Antibiotic resistance is a major contributing factor to global morbidity and mortality and is associated with inappropriate medication use. However, the level of antibiotic consumption and knowledge about antibiotic resistance in Ghana is inadequately quantified. Our study identifies strategies for improved stewardship of antibiotics to prevent the proliferation of resistant pathogens by assessing the level of antibiotic knowledge, attitudes, and consumption behaviors by region, gender, age, and education in rural and urban Ghana.A cross-sectional study was conducted in 12 communities in the urban Greater Accra and rural Upper West regions of Ghana. A questionnaire survey was administered to 400 individuals aged 18 years and older in selected locations during September–October 2018 to collect data on individual knowledge, attitudes, and practices concerning antibiotics and antibiotic resistance. Multivariate analysis was used to investigate the association between demographic characteristics and knowledge, attitudes, and related behaviors.Amoxicillin, Amoxicillin-clavulanic acid, Ampicillin, Ciprofloxacin, and Metronidazole. Women and older adults had higher knowledge compared to their respective counterparts (p < 0.01). Furthermore, prudent antibiotic use was significantly more prevalent in women than men (p < 0.05). Although no regional differences were found in overall knowledge, compared to urban residents, individuals residing in rural settings exhibited higher knowledge about the ineffectiveness of antibiotics for viruses like the cold and HIV/AIDS (p < 0.001). Two hundred and fifty-two (63%) respondents were unaware of antibiotic resistance. There was generally a low level of self-efficacy among participants regarding their role in preserving the effectiveness of antibiotics.Over 30% (125/400) had not received a doctor’s prescription during their last illness. Seventy percent (278/400) had taken at least one antibiotic in the year prior to the survey. The top five frequently used antibiotics were Antibiotic knowledge, attitudes, and use varied significantly across demographics, suggesting a context-specific approach to developing effective community interventions. Resistance of bacterial pathogens to standard antibiotic therapy is a major component of the broader emergence of the Antimicrobial Resistance (AMR) menace that is threatening gains made over the past century to curb the global burden of disease, particularly in Africa –4. AlthoThe AMR challenge is further exacerbated by globalization and an increase in transnational travel and trade which inevitably create opportunities for the rapid spread of infectious pathogens , 10. RecWhile drug resistance is the product of multiple, systemic processes, one of the most common determinants is individuals’ compliance to prescriptions and prudent use, and hence introduces a behavior change requirement –19. StudGhana has a population of about 30 million, of which 54.8% is urban . Life exAntibiotic Resistance: Multi-Country Public Awareness Survey, developed and validated by the World Health Organization (WHO) [We adapted the on (WHO) . The orion (WHO) . To incrIt’s ok to use antibiotics that were given to a friend or family member, as long as they were used to treat the same illness”; Question: “It’s ok to buy the same antibiotics, or request these from a doctor if you’re sick and they helped you get better when you had the same symptoms.” Response: True/False/I don’t know. The outcome ranged from 0 to 21, with a higher score indicating better knowledge. Attitudes was defined on a Likert scale and determined whether a person agreed strongly, agreed slightly, neither agreed nor disagreed, disagreed slightly, or disagreed strongly with a set of six statements regarding one’s perceptions about actions to reduce antibiotic resistance. An average score was determined, ranging from 1 to 5. The final dependent variable, Practices, was based on a total score for three items that assessed appropriate use of antibiotics. For example, Question: “On that occasion did you get the antibiotics (prescription) from a doctor?”; Question: “On that occasion did you get advice from a doctor, nurse, or pharmacist on how to take them?” Response: Yes/No/Cannot remember. We made a similar decision for Practices as for Knowledge, where any response other than the correct was considered incorrect. Antibiotic use (Practices) was defined appropriate only if one correctly answered all three questions, and inappropriate if otherwise.Three outcomes were examined- Knowledge, Attitudes, and Practices. Knowledge was examined based on the number of correct responses to ten questions regarding different infections that could be treated with antibiotics, three questions relating to knowledge about prudent use of antibiotics, and eight questions about antibiotic resistance. For example, Question: “We selected four main independent variables to include in our analysis; place of residence/region , gender , education ), and age . This was based on similar KAP studies which found significance for these variables , 23, 31..1.We first examined several of the individual items for the Knowledge, Attitudes, and Practices outcome variables separately to understand the percent breakdown in our overall sample. Then we looked at the differences in responses to individual items by region, gender, age, and education using Chi-square and unadjusted regression analyses. We conducted three regression models to examine differences in Knowledge, Attitudes, and Practices scores by the demographic characteristics of interest , starting with unadjusted models, followed by multivariate analysis using ordinary least squared regression models for the Knowledge and Attitudes outcomes, and logistic regression for the Practices outcome to derive estimates net of other covariates. We retained the same independent variables in all models. Data were analyzed using Stata/SE 15n = 400) had an equal representation from both regions, with 26 (6.5%) more male respondents than female. Over half of the participants were between the ages of 18 and 34 years. Two-hundred and nineteen (55%) had received a university degree or were currently enrolled in one. In comparison with the UWR, the GAR had 56 more residents who had at least a senior high or vocational school degree. Further, more than twice as many women than men had no formal education; 28 (15%) women compared to 11 (5%) men.Table Figure p < 0.01; 95% CI: 0.12–0.50) (Table p < 0.001). However, we found no effect of place of residence on overall knowledge.Generally, bivariate and multivariate results were comparable, with significant differences observed for gender and age. Women had 0.31 points higher on the Knowledge scale compared to men  compared to the referent primary/lower education group.Table Amoxicillin, Amoxicillin-clavulanic acid, Ampicillin, Ciprofloxacin, and Metronidazole.In the last year prior to the survey, 132 (66%) and 146 (73%) of GAR and UWR residents, respectively, had taken at least one antibiotic. Of these, more men than women reported taking antibiotics. Further, 275 (69%) received a doctor’s prescription, while 95 (24%) assumed it was alright to share antibiotics with friends and family. The majority of participants without a doctor’s prescription purchased antibiotics from a pharmacy . Moreover, some individuals had used more than one type of antibiotic, with one respondent taking up to five antibiotics during their last illness. The top five frequently used antibiotics were p < 0.05; 95% CI:(1.19–4.90) .Among individuals aged 18–34 years, more residents of the GAR than UWR reported prudent antibiotic use Fig. . Also, bMost study participants acknowledged the importance of using antibiotics only prescribed by a doctor. However, not all participants received a prescription during their last illness, which suggests that knowledge does not necessarily translate to good practice. This finding underscores the challenge of changing human behavior and suggests the need for new approaches to promote better stewardship of antibiotics at the community level. Similar to previous studies , 31, 32,The absence of an association between place of residence and overall knowledge could be attributed to the fact that although the UWR is predominantly rural, its capital town, Wa, may exhibit some urban characteristics in comparison to the rest of the region. Hence, surveying other communities beyond the Wa vicinity may yield differences. Nonetheless, we did find significance in terms of individual items regarding knowledge about infections that did not require antibiotic therapy Fig. ; residenThe average Attitudes score of over 4.39 out of 5 suggests that, overall, individuals had a positive perception about important steps to reduce the spread of antibiotic-resistant pathogens. However, the large number of participants who believed there was not much they could do to stop antibiotic resistance reflects low self-efficacy and calls for tailored approaches to reach the public. Compared to individuals with only a primary education or lower, persons with a tertiary education showed more positive attitudes towards actions to reduce antibiotic resistance, reiterating the need to reach the most vulnerable. Continuous public awareness remains paramount, given that many were unaware about their role in alleviating resistance despite adequate understanding of the importance of using antibiotics prudently.Amoxicillin, Ciprofloxacin, and Metronidazole. Likewise, Amoxicillin and Ampicillin were among the most frequently used antibiotics consumed by tertiary students in Ghana [An important aspect of the original study which our survey sought to further develop was to identify a list of frequently used antibiotics by the public. We found our list to be similar to that of Versporten and colleagues  who repoin Ghana . It is win Ghana ; hence, p < 0.05; 95% CI: 1.04–2.48).Our results also shed light on the problematic issue of self-medication and access to antibiotics without prescription , 22. AboOur study has several strengths. This is the first extensive survey conducted in the Greater Accra and Upper West regions of Ghana to examine public use of antibiotics, as well as the level of knowledge and attitudes towards antibiotic resistance. We enhanced the original survey instrument by inquiring about specific antibiotics used during the last time of infection. In addition, our study provided a snapshot of both the rural-north and urban-south settings, allowing for more tailored interventions. Still, our study has some limitations. First, the study included residents from two regions, hence, findings are not generalizable to the rest of the country. Nonetheless, our sample composition was found to be comparable with Ghana’s DHS  data in To the best of our knowledge, this study is the first to compare antibiotic knowledge, attitudes, and practices in diverse population groups within both the rural northern and urban southern regions, while identifying specific types of antibiotics frequently used. Our study sheds light on the need to create targeted health interventions particularly for younger individuals and the male population, given the prevalence of low knowledge and inappropriate antibiotic use in these groups. For instance, women may be more likely to access healthcare facilities given their role as caretakers, which may have explained the higher level of knowledge observed in this group. We therefore propose expansion of sustained public educational programs. As indicated by our findings, participants who had heard of the WAAW campaign exhibited better knowledge about antibiotic resistance. We also suggest that further studies be conducted to explore the reasons for non-compliance despite one’s knowledge about appropriate behavior. Another important factor worth examining is the influence of community pharmacists and doctors given their pertinent role as dispensers. In addition, we found low levels of self-efficacy among participants regarding their ability to contribute to the reduction of antibiotic resistance. Hence, community health interventions would benefit from incorporating relatable and applicable strategies that can be easily adopted by individuals. One of the strategic objectives of Ghana’s five-year NAP is to educate the public on responsible use of antimicrobials, with related activities currently set for 2018–19. Extending efforts through subsequent years would be helpful to ensure individuals receive consistent and up-to-date health information.


Antibiotic misuse and other types of unnecessary use of antibiotics can contribute to accelerate the process of antibiotic resistance, which is considered a global concern, mostly affecting low-and middle-income countries (LMICs). In Mozambique there is limited evidence on community knowledge and practices regarding antibiotics and antibiotic resistance. As part of the ABACUS project, this paper describes knowledge and practices of antibiotic use among the general population in the semi-rural district of Manhiça to inform evidence-based communication intervention strategies for safer antibiotic use.The study was conducted in Manhiça, a semi-rural district of Southern Mozambique. Sixteen in-depth interviews and four focus group discussions (FGDs) were conducted with community members to explore lay knowledge and practices regarding antibiotics and awareness of antibiotic resistance. The qualitative data was analysed using a combination of content and thematic analysis. The SRQR guidelines for reporting qualitative studies was performed.Although participants did not hold any consistent knowledge of antibiotics, their visual recognition of amoxicillin (distinct red yellow capsule) was acceptable, but less so for different types and brands of antibiotics. The majority of participants were aware of the term ‘antibiotic’, yet the definition they gave was rarely backed by biomedical knowledge. Participants associated antibiotics with certain colours, shapes and health conditions. Participants reported common habits that may contribute to resistance: not buying the full course, self-medication, sharing medicines and interruption of treatment. Most had never heard of the term ‘antibiotic resistance’ but were familiar with the phenomenon. They often understood the term ‘resistance’ as treatment failure and likened ‘resistance’ to non-compliance, ineffective medication, disease resistance or to an inability of the physical body to respond to it.There is a broad understanding of the importance of medication compliance but not specifically of antibiotic resistance. In addition, there is a recognized gap between knowledge of responsible drug compliance and actual behaviour. Future qualitative research is required to further explore what determines this behaviour. The existing ability to visually identify amoxicillin by its distinct red and yellow appearance is informative for future awareness and behavioural change campaigns that may incorporate visual aids of antibiotics. Antimicrobial resistance (AMR) is considered a global public health problem particularly affecting low- and middle-income countries (LMICs) , 2. The The factors determining use of antibiotics from the demand side are influenced by several aspects, including: consumers’ lack of knowledge about appropriate antibiotic use and its implications, as well as beliefs, expectations and personal experiences with antibiotics , 8–17.Although the evidence of absolute consumption of antibiotics is most numerous in high-income regions, such as Europe, antibiotic consumption is growing the fastest in LMICs . In addiIn the case of Mozambique, besides the inexistence of specific antibiotic regulation, the “Medicines law”  defines The limited evidence presented thus far suggests that there is much to be done with regards to understanding and addressing both the supply and demand-driven factors that determine inappropriate antibiotic use, yet it is precisely in such contexts where regulations are not enforced that the knowledge of the general public (the demand side) can play an important role in the reduction of inappropriate use of antibiotics , 19, 31.Awareness studies that evaluate lay knowledge of antibiotics and the factors underlying the unsafe use of antibiotics are considered crucial in order to inform efforts to improve community understanding and best practices in low-resource countries . KnowledThere is limited qualitative research published to date regarding community knowledge of antibiotics or antibiotic resistance and practices regarding antibiotic use in Mozambique, especially with regards to rural areas. This study was designed to address this knowledge gap. The objective of the study was to use a bottom-up approach to describe different dimensions of community knowledge of antibiotics and practices regarding antibiotic use in Mozambique from the perspective of community members so as to provide much-needed empirical evidence for message development and positioning in the context of information, education and communication (IEC) strategies to improve appropriate use of antibiotics.This paper is based on analysis drawn from an observational mixed-methods multi-country study – the ABACUS study (Antibiotic Access and Use). ABACUS investigated ‘community-level antibiotic access and use in 6 LMICs  in order to inform the design of, and identify targets for, community-based interventions serving to promote appropriate antibiotic use . The qua2 and located ~90Km from Maputo, the capital city of Mozambique. The study was implemented by the Manhiça Health Research Centre (CISM), which runs a Health and Demographic Surveillance System (HDSS) covering a population of 198,000 inhabitants registered as permanent residents and distributed across 44,000 households. Within the HDSS study area there are 12 health centres and two hospitals; the Manhiça District Hospital (MDH) and Xinavane Rural Hospital  has been a municipality since 1998. The majority of the population lives in rural areas and most are engaged in subsistence farming, labour work in sugar cane plantations and sugar refining companies, and small-scale businesses. The population is mainly from the Xironga and Xichangana ethnic groups. Nearly half of all women (47%) and a quarter of all men (24%) are illiterate . The stuIn Mozambique, four focus group discussions (FGDs) and 16 In-depth interviews (IDIs) were conducted between April and May 2017. The use of IDIs and FGDs was purposively chosen for this analysis in order to gain an in-depth understanding of the topic through triangulation. The IDIs and FGDs were conducted by two trained social science research assistants with a combination of medical and social science backgrounds to ensure a good balance between the capacity to engage in in-depth discussions on social behavioural aspects and being familiar with the biomedical implications of the topics of interest.. These interviews were conducted one-on-one with community members that included mothers of children under 5 years old as well other adult male and female participants (aged > 18) regardless of parenthood status , a non-steroidal anti-inflammatory drug ‘Ibuprofen’ (circular red tablet without slot), and an antibiotic ‘Amoxicillin’ , Metronidazole (circular yellow tablet with slot), Co-trimoxazole (circular white tablet with slot), Erythromycin (capsule with red and yellow lids) and Azithromycin (capsules with white lids). If antibiotics were recognized, participants were asked whether they or their relatives had ever obtained the antibiotics and the conditions they aimed to treat.This technique allowed the interviewers to maintain the privacy and confidentially of the participants and allowed them to comfortably express their opinions, knowledges, experiances, and practices regarding antibiotics in detail without the pressure of a group . These is aged > 8 regardlaccess to treatment; suppliers of medicines; knowledge and practices regarding antibiotics; and antibiotic resistance. The first two sections consisted of open-ended questions. The third section started with an open-ended question about knowledge of antibiotics supported by the use of show-cards to assess the recognition of five antibiotics (the same exercise conducted in the IDI). For the fourth section, the guide contained a hypothetical case scenario illustrating a concrete case of resistance upon which participants were encouraged to react, comment and discuss. Finally, participants were asked if they had ever heard of antibiotic resistance, its causes and implications.The focus group discussions generated discussions and debates about the topic discussed at hand from participant’s own views . Each diDifferent groups were selected through stratified random sampling covering the 4 administrative posts. The IDIs participants consisted of 8 mothers of children under 5 years of age, and a group of non-parents: two females and two males ≥18 and < 60 years old and two females and two males ≥60 years old. For the selection of this target group, stratified random sampling was applied whereby two participants that met the criteria were randomly selected from each Administrative Post based on the HDSS database. The FGDs participants were also selected through stratified random sampling, however this time sampling was based on age and gender and did not require a proportional distribution amongst Administrative Posts.The FGD sampling frame encompassed all individuals registered in the HDSS with study specific inclusion criteria. The study intended to convey four distinct groups of participants, namely: Females ≥18 and < 30 years old, Males ≥18 and < 30 years old, Females ≥30 years old and Males ≥30 years old. Each target group was randomly matched to one of the four Administrative Posts  carried out quality control by checking the audio with the transcription to identify and then amend any error that emerged. In addition, a matrix was designed, where the rows represented the reference of the participant and the columns the questions addressed  or in Portuguese  depending on participants’ preference and were audio-recorded using digital voice recorders. Recorded data was archived in digital format and was transcribed analysis  began byanalysis , particuanalysis . The preanalysis ., followed by administrative approval by the Mozambican Ministry of Health . All participants were de-identified by only linking them to their DSS unique identification numbers to guarantee confidentiality.All data collection was conducted after obtaining voluntary, signed informed consent from each participant, as well as permission to record individual interviews and group discussions. Ethical approval for the study was obtained from CISM’s Institutional Review Board The results are presented in descriptive format under four major themes extracted from the IDIs and FGDs: (i) General knowledge of antibiotics; (ii) Visual recognition of antibiotics; (iii) Antibiotic use; (iv) Awareness of antibiotic resistance. Quotes from the respondents within each category are presented to illustrate the findings.n = 5), between 30 and 59 (n = 6) and over 60 years (n = 5). With regards to education, 5 participants had received no education, and the remaining 9 participants did not completed secondary school and 2 did not respond. Of these respondents 9 were literate and 5 illiterate. Domestic workers and farmers made up the majority of participants occupations (n = 6 and n = 7 respectively)  adult females younger than 30, 2) adult females older than 30, 3) adult males younger than 30 and 4) adult males older than 30 Antibiotics, well I have only heard the name. They are normally for pains like, STDs, wounds … you see? Things like that is my understanding. When questioned about the usage of antibiotics, the majority of the participants that had heard of the term were able to indicate the conditions they perceived to be treated by antibiotics, which were: malaria, infections, sexually transmitted diseases, tuberculosis, cough, fever, body pain, stomach pain, wounds and pain in the uterus, wounds, toothache, headache, illnesses related to the bones, rheumatism, dermatological problems, foot ailments, constipation, dysentery, and mouth defects. The vast majority of the participants in this study cited more than one condition perceived to be treatable by antibiotics.I am not really sure, I only know there are pills that tackle infections, but knowing that this is an antibiotic, that that is an antibiotic … I do not know the qualities of the pills. The remaining participants that had also heard of antibiotics were not able to describe them in any sense and claimed they did not know what they were for. Although the majority of participants understood antibiotics as medicines, it should be pointed out that one participant understood antibiotics as a disease and claimed to have never heard of antibiotics because he never got ill.The perceived definition and purpose of antibiotics was further captured through three close-ended questions. When asked what antibiotics were, with the intention to lead participants to talk about their purpose, there were mixed responses, with some of the respondents reporting that they did not know what antibiotics were, while a few participants responded that antibiotics were drugs against infection and others thought that they were drugs that served to combat high blood pressure. Furthermore, the majority of respondents reported that they did not know what antibiotics do, while only a small minority stated that they kill bacteria. In response to a question surrounding antibiotic usage, most of the respondents said they did not know what antibiotics should be used for, whilst few answered that they should be taken to treat bladder infections, muscle pain or weakness.It is important to note that none of the respondents of the three closed-ended questions provided consistently -sound answers, meaning that even those that did provide a correct answer, then gave a contradicting answer to the following question. For example, of the two participants that correctly indicated that antibiotics are used to kill bacteria, both went on to give wrong answers to other questions related to knowledge and purpose of antibiotics. These responses therefore indicate inconsistency in participants’ understanding of antibiotics, with each seeming to answer each question arbitrarily , and others pointed to the picture of Paracetamol  and colours (red and yellow). Among those who initially responded that they had not heard of antibiotics, the majority did not visually identify antibiotics, however a few correctly did identify them.When the second show-card with photos of five different antibiotics was displayed , none of the participants recognised all five as antibiotics. The vast majority visually recognized 1–3 of the antibiotics, with Amoxicillin being repeatedly the most frequently recognised. To most of them, the basis for the recognition of any antibiotic was their own, or their relatives’, experience of acquiring and using antibiotics , led patients to resort to private pharmacies, which are less affordable. As a result, patients did not purchase the full course. Therefore, medicines being out of stock and lack of money were reported as factors resulting in purchasing an incomplete course of treatment.Some participants acknowledged that self-medication is a common practice, particularly with over-the-counter medication, such as ‘Paracetamol’. They explained that sometimes one might simply have a headache which, in their view, does not require going to the hospital. Participants also mentioned cold or flu and stomach-ache as conditions not requiring hospital assistance and suitable for home treatment. However they did not specify the type of medication used in this instance therefore antibiotics could be one of the choices since participants used the terms antibiotic and Paracetamol interchangeably when asked about their self-medicating practices regarding antibiotics. Again, this suggests that the term ‘antibiotic’ may have been used among participants to describe drugs in general, rather than just antibiotic drugs.I won’t deny it, sometimes I also do that [laughter], I take pills and when I see I am better, especially if the pills are bitter, I stop taking them, I quit. When asked about in-depth adherence, participants recognized the importance of taking the full course of medications and finalizing treatment as instructed. Few respondents reported quitting the medication before the prescribed treatment was completed. However, they claimed it was important that the patient felt good before they did so. Only one participant stated they stopped due to the “bitterness” of the drug. Participants generally perceive that the health care provider plays an important role in advising on treatment compliance.Yes, I buy it to take it until it finishes [but] when there is some left and I already feel good, I keep it to take [it] again. Participants unanimously denied that they buy a larger amount of medicines than those prescribed . However, the majority of participants eventually disclosed that they do recurrently store medicines for future use. According to them, there are some medicines that health providers often recommend, which can be dispensed in excess because the pre-packaged amount of drugs within one unit (e.g. a blister pack of tablets) often exceeds the maximum amount prescribed. In those instances, participants referred that they keep them in case themselves or relatives present the same symptoms or disease. Leftover medicines are perceived to be mostly due to interrupted medication rather than purchasing drugs in excess.I keep them so that if I become ill again, if I have them I take them … if when I take them they do not have the same effect, [if] I feel I do not get better even taking them [stored medication] then I go to the hospital. It was noticed that those participants who do keep medicines for future use claim to only take them if it is within the expiration date. The expiration date was mentioned as important criteria to consider when taking medicines stored at home. Interestingly, most of the respondents reported that it is common practice to first take the medicines at hand and only after seek attention at the hospital.Despite the suggestion that in this setting there is a practice of storing medicines for future use, most participants claimed that they do not share with, nor receive medicines from, others, mainly because they cannot tell whether the disease or condition to be treated is the same. The need to go to the hospital for adequate diagnosis and receive the appropriate medicines was repeatedly emphasized.Here at home we are all siblings, we all have children [so] when they have [medication] or I also have and my son also starts with it [symptoms], they give me and I make him take it. Yet some participants did disclose that sharing medication is a common practice and that they are used to share with, and receive medicines from, others, in particular relatives and other household members.They identified two cases in which sharing medication is justified: compatible symptoms and conditions perceived as non-threatening. Regarding compatible symptoms, this referred to cases in which medication was shared because the receiving person had symptoms similar to those for which the medication had originally been prescribed and used. On the other hand, participants argued that some non-threatening conditions, such as headaches, could be treated with stored medication that did not require prescription.When there are left-overs [medication], those from the hospital, we say those are no longer useful so we throw them away because then when you go take them they can make you ill, even die, because it is rotten. Participants who claimed not to store medicines for future use revealed the habit of throwing away the remaining medicines or, in a few cases, of returning them to the hospital. One important factor mentioned was that if the medicine expired it could cause other diseases or even death, besides being potentially dangerous for children’s health in the event of unsupervised consumption.When asked directly if they had heard of antibiotic resistance, respondents consistently stated that they had never heard of the term. Amongst the few that did recognize it, it was argued that antibiotic resistance happens when either the disease or the body resists the effects of the medication.The hypothetical case scenario featuring a patient seeking medical care at a hospital helped probe further participants’ perceptions of the phenomenon. When presented with this scenario, the majority of participants were familiar with the illustrated phenomenon, even if they could not attribute a specific name to it.Hypothetical case scenario:“A person living in this community had a certain health condition. He went to the hospital and was given some the most appropriate medication for his condition. He took the full course of the medicine but he did not feel better. A few days later he went to another hospital for the same condition and he was given the same medicine that he was given at the first hospital. Once again, he took the full course of the medicine as the doctor instructed and still did not feel better.”Overall, they discussed a variety of factors that could be causing the treatment to fail repeatedly, which branched into four overarching categories: 1) behavioural, 2) physiological, 3) pharmacological and 4) pathological.Participants were aware of the risk of treatment failure and they understood that one of the main factors behind this was sub-optimal adherence. They expressed doubts about the extent to which what other people report in terms of adherence correlates with what they do in practice, and felt that it is a common practice not to adhere with the medical prescription provided, even if a patient claims to do so. Therefore, even though the presented scenario described a case in which adherence was practiced, most of the discussions revolved around the failure to do so as a crucial factor leading to treatment failure. Sub-optimal adherence was understood as not observing the prescribed duration of the treatment, and not adhering to requirements such as avoiding alcoholic drinks and respecting the validity date.“this disease will stay with the person forever, even if she takes medication correctly”. .Along the same lines, in the context of treatment success, participants recognised the importance of observing the treatment timeframe and mentioned “interruption of treatment”, specifically as soon as symptoms decrease or disappear, as a behaviour that can lead to treatment failure. Taking medications on an empty stomach was also mentioned as a factor compromising treatment efficacy, manifested by the patient not getting better or being subject to additional health problems, even if the medicine is taken as prescribed. According to one participant, I would seek the prescription first at the doctor [isn’t it?]... An authorized person, so they could dictate [give orientation] it to me properly because if I go to buy I will not know how to use ... I will use it recklessly I will create more problems than those [laughs] I had. When asked about the most appropriate conduct, respondents recognised the hospital as the source of correct treatment and emphasized the need to comply with the treatment in order to avoid treatment failure.But this is not the issue, that the pills are of poor quality, that they don’t work, no, they do work but it depends on each person’s organism. Despite the fact that behavioural factors were the most cited, one group  considered that the problem illustrated in the hypothetical scenario was not behavioural but rather related to the individual’s body. In addition, participants understand that each body reacts differently, that there are particular individual characteristics  that lead to resistance.p (≥30 years), perceived the cause of the resistance to treatment to be rooted in the medication itself. These participants considered that, in some cases, the medications they are given are ineffective and are the origin of treatment failure. In this sense, the treatment itself is considered the source of its failure.We had those pills they called Rosoquina, Rosoquininas, that did not do us good because when one took them, often, it would cause an itch and it would seem like one was cured even though they had not worked. After discussing the hypothetical scenario, a few participants in the male grouThis is what causes the person to die, take the medicines, pick up those diseases that are resisting, they don’t go away, at last [you] die, [while] taking those antibiotic tablets, the ones they say that they are Amoxilina (Amoxicillin). One participant referred to resistance as a phenomenon that takes place in the disease itself, as a property of certain diseases that are resistant to treatment and thus lead to its failure:This was the only participant that specifically referred to antibiotics, as well as providing the name of a concrete antibiotic (Amoxicillin), when discussing resistance to treatment success.To the best of our knowledge, this is the first qualitative study undertaken in Mozambique aiming to describe the different dimensions of community knowledge of antibiotics and antibiotic resistance, as well as practices regarding antibiotic use. This aligns with a recent statement regarding the scarcity of evidence on self-medication and other aspects of antibiotic use in Africa .In this study, we identified key dimensions that situate participants’ knowledge of antibiotics (or lack thereof): i) those who visually recognized antibiotics, were aware of the term “antibiotic” and could provide some definition based on the colour, shape and the illnesses they perceived were treatable through antibiotics (even if inaccurate), ii) those who visually recognized antibiotics but were unaware of the term nor could they provide any definition linked to it, iii) those who could not visually recognize it, nor were familiar with the term, nor could define it in any way. The majority of participants fell into the first group.(Amoxicillin) which is provided as a distinct red-yellow capsule and is also named ‘red & yellow’. Poor knowledge of antibiotics among the general population has been reported in different studies in LMICs [The results from the different attempts to support participants in conceptualizing antibiotics in their own terms suggest that there is limited knowledge of the concept “antibiotic”, as none of the participants provided an elaborate and consistent definition of antibiotics that does not contradict biomedical knowledge. Their conceptualisation seems to have been limited by the characterisation of the medicine based on the appearance and use of the dominant antibiotic class in this setting in LMICs , 46, 47 in LMICs . Yet in The limited understanding of the treatment indications of antibiotics found in this study was consistent with existing literature , 47, 48.Despite the fact that antibiotics in Mozambique may be presented in different pharmaceutical forms or capsules of colours which may confuse the users, one important finding was the ability of some participants to define antibiotics, influenced by their familiarisation with Amoxicillin, which locally is typically presented in the form of yellow and red tipped capsules. This finding is concordant to the recent research conducted by Torres 2019) in Mozambique, which reported that participants reported to know Amoxicillin, describing the capsules with in red and yellow colour . Apart f9 in MozaLooking at perceptions of the treatment purpose of antibiotics, participants mentioned a variety of conditions, including those that are not treatable by antibiotics. Subtle misconceptions like this could lead to inappropriate use and potentially precipitate and/or sustain the problem of resistance , 19, 20.In alignment to studies in other settings , 47, 57,None of the participants in the individual interviews seemed to be familiar with the term or the concept of antibiotic resistance, yet the dynamics during FGDs (which relied on participants reacting to the presentation of a “resistance” case scenario), allowed participants to relate to the phenomenon and elaborate on it, even though practically no one had heard the term before. This is in accordance with a study conducted in India, which found that none of the participants recognised the term “antibiotic resistance”, but following a brief description, some participants were familiar with the concept . RespondThe various discussions with participants consistently revealed that they do not associate the pathogenic agent of the disease into the equation of antibiotic resistance, as, in their view, it is either the result of misuse, or it is the body, the disease or the drug itself that becomes resistant, leading to treatment failure. Among these conceptions, some alignment with biomedicine was revealed with regards to the concept of antibiotic stewardship, in which misuse leads to resistance. However, the majority of respondents only seen at an individual level and not at a macro, environmental level. In other words, antibiotic resistance affecting an individual is blamed on that individual’s inappropriate behaviour and framed as a phenomenon whose cause and effects are located exclusively within that individual. In this way, other factors that could lead to resistance are ruled out, including the possibility of being infected by already carrying resistance to a specific antibiotic. Attribution of antibiotic resistance to the individual level, rather than an acquired property of bacteria was also found in a study conducted in 9 European cities .Regarding stewardship, the finding on the gap between participants’ theoretical knowledge of appropriate antibiotic use and their behaviour is consistent with studies conducted in high-income countries, such as a large household survey in Great Britain that found that 87% of respondents who did not complete their last course also said that a course of antibiotic should always be completed .There is extensive lay knowledge built around exposure to treatments and medicines, mostly as a result of people’s own experience and the interpretation given to such experience; this non-medical knowledge shows that lay people do think about and conceptualize drugs in general, within which they fit concepts around antibiotics and resistance in terms that are intelligible to their own realities. In order to better reach communities and improve community awareness it is important to reflect on how lay people conceptualize resistance, considering that they do not yet differentiate antibiotics from other classes of medicines, nor do they understand fully the indications of this class of drugs, even if to some extent they are able to visually recognize a common antibiotic by relating its image to the term ‘antibiotic’. Future campaigns need to consider these lay understandings and tackle gaps in knowledge or misinformation. This disparity between lay and biomedical concepts is not to say that a higher level of knowledge is not possible to attain in our settings. In fact, the HIV/AIDS epidemic has proven that complex terms such as “virus” and “antiretroviral” were certainly discussed with literacy-limited community members –62. A paLastly, health policies should also consider the structural problems pointed out in this study, including self-medication which is a result of easy accessibility, and practices around sharing medications which is potentially a result of self-diagnosis and misinformation at the level of the supplier, be this at the hospital or pharmacy. Given the demand side issues highlighted in this study it is crucial for health providers to take more responsibility in controlling access to antibiotics. Nevertheless, the existing trust that participants in this study expressed with regards to formal antibiotic providers represents an opportunity for developing and targeting specific educational interventions and to inform policy to promote the appropriate use of antibiotics.Being a qualitative study, the strength of the study was the level of depth and multiple dimensions captured with regards to knowledge of antibiotics and antibiotic resistance. Nonetheless, the study was designed to capture people’s ranges in perceptions and not the magnitude of the problem. Therefore, it has not captured how extensive or recurrent these constructs and practices are but rather what people consider to be common. As we pointed out, we cannot guarantee that participants were always referring to antibiotics throughout the interviews and discussions since, in spite of the regular use of prompts and visual aids to help focus the conversation on antibiotics, respondents would often interchangeably make reference to antibiotics and other medicines, conflating the two. Thus, the depth of some discussions where the term “antibiotics” was used were limited due the fact that participants did not seem to express confidence in their reference to antibiotic. Additionally, the fact that participants knew the study was related to antibiotics may have induced them to use the term “antibiotic” more than they would have in normal conversation when talking about medications. An additional limitation of this study is the fact that, despite the effort to discuss “antibiotic resistance” by making use of a hypothetical scenario, participants did not use the term “resistance to antibiotics”.Limited and inconsistent knowledge about antibiotics and antibiotic resistance were the main findings of this study. However, participants did build some constructs around these concepts, namely that antibiotics (mainly Amoxicillin) are yellow and red capsules used to treat a non-specific range of complaints, and that resistance refers to the effects of sub-optimal adherence and behavioural, physiological, pharmacological and pathological factors. These constructs were built on the basis of their lived experiences of antibiotic usage. Treatment failure is conceptualised at the individual level, not as a public health concern. In addition, in spite of awareness of the importance of medication compliance, participants acknowledge it is common to not abide by it. Thus, further research to understand this discrepancy between the knowledge of responsible medication compliance and current practices, as well as tailored interventions that tackle inappropriate use and behavioural change, are crucial and should be prioritized. The existing trust in drug providers represents an opportunity to train and use drug providers as a medium to communicate accurate information about antibiotic use and resistance.Additional file 1.Additional file 2.Additional file 3.Additional file 4.


Probabilistic Programming offers a concise way to represent stochastic models and perform automated statistical inference. However, many real-world models have discrete or hybrid discrete-continuous distributions, for which existing tools may suffer non-trivial limitations. Inference and parameter estimation can be exceedingly slow for these models because many inference algorithms compute results faster (or exclusively) when the distributions being inferred are continuous. To address this discrepancy, this paper presents Leios. Leios is the first approach for systematically approximating arbitrary probabilistic programs that have discrete, or hybrid discrete-continuous random variables. The approximate programs have all their variables fully continualized. We show that once we have the fully continuous approximate program, we can perform inference and parameter estimation faster by exploiting the existing support that many languages offer for continuous distributions. Furthermore, we show that the estimates obtained when performing inference and parameter estimation on the continuous approximation are still comparably close to both the true parameter values and the estimates obtained when performing inference on the original model.


Medical emergency teams (MET) are mostly led by physicians. Some hospitals are currently using nurse practitioners (NP) to lead MET calls. These are no studies comparing clinical outcomes between these two care models. To determine whether NP-led MET calls are associated with lower risk of acute patient deterioration, when compared to intensive care (ICU) registrar (ICUR)-led MET calls.The composite primary outcome included recurrence of MET call, occurrence of code blue or ICU admission within 24 h. Secondary outcomes were mortality within 24 h of MET call, length of hospital stay, hospital mortality and proportion of patients discharged home. Propensity score matching was used to reduce selection bias from confounding factors between the ICUR and NP group.p = 0.03). Of the secondary outcome measures, mortality within 24 h  and hospital mortality  were higher in ICUR-led MET calls. Propensity score-matched analysis of 263 pairs revealed the composite primary outcome was comparable between both groups, but NP-led group was associated with reduced risk of hospital mortality  and higher likelihood of discharge home .A total of 1343 MET calls were included . On Univariable analysis, the incidence of the primary outcome was higher in ICUR-led MET calls (26.7% vs. 20.6%, Acute patient deterioration was comparable between ICUR- and NP-led MET calls. NP-led MET calls were associated with lower hospital mortality and higher likelihood of discharge home.The online version contains supplementary material available at 10.1186/s13054-021-03534-4. Over the last two decades, establishment of rapid response systems (RRS) in healthcare services has led to a reduction of in-hospital mortality and incidence of in-hospital cardiac arrests . ReductiPhysicians attending these MET calls generally have other defined roles. Attendance at MET calls was known to cause significant disruption to the critical care physicians’ usual activities , 8. To rThe NPMET study was identified as a quality assurance activity and was approved by study site Research Ethics Committee .Retrospective study of all MET calls between June 1, 2016, and March 9, 2018, in an Australian tertiary ICU.Admitted patients who had acute clinical deterioration to warrant a MET call during the study period.All rapid response calls (RRC) are entered in Riskman database. All patient medical records are scanned in a digital medical record system. Both these databases will be interrogated to find MET calls, eligible for inclusion. Data regarding physiological observations are extracted from RRC observation form, scanned into digital medical record system. Demographic data, diagnoses, discharge destination and hospital outcome will be derived from iPM. Health information services (HIS) at Peninsula health, scan all inpatient medical records to determine comorbidities and Charleston Comorbidity Index (CCI). This information will be extracted from HIS database. Acute Physiological and Chronic Health Evaluation score II and III recorded in COMET database, for all patients admitted to ICU. These data along with admission and discharge time, for patients admitted to ICU, will be extracted using COMET database. Data for treatment provided, outcome and alteration in goals of care are entered into Riskman database and were extracted for the study.RRS at the study site comprises two-tiered efferent limb, 1) comprising single criterion-triggered MET response for patients meeting physiological observation thresholds or staff concern triggers . These two members have received endorsement from the Nursing and Midwifery Board of Australia to practice as Nurse Practitioners. The nurse practitioners have an advanced scope of practice which enables them to prescribe medication within a hospital approved formulary, order and interpret diagnostic investigations, refer to specialist teams and commence treatment. Their scope of practice includes advanced life support interventions including insertion of intra-osseous access, laryngeal mask airways and code team leadership. NP service was provided by two nurse practitioners and was available to be rostered for 8 h between 08:00 and 22:00 h (08:00–16:00 or 14:00–22:00), all days of the week including weekends. When NPs were not rostered, ICUR were assigned the role of attending and leading MET calls. All ICURs had at least four years of work experience after completing under-graduation, at least 9 months of which was spent either in ICU or emergency department resuscitation area under supervision of specialist consultants. All ICURs were either advanced emergency department trainees or registered as a trainee with College of Intensive Care Medicine (CICM). All ICURs received formal training toward recognizing and responding to critical patient deterioration, vascular access procedures and basic airway management techniques. Majority of ICURs were trained to perform advanced airway management including endotracheal intubation. Both NPs and ICUR could receive guidance from an ICU consultant physically present during business hours (08:00 to 18:00 h) and were on call out of hours (18:00 to 08:00 h).They were the first (index) MET call for that hospital admission; andoccurred between June 1, 2016, and March 9, 2018; andwere led by either ICUR or NP.MET calls were included in the analysis if.MET calls were excluded from the analysis if both NP and ICUR attended, neither NP nor ICUR attended, no record of attendees in MET call record or patients not admitted to hospital.Primary outcome is a composite outcome comprising of either recurrence of MET call, occurrence of code blue or ICU admission within 24 h of index MET call.Secondary outcomes were mortality within 24 h of index MET call, length of hospital stay, hospital mortality and proportion of patients discharged home.Continuous variables were summarized using mean and standard deviation (SD) or median and interquartile range (IQR) depending on the underlying distribution of the data. Categorical variables were reported as counts and percentages. Comparisons between groups (NP vs. ICUR) were made using the Student’s t test for normally distributed continuous variables, Wilcoxon rank-sum test for non-normally distributed continuous variables and Chi-square or Fisher’s exact test as appropriate for categorical variables.Propensity score matching was used to reduce selection bias from confounding factors between the ICUR and NP group. The individual propensities for being in the ICUR-led group were estimated with the use of a multivariable logistic regression model that included age, Charlson Comorbidity Index (CCI), weekend (Saturday and Sunday) occurrence of MET call, out of hours occurrence of MET call, “not for resuscitation” plan prior to MET call, triggering of MET call due to oxygen saturation < 90% and diagnoses  as the predictor variables. This propensity score was used to match patients managed by ICUR to those managed by NP using a one-to-one nearest neighboring matching with a caliper width of 0.15 times the standard deviation. Standardized differences were calculated to assess the balance of covariates between ICUR and NP groups. Primary and secondary outcomes were compared between ICUR- and NP-led groups using conditional logistic regression taking into account the matched design with results reported as odds ratios (OR) and 95% confidence intervals (95% CI). Sensitivity analysis was also performed using a multivariable logistic regression model that included the same covariates as the propensity score model to ensure robustness of the primary analysis.All reported p values are two-sided, and a p value less than 0.05 was considered to indicate statistical significance.n = 2437) and attendance of MET calls by both NPs and ICUR (n = 689). The other reasons for exclusion are provided in Fig. In total, 5272 MET calls occurred between June 1, 2016, and March 9, 2018. Of these, 1343 (25.5%) MET calls were included in the analysis .Out of 1343 patients, 1322 (98.4%) had triggers recorded in MET call documentation (Table p = 0.02) and oxygen saturation level  were different between the groups , fluid bolus administration  and performing ECG  were more frequent during NP-led MET calls. Occurrence of change in resuscitation status was similar in both groups .A comparison of interventions performed during attendance for MET call is presented in Table p = 0.03). There were fewer ICU admissions within 24 h of index MET call in NP-led MET calls as compared to ICUR-led MET calls .The primary and secondary outcomes in both groups are presented in Table p = 0.002) and lower hospital mortality . The hospital length of stay  and proportion of patients discharged home  were comparable.NP-led MET calls were also associated with lower mortality within 24 h of index MET call . The likelihood of discharge home was also higher in NP-led MET calls as compared to ICUR-led MET . NP-led MET calls showed a trend toward decreased mortality within 24 h of index MET call, but this did not reach statistical significance ; p = 0.06).The propensity-matched analysis included 263 pairs of patients. The distribution of propensity scores appeared to be similar in both groups. Furthermore, the average propensity score was also similar [mean (standard deviation) 0.446 0.161) in registrars and 0.435 (0.155) in nurse practitioners] in each group. A comparison of propensity-matched groups with regard to baseline characteristics and the characteristics of MET calls and the standardized differences are presented in Tables 61 in regp = 0.035).On multivariable analysis, neither NP- nor ICUR-led MET calls were independently associated with composite outcome. However, ICUR-led MET calls were independently associated with increased hospital mortality , higher mortality within 24 h  and higher hospital mortality  in ICUR-led MET calls (Additional file Comparison of baseline characteristics revealed no significant differences between NP- and ICUR-led MET calls (Additional file This study aimed to compare clinical outcomes between NP- and ICUR-led MET calls. In the clinical outcomes studied, this study showed no difference in acute deterioration, but a reduction in hospital mortality, and an increased likelihood of discharge home in NP-led MET calls. To our knowledge, NPMET is the first study that directly compared clinically important patient-centered outcomes between NP- and ICUR-led MET calls. Given the retrospective nature of this study, propensity matching was performed to avoid the influence of confounders between the groups. The balance of covariates after propensity matching confirms that both groups are comparable. All other studies either used a retrospective before and after design, focused on recognition of systemic inflammatory response syndrome, measured post-ICU discharge interventions instead of MET call leadership, did not have ICUR-led MET calls for comparison or measured active surveillance for deteriorating patients rather than MET call leadership –15.The organization and governance of MET teams in different organizations are variable and are largely dependent on the availability of personnel . To the It is possible that the differences in the outcomes could also be due to differences in interventions that were performed during the MET calls. Interventions such as IV cannulations, administration of fluid bolus, and performance of ECGs were significantly higher in NP-led MET calls. While the retrospective nature of our study does not allow us to further define the influence of these interventions on the outcomes, it is possible that early correction of the physiological abnormalities during an acute deterioration could have contributed to better outcomes in these MET calls . The othFurthermore, as NPs are exclusively rostered for liaison between ICU services and ward-based teams, their awareness of the environment and knowledge of available resources during crises can better direct patient management during and after MET calls. A recent in-depth interview study exploring human factors for successful airway management found that knowledge of equipment location and storage, experience and learning, teamwork and communication can all have a positively influence . AdditioTo the best of our knowledge, NPMET is the first study that directly compared clinical outcomes between MET calls led by NP and ICUR. This study had a large sample size of over 1300 MET calls that has enabled us to identify important differences in outcomes between NP- and ICUR-led MET calls. In spite of the retrospective nature of this study, data were largely available on the reasons for MET calls, timing and the interventions that were performed during MET and the outcomes we assessed. The propensity matching of our patients provided good balance of the variables including the timing of MET calls, triggers and comorbidities that could influence the outcome. This facilitated a robust comparison of the differences in the characteristics, interventions performed during the MET calls and the outcomes of MET calls led by NPs and ICUR.Despite using propensity matching to ensure MET calls in the analysis are comparable between NP led and ICURs, there may be unknown confounders. Delay in activation of rapid response calls of 15 min or more is known to be associated with higher risk of hospital mortality . We coulNPMET study showed that the primary composite outcome comprising of recurrence of MET call, occurrence of code blue or admission to ICU, all within 24 h, was not different between NP-led and ICUR-led MET calls. NP-led MET calls were associated with lower hospital mortality and higher likelihood of discharge home. Multi-center studies comparing NP and ICUR/physician-led MET calls may further help in generalizing the findings of our study and identify the optimal organization of MET teams for clinical and cost-effectiveness.Additional file 1. Supplementary Information—E Tables 1–8.


Antibiotic use over several decades is believed to be associated with colorectal adenomas. There is little evidence, however, for the effect of more recent antibiotic use on frequency of colorectal cancers.A case control study used the RCGP’s Research and Surveillance Centre cohort of patients drawn from NHS England. In all, 35,214 patients with a new diagnosis of colorectal cancer between 1 January 2008 and 31 December 2018 were identified in the database and were matched with 60,348 controls. Conditional logistic regression was used to examine the association between antibiotic prescriptions and colorectal cancer.p < 0.001).A dose-response association between colorectal cancers and prior antibiotic prescriptions was observed. The risk was related to the number and recency of prescriptions with a high number of antibiotic prescriptions over a long period carrying the highest risk. For example, patients prescribed antibiotics in up to 15 years preceding diagnosis were associated with a higher risk of colorectal cancer (odds ratio (OR) = 1.90, 95% confidence intervals (CI), 1.61–2.19, Antibiotic use over previous years is associated with subsequent colorectal cancer. While the study design cannot determine causality, the findings suggest another reason for caution in prescribing antibiotics, especially in high volumes and over many years. This suggests that the balance of the organisms making up the gut microbiota may be a significant factor determining cell mutation and subsequent cancer risk.Accumulating evidence suggests that the human intestinal microbiota contributes to the aetiology of colorectal cancer (CRC), not only via the pro-carcinogenic activities of specific microorganisms but also via the influence of the wider microbial community.11 The increasing list of potentially carcinogenic bacteria provides support for the hypothesis that the development of cancer is driven by mechanisms and/or pathways that are common to many bacterial groups rather than a single organism. These observations have led to suggestions that targeted antibiotics, probiotics or prebiotics may have a role to play in CRC prevention or treatment.13Analyses of faecal samples from patients with CRC compared with controls have identified over and under representation of some bacterial species in the cancer patients, though results have not been consistent.13 Support for this hypothesis comes from the US Nurses’ Health Study, a cohort of over 16,000 women, where there was a clear association between prior antibiotic use and subsequent colorectal adenoma, a well-recognised precursor of carcinoma.14 Indeed, prior use of antibiotics, a common prescription in health care, provides a ‘natural experiment’ to explore the association between antibiotics and CRC risk. We therefore used a large clinical database with records of a colorectal cancer diagnosis together with preceding antibiotic use to test the hypothesis that the frequency of antibiotic prescribing over several years increases the risk of subsequent colorectal cancer diagnosis.Antibiotics are also known to produce dysbiosis in the microbiome and this disturbance may facilitate the sorts of cellular damage known to precede cancerous growths.15 RCGP RSC practices have had long-term feedback about data quality, most recently via a dashboard.16A retrospective case-control study was implemented within a cohort of patients registered in the UK’s Royal College of General Practitioners’ (RCGP) Research and Surveillance Centre (RSC). The RCGP RSC extracted pseudonymised data for a cohort of around 2 million patients registered in over 260 participating general practitioner (GP) practices at the time of this study, and represents the principal primary care public health surveillance data used by Public Health for England (PHE). Almost everyone in the UK is registered with a general practice, which provides and coordinates most of their health care. General practices have been computerised since the 1990s recording key clinical data using Read codes. Treatment records are generally complete as electronic prescribing is widely used. Patients in the database have been found to be representative of the UK population in terms of gender and age, with slight under-representation of people from a minority ethnic background and less deprived communities.17 Cases were all patients, aged 18 and over, with a first ever record of CRC (the index date) during the study period. All cases had at least 12 months of clinical record before the diagnosis of CRC. Cases were matched on year of birth (within 2 years to increase the probability of identifying four controls for each case), gender, index date and the same general practice with up to four controls. Controls were assigned the index date of diagnosis of the matched case and were patients without a CRC diagnosis who were alive, registered with the practice and with at least 12 months of clinical record prior to the index date. Patients with a diagnosis of inflammatory bowel disease were excluded from the study.The study population consisted of all patients with newly diagnosed CRC between 1 January 2008 and 31 December 2018 in the RSC database. Data were extracted from the RSC in April 2019. The cohort of CRC patients was identified using Read codes selected in our previous research.18 and quinolones (BNF 5.1.12) given their broad spectrum of activity. The last date of antibiotic prescribing was calculated as the time gap from the last date of a relevant drug prescription in relation to the index date for CRC .The number of antibiotic prescriptions issued to patients represented the primary variable of interest. RCGP RSC has reliable antibiotic prescribing since 2003 so the maximum exposure was up to 15 years. Antibiotic drugs included were those in the British National Formulary (BNF) chapter 5.1 excluding anti-tuberculous and anti-leprotic drugs. All antibiotic prescriptions after the study start date  and before the index date for CRC were included. Three different exposure variables were developed, namely cumulative number of prescriptions, specificity (subtypes) of antibiotic drugs and date of last prescription. For the cumulative number of prescriptions, patients were grouped according to the number of relevant antibiotic prescriptions  issued over specified total time periods before the index date . Two classes of antibiotic were chosen for specific analysis across the three time periods, penicillins (BNF 5.1.1) on the grounds they were most frequently prescribed2, total cholesterol  and a series of long-term conditions as markers of frailty included as binary variables: coronary heart disease (CHD), stroke, chronic obstructive pulmonary disease (COPD), liver disease, type 2 diabetes, depression and dementia. For each covariate the value closer to the study baseline (start date) was considered.Factors known or proposed to impact the association between antibiotic prescribing with CRC were a priori included as covariates in the analyses. These included deprivation (quartiles of the Index of Multiple Deprivation 2010), ethnicity , smoking , body mass index (BMI); <18.5, 18.5–24.9, 25–29.9, >29.9 kg/m19 and Greenland,20 the analyses did not adjust for multiple comparisons. The analyses were implemented in Stata version 15. .Descriptive analyses were used to compare baseline differences between cases and controls. Participants were followed-up from the study start date, that is from the beginning of possible antibiotic recording, to the study end date, the index date when CRC was diagnosed. Conditional logistic regression was employed to estimate odds ratios and 95% confidence intervals (CIs) for the association between CRC and previous antibiotic prescriptions. The main analysis modelled antibiotic prescription with overall CRC risk by including all drug classes  within the same estimation model across three time periods, 1 year, 5 years, and ‘ever’ prior to the index date. Separate models were estimated for type of antibiotic drugs (penicillins and quinolones) and last date of antibiotic prescribing. The analyses adjusted for the main hypothesised confounding variables described above. The analyses excluded all antibiotic prescriptions issued within 6 months before diagnosis to reduce the risk of protopathic bias. A sensitivity analysis was also carried out by excluding prescriptions issued 12 months before the diagnosis to examine a longer protopathic period. Data for study covariates were not available for all participants and we implemented multiple imputation with chained equation (10 imputed datasets) to address missing data concerns. Following Rothmanm) = 6 years, interquartile range (IQR) = 4–7) were identified in the database that were matched with 60,348 controls   overall increased probability of antibiotic prescribing over the whole study period, following subjects up to 15 years. There was also a gradual increase in colorectal cancer risk with the number of antibiotic prescriptions. For instance, the probability of colorectal cancer increased from 47%  for one antibiotic prescription to 103%  after more than 10 prescriptions. A similar pattern, though lower estimates, was observed within the 5-year time interval. The 1-year time interval-based findings showed an association with colorectal cancer, the risk, however, declined with the number of prescriptions.Figure p < 0.001 and OR = 1.29, 95% CI, 1.04–1.53, p < 0.001, respectively). The strength of the association between both quinolones and penicillin with colorectal cancer increased with an extended exposure interval.The analyses stratified by two major antibiotic groups Fig.  indicateAnalyses that explored the association between the time since the last antibiotic prescribed with the risk of colorectal cancer revealed a positive association between the last antibiotic prescription and a CRC diagnosis whatever the time interval since the last prescription Table . The patSensitivity analyses that extended the protopathic bias interval to 12 months prior to the index date, revealed similar patterns to the main study findings .14 The relationship was dose-related with longer periods of antibiotic consumption leading to higher rates of adenomas. If antibiotic prescriptions in earlier decades predisposes to adenomas might the more recent use of antibiotics lead those lesions to become malignant? Whereas the Nurses’ Health Study found no relationship between antibiotic use in the 4 years immediately prior to diagnosis and the occurrence of adenomas, this current study, examining colorectal cancers as the endpoint, did show an association between antibiotic use and cancers. The highest odds ratios were observed in periods furthest from the diagnosis and after use of high numbers of antibiotic prescriptions suggesting an accumulation model for cancer emergence.Results from the US Nurses’ Health Study found an increase in colorectal adenomas with antibiotics prescribed over the preceding four decades.21 identified all cancers diagnosed between 1998 and 2004 in a Finnish clinical cohort and linked these to antibiotics prescribed in an earlier 3-year period between 1995 and 1997. Several cancers showed a significant association with the previous number of antibiotic prescriptions . Bousi et al.,22 in a case control study using the THIN  database derived from primary care records in the UK, found that penicillin use was associated with increased diagnosis of colorectal cancer with the risk being greatest in the immediate year prior to diagnosis—a finding they attributed to possible protopathic bias  because of prescribing for early, non-specific disease manifestations. Antibiotic use before a year prior to diagnosis, however, was not reported as having a significant association with subsequent cancer. Dik et al.23 also used a case control design to study the effect of antibiotic use between 1 and 6 years prior to colorectal cancer diagnosis in a Dutch health insurance database. They found an adjusted odds ratio of 1.26 (CIs 1.11–1.44) for a high (≥8) number of antibiotic prescriptions in the designated 5-year period prior to diagnosis.A number of other studies examining shorter periods of antibiotic exposure support an association between prior antibiotic use and colorectal cancer, albeit with smaller effect sizes. Kilkkinen et al.25 In this study, moreover, those patients with repeated antibiotic prescriptions over many years seemed most at risk of CRC. High numbers of antibiotic prescriptions, however, in the year immediately preceding diagnosis  appeared to have a possible protective effect against CRC. If one hypothesis for the long-term effect of antibiotics is microbiome dysbiosis, it is possible that in the short-term, intensive high-volume antibiotics—more than 10 antibiotic prescriptions in what amounts to a 6-month period is likely similar to a continuous course—may remove specific organisms that have been suggested to have a carcinogenic effect. This might indicate that specifically targeted narrow spectrum antibiotics may have a different effect compared with broad spectrum ones.The study reported here used a wider range of years of antibiotic exposure, examining 1 year prior, 5 years prior or ‘ever’ (up to about 15 years prior). Although there are reports that the microbiome recovers rapidly from a short challenge with antibiotics this seems dependent on the type of antibiotic.27 These symptoms may lead to both increased GP consultations  and a greater likelihood of receiving a prescription for minor infections. We addressed this potential protopathic bias in all our analyses by excluding antibiotic prescriptions in the immediate 6 months prior to the CRC diagnosis. To allow for the possibility that the protopathic period was longer than 6 months we conducted a sensitivity analysis that excluded all prescriptions in the year preceding diagnosis: this showed no reduction in the long-term association of antibiotics with colorectal cancer.Several studies have suggested that the ‘symptomatic’ pre-diagnosis period in colorectal cancer is longer than had been assumed with various non-specific symptoms, such as fatigue and malaise, occurring in the months prior to diagnosis.29), but most antibiotics are prescribed for upper respiratory tract infections.18 The RCGP RSC database only included prescriptions issued in general practice though most antibiotic prescribing is known to be from primary care.30 Our exposure variable was the number of antibiotic prescriptions, but we had no information on the dose or duration of each course and whether this differed between the cases and controls. We have no direct evidence that prescribed antibiotics were actually consumed by patients, however, non-adherence is likely to be common to both cases and controls and unlikely to bias the observed estimates.It is important to stress that a case control study can only show associations, not causality, and may be subject to residual confounding. The study adjusted for confounders documented by previous studies to influence the association between antibiotic prescribing and CRC incidence but cannot rule out unknown confounders. Family history of CRC represents an important unmeasured confounder in our study, as this information is poorly captured in clinical records. However, 99% of our study cases were over 40-years-old at the time of CRC diagnosis, which limited the impact that biological predisposition may have on CRC prevalence. Antibiotics may have been given for gastro-intestinal complaints (we excluded patients recorded as having inflammatory bowel disease given its known association with CRCIn conclusion, earlier studies have indicated an association between antibiotic use and colorectal cancers and adenomas. Using a case control design, our study adds weight to these findings and explores the importance of the ‘susceptible’ time period before the cancer diagnosis as well as the effect of the number of antibiotic prescriptions. The strongest associations were found between CRC diagnosis and prescribed antibiotics over a long time period and also with the overall frequency of antibiotics prescribed—though high numbers of prescriptions over a shorter time period may have provided protection though a different mechanism. Reassuringly the ‘risks’ from taking an antibiotic seems to decline over time; if the oncogenic mechanism is damage to the gut microbiome this might indicate it is given the opportunity for recovery. Nevertheless, the study adds to the emerging hypothesis that antibiotic consumption is related to the occurrence of colorectal cancer and suggests a further reason for caution in antibiotic prescribing.Figure S1


ObjectiveOur goal was to evaluate upper eyelid laxity by digital distraction, with the aim to determine sleeping laterality and the likelihood of obstructive sleep apnoea (OSA), and correlate these findings with polysomnography (PSG).DesignWe conducted a prospective, single-centre multidisciplinary study in a large sleep and respiratory department and an ophthalmology department within a tertiary referral university teaching hospital.MethodsPatients with known OSA were evaluated using techniques based on the Lateralising Eyelid Sleep Compression (LESC) study. Upper eyelid laxity was assessed by two masked investigators, and the eyelid side with greater laxity was regarded as indicative of that patient’s sleeping laterality: ‘investigator-detected sleeping laterality’ (ID SL). Each patient was then asked about the laterality of his or her accustomed sleeping position: ‘patient-reported sleeping laterality’ (PR SL). PSG was conducted according to the standard protocol of the Department of Sleep and Respiratory Medicine (DSRM). ‘Polysomnography-detected sleeping laterality’ (PSG SL) permitted the extraction of sleep positional data by two masked sleep scientists.Resultss =0.33). However, PSG SL did not correlate with sleeping laterality compared with both ID SL and PR SL.The reliability of the LESC technique for diagnosing ID SL was demonstrated to be statistically significant (p<0.01). Upper eyelid laxity was significantly greater on the patients’ sleeping side . There was a significant correlation between PR SL and ID SL (rConclusionThis study confirms that there is a statistically significant correlation of sleeping laterality with increasing upper eyelid laxity in OSA. Counterintuitively, PSG SL correlated poorly with ID SL and PR SL. This may likely be explained by the technical limitations implicit in current PSG techniques. Floppy eyelid syndrome (FES) is a condition characterised by a totally evertible upper eyelid and a pliable tarsal plate, with inflamed conjunctiva. FES may result in ocular discomfort, blurred vision, and papillary conjunctivitis ,2. It isPolysomnography (PSG) is the gold-standard method for OSA diagnosis, but its use as an accessory tool in the diagnosis of FES has not previously been studied in the literature 3.4]. The current masked, prospective study compared sleeping laterality in individuals with definite or highly suspected OSA by three methods. These were ‘investigator-detected sleeping laterality’ (ID SL), ‘patient-reported sleeping laterality’ (PR SL), and ‘polysomnography-detected sleeping laterality’ (PSG SL). This study is the first to compare PSG SL with PR SL and ID SL. It was postulated that in patients with suspected OSA, greater upper eyelid laxity would be observed on the sleeping side, confirming the findings of the Upper Eyelid Distraction Assessment (UEDA), performed by our group in 2014  or mean ±standard deviation. Spearman’s rho (ρ) and Pearson’s correlation analysis were performed to assess the variability of investigator findings. A paired t-test analysis was used to assess the difference in upper eyelid laxity between the sleeping and non-sleeping sides. Spearman’s ρ correlation analysis was used to assess the relationship between upper eyelid laxity and the sleeping side. A p-value of <0.05 was considered statistically significant.Twenty-eight patients were recruited from the DSRM, Prince of Wales Hospital in Sydney, Australia. The median age of the patients was 58 years (range: 42.25-73.75 years), and 71% of the cohort was male.The upper eyelid laxity examination was assessed for reliability using Spearman’s ρ and Pearson’s two-tailed correlation analysis. The former was used to assess ID SL, while the latter was used to assess investigator distraction distance measurements for both right and left upper eyelids. UEDA was found to be correlated with the distraction distance at a statistically significant level p: 0.01) . The five patients who did not report a preferential sleeping side were excluded from the PR SL analysis. The mean value of the UEDA distance on the sleeping side was 4.9 ±1.7 mm, while the corresponding figure for the non-sleeping side was 4.1 ±1.5 mm. A paired t-test analysis showed that the difference in laxity was statistically significant .Spearman’s ρ correlation analysis was employed to assess the relationship between PR SL, ID SL and PSG SL. A significant association was found between PR SL and ID SL. The association between PSG SL and either ID SL or PR SL was not found to be significant Table .While FES was first described by Culbertson and Ostler in 1981, its pathogenesis remains unclear ,5. The pFES often affects the eyelid that corresponds to the side of the head on which the patient customarily sleeps ,5. As a OSA is a chronic condition caused by a complete or partial obstruction of the upper airway during sleep, causing snoring, choking, frequent nocturnal awakenings, disrupted sleep, and daytime hypersomnolence ,10. It iIn the adult population, the diagnosis of OSA is defined by more than five apnoea and hypopnoea events per hour of sleep associated with daytime hypersomnolence. The prevalence of OSA is approximately 2-5% in women and 3-7% in men ,11. The OSA is an independent risk factor for cardiovascular and cerebrovascular disease, and metabolic disorders including type 2 diabetes. These include sudden death, myocardial infarction, stroke, depression, anxiety, hypertension, waking unrefreshed, daytime somnolence, dementia, loud snoring, apnoeic episodes with sudden distressed waking and microsleeps (occasioning sudden death when driving) . In addiOSA is also associated with numerous ophthalmological conditions including FES, associated with painful eyes on waking because of corneal ulceration and papillary conjunctivitis, non-arteritic anterior ischaemic optic neuropathy, progressive astigmatism-against-the-rule, and keratoconus. Upper and lower eyelid ptosis, lower lid entropion and ectropion, and normal-tension glaucoma are also associated with it -5,12-14.This study is the first to examine the use of PSG as an accessory tool in the diagnosis of FES by looking at the relationship between PR SL, ID SL, and PSG SL.Correlation between PR SL and ID SLThe findings of this prospective, multidisciplinary, masked, single-centre study demonstrated a significant correlation between PR SL and ID SL. Additionally, the findings demonstrated a significant difference in upper eyelid laxity between dominant sleeping and non-dominant sleeping sides. This supports the hypothesis proposed in a study by Figueira et al.  (a studyChambe et al. have reported that outright FES is more commonly observed with increasing severity of OSA . While nThe application of UEDA is useful in determining sleeping laterality and the possible diagnosis of OSA. Not only is it straightforward to perform, but it is also economical, and takes generally no more than 5-10 seconds of the clinician’s examination time. Adding to the work of Figueira et al., the current study confirms the reproducibility of the LESC study . It coulGiven the sequelae of FES, as outlined above, referral to an ophthalmologist may be warranted for further detailed visual system assessment of the patient with suspected OSA. This is important clinically, as there are effective medical and surgical interventions to manage the eyelids and ocular surface in FES, as well as the ophthalmological complications of lax eyelids in general. Our group recently described what appears to be a highly effective new technique for surgical management of FES .Limitations of PSG in diagnosing sleeping lateralityThe current study disclosed a discrepancy in defining sleeping laterality between its different assessment techniques. The finding that PSG SL was not significantly associated with either ID SL, or PR SL, was unexpected, highlighting potential issues in objectively determining sleeping position by PSG, given the current technology. This indicates that PR SL and ID SL are useful in determining sleeping laterality and may facilitate the diagnosis of FES and OSA.The lack of association between PSG SL and sleeping laterality by PR SL and ID SL suggests that the underlying issue may not be subjective patient-reporting, but rather the reliability of the PSG data using current techniques. Indeed, the inaccuracies of positional sensors used in PSG in determining sleeping positions have been previously reported . It is aThe relatively disruptive nature of a PSG assessment to an individual patient may also play a role in changing patient-sleeping patterns ,18. A phThus, despite the limitations of PSG in detecting sleep laterality, UEDA appears to have a promising role in the future of OSA diagnosis. Further research is required to determine if UEDA can be utilised as a definitive screening tool for OSA, and larger prospective observational studies may be required. These should consist of improved sleep laboratory technology for detecting head position, particularly in relation to eyelid compression by the pillow.Detection of upper eyelid laxity or FES by the ophthalmologist, family medicine practitioner, or respiratory physician may ultimately assist in confirming the diagnosis of OSA. If UEDA is employed as a screening technique, and demonstrates asymmetric and prominent eyelid laxity, OSA may be considered as a possible underlying diagnosis. While increased upper eyelid laxity was confirmed to be associated with sleeping laterality in OSA, PSG SL correlated poorly with ID SL and PR SL. This may be explained in part by technical limitations implicit in current PSG techniques.In the future, the objective determination of sleeping laterality may be assisted by more sophisticated head-sensing and eyelid position-sensing technology in sleep laboratories. Individual patients with suspected OSA may warrant referral to an ophthalmologist for evaluation of lax eyelids as well as FES and associated ophthalmological abnormalities.