. Data consist of patient characteristics , consultation information , medication information , and facility information .To estimate appropriate antibiotic prescribing, antibiotic appropriateness for every possible diagnosis of the Japanese National Health Insurance (NHI) was assessed by a panel of six infectious disease specialists at the Disease Control and Prevention Center, National Center for Global Health and Medicine Hospital, Tokyo, Japan. Japanese NHI code is more detailed than ICD 10, and each ICD-10 code include equal or more than one NHI code. Each diagnosis of the NHI was assigned to two experts who independently assessed whether antibiotic treatment for a diagnosis was necessary. If the assessment for each diagnosis between the two experts did not match, then all six experts discussed at a round table and made a collective decision on the appropriateness of these diagnoses . The valTo calculate the antibiotic prescribing rate at NB-ARTI consultations, we extracted the dataset comprising ARTI consultations from the original database. These data were associated with visits to outpatient clinics or other outpatient departments of hospitals by patients diagnosed with ARTI . We thenWe analysed the monthly antibiotic prescribing rates per 100 NB-ARTI consultations conducted in outpatient clinics. In this analysis, the numerator was the number of consultations during which an antibiotic was prescribed for NB-ARTI at a consultation during each month, and the denominator was the number of consultations at which NB-ARTI was diagnosed during the same month. We then conducted a simple regression analysis to compare the NB-ARTI diagnosis rate per ARTI consultation and the antibiotic prescribing rate per NB-ARTI consultation, to determine whether the reduction in antibiotic prescribing rate was affected by the reduction in the number of NB-ARTI diagnoses. Another simple regression analysis was carried out to compare the longitudinal trends in antimicrobial prescribing in the various age groups. In bivariate analyse, we compared the antibiotic prescribing rates by patient age group, the pharmacological classification of the antibiotic, and diagnosis. We categorized health facilities into clinics without beds, clinics with up to 19 beds, general hospitals with more than 20 beds, university hospitals, and national or municipal hospitals. Consultations were classified according to whether they were conducted during normal working ours (defined as between 8:00 h and 18:00 h on a weekday) or out-of-hours . In Japan, NHI covers almost all the population, but in addition, local governments subsidize children’s healthcare, and the policy is usually implemented from the beginning of the fiscal year (April to March). During the study period, almost all the relevant local governments introduced and continued these subsidies. To consider the potential difference in antibiotic prescribing rates due to health subsidies by local governments, patients were categorised into nine age groups: 0–3 years, 4–6 years, 7–12 years, 13–18 years, 19–29 years, 30–39 years, 40–49 years, 50–59 years, and ≥ 60 years. Longitudinal trend of antibiotic prescribing rate was evaluated by the simple linear regression model to analyse the correlation between antibiotic prescribing and time change. Multivariate logistic regression analyses were conducted to determine the association between characteristics of patients and health facilities and antibiotic prescribing. All statistical analyses were performed using Stata 15.1 . P values < 0.05 were considered statistically significant.The study was approved by the Institutional Review Board of the National Center for Global Health and Medicine Hospital . The data obtained from JMDC Inc. was completely anonymized before we analyze it. Therefore, subjects’ informed consent was not required.The mean monthly antibiotic prescribing rate per 100 NB-ARTI consultations during the study period was 31.65 . The res“acute upper respiratory infections” and “acute bronchitis”, “acute pharyngitis”, and “acute bronchitis”) yielded higher antibiotic prescribing rates than consultations with single ARTI diagnoses such as “acute upper respiratory infections” (24.03 antibiotic prescriptions/100 NB-ARTI consultations) or “acute pharyngitis” (12.03 antibiotic prescriptions/100 NB-ARTI consultations).Commonly reported diagnoses among NB-ARTI consultations were “acute bronchitis” , “acute upper respiratory infections” , and “acute pharyngitis”  . AntibioThe monthly antibiotic prescribing rate per 100 NB-ARTI consultations decreased by 19.2% from April 2012 (34.36 antibiotic prescriptions/100 NB-ARTI consolations) to June 2017 (27.77 antibiotic prescriptions/100 NB-ARTI consultations). The prescribing rate of third-generation cephalosporins, macrolides, fluoroquinolones, and other antibiotics decreased by 20.5%, 24.9%, 13.0%, and 32.9%, respectively, between April 2012 and June 2017 . There wAs shown in We conducted further analysis focusing on the prescription pattern by facility specialty. The trend of odds ratio for antibiotic prescription stratified by facility specialty indicated that antibiotic prescribing for NB-ARTI decreased in every specialty. The reduction of antibiotic prescribing among paediatric clinics was substantial; paediatric clinics prescribed only one-third of antibiotics in FY2017 compared with that in FY2012 .This study provides important findings on the recent practice and trend of antibiotic prescribing for NB-ARTI in Japan. We found that the mean monthly antibiotic prescribing rate for NB-ARTI was 31.7% during the study period, which is lower than previously reported in Japan –11. ThisThe proportion of broad-spectrum antibiotics prescribed among all antibiotics prescribed for NB-ARTI in the dataset was similar to that reported by a previous study that used the same data source . AccordiImportantly, we found a trend or antibiotic prescribing for NB-ARTI to decline. However, the simple regression analysis of the trend in the NB-ARTI diagnosis rate per ARTI consultation versus the antibiotic prescribing rate per NB-ARTI consultation showed that this negative trend in prescribing rate was not associated with the downward trend in the number of diagnoses. Even with consideration of changes in the diagnostic rate, the decrease in antibiotic prescribing rate remains obvious. Based on multivariate analysis results, the antibiotic prescribing rate has significantly decreased since FY2012, especially in paediatrics clinics, even after controlling for confounding factors related to the antibiotic prescribing rate. In Japan, most local governments/municipalities subsidize children’s healthcare costs, and children can receive healthcare services free of charge in most cases . TherefoIn this study, patients of working-age who are employed and registered as members of the NHI were identified as factors associated with inappropriate antibiotic prescribing. A previous study conducted in Japan also showed that patients aged 20–29 years were likely to receive antibiotic prescriptions . Other sWe also found that antibiotics were prescribed more often for NB-ARTI in clinics with and without beds than in outpatient departments inside general hospitals. In particular, 90% of antibiotic prescriptions for NB-ARTI were issued by clinics without beds, which account for 85% of medical healthcare institutions in Japan . PreviouThe factors associated with antibiotic prescribing for ARTI have been studied in other countries. These factors include time pressure, the patient expectation for antibiotics, diagnostic uncertainty, and poor doctor-patient communication ,21,22. DThis study has several limitations. Because JMDC is a database comprising data from large companies’ insurance union, data from retired employees are not included. We analysed the appropriateness of antibiotic prescribing based on the diagnosis obtained from medical claims submitted for reimbursement in the NIH system; therefore, diagnoses used in this study were not necessarily validated with actual clinical symptoms. Unfortunately, there is no robust information and there have been no studies to validate the diagnoses listed in medical claims in Japan. Based on the actual handling of medical claims in Japan, we processed the dataset by linking the consultation data file and the diagnosis data file under the condition of ≤ 30-day gap between the consultation date and the diagnosis date. Because the accuracy of the date of diagnosis is vague, there is a possibility that the antimicrobial prescribing rate is different according to the method used to link these datasets. In addition, there might have been minor discrepancies between the specialty listed in the JMDC database and the actual specialty at each facility,because JMDC extracted information regarding the specialty only the first listed specialty registered in the list kept by the Japanese Ministry of Health, Labour, and Welfare .In conclusion, our study revealed longitudinal trends and detailed characteristics of antibiotic prescribing for NB-ARTI in Japan. The results also provided insights into the inappropriate practice of antibiotic prescribing for NB-ARTI in Japan, which highlights optimal targets for ASP in outpatient settings. Education and awareness for adults and promotion of ASP among physicians in clinics without beds will be key drivers to reduce inappropriate antibiotic prescribing in Japan.S1 FigAbbreviations: J01DD, third-generation cephalosporins; J01FA, macrolides; J01MA, fluoroquinolones; J01C, penicillins; Total Abx, total antibiotics prescribing for non-bacterial acute respiratory tract infections.(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.


Polymicrobial interactions play an important role in shaping the outcome of antibiotic treatment, yet how multispecies communities respond to antibiotic assault is still little understood. Here we use an individual-based simulation model of microbial biofilms to investigate how competitive and mutualistic interactions between an antibiotic-resistant and a susceptible strain (or species) influence the two-lineage community response to antibiotic exposure. Our model predicts that while increasing competition and antibiotics leads to increasing competitive release of the antibiotic-resistant strain, hitting a mutualistic community of cross-feeding species with antibiotics leads to a mutualistic suppression effect where both susceptible and resistant species are harmed. We next show that the impact of antibiotics is further governed by emergent spatial feedbacks within communities. Mutualistic cross-feeding communities can rescue susceptible members by subsidizing their growth inside the biofilm despite lack of access to the nutrient-rich and high-antibiotic growing front. Moreover, we show that antibiotic detoxification by resistant cells can protect nearby susceptible cells, but such cross-protection is more effective in mutualistic communities because mutualism drives mixing of resistant and susceptible cells. In contrast, competition leads to segregation, which ultimately prevents susceptible cells to profit from detoxification. Understanding how the interplay between microbial metabolic interactions and community spatial structuring shapes the outcome of antibiotic treatment can be key to effectively leverage the power of antibiotics and promote microbiome health. Pathogens -microorganisms that make us sick- often live within dynamic and complex multispecies communities, where they may not only compete for limiting resources but also exchange beneficial resources or services with other resident species. While antibiotics are commonly used to get rid of such harmful microbes, the community-wide effects of antibiotic treatment and its consequences for antibiotic resistance are still not well understood. How do competitive or mutually beneficial interactions between antibiotic resistant and susceptible species influence community resistance to antibiotics? Here we investigate this question using a computational model. We find that antibiotic exposure favours the resistant lineage when resistant and susceptible strains are competitors but harms both types when they are mutualists. With antibiotic-detoxifying resistant cells, cross-protection of susceptible cells is more effective in mutualistic communities because mutualism drives mixing of susceptible and resistant cells. In contrast, competition leads to their segregation, precluding susceptible cells to profit from their competitor’s local detoxification. Our findings highlight that knowing not only what species are present but also how they interact with each other and arrange themselves in space is central to understanding antibiotic resistance and to informing the development of strategies that promote microbiome health. The human body is home to extraordinarily diverse microbial communities, or microbiomes . Metabolde novo antibiotic resistant mutants and/or the competitive release of new or existing antibiotic resistant strains [C. difficile infection, especially following treatment with broad-spectrum antibiotics. Such antibiotic therapy disrupts the normal gut microbiome composition, killing protective resident species, thus leading to the overgrowth of C. difficile [Plasmodium chabaudi clones [P. chabaudi strains is resource availability [A major concern when using antibiotics is the potential emergence of  strains . Competiifficile . Competii clones –22, withi clones . A key flability ,24. For lability .S. typhimurium was able to enhance its antibiotic tolerance by sensing indole produced by the commensal E. coli [S. aureus, which was protected from beta-lactam antibiotics when enclosed within a layer of resistant beta-lactamase producing P. aeruginosa [S. pneumoniae can protect chloramphenicol- susceptible S. pneumoniae by degrading chloramphenicol intracellularly, which then lowers the extracellular concentration of antibiotic in their neighbouring environment. Together, these examples highlight the importance of the interplay between species and strain metabolic interactions, their spatial arrangement, and the mode of resistance in shaping the outcome of antibiotic resistance. Although we use the terms strain and species interchangeably, we anticipate that competitive interactions will dominate among strains of the same species, whereas more diverse ecological interactions will be more common among species with more distinct metabolic profiles.While there has been a strong focus on competition as a driver of antibiotic resistance and virulence, mutualistic and exploitative interactions among co-infecting bacteria have also been associated with enhanced virulence ,25,26 an E. coli . Anotherruginosa . In addiruginosa ,28–30, rruginosa ,31,32. FTop-down sequencing approaches have revealed important correlations between microbiome composition and host health , yet boSince microbes typically grow in multispecies, surface attached micro-colonies and biofilms ,36, it iE. coli strains [To investigate the mechanistic and demographic underpinnings of community-mediated resistance in a spatial context, we implemented a mechanistically-explicit individual-based model consisting of an antibiotic-resistant (R) and a susceptible (S) species (or strain). Our model extends an established individual-based framework that simulates the growth and division of cells on an inert surface with explicit diffusion of nutrients and metabolites ; “exploWe first confirm that our metabolic interactions defined in We next ask: how does the type of ecological interaction between resistant and susceptible strains influence the community response to antibiotic perturbation? Generally, we find that the density of susceptibles decreases with increasing levels of antibiotics, regardless of their interaction with the resistant strain . WhetherIn sum, our results suggest that antibiotic perturbation leads to the competitive release of the resistant species when the susceptible and resistant species are competitors and to the suppression of the resistant species when the two species are mutualists.In the model presented above, we assume that there are no fitness costs of resistance. The no-cost scenario reflects cases where the resistant strain has either acquired compensatory mutations that alleviate the cost of resistance  or when The results in How does applying antibiotics influence competition-mediated sensitivity and mutualism-mediated robustness to initial conditions? Unlike in our simple equal competitor scenario without antibiotics, applying antibiotics to the competitive community switches the system to a state where the resistant species is generally favoured independently of initial proportions and spatial distribution . This reSo far we have assumed that antibiotic resistance in a focal cell has no impact on the abundance of antibiotic encountered by other cells. However, resistance often occurs through antibiotic degradation, leading to a reduction in the levels of antibiotics present in the local environment of a focal resistant cell (i.e. detoxification) ,31,32,46Previous work has shown that competitors generally tend to segregate as they grow and divide while mutualists tend to mix ,48,49; a. TherefoTo further test the impact of spatial patterning, we ran a new set of simulations where the resistant and susceptible types are now initially segregated. We predict that spatial segregation should accelerate the decline of non cross-feeding susceptibles because there are no mutual benefits driving the mixing of susceptible cells with detoxifying resistant cells, but only the exploitation of detoxification by susceptibles. Consistent with this prediction, we find that in the non cross-feeding media, the proportion of susceptibles initially decreases more quickly when resistant and susceptible cells start segregated . But in Microbes live in metabolically-connected and spatially extended multispecies communities . Understde novo resistant clones may remain trapped and starved within the inner region of the colony, layered with growing sensitive cells. When high antibiotic concentrations are applied, however, the sensitive cells are killed and eventually removed from the growing front, thus freeing space and resources that can then be taken up by the resistant cells. A similar finding has been observed in the context of chemotherapy using a computer simulation of tumor growth [Competitive release occurs when two species compete for shared limiting resources and the removal of one species liberates resources that can be used by the other species, which then increases in density. Because of higher density, the probability of getting mutations that further improve the fitness of the resistant strain increases, potentially leading to higher rates of resistance . The rolr growth . We can r growth ,20,57. Ur growth ,59.Although ubiquitous, microbial competition is not universal . The oraThe potential for susceptible cells to be protected against antibiotics is in principle enhanced when resistant bacteria can detoxify their environment. Empirical evidence of cross-protection of susceptible cells by antibiotic-resistant detoxifying cells is accumulating in the literature, and has been documented both within the same species ,28,64–67In contrast, competition leads to segregation, which ultimately prevents susceptible cells to profit from detoxification. This finding is in line with previous work on the evolution of cooperation in microbial biofilms showing that competition leads to the formation of clonal groups (high segregation) that insulates enzyme-secreting strains from non-secreting strains, thus precluding non-secretors from receiving the benefits of the secreted products ,71. Our Our results are based on the assumption that the antibiotic is applied at time 0, thus before any interaction between resistant and susceptible cells has taken place. In a clinical context, however, antibiotics will likely be applied to an already established microbial community with a given ecological and spatial structure that reflects the no antibiotic case. How does the timing of antibiotic administration impact our results? We ran a new set of simulations where the antibiotic is now added after 4h, 12h, or 24h of biofilm growth, and found that adding antibiotics at later stages of biofilm development generally favours the susceptible strain, and can even prevent the competitive release of the resistant strain . This poOur model assumes that all the interactions are symmetric. Any deviations from the baseline dynamics are therefore due to the effect of the antibiotic and/or the cost or resistance. Interactions between resistant and susceptible strains may, however, be asymmetric, potentially changing the benefits and costs of interactions. How can asymmetries impact the outcome of antibiotic treatment? When resistant and susceptible species are mutualists, their interests are largely aligned. As such, the cross-feeding and cross-protection benefits received by susceptible cells depend on the growth of its mutualist resistant partner. If susceptibles start outgrowing the resistant type, the reciprocal benefits of mutualism are diminished, and this will ultimately harm susceptibles due to the lower provision of food and lower detoxification by resistant cells. This negative feedback can help stabilize the mutualistic interaction, and consequently, the response to antibiotic treatment.Clearly, hosts play a crucial role in shaping the composition and structure of their microbiomes, not only by providing shelter and food to their resident microbes, but also by producing antimicrobial cells and molecules that inhibit or kill potential enemies . In turnOur work focuses on a two-strain or two-species microbial community living in a simple environment (one/two resources and a single antibiotic), which is undeniably an oversimplified view of natural microbial ecosystems. Although our results are likely not generalizable to the large diversity of microbiomes, such minimal microbiome approach allows us to identify testable principles of community-mediated antibiotic resistance which can lay the foundations for further research on more complex communities. For instance, it would be interesting to extend our model to investigate the outcome of antibiotic treatment in a community consisting of isogenic resistant and susceptible strains plus a third resistant or susceptible strain that acts as a mutualist or competitor. Testing these ideas in more diverse communities and complex environments will help elucidate both general and system-specific principles that determine the outcome of antibiotic therapy.In sum, our results suggest that the interplay between the metabolic and spatial relationships of resistant and susceptible strains within a community plays an important role in shaping the outcome of antibiotic treatment. Understanding this relationship can therefore be key to develop effective control strategies. We expect that the spatial segregation and lower density of competitive communities should facilitate the clearing of an infection because the target sensitive species is isolated from the resistant species, and as such, more vulnerable to antibiotic clearance. In such competitive scenario, a priority is to maintain competitive suppression, and therefore using narrow-spectrum antibiotics may be more effective than broad-spectrum antibiotics. In contrast, the spatial mixing and higher densities of mutualistic communities will make it harder to clear the target species. Under such mutualistic conditions, narrow-spectrum and bacteriostatic antibiotics may therefore be less effective as cross-protection and cross-feeding increase the likelihood that sensitive cells will be able to resume growth once the concentration of the bacteriostatic antibiotic falls below levels permissive for growth. One potential treatment strategy for the control of mutualistic communities would be to first disrupt the mutualism, e.g. through a diet change that induces a shift in metabolic interaction , to loweOur model is an extension of an established, empirically tested individual-based framework that simulates the growth and division of cells on an inert surface. This modelling framework has been used extensively over the past decade to understand the behaviour, ecology, and evolution of microbial communities, including studies looking at the drivers of genotypic spatial segregation in biofilms and its consequences for within-species ,77 and bFor the full list of symbols used in the model and specific parameters used in the simulations, see sR) in a community consisting of resistant and susceptible cells indicates the degree to which resistant cells are spatially segregated from susceptible cells, and is measured aspR_local is the proportion of resistant cells within their local neighbourhood and pR_global is the proportion of resistant cells in the whole population. Thus, the closer s is to 0 the more mixed (randomly distributed) S and R cells are within the community, whereas the closer s is to 1 the more segregated (or assorted) they are. In addition, the proportion of R cells in their local neighbourhood is calculated as follows. For each individual cell (ci) of type R in a population of N = NR + NS cells, we identify all neighbour cells (cj) falling within a 10μm radius neighbourhood distance and define the proportion of cells identical to ci in the neighbourhood of ci as:Nd is the number of cells falling within a distance of 10 μm, and where g = 0 if ci and cj belong to different types or g = 1 if ci and cj belong to the same type. The proportion of resistant cells in their local neighbourhood is then defined as:The segregation index calculation used here has been described in detail in  and is aS1 FigAntibiotic assault leads to strong competitive release of the antibiotic-resistant strain when the susceptible strain is a strong competitor (interference competition and exploitation competition media), to weak competitive release of the antibiotic-resistant strain when susceptibles are weak competitors (non cross-feeding media), but to a reduction in resistant density when they are mutualists  (cross-feeding media).(PDF)Click here for additional data file.S2 FigShown are the densities of R (red) and S (blue) in coculture and the sum (grey). We can see that cost of resistance has a strong effect on coculture densities when R and S are competitors and antibiotics are absent, but little to no impact when antibiotics are present or when R and S are cross-feeding mutualists. Here we consider that costly resistance leads to a reduction in the maximum intrinsic growth rate (e.g. 0.1 indicates a 10% cost) see .(PDF)Click here for additional data file.S3 FigSimulations are seeded 1:1 with 60, 120 (default), or 960 cells of each type. Biofilms are grown for 36h. Resistance is non-costly or costly (c = 0.2).(PDF)Click here for additional data file.S4 FigA. We can see that, in the interference competition medium, the most common type wins (positive frequency-dependent selection) when no antibiotics are present, but applying antibiotics to the medium shifts the balance towards resistant species being favoured irrespective of initial conditions. In the cross-feeding medium, however, susceptibles merge towards an equilibrium proportion that is independent of initial proportions but that decreases with increasing level of antibiotics. B. Segregation index of communities shown in S4A. See Here we vary both the initial proportion of S cells  and the degree of mixing between S and R cells  at inoculation. (PDF)Click here for additional data file.S5 FigShown are representative profiles of the average of solute concentrations  as a function of community height after 24 hours of growth. The gray horizontal dashed line shows the mean of the height of the biofilm. The two species are seeded randomly and at 1:1.(PDF)Click here for additional data file.S6 FigPlotted are the densities after 36h of coculture growth. At inoculation, the two types are seeded randomly and at 1:1.(PDF)Click here for additional data file.S7 FigThe two types are seeded randomly and at 1:1.(PDF)Click here for additional data file.S8 FigAntibiotics are added at 0h (default), or after 4h, 12h, or 24h of biofilm growth. Shown are the coculture densities of R and S for every 4 hours from the time the antibiotic is added to 36h of biofilm growth in total . We can see that later antibiotic addition favours susceptibles, and can even prevent the competitive release of the resistant strain. This effect is stronger with detoxification and when antibiotic concentrations are low. In the simulations, resistance is costly (c = 0.2).(PDF)Click here for additional data file.S1 MovieVideo showing that without cross-feeding, the resistant (red) and susceptible (blue) cells remain spatially segregated. Related to (MOV)Click here for additional data file.S2 MovieVideo showing cross-feeding between resistant and susceptible cells drives species mixing. Related to (MOV)Click here for additional data file.S3 MovieVideo showing that without cross-feeding, there are no mutual benefits driving the mixing of susceptible cells with detoxifying resistant cells, therefore precluding susceptible cells to fully profit from antibiotic detoxification. Related to (MOV)Click here for additional data file.S4 MovieVideo showing that cross-feeding coupled with antibiotic detoxification provides the greatest rescue effect for susceptible cells. Related to (MOV)Click here for additional data file.


This paper presents finite element (FE) modeling of the debonding behavior of fiber reinforced polymer (FRP)-to-concrete interfaces subject to mixed-mode loading, which is realized through a peeling test of FRP composites externally bonded onto a concrete substrate. A cohesive zone model (CZM) is implemented into the FE model to represent the behavior of the FRP-to-concrete interface. Two element schemes (orthotropic plane stress element and beam element) were employed to simulate the behavior of FRP composite plate in the peeling test. The orthotropic plane stress element scheme, bearing a clear physical background and with an easy definition of the material property parameters following the composite mechanics, is found to be superior to the beam element scheme, and thus is utilized to conduct parametric studies. The influences of the peeling angle, the interfacial parameters , the interfacial damage evolution law (DEL), the coupling of mode-I and mode-II components), on the mixed-mode failure of the FRP-concrete-interface are carefully investigated. The results showed that the mode I component plays a critical role in the debonding failure of FRP-to-concrete interfaces even when the peeling angle is very small. The failure of FRP-to-concrete interface transits promptly from a mode II-dominated one to a mode I-dominated one when the peeling angle increases to a relatively small value  and subsequently the peeling force  decreases dramatically. Such mixity of the mode I and mode II components should be appropriately considered for refining the analysis of FRP-strengthened RC beams and the FRP debonding strength design, for which a pure mode II interfacial failure was usually assumed. Externally bonded fiber reinforced polymer (FRP) plates or sheets are now widely recognized as an effective technique for strengthening reinforced concrete (RC) structures ,2,3,4. IDebonding of FRP in FRP-strengthened RC members is associated either with the discontinuity of FRP composites  or with the discontinuity of concrete . Both lead to normal and/or shear stress concentration at the FRP-to-concrete interface. This paper deals with the latter discontinuity, which is believed to be more critical, since it is impossible to utilize efficiently the FRP strength while keeping the concrete un-cracked unless the concrete is prestressed.In a plane FRP-strengthened RC member, a concrete crack may exhibit two different types of displacements: one is the opening of the crack a, which Among the three types of debonding failure, the mode II failure of the FRP-to-concrete interface has been studied most extensively . As a result, the interface is subject to both normal and shear stresses, leading to a mixed-mode fracture condition. This test has been popularly used to evaluate the fracture properties of a bondline  in mechanical and material engineering GI=6ng force ; E is th1fG and 2fG are the interfacial fracture energies under pure mode I and mode II conditions, respectively. Obviously, with the combined use of Equations (1)–(3) (or Equation (4)), the relationship between the peeling force peelF and the peeling angle θ can be obtained. However, the closed-form solutions presented above can only be used to predict the steady state peeling force of the FRP-to-concrete interface, as explained later. In addition, the nonlinearity of FRP-to-concrete interfaces, which has been proven to be very significant particularly when the mode II loading effect is predominant, cannot be appropriately considered in the above solutions.A fracture energy-based failure envelope is needed to govern the mixed-mode fracture propagation of FRP-to-concrete interfaces. Two typical failure criteria have been adopted by previous researchers for FRP-to-concrete interfaces subjected to mixed-mode loading ,45: (3)Gσ and τ are the peak normal stress and shear stress in the interface at the initiation of the mixed-mode debonding; σ0 and τ0 are the peak normal stress and shear stress in the interface at the debonding initiation of the interface under a single mode I and mode II loading, respectively. The other criterion is to assume that the normal and shear stresses have coupled effects and the mixed-mode interface debonding will initiate when the following stress condition is reached: these two equations are referred to as damage initiation law (DIL) hereafter.A two-dimensional (2D) FE model is employed in the current paper to simulate the peeling test to overcome the limitation of the closed-form solutions. The FRP elements are directly connected to the fixed boundaries through cohesive elements. The interface is dimensionless and its relative displacement represents the overall damage of the bonding layer including that of the thin layer of concrete adjacent to the bonding adhesive. Therefore, the concrete substrate itself is assumed to be rigid where no damage occurs. When the stiffness of concrete substrate is much larger than that of FRP lamina, this assumption is rational and this assumption has been widely used in previous studies ,17,37. ASimilarly, the two damage evolution laws (DELs)  and (4)) introduced above are used in the FE analysis for comparative studies.In the FE model, two element schemes are adopted to simulate the FRP lamina, i.e., orthotropic 4-node plane stress element, and 2-node linear elastic beam element, as used for the above LEFM analysis . In ordeE1, the transverse Young’s modulus E2, the major Poisson’s ratio v12 and the in-plane shear modulus G12) can be obtained from the two constituents  and their volume fractions based on the mechanics of materials approach [fE and mE are elastic modulus of fibers and epoxy matrix, respectively; fv and mv are Poisson’s ratio for fibers and epoxy matrix, respectively; fV and mV are volume fractions for fibers and epoxy matrix, respectively.A unidirectional FRP lamina can usually be treated as an orthotropic material whose mechanical properties in the fiber direction are different from those in the other two orthogonal directions. That is, the elastic modulus, shear modulus and Poisson’s ratios are different in different directions. In Scheme 1, the FRP lamina is modeled as plane stress element, and the mechanical properties of the FRP lamina  matrix are usually uniformly distributed in the FRP section. As a result, the volumetric ratio of fibers is always a constant regardless of the stiffness of the FRP lamina and can be determined according to the manufacturer’s data. For the wet lay-up process, the FRP lamina can be discretized as dry fiber sheet layers and epoxy layers . Figure L = 150 mm, pure model I fracture energy 1fG = 0.1 N/mm, pure mode II fracture energy 2fG = 0.4 N/mm, peak strength in normal direction 0σ = 2 Mpa, peak strength in tangential direction 0τ = 4 MPa. The FRP lamina is assumed to be formed through the wet lay-up process and the total thickness of one layer of FRP lamina t = 1 mm   see a. In addr sheet, a, the car sheets b, which In Scheme 2 b, the FReE and et are the equivalent elastic modulus and equivalent thickness of the equivalent beam, respectively. For the case of one layer of fiber sheet, the calculated values are eE = 230.6 GPa, et = 0.376 mm; while for the case of two layers of fiber sheets, these two parameters are eE = 141.1 GPa, et = 1.22 mm.Equation (14) can be rewritten as:1a/G1b and G2a/G2b ratios, which determine the stiffness of the cohesive laws once the fracture energy and peak strength values are fixed, are assumed to equal to 2/3 and 1/9 in all the analyses. Two peel angle 20 and 80, which represent the relatively small angle and large peel angle, respectively, are observed. It can be seen that, generally, the entire debonding process has two phases: the initial phase and the steady peeling phase  were used in the FE analysis. It can be seen from Parametric studies were conducted on the cases of different peel angles, with all the other parameters the same as those used in the previous studies for one layer of fiber in the FRP lamina. It can be seen from E and thickness t) of the FRP lamina and the fracture energy of the interface  are fixed, the peeling force is determined. Under the same fracture energy  configuration, however, the shape of the cohesive laws may differ significantly. A ratio of a/GbG is introduced here to define the shape of the cohesive laws, where aG is the initial fracture energy (the area underneath the ascending portion of the cohesive law) and bG is the area under the descending branch, which is the difference between fG and aG .In the analytical model, once the properties  for both normal and tangential directions are adopted, leading to 9 sets of combinations for G1a/G1b and G1a/G1b  leads to different load-displacement behaviors . However, the time when the interface shear failure occurs is determined by the initial normal stiffness of the interface . One point worth mentioning is that, in the case for which G1a/G1b = 3:2, G2a/G2b = 3:2 and the peel angle = 20 , the debonding process shifts rapidly from mode II-dominated to mode I-dominated. Below this angle, the mode I and mode II components have comparable amplitudes, so their coupling effect is very significant.The orthotropic plane stress element scheme seems to be most appropriate for the simulation of the FRP lamina during the mix-mode debonding of FRP-to-concrete interfaces and the mechanical properties can be determined based on the composite mechanics.In case of large peel angle , both the DIL and the DEL have an insignificant influence on the peeling process; while, when the peel angle is relatively small, both the DIL and DEL have a significant influence on the peeling force. The quadric DIL leads to higher peeling force than the maximum cohesive strength DIL. Besides, the power DEL leads to higher peeling force than the linear DEL.Analyses of the full-range mixed-mode debonding process helps to achieve a thorough understanding of phenomena observed in the peeling test of an FRP-to-concrete interface, in terms of the global load-displacement curves, and the local strain distributions along the FRP lamina length as well as the stress-strain evolution history at different load levels.Comprehensive FE modeling has been conducted to reveal the debonding mechanisms of FRP-to-concrete interface subjected mix-mode loading, which is realized through simulating a typical peel test. Through the implementation of the cohesive zone models coupled in normal and tangential directions and appropriate simulation of the FRP lamina, the following conclusions can be drawn:


Mobile phone apps have been shown to enhance guideline adherence by prescribers, but have not been widely evaluated for their impact on guideline adherence by prescribers caring for inpatients with infections.To determine whether providing the Auckland City Hospital (ACH) antibiotic guidelines in a mobile phone app increased guideline adherence by prescribers caring for inpatients with community acquired pneumonia (CAP) or urinary tract infections (UTIs).We audited antibiotic prescribing during the first 24 hours after hospital admission in adults admitted during a baseline and an intervention period to determine whether provision of the app increased the level of guideline adherence. To control for changes in prescriber adherence arising from other factors, we performed similar audits of adherence to antibiotic guidelines in two adjacent hospitals.The app was downloaded by 145 healthcare workers and accessed a total of 3985 times during the three month intervention period. There was an increase in adherence to the ACH antibiotic guidelines by prescribers caring for patients with CAP from 19% (37/199) to 27% (64/237) in the intervention period (p = 0.04); but no change in guideline adherence at an adjacent hospital. There was no change in adherence to the antibiotic guidelines by prescribers caring for patients with UTI at ACH or at the two adjacent hospitals.Provision of antibiotic guidelines in a mobile phone app can significantly increase guideline adherence by prescribers. However, providing an app which allows easy access to antibiotic guidelines is not sufficient to achieve high levels of prescriber adherence. In response to the growing threat of antibiotic resistance, antibiotic stewardship programmes in primary and secondary care have introduced myriad prescribing and decision support tools in order to improve rates of appropriate antibiotic prescribing . Whilst The deployment of computerized decision support (CDS) on non-mobile platforms has repeatedly been shown to improve adherence to antibiotic guidelines, reduce mortality rates, and decrease the prevalence of antibiotic resistance . DespiteThe widespread use of smartphones by healthcare workers has led to a proliferation of smartphone applications (apps), including many that have made antimicrobial guidelines readily available throughout the healthcare workplace . DespiteIn light of the success of apps in improving adherence to guidelines for the treatment of depression and cardiac arrest , 14, it Recent studies that documented low rates of adherence to the Auckland City Hospital (ACH) antibiotic guidelines for the treatment of community acquired pneumonia (CAP), and uriWe designed our study to test the hypothesis that the introduction of the SCRIPT app, which provides the ACH antibiotic guidelines in a user-friendly, decision-making process format, would increase prescriber adherence to these guidelines. We investigated the early impact of SCRIPT on the initial empiric treatment of adult patients admitted to ACH with either community-acquired pneumonia (CAP) or urinary tract infection (UTI). The study was approved by the New Zealand Health and Disabilities Ethics Committee (reference number: 16/STH/6).The existing ACH antibiotic guidelines were directly mapped into decision trees , that branched out to the eventual antibiotic treatment recommendations.The user interface and functionality of the app was designed in collaboration with the Design for Health and Wellbeing Lab (ACH). Following a rigorous quality assurance process involving test users and clinicians from our research team, the ACH Antibiotic Stewardship Committee approved the app’s publication on the iOS and Android app stores. When accessing the app, users of SCRIPT consented to collection of anonymous data regarding their app usage via an in-built feature of the app.ACH, Middlemore Hospital (MMH) and North Shore & Waitakere Hospitals (NSH/WTH) serve a combined population of approximately 1.6 million people resident within the Auckland metropolis.The study retrospectively measured prescriber adherence to the ACH antibiotic guidelines in adult patients (>18 years) with CAP  or UTI , who had been admitted to ACH for ≥4 hours during baseline and intervention periods in 2016. The initial antibiotic prescription(s) in the first 24 hours of admission for patients admitted during the baseline period (1 January 2016 to 31 May 2016), before SCRIPT was released, was compared with that for patients admitted during the intervention period (1 June 2016 to 31 August 2016) after SCRIPT had been made available for all ACH prescribers. Hospital data from the previous three years indicated that a three month period would include an appropriate number of patients (200) to provide sufficient power to detect our estimate of SCRIPT’s impact.To allow for potential confounding by other concurrent factors, we also measured prescriber adherence to the relevant antibiotic guidelines in adult patients admitted for ≥4 hours to MMH and NSH/WTH during the same baseline and intervention periods. SCRIPT was introduced from 1 June 2016, coinciding with both the beginning of a junior doctor rotation, and the beginning of the intervention period. Since junior doctors may move between these regional hospitals on 3-monthly rotations, the study periods intentionally coincided with the beginning of a junior doctor rotation. In the first two weeks of the intervention period, educational sessions, posters and intranet advertisements were employed to socialize the app and facilitate its uptake by clinicians at ACH.Antibiotic stewardship activities at MMH and NSH/WTH, which uphold the same principles as those at ACH, continued during the study period, but no major interventions to improve the management of CAP or UTI were undertaken. To prevent app usage by clinicians in MMH and NSH/WTH, SCRIPT was restricted to ACH clinicians through unique activation passcodes linked to active ACH e-mail accounts. In all of the hospitals, antibiotic guidelines remained accessible through their respective pocket guides, posters, and intranet sites. Electronic prescribing and other decision support tools were not introduced during the study period.We calculated that samples of 200 cases of CAP and 200 cases of UTI admitted to ACH during the baseline and intervention periods would be required to achieve 90% power to detect an absolute 15% improvement in prescriber adherence to antibiotic guidelines at ACH (α = 0.05). We therefore measured guideline adherence in over 200 randomly selected cases of CAP and UTI, during the baseline and intervention periods, at ACH, MMH and NSH/WTH. We then compared changes in levels of guideline adherence at ACH with those at MMH and NSH/WTH to determine whether any changes in prescriber adherence at ACH could confidently be ascribed to the introduction of the SCRIPT app.Patients were excluded if, on review of their records, they were not diagnosed with CAP or UTI during the first 24 hours of their admission; or if their diagnosis was miscoded ; or if they were transferred to the hospital from another secondary care facility where antibiotic treatment had already been initiated.Manual data collection and system level data extraction were used to collect study data. A case report form (CRF) was developed using REDCap  data capture tools hosted at the University of Auckland; two research pharmacists completed a CRF for each randomly selected episode. For patients admitted to ACH, antibiotic details  were collected using the CRF. For patients admitted to the other hospitals, antibiotic data was collected by system level data extraction from the relevant eMedicines systems (ePrescribing and/or Pyxis medicine cabinets). The same system level data extraction methods were used for demographic and admission data . Manual data collection was necessary for clinical data .Data quality was ensured by independent re-collection and review of 10% of the data. Any interpretative uncertainties of clinical data were resolved by review and discussion by at least two study clinicians. For example, a chest X-ray report stating “there is increased air space opacity in the right lower lobe” was interpreted as “consolidation” (pneumonia).The clinician’s diagnosis and other relevant information documented in each case’s notes, during the first 24 hours of their admission, were used to determine whether treatment given during this period was guideline adherent. For cases with an otherwise unspecified diagnosis of “urinary tract infection”, we retrospectively considered all patients with flank pain or hypotension to have had pyelonephritis, and those with neither of these features to have had cystitis .We defined management as adherent if the antibiotic(s) prescribed, and their dose(s) and route(s) of administration, were consistent with the relevant hospital guidelines. Cases that had been prescribed a guideline-adherent antibiotic regimen during the first 24 hours of their admission were considered to be adherent regardless of whether, or not, they had also received other guideline non-adherent regimen(s) (e.g. prescribed by a different clinician) during the first 24 hours.We defined appropriate treatment as any treatment that was neither over-treatment nor under-treatment. We defined over-treatment as prescription of inappropriately broad-spectrum agents. For example, prescription of cefuroxime plus erythromycin for a patient with an admission diagnosis of CAP and a CURB-65 score of 1 was considered overtreatment. We defined under-treatment as prescription of inappropriately narrow-spectrum or ineffective agents. For example, prescription of trimethoprim or nitrofurantoin for a patient with an admission diagnosis of pyelonephritis was considered under-treatment.For cases with a diagnosis of CAP documented in their notes during the first 24 hours of admission, but without a documented CURB-65 score, we calculated the score using the relevant clinical data. For cases without a serum urea result, we calculated the CRB-65 score . ManagemWe used IBM SPSS  version 25 to analyse all data. Continuous variables were reported as medians with interquartile ranges (IQR). Categorical variables were expressed as numbers or percentages. The baseline and intervention period rates of adherence and appropriate treatment were compared with Pearson’s chi-squared test.The guidelines for management of CAP in NSH/WTH depended upon the SMART-COP pneumonia severity score , while tOnly 53 prescribers downloaded SCRIPT during the first month of the intervention period. This number rose gradually to 145 healthcare workers by the end of the study and the respiratory guidelines were the most frequently accessed during the study.The approximate average number of times that SCRIPT guidelines were accessed by each user was 21 in June (1097/53), 12 in July (1366/112) and 11 in August (1522/145). The median time spent using the CAP guideline on SCRIPT was 11 seconds (IQR 7–17) and the median time spent using the UTI guideline was 18 seconds (IQR 12–29).Most of the demographic and clinical features of the CAP cases did not differ significantly between the baseline and intervention cohorts at ACH . HoweverDifferences were apparent between the ACH and MMH CAP cohorts with regard to ethnicity, the presence of consolidation on CXR, the proportion of patients with a clinical diagnosis of pneumonia, the CURB-65 scores, the median length of stay, and the mortality rate . The populations served by these two hospitals differ considerably in terms of socio-economic status, with a higher prevalence of deprivation observed in the MMH population . 160/856p = 0.04). There was a marked increase in adherence in the 59 patients with severe pneumonia (CURB-65 3–5), from 7% in the baseline period to 29% in the intervention period (p = 0.03). There was also a significant increase in the prescription of appropriate treatment at ACH, from 44/199 (22%) during the baseline period to 77/237(32%) during the intervention period (p = 0.02). In contrast, at MMH, there was no change in the rates of guideline adherence  or in the prescription of appropriate treatment  during the intervention period, p = 0.84).37/199 (19%) patients with CAP at ACH were prescribed guideline adherent treatment during the baseline period, and this improved to 64/237 (27%) during the intervention period , reflecting the differences in the populations served by these hospitals . In a toGuideline adherence for patients with UTI at ACH did not change significantly between the baseline period and the intervention period. During the baseline period 98/209 (47%) patients were prescribed guideline adherent treatment and during the intervention period 106/211 (50%) patients were prescribed guideline treatment (p = 0.49). At MMH (95/211 (45%) during the baseline period and 80/201 (40%) during intervention period, p = 0.28) and NSH/WTH (50/211 (24%) during the baseline period and 59/206 (29%) during the intervention period, p = 0.25), there were no significant changes in the rate of guideline adherence between the baseline and intervention periods. Furthermore, there were no significant changes in the prescription of appropriate treatment between the baseline and intervention periods at any of the hospitals.The introduction of the SCRIPT antibiotic guideline app at ACH had a statistically significant, positive impact on prescriber adherence to the ACH antibiotic guidelines in patients with CAP. The rate of antibiotic guideline adherence improved by an absolute value of 8%, a relative increase of 42%, despite relatively slow uptake of the app. Importantly, in CAP, the introduction of SCRIPT was associated with a statistically significant rise in appropriate treatment (reductions in both over-treatment and in under-treatment). Whilst over-treatment with unnecessarily broad-spectrum antibiotics may cause harm by accelerating the development of antibiotic resistance, the potential consequences of under-treatment can be more immediately detrimental to patients. Although the 30-day mortality in the patients with CAP was not significantly reduced during the intervention period, this study was not designed to detect a significant change in patient outcomes, such as 30-day mortality or the rate of hospital readmission; larger studies would be required to answer such questions.Our study is consistent with a recent meta-analysis of antibiotic stewardship measures, which concluded that point-of-care information is beneficial for stewardship . MoreoveOur study is consistent with many others that have shown how difficult it is to change prescriber behaviour –23. The The reasons for the marked difference between CAP and UTI in the rates of guideline adherence are not immediately clear. Low rates of CURB-65 score documentation were paralleled by low rates of documentation of specific UTI diagnoses. The UTI decision tree in SCRIPT has a minimum of six branch points, compared with only three for CAP; this results in more questions and decision points, before the clinician using the app obtains the treatment recommendation. Whilst this was due to the complexity of both establishing the UTI diagnosis and the consideration of other factors , it is difficult to ascertain if this was a deterrent to SCRIPT use as there was little difference in the average time taken to access the SCRIPT recommendation .The frequency of accessing SCRIPT was high in comparison with a study conducted in London, reported by Charani, et al . In thatIn summary we found that the introduction of a smartphone app, that made the ACH antibiotic guidelines readily available to all ACH clinicians, was associated with a statistically significant increase in prescriber adherence to the guidelines in patients with CAP. While it is likely that the full impact of SCRIPT would only be observed after the app has become embedded into clinical practice over a longer time period, our study shows that release of an antibiotic guideline app will lead to almost immediate improvements. However, we also found that, despite high usage of SCRIPT, clinicians very commonly failed to perform those assessments necessary to determine the optimum treatment, most importantly through measuring the severity of illness in patients with CAP (by use of the CURB-65 score) or deciding on the site of infection in patients with a UTI (pyelonephritis or cystitis). Improvements in the care of patients with common infections requires more than making guidelines readily available.SCRIPT has continued to be promoted since the completion of this study, and up to June 2018 there have been over 3000 downloads within ACH. We intend to perform further studies of the temporal changes in the level of prescriber adherence; and the reasons given by clinicians for failure to use the guideline and adhere to its evidence based recommendation.


Migration testing of chloride under an electric field is a fast and effective method to determine the corrosion resistance of reinforced concrete against chloride. In this study, a series of admixture-involved (fly ash and slag) concrete specimens were produced for an accelerating chloride diffusion test in 3% NaCl solution under an electric field and natural chloride diffusion in 165 g/L NaCl solution under immersion conditions. Then, the chloride profile and pore structure of concretes aged 56 and 91 days were compared to investigate the effect of the electric field on chloride diffusion as well as the microstructure of the concrete. The results showed that, under accelerating electric field conditions, the degree to which chloride refined the internal pore structure of the concrete was weaker than that under natural immersion conditions. The applied electric field changed the pore structure inside the concrete, but it had little effect on the distribution of total, free, and bound chlorides and their mutual relationship. In addition, it is necessary to consider that the electric field effect on chloride migration varies with the concrete mix proportions. The corrosion of steel in concrete is primarily due to the ingress of the chloride ion, especially in marine environments . The chlNatural immersion and electric field acceleration are the two experimental methods for studying the migration of chloride ions in concrete ,4,5. ComThe ASTM C1202 experimental method was developed by the American Society for Testing and Materials for the determination of chloride ion penetrability and is widely used owing to its convenience, time savings, and high repeatability . In thisThe chemical compositions of Portland cement, fly ash, and slag are shown in The mortar was agitated following the reported agitation method for high-performance concrete . The agiA rapid chloride permeability test was carried out on the concretes in accordance with ASTM Standard C1202  to accel, and the immersion liquid was agitated and shaken once a week to ensure that the chloride ions diffused uniformly into the concrete.In order to accelerate the chloride ingress, the concentration of NaCl was designed as 165 g/L (mass fraction 14%) as per NT Build 443 . ChloridAfter the rapid chloride permeability test or natural immersion experiment, the concrete was cut using a 2.6 mm diamond saw blade. To reduce the influence of the heat generated by friction during the cutting process on the chloride ions’ distribution, a low-speed dry cutting process was adopted with a cutting speed of 250 rpm. Each specimen was cut from the end contacting the NaCl solution. Each specimen was cut into 6 layers, and each layer had a thickness of 6 mm. Powder samples and bulk samples were collected during the cutting process. The diagrammatic sketch for the cutting process can be seen in 3 solution. The mixture was shaken at 120 rpm for 24 h at 30 °C and then filtered. The concentration of chloride ions in the filtrate was immediately analyzed by titration to obtain the concentration of acid-soluble chloride ions, i.e., the concentration of total chloride ions. The other portion of the powder sample was immersed in 100 mL of distilled water to obtain the concentration of water-soluble chloride ions, i.e., the concentration of free chloride ions. The concentration of bound chloride ions can be calculated by the difference between the concentration of total and free chloride ions.The measurement of the chloride ion concentration was carried out according to the Chinese Standard JTJ 270-98 Testing code of concrete for port and waterway engineering ,21. FourMercury intrusion porosimetry (MIP) was employed to characterize the pore structure. An Autopore IV 9500 from Micromeritics was the device employed. The maximum yield pressure was 227 MPa, which enables the measurement of pore diameters from 1,000,000 nm down to 5 nm. Samples with a diameter of 30 mm and length ranging from 20 mm to 30 mm were fabricated and dried in an oven at 105 °C for 24 h before testing.λ = 1.5406 Å). The maximum angular range of the XRD test conducted in this study was 5 to 90° (2θ), and the final tested range was selected as 10 to 70° (2θ). An accelerating voltage of 40 kV, emission current of 100 mA, and scanning speed of 6 °/min were used.To determine the crystal phase composition of the prepared powders, X-ray diffraction (XRD) measurement  was carried out at room temperature by using a Rigaku D/max diffractometer  with Cu Kα radiation , Shimadzu, Kyoto, Japan). During the experiment, the crucible of alumina pool was used and about 40 mg of sample was filled to the crucible. All the tests were carried out at a heating rate of 10 °C/ min up to 800 °C and a cooling rate of 50 °C/min in a dynamic nitrogen atmosphere.Surface characterization of tested concrete samples was carried out by scanning electron microscopy (SEM) analysis using a SU8020 . Samples with a diameter of 30 mm and length ranging from 20 mm to 30 mm were fabricated. The samples were sprayed with gold in high vacuum. The thickness of the coated layer was about 4 nm. An accelerating voltage of 20 kV was used.Linear, Freundlich, and Langmuir isotherms are commonly used to fit the relationship between the total and free chloride ions ,22,23. TYuan  recognizC is the concentration of total chloride ions in concrete, t is the exposure time of concrete to a chloride ion environment, D is the migration coefficient of chloride ions.Fick’s second law is based on the following three assumptions: (1) The materials are permeable and the internal diffusible medium is homogeneous; (2) there is no chemical reaction, physical absorption, and bonding between materials and the diffused substance; and (3) the diffusion characteristic of materials will not change as the time and concentration vary. The diffusion of chloride ions can be seen to follow Fick’s second law only when the three assumptions mentioned above are satisfied. It is assumed that the migration of chloride ions in concrete under natural immersion conditions is consistent with Fick’s second law  as shownt at a distance, 0C and sC are the initial and surface chloride ion concentrations, respectively; and erf is the error function. The concentration distribution of chloride ions in each group of concrete samples was fitted to Equation (2). The migration time under the electric field acceleration condition was 6 h, and the diffusion coefficient obtained here is the instantaneous value, insD, whereas the migration times under natural immersion conditions were 35 days and 70 days, and the corresponding diffusion coefficient was the apparent value, appD. Both the modeled concentrations and the measured concentrations are compared in Equation (1) can be expressed by Equation (2) with proper initial and boundary conditions, namely, C=0 :(2)C was the instantaneous value, whereas the other one examined in natural immersion conditions (35 or 70 days) was the apparent value. In order to compare these two diffusion coefficients, the apparent diffusion coefficient should be transformed to the instantaneous diffusion coefficient. As the diffusion coefficient decreases as the concrete age increases, a time-variant diffusion coefficient could be determined based on Equation (3) below :(3)DinsThe instantaneous diffusion coefficient, =t2′−t1′ , shown b=t2′−t1′ :(4)Dapp could be transformed to:Based on the equations above, the apparent diffusion coefficient could be transformed to the instantaneous diffusion coefficient. In this regard, for a certain moment, tion (6) :(6)tins′Based on the calculated 2O3 content than ordinary Portland cement, more hydrated aluminate products are formed in fly ash and slag containing concrete to strengthen the solidification of chloride ions, thus decreasing the diffusion rate [2 incorporated in both fly ash and slag could react with the portlandite (CH) produced by cement hydration to form more C-S-H gel , enhancing the physical adsorbability of concrete to chloride ions and refining the internal porosity as well [ion rate ,33. Furt as well . Hence, The pores in concrete are usually classified into three types: Harmful pores (diameter > 50 nm), less harmful pores (20 nm ≤ diameter ≤ 50 nm), and harmless pores (diameter < 20 nm) . Pore-siAs shown in In addition, as shown in 3A in concrete. This product has a large volume and can refine the pore structure of concrete [Many studies have shown  that aftconcrete ,13. TherAs shown by the analysis results of the chloride ion concentrations in 2O3 content, into ordinary concrete can form more aluminate hydration products, making it more likely that Friedel’s salt will form between the aluminate hydration products and the chloride ions. Fly ash is higher than slag in Al2O3 content, and both are higher than ordinary Portland cement. Therefore, when placed under the same conditions of electric field acceleration, fly ash concrete has a higher probability of forming Friedel’s salt than slag concrete, and both have a higher probability than ordinary concrete. Under natural immersion conditions, given the high chloride ion concentration in the solution and the long contact time with the aluminate hydration product, a higher Friedel’s salt content can be formed in concrete with various mix proportions [The addition of fly ash and slag, both containing a higher Alportions ,22, leadportions . Besidesportions . TherefoR, as per Equation (7). The results are shown in m0 is the area proportion of CH or Friedel’s salt peak registered by the reference group, P-N; m1 indicates the area proportion of CH or Friedel’s salt peak comprised of each examined group (P-E/F-N/F-E/G-N/G-E). The DTG curve was obtained by taking the derivative of the tested thermalgravimetric profile, and the various peaks represented the mass variation in terms of each hydrated product right before and after the thermal decomposition. The mass loss of the examined hydrated product could be determined by calculating the peak area. Eventually, together with the total mass, the mass percentage of each hydrated product was therefore determined—see X-ray diffraction, differential thermogravimetric analysis (DTG), and scanning electron microscopy (SEM) measurements were performed on the 91-day concrete samples treated with two conditions of chloride ion migration, and the measurement results are shown in - or as Kezul’s salt) [As shown in both ’s salt) . Therefo3A. Moreover, the low chloride ion concentration in the immersion solution under accelerating electric field conditions is not conducive to the formation of Friedel’s salt [Again, the peak intensity, sharpness, and area of Friedel’s salt were much lower under electric field, indicating a worse crystallinity. In addition, some peaks around the peak of Friedel’s salt might belong to Kezul’s salt  ,41. Thisl’s salt ,22,42. Tl’s salt ,44, whicl’s salt ,45, resul’s salt ,41. BesiSeen from the XRD and DTG results, for both fly ash and slag, the corresponding samples aged for 91 days registered a lower CH content as compared to ordinary concrete, and this should mainly be attributed to the pozzolanic activity. Besides, the electric field was found to have the potential to yield the dissolution of CH and Friedel’s salt, leading to a negative influence on the compactness of the pore structure of concrete. However, the pore structure was refined in the presence of fly ash and slag due to the formation of C-S-H gel through pozzolanic reactions. Furthermore, the dissolution of CH under the electric field may cause less of an effect on the pore structure than ordinary concrete, because a part of CH has already been consumed to form C-S-H gel prior to dissolution.3A is hexagonal with a size below 1 μm and is smaller than Friedel’s salt [3A, making it difficult to identify. This is mainly because, under electric field conditions, chloride ions take a short time to react with C3A hydration products, making the formed Friedel’s salt small in size and dispersed in distribution. Moreover, the chloride ion concentration is low, which is not conducive to the formation of Friedel’s salt and may even result in the dissolution of Friedel’s salt to form Kezul’s salt [3A hydration products, which facilitates the formation of large flake-shaped Friedel’s salt. Moreover, the chloride ion concentration is high, which is beneficial to the growth of Friedel’s salt and prevents it from dissolving [l’s salt , it is dl’s salt . This col’s salt . In contssolving ,41. Ther(1)Chloride ion ingress into concrete can change the pore structure of the concrete. Compared with accelerating electric field conditions, chloride ions provide a greater degree of pore-structure refinement in concrete under natural immersion conditions.(2)Whether under natural immersion conditions or under accelerating electric field conditions, the concentrations of total chloride ions have a significant linear relationship with those of free chloride ions and those of bound chloride ions. The applied electric field changes the concentration of chloride ions migrating into the concrete and their ingress rate, thereby changing the morphology and crystallinity of Friedel’s salt. However, the electric field has little effect on the distribution of total, free, and bound chloride ions and their mutual relationship.(3)The concentration distribution of chloride ions in concrete under accelerating electric field conditions can be fitted as per Fick’s second law. The electric field has varying degrees of an accelerating effect on chloride ion migration in concrete with different mix proportions. In particular, the accelerating effect is greater in ordinary concrete than in slag concrete and is weakest in fly ash concrete. This was mainly attributed to the fact that the electric field results in the dissolution of CH and Friedel’s salt, leading to a negative effect on the compactness of the pore structure of concrete. However, the pore structure is refined in the presence of fly ash and slag due to the formation of C-S-H gel through pozzolanic reactions. Furthermore, the dissolution of CH under an electric field may have less of an effect on the pore structure than ordinary concrete, because a part of CH has already been consumed to form C-S-H gel prior to dissolution. Therefore, when evaluating concrete durability by accelerating chloride ion migration under an electric field, it is necessary to consider the varying degrees of the electric field effect on chloride ion migration in concrete with different mix proportions.The distribution law of chloride ions and microstructural characteristics in concrete treated with two types of migration conditions, electric field conditions versus natural immersion conditions, were compared, giving insight into the effects of different chloride migration modes on the distribution law and microstructural characteristics. The main conclusions are as follows:


Recent research implicates antibiotic use as a potential contributor to child obesity risk. In this narrative review, we examine current observational evidence on the relation between antibiotic use in early childhood and subsequent measures of child body mass.We searched PubMed, Web of Science and the Cochrane Library to identify studies that assessed antibiotic exposure before 3 years of age and subsequent measures of body mass or risk of overweight or obesity in childhood.N = 2 60 556; maximum overall aOR reported: 2.56, 95% CI 1.36–4.79, N = 616], with no clinically meaningful increases in weight reported (maximum increase: 1.50 kg at 15 years of age). Notable methodological differences between studies, including variable measures of association and inclusion of confounders, limited more comprehensive interpretations.We identified 13 studies published before October 2017, based on a total of 6 81 332 individuals, which examined the relation between early life antibiotic exposure and measures of child body mass. Most studies did not appropriately account for confounding by indication for antibiotic use. Overall, we found no consistent and conclusive evidence of associations between early life antibiotic use and later child body mass [minimum overall adjusted odds ratio (aOR) reported: 1.01, 95% confidence interval (95% CI) 0.98–1.04, Evidence to date is insufficient to indicate that antibiotic use is an important risk factor for child obesity, or leads to clinically important differences in weight. Further comparable studies using routine clinical data may help clarify this association. Child obesity is a public-health issue of increasing global concern. In 2013, the age-standardised prevalence of overweight and obesity among children and adolescents aged <20 years was estimated to be 23.8% and 22.6% in high-income countries, and 12.9% and 13.4% in low- and middle-income countries, among boys and girls, respectively  . Five stSex-specific differences in susceptibility to infections and in drug pharmacokinetics have been previously observed in humans –42. PoteData from animal models suggest that earlier antibiotic exposure may have the capacity to more notably alter the intestinal microbiome, inducing metabolic changes leading to increased adiposity . Similarp for linear trend >0.1 in all cases; Increased exposure to antibiotics in early life through repeated courses may be expected to result in more pronounced alterations in the intestinal microbiome, with potentially greater metabolic effects. The existence of a dose-dependent relationship between antibiotic use and childhood obesity risk would therefore be important to examine. Seven studies assessed the relation between the number of antibiotic courses and measures of child body mass –31, 33  define all exposures and outcomes, including their respective time windows, consistently with previous studies, (ii) consider using multiple analytic methods as employed in previous research and (iii) control for all confounding factors included in previous studies, including accounting for confounding by indication. As stronger evidence emerges regarding the characterisation and contribution of related measures in childhood, such as waist circumference, to future disease risk, studies may also consider such measures as potentially important outcomes , 47. GivThe evidence reviewed here is insufficient to justify the risk of child obesity as an important reason to limit antibiotic use. However, multiple other reasons exist for improving monitoring and management of antibiotic use, including the development of antibiotic resistance. The importance of antibiotic stewardship programmes to achieve appropriate use of antibiotics is increasingly being recognised, with recent evidence suggesting notable effects of such initiatives on overall antibiotic use, infection incidence and other patient outcomes in hospitals –50. The We followed a systematic literature search and selection method to identify all relevant studies investigating the relation between early life antibiotic use and child obesity, and present here a detailed qualitative synthesis of identified studies. However, certain limitations must be considered. We included only English language publications in our search, and are unable to rule out publication bias, although the presence of such bias would support our interpretation of the current evidence. The inability to quantitatively synthesise effect estimates limits our ability to present more definitive conclusions, and points towards the need for more harmonised methods to assess this association. Finally, this review examined only exposure to antibiotics for medical use, and did not capture potential exposure through other methods, such as low-dose antibiotics present in food. Although this has been recognised as a potentially important source of exposure , 53, fewIn this review, we observed no robust evidence implicating antibiotic use as an important risk factor for child obesity, with notable heterogeneity among studies limiting more conclusive interpretations. Further more detailed, comparable studies are required to clearly determine the existence of such associations. Regardless, there is a well-justified need to achieve more appropriate use of antibiotics . Further