The viable but non-culturable (VBNC) state, a unique state in which a number of bacteria respond to adverse circumstances, was first discovered in 1982. Unfortunately, it has been reported that many foodborne pathogens can be induced to enter the VBNC state by the limiting environmental conditions during food processing and preservation, such as extreme temperatures, drying, irradiation, pulsed electric field, and high pressure stress, as well as the addition of preservatives and disinfectants. After entering the VBNC state, foodborne pathogens will introduce a serious crisis to food safety and public health because they cannot be detected using conventional plate counting techniques. This review provides an overview of the various features of the VBNC state, including the biological characteristics, induction and resuscitation factors, formation and resuscitation mechanisms, detection methods, and relationship to food safety. The viable but non-culturable (VBNC) state, a special physiological state, was first discovered and presented by The concept of VBNC has attracted great attention in the fields of microbiology, because it has upset the traditional concept of microorganismal growth. Unlike normal cells, VBNC cells cannot be grown in conventional culture medium, and thus, conventional methods of detection cannot be used to detect bacterial pathogens in the VBNC state. Thus, challenges are encountered in the detection of pathogens. To date, researchers have identified 85 species of bacteria that can enter the VBNC state, including 18 non-pathogenic species and 67 pathogenic species. Some foodborne pathogens retain virulence after entering the VBNC state, which may be due to their rapid resuscitation into culturable cells under certain conditions .Listeria monocytogenes resuscitated by incubation with embryonated egg regained virulence identical to that of culturable cells   . Table 1Shigella can take up methionine for protein synthesis, thus demonstrating that bacteria in the VBNC state can exchange outside material.Although VBNC bacteria lose culturability on normal culture medium, this does not mean that these cells are equivalent to dead cells. For example, the membrane of dead cells is damaged so that the genetic material in the cell cannot be preserved and expressed, while VBNC cells have a complete membrane structure that ensure the genetic information is not lost . MoreoveAlthough VBNC bacterial cells have many common features with culturable cells, a series of physiological changes occur during the transition from the normal state to the VBNC state, including slowing down of the absorption of nutrients and reduction of the level of macromolecular synthesis and metabolism, the concentration of the cytoplasm and total proteins . In summSalmonella typhi exhibiting metabolic activity were decreased in size and coccoid in shape compared with the normal rod-shaped cells  were observed in VBNC cells of Linder K . These rs aureus . MoreoveVibrio cholera, which indicated that these large molecules could be used as the primary energy source to maintain the survival of cells  could still be expressed in the VBNC state of E. coli O157:H7 by reverse transcription PCR. Moreover, in a study examining food safety risk factors, E. coli O157: H7 exhibited the potential virulence, and stable expression of the toxin gene  and the production of enterotoxin were observed in VBNC cells. In addition, the VBNC cells of C. jejuni also retained the ability to invade human intestinal epithelial cells (E. coli (ETEC) entering the VBNC state maintain the expression of virulence genes eltB and estA encoding the LT and STh enterotoxins, enterotoxins were not produced as determined using GM1-ELISA methods. Nonetheless, there is the potential danger in VBNC cells that are still pathogenic and even cause fatal diseases, which may be due to rapid resuscitation in suitable condition , which is expressed by the rpoS gene, is a stationary-phase sigma factor that allows bacteria to survive under different environmental stresses  ppGpp modulated by protein RelA may be an inducer of the VBNC state and that cells lacking ppGpp are less likely to enter the VBNC state  . This ca strains . AdditiopoS gene . It is pNC state . It is kNC state . Thus, tFigure 1).The persister state was first described by The above research about the formation mechanism of VBNC mainly focused on hypotheses and reasoning. At the molecular level, the research was mainly focused on the gene or protein level with some functions, which only partly reflected the formation mechanism of VBNC state. However, the study focused on the single and individual mechanisms, the lack of a comprehensive and systematic analysis. Most of the literatures to a single transcriptomics or proteomics approaches, the lack of integration analysis of the both, it is difficult to achieve information complement and functional verification . With thAt present, the method used to detect VBNC cells is mainly based on two key characteristics of VBNC cells: viability and non-culturability. Generally, if bacteria lose culturability but are still viable, they can be considered to have entered the VBNC state. Thus, using the conventional plate counting technique to confirm the cells in a non-culturable state is the first major step used to detect VBNC cells, followed by the estimation of viable cells using other methods.® BacLightTM fluorescence staining method based on the cell membrane structure integrity  based on the substrate absorption ability , the resntegrity .E. coli O157:H7 VBNC cells on the surface of lettuce and spinach plants by PMA-qPCR, which provided a detection limit of 103 CFU/g leaf, suggesting that PMA-qPCR was an appropriate technique to detect the VBNC cells of foodborne pathogens in contaminated vegetables. PMA can also be combined with LAMP. E. coli O157 cells within 1 h by PMA-LAMP. V. parahaemolyticus. The second method is based on molecular diagnostic approaches to detect gene expression or gene amplification selectively, such as reverse transcription PCR, quantitative real-time polymerase chain reaction (qRT-PCR) and loop-mediated isothermal amplification (LAMP). Bacterial mRNAs have been proposed as markers for cell viability because they are very unstable molecules with very short half-lives inside the cell . Thus, iThe other methods focus on the identification of VBNC cells using biological sensors, especially gene sensors and receptor sensors that are biosensors based on DNA . A DNA oRecently, novel detection methods have also developed for separating cells based on their physiological states . FluoresDuring the process of food processing and storage, there are numerous factors that induce foodborne pathogens to enter into the VBNC state. In general, the factors  create worse bacteria growth conditions that may stress the bacterial cells into the VBNC state. The physical factors that induce the VBNC state of bacteria mainly include low/high temperature , drying E. coli O157, C. jejuni, V. parahaemolyticus, L. monocytogenes, and S. aureus, have been validated to enter the VBNC state under low temperatures conditions . Resuscitation can also be mediated by different kinds of chemical stimuli, including sodium pyruvate , thus confirming that pyruvate was one of the key molecules in the process of resuscitation by triggering the synthesis of macromolecules such as DNA and protein.An increase in temperature is a common physical stimulus to resuscitate most VBNC cells induced by low temperature, such as pyruvate , amino apyruvate , and Twepyruvate . It is wV. cholerae could be converted into a culturable state after co-cultivating with eukaryotic cells. However, another study showed that VBNC C. jejuni cells could form colonies on agar plates after co-cultivation with Caco-2 cells, but most VBNC cells could not be resuscitated : one is that the breakdown product(s) of peptidoglycan by Rpf may interact with other factors and function as ‘second messengers’ to stimulate the resuscitation and growth of VBNC cells; the other is that Rpf is required to cleave peptidoglycans with inhibitory properties that are distributed in specific areas of the dormant cell wall and thus promote cell division and growth resumption , a highly conserved protein composed of 220 amino acids that is directly related to the resuscitation of VBNC cells, has been demonstrated to restore the growth and reproductive ability of VBNC cells . Rpf proell wall . There asumption . To provC. jejuni could respond to quorum-sensing (QS) signaling molecules , which indicated that biofilm formation was blocked and the entry of cells into the VBNC state was delayed. It was speculated that QS signaling molecules were related to formation of the VBNC state. This conjecture was further confirmed by V. vulnificus but also that the AI-2 deletion mutant lost resuscitation ability from the VBNC state. V. cholera was dramatically improved by the addition to the enrichment medium of biologically synthesized AIs, suggesting that these molecules might signal to dormant cells and then improve conditions for better growth. Furthermore, rpoS deletion mutant strains could not be resuscitated even with the addition of exogenous AI-2. This result shows that RpoS is not only a significant protein for VBNC formation but also an important participant in the resuscitation process mediated by AI-2.In contrast, Vibrio vulnificus. V. cholerae O1. VBNC Legionella pneumophila that retained the capacity to infect the amoeba, which is its natural host  and enteroaggregative E. coli (EAEC), involving more than 3000 cases of bloody diarrhea and haemolytic uremic syndrome. Unfortunately, the local detection department failed to detect or isolate the E. coli O104:H4 strain from the source of contamination until a small amount of the pathogens were isolated from the patients , we have described the role of VBNC pathogens in public health and food safety, and even their involvement in many foodborne outbreaks; however, there is no evidence to show that VBNC pathogens directly caused the outbreak. We propose that one of the most possible reasons is the undetectability of VBNC cells. Recent findings showed that 20% of illnesses can be linked to known pathogens, but the remaining 80% are due to unspecified or unidentified agents , indicatpatients . We suggaw, disinfectant and chemical composition) and environmental factors  act simultaneously on contaminating bacteria leading to the VBNC state. This alone poses a significant risk to the public health and food safety, as these bacteria cannot be detected by commonly used techniques (The presence of VBNC cells in food is widely documented . Food ischniques . This richniques . Furtherchniques . These sAfter decades of research, the VBNC concept has attracted great attention for a variety of foodborne pathogens and the corresponding adaptation mechanisms. It seems clear that the conditions, factors and regulators during the induction and resuscitation of the VBNC state play prominent roles in some strains. However, the formation and resuscitation mechanism of the VBNC state remain unclear and thus require further study. The abilities of VBNC cells to evade detection by conventional plate counting techniques, to tolerate stressful environments including food pasteurization processes and antibiotics, and to resuscitate with virulence and cause disease could pose a great threat to food safety and infectious disease prevention. Therefore, the development of rapid, sensitive, cost-effective, and easy-to-operate methods for detection of the VBNC state is an urgent need. In conclusion, the potential application of fundamental research examining the VBNC state is very important to prevent foodborne infections, protect food safety and identify new treatments to reduce the risk of disease caused by foodborne pathogens.XZ, JZ, and TD wrote the manuscript. CW and C-WL participated in its organization and helped to draft the manuscript. XZ, JZ, and TD revised the manuscript critically for important intellectual content. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In heroin injectors, there have been a number of outbreaks caused by spore-forming bacteria, causing serious infections such as anthrax or botulism. These are, most likely, caused by injecting contaminated heroin, and our aim was to develop a filter that efficiently removes these bacteria and is also likely to be acceptable for use by people who inject drugs .A prototype filter was designed and different filter membranes were tested to assess the volume of liquid retained, filtration time and efficiency of the filter at removing bacterial spores. Binding of active ingredients of heroin to different types of membrane filters was determined using a highly sensitive analytical chemistry technique.Bacillus spp., which are spore-forming soil bacteria. To remove these bacteria, a prototype filter was designed to fit insulin-type syringes, which are commonly used by people who inject drugs (PWIDs). Efficient filtration of heroin samples was achieved by combining a prefilter to remove particles and a 0.22 μm filter to remove bacterial spores. The most suitable membrane was polyethersulfone (PES). This membrane had the shortest filtration time while efficiently removing bacterial spores. No or negligible amounts of active ingredients in heroin were retained by the PES membrane.Heroin samples that were tested contained up to 580 bacteria per gramme, with the majority being This study successfully produced a prototype filter designed to filter bacterial spores from heroin samples. Scaled up production could produce an effective harm reduction tool, especially during outbreaks such as occurred in Europe in 2009/10 and 2012.The online version of this article (doi:10.1186/s12954-016-0122-1) contains supplementary material, which is available to authorized users. Bacillus and Clostridium, leading to severe skin and soft tissue infections such as anthrax, wound botulism, gas gangrene and tetanus [Clostridium novyi infection amongst PWIDs in Scotland, with an 87% fatality rate [In Europe, there are around 1.3 million problem opioid users, the majority of whom inject . Since 2ity rate , with fuity rate . Harm reity rate . An alteBacillus and Clostridium species are commonly found in soil, dust and human/animal faeces and are thought to contaminate brown (base) heroin during production, storage and transportation [ortation . CharactBacillus anthracis (the causative agent of anthrax) spores is ~0.8 μm [Many PWIDs filter their heroin before injection, but this only removes particulates to prevent needle blockage and, most likely, reduces small blood vessel damage. Often, PWIDs use homemade pieces of material from cotton wool or cigarettes; these are not sterile and could be a further source of contamination . Some ne ~0.8 μm . Whether ~0.8 μm  thus redBacillus and Clostridium species is contaminated heroin [As mentioned above, the main cause of infections with d heroin –5, 11. Td heroin . These pd heroin , and effwww.ncbi.nlm.nih.gov/nucleotide).To get an indication of the microbial contamination in samples of heroin we obtained from the local police in Bristol from several police seizures across the Avon and Somerset constabulary area, the bioburden was determined using a plate-based method. In brief, 100 mg samples of heroin were suspended in 1.5 mL phosphate buffered saline (PBS), vortexed for 15 min and further diluted tenfold. Fifty microlitres was plated on brain heart infusion (BHI) agar (Oxoid) or Sabouraud agar (Oxoid). To detect bacteria, the BHI agar plates were incubated aerobically at 37 °C for 24 h or anaerobically in a GasPak container (Becton Dickinson) at 37 °C for up to 10 days. To detect fungi, Sabouraud agar plates were incubated aerobically at 28 °C for 7 days. To identify microbial species, the 16 ribosomal RNA gene from a number of colonies was amplified by the polymerase chain reaction (PCR), using OneTaq polymerase (New England Biolabs) and one of three oligonucleotide pairs , 15 mm Minisart RC15 , 13 mm Millex GV  and 4 mm Millex GV  and a Swinnex filter holder . For the latter, we tested all suitable types of membrane that were available with the correct diameter and pore size : hydrophilic polyvinylidene fluoride (PVDF), polytetrafluorethylene (PTFE), mixed cellulose ester (MCE), polyethersulfone (PES) and hydrophilic nylon. Where indicated, membranes were combined with a glass fibre prefilter .To determine the retention (hold-up) volume of filtration devices, heroin samples were prepared as above, and the volume of the solution was measured using a 1-mL insulin-type syringe. After filtration, the volume was measured again with a 1-mL syringe to determine the loss in volume.v/v) to a final concentration of 800 ng/mL with the addition of an internal standard . Heroin in samples was then quantified by liquid chromatography coupled with tandem mass spectrometry) LC-MS/MS using a Waters Acquity UPLC system and Waters Xevo TQD triple quadrupole mass spectrometer with a Chiralpak CBH HPLC column  as described [Heroin samples were prepared as above and the volume of the solution was adjusted to 2 mL with distilled water. The volume used was more than in a normal heroin preparation, which could have increased solubility of active ingredients, but the main aim here was to analyse the effects on concentrations of active ingredients before and after filtration through different types of membranes. This was done by dividing each sample into two aliquots; 1 mL was filtered and the other 1 mL was kept unfiltered. Filtration was performed with Swinnex filter holders and membranes listed above. In each case, the assembly consisted of a prefilter with membrane, except when the prefilter was tested on its own. Heroin samples were diluted with distilled water/methanol , re-suspended in 10 mL water and centrifuged again, re-suspended in PBS and stored at 4 °C.Bacterial spores of ilis 168  were harilis 168  and furtB. subtilis spores were added to a final concentration of ~108 spores/mL. These samples were filtrated, and the flow-through was plated on LB agar plates for enumeration.Heroin samples were prepared as above and The filtration device was made from machine-grade polycarbonate , manufactured using standard machine tools. The two main parts (syringe holder and the filter collar) were screwed together. A butyl rubber O-ring was used around the syringe port to prevent the air leakage (the O-ring).2–3.7 × 104 organisms per gramme heroin [Clostridium spp., were not found, and also, no fungal contaminants were isolated.A critical factor in sterilisation of products such as drugs or food is the bioburden, i.e. the number of microbes contaminating the product. The higher the bioburden, the greater the chance that some viable microbes are still present after a sterilisation process. It is thus important to know the bioburden before any process of removing or killing microbes is employed. A number of studies have shown that 90–95% of heroin samples are contaminated with bacteria (mainly bacilli) without reporting the bioburden (see ), while e heroin . There mBacillus species: three colonies were identified as B. licheniformis, two as B. pumilus, two as B. subtilis, one as B. thermolactis and one as B. massiliosenegalensis. The coccoid organism isolated was identified as Staphylococcus hominis.Gram staining of 20 bacterial colonies from the BHI agar plates showed that all were Gram-positive, with one being coccoid and the remainder rod-shaped. From these, 11 colonies were identified to the species level, using the commonly used method of sequencing of the 16rRNA gene and comparing this to known sequences in a nucleotide database. The rod-shaped bacteria were all identified as In order to remove bacteria (including spores) from heroin, filtration would be the only method that is practical, as the heating of heroin during its preparation does not kill bacterial spores (see below and Ref ). PWIDs We first tested loss of filtration of heroin samples using existing syringe filters that are available for laboratory research. This included standard syringe filters with different diameters  and a Swinnex filter housing which allows for assembly of the filter casing with a 13 mm membrane of choice. In case of the filters with membrane diameters of 13-25 mm, losses ranged from 7.5% (13 mm Millex GV filter) to 44% (Minisart RC25 (25 mm) filter  technique. The main active ingredients were diamorphine DIM 82.2%) and 6-monoacetylmorphine (6-MAM 17.6%), with a small amount of morphine being present (0.2%). Next, we determined the amount of these ingredients before and after filtration through six types of membranes  that were assembled in a Swinnex filtration device. Filtration with most of the membranes showed little or no loss of active ingredients , followed by filtration. After this, samples were tested for contamination with B. subtilis spores by plating on agar plates and incubation at 37 °C. No growth was observed after filtration, demonstrating that the filtration device removed bacterial spores efficiently.We tested the capability of removing bacterial spores from heroin with the prototype filtration device and a PES membrane. To this purpose, a 0.8 mL heroin sample was spiked with n = 3), which cools down to 30 ± 2 °C in 4 min. We tested whether filtration of heroin that was still hot would affect filtration, e.g. by damaging the membrane or enlarging the pore size due to the increased temperature. To test this, heroin samples spiked with B. subtilis spores were heated to 75 °C and then filtrated either immediately or after 10 min of cooling. In both cases, no spores passed through the filter device, showing that temperature of the heroin does not affect the performance of the PES membrane.During preparation, heroin is heated in the presence of acid to aid dissolution. Directly after preparation, we measured the temperature to be 70 ± 5 °C  after heating B. subtilis spores in the standard heroin preparation. These survival rates may not be the same for spores from other bacteria, but a previous study also showed that C. novyi spores survive the heroin preparation process [Notably, heating in the presence of acid and heroin does not affect viability of  process .The prototype filter was tested as well to find out whether it can be re-used, as this is something that should be discouraged due to sharing risks. After using the filter once, a second heroin sample was prepared, and the same filter was used again. We found that the filtration process was not efficient; out of 770 μL heroin sample before filtration, only 100 μL passed through the filter into the syringe. This is due to a layer of particles (filter bed) that formed on the filter membrane during the first filtration process, thus leading to blockage of the device for further use. Thus, the prototype would discourage sharing and reuse. It should be noted that there may be variation in batches of heroin and preparation procedures by PWIDs; reusability with such varying conditions was not tested by us.Bacillus spp., which are sporulating bacteria that are normally found in soil. It is not surprising that mainly sporulating bacteria were found, as production of heroin from opium involves several steps that require heating and treatment with various chemicals [B. anthracis or Clostridium species. One colony was identified as S. hominis; this is a non-sporulating bacterium that is commonly found on skin and it probably contaminated the heroin after production, e.g. during packaging.Heroin contaminated with bacteria may lead to outbreaks of infectious diseases. The majority of the bacteria identified in brown heroin that we obtained from the local police were hemicals , and onlThe number of bacteria found in the heroin that we obtained was ~580 bacteria per gramme, which is within the range that was published before . This doB. subtilis, which is a non-pathogenic relative of B. anthracis (and is thus much safer to work with), with spores that are smaller than those of most other sporulating bacteria, including B. anthracis [B. subtilis spores will thus also efficiently remove spores from most bacterial species.Current options for PWIDs to filter heroin include the use of homemade filters from cigarette filters or cotton pellets or purpose-made filters provided by pharmacies or harm reduction programmes  that remove particulates from heroin , 8, 10. nthracis . Thus, aA limitation of our study was that experiments were performed with heroin prepared in a standardised manner. However, there can be considerable variation between both batches of heroin (e.g. different cutting agents) and heroin users’ practise; such variations were not tested in our laboratory setting.The prototype filtration device was designed in such a way that it would accommodate syringes with fixed needles, such as insulin-type syringes. That would allow for the preparation of heroin in a simple step by directly drawing up heroin through the filter into the syringe, similar to practises currently used by PWIDs who use products such as Sterifilt® filters . Due to We demonstrated that the prototype filter is effectively ‘single use’ because it blocks on reuse, so it could potentially discourage reuse and sharing. This has advantages for PWIDs in terms of reducing health risks. We also showed that the prototype filter does not retain any significant amounts of drug for a standardised heroin sample, and therefore, there is no motive to save them for ‘bashing down’ at a later date when no drug or money is available. This feature may of course make it unacceptable to some PWIDs, who could find this a daunting prospect.We envisage that after user acceptability testing and suitable production scale-up, our filter could form the cornerstone of infection prevention during anthrax or other spore-forming bacteria outbreak amongst PWID. It could be distributed through Needle and Syringe Programmes (NSPs) at the first detection of an outbreak or ideally supplied continuously. If used for every injection, it would make the use of sterile water (used by some PWIDs) less of a necessity, as any microbes and particles, e.g. from tap water, would also be removed during filtration.Infections in PWIDs are common, with one potential source of bacterial pathogens being the heroin itself. There have been several outbreaks of infections by spore-forming bacteria in PWIDs, resulting in high morbidity and mortality. It is thus important to test and develop filtration devices which can remove bacterial spores and prevent such outbreaks. In this paper, a filtration device was developed which removes bacteria and particulates, is potentially easy for PWIDs to use and does not collect active ingredients, thus does not reduce the ‘high’. A future version needs to be streamlined, as the prototype is too bulky and its manufacture would be expensive. Such an improved device could be provided to attract PWIDs to existing injecting equipment programmes (IEPs) across Europe and beyond, especially during an outbreak of anthrax or other spore-forming bacterial infections. The overall aim of our filter is to reduce the health impact of injecting drug use and save healthcare costs.


To identify the elite of authors about the subject adherence to antiretroviral therapy; to identify the journals turned to publishing articles about adherence to antiretroviral therapy; and to identify and analyze the most commonly used words in abstracts of articles about adherence to antiretroviral therapy.A bibliometric study conducted through the Scopus base. We used articles published between 1996 and 2014, after application of the eligibility criteria, there were composed the sample with 24 articles. The data were analyzed descriptively. Were used the laws of bibliometric  and the conceptual cloud map of words, through the program Cmap tools.Lotka’s Law identified the 5 authors more productive . Bradford is impaired in this study. Concerning Zipf, 3 zones were determined, 31.47% of the words with in the first zone, 26.46% in the second and 42.06% in the third. In the conceptual map, the words/factors that positively and negatively influence adherence were emphasized, among them the need for more research in the health services.There are few publications about the accession to antiretroviral therapy, and the scientific production is in the process of maturation. One can infer that the theme researched is not yet an obsolete topic. It should be noted that the Bibliometric was a relevant statistic tool to generate information about the publications about the antiretroviral therapy. Approximately 36.7 millions of people lived with HIV/AIDS in the world, till the end of 2015 ;Human Immunodeficiency Virus) and who have the medical indication to receive it  with 122 occurrences.When applying the first Law of Zipf (k=r.f). 3 zones were determined. In line with the theory, the two first zone should contain, each one, 991 words and the third, with 992. Empirically, achieved 936 words on the first zone (31.47%), 787 on the second (26.46%) and 1.251 on the third (42.06%). It was successively designed by the Zipf law as trivial or basic zone, interesting information, and for the last, noise.The key-words table was ordered according to the frequency that the word occurred and its respective series order (r). Low order of the series corresponds to high words frequency, while the high order of the series corresponds to a low frequency, phenomenon designed by Zipf as the “less effort law”.At the order of series containing two or more different words and with the same frequency, was conducted the pattern “mm”, obtained through the division of the sum of ® by the number of words correspondent to it. The zones are stablished according to the collor, being light gray zone 1, medium gray zone 2 and grey zone 3.n=I1x2/n (n=1). Where In is the occurrence frequency of the word, I1 the total of words occurred 1, and the constant 2 to any language. The results show a little difference between the theoretical and empiric values to the frequencies 2, 3, 4 and 5. In this way, the frequency 2 that should be 152 words was empirically of 164, the frequency 3 from 76 was of 76, the frequency 4 from 46 was 58, and the frequency 5 from 30, was computed empirically 34.The distribution behavior of the words when applying the second Law of Zipf IThe transition point (T) was defined by the calculus of the formula proposed by Goffman. The result obtained was T=28 that, in turn, is located in the first zone, next to the board of the zone 2. This law describe the mathematical relation among the words, allowing classifying them as high and low frequency. The first law of Zipf shows that that, in some moments, there was a constant that proximate among the series orders. (r) The It is observed that were considered factors that influences positively the adhesion to the TARV: Quality of life, Home visits, Pharmacy refill Record, the Electronic monitoring. About the factors that influence negatively the adhesion: Drugs user and Substance abuse, social isolation and the necessity to health services research.In relation to the study publication year, the numbers present a discrepancy during the years. In this context, regarding the antiretroviral therapy, there was the consolidation of the therapeutic standard, from 1996 to 1999, starting from the advent of the new antiretroviral classes, which allowed originating the antiretroviral combined therapy This time, in the temporal clipping established to the study, it is observed that the publications began from 2000, what is passively related not only to the introduction of the TARV combined at the precedent years, but also at the necessary time space to elaboration and study conclusion evolving the thematic. This fact doesn’t prevent the existence of previous publications in 2000 in other data basis, or on the own used basis (Scopus) in a period before 1996.Another relevant fact is that in 2002 was instituted the Global found to the combat against the AIDS, tuberculosis, and malaria, aiming to invest in resources to combat the epidemics from those grievances, including the extension to the access to TARV, providing thus, an increasing at the international consumption of those medications . This po2), was obtained the value equivalent to 0.0387. The oscillation between the publication year and the number of published articles shows a dispersion of the publication throughout the years. This allow us to infer that, although the TARV is a therapeutic modality of world reference at the HIV/AIDS treatment, more than 20 years, it is still published a little at the data basis researched regarding the adhesion to the antiretroviral. This is a concerning result, bearing in mind that it is necessary a continuous elevation to the TARV adhesion so that the viral charge levels can be kept undetectable [Referring to the determination coefficient , the qualitative aspect determined by the index h allows us to infer that the 24 articles manifest on the publication vehicle, so ever relatively shows a quantity little expressive. The journals which the authors published their articles, 33% are stratified in Qualis A1 and A2, while the journals B1 and B2 summed 30%.Although the Lotka Law doesn’t determine in this study a elite group, bearing in mind that quantitatively the minimum percentage of 50of the total production is not produced by the 5 more productive authors, according to the determination of the square root of the total production law (Lotka law), the quality of those authors can be proved through the h index from which deserves to be highlighted that the average of this index among the five more productive authors is 50.5, allowing, thus, infer that the theme is being researched in renamed centers of research, thus, infer that the theme is being researched in renamed researched centers, by researchers of the best lineage. They are: Friedland, G.H. and An-dres, L.A.: Aids program, Yale University, School of Medicine, New Heaven, United States; Bova, C.A: Division of infectious Diseases, University of Massachusetts, Worcester, MA, United States; Davks KL: Department of Health Economics, RTI Health Solutions, Research Triangle Park, NC, United States and Dieckhaus, KD: Department of Infectious Diseases, University of Connecticut Health Center. Farmington, CT, United States.As for the knowledge area, it was noticed that a prevalence of publication on the medicine area. This fact can be related to the therapeutic questions of the HIV/AIDS, seen that it is the doctor professional who is in front of the choice, use and collateral effects of the antiretroviral. However, to promote the integrality of the care in HIV/Aids it is essential that the multi professional team conduct interventions of adhesion tot the TARV, of an articulated way, and above all, with the doctors. In this way, it is reasonable infer that there is few interest by the others professionals who aren’t doctor in research about the TARV adherence, suggesting still that it is not homogenous the professional integration about this thematic .The magazines where classified according to the most impact factor. The journal Clinical Infectious Diseases (CID) appear as the first of the series order of the Bradford table which metrics of the Scientific Journal Rankings – SJRe index h are, respectively, 4.34 and 247. This is stratified on the Qualis/CAPES as A1. Maybe what can justify this classification is the fact that a reference journal in publications on the infectious diseases area, that reaches a great international public with its theme about the clinical descriptions of the pathologies, infection prevention, evaluation of treatments used currently, therapeutic innovations, as well as the diagnostic founds and the treatments that are being conducted.For being a really specific theme (TARV), the production counts with magazines highly specialized, as it is the case of the AIDS magazines, Journal of Acquired Immune Deficiency Syndromes, AIDS Reviews, AIDS and Behavior, Infectious Disease Clinic of North America, AIDS Care-Psychological and Socio-Medical Aspects of AIDS/HIV. Magazines that present also a high impact and, therefore, really desired, in its great majority by cutting-edge researchers, above all the one who produce clinical researches.Regarding the institutions headquarters of the researches, the majority was in the United States of America – USA. This fact can be related to the historical-scientific aspects, in which the USA was the pioneer country on the HIV/AIDS discovery, as well as the studies evolving the antiretroviral. It is still noteworthy that although Africa presents the world greatest indicators of morbid mortality by aids , only a The use of the Cmap tools program provided the construction of the conceptual map which facilitated the reorganization in a graphic and visual way of the key-words contained on the articles abstracts selected by the research, listing thus the factors that influence positively and negatively the antiretroviral therapy adherence.Regarding the positive factors, it is remarkable the word quality of life, according to authors, the Family Health Unity is a space that aims to guarantee the health caring to the users and promote life quality , seen thThe association of the words: Home visits, Directly observed therapy, nursing and Pharmacist, are related to the importance of a multi professional assistance to the patients living with HIV/AIDS and with the actions that could improve the adhesion to the medication therapy, although there are professionals who says that the work overload and the reduced human resources on the health services hinders the home visits, preventing to guarantee a more effective following to those users.We can also quote on the context positive factors to the adherence, the Pharmacy refill Record and the electronic monitoring, which are considered mechanisms of analyses of quantity and periodicity of the acquisition of the medications, besides being an alert to identify which patients present a potential risk to the non medication adherence. Those electronic registers besides verifying the irregular withdraw is possible to identify on the patients reports, the ones who complains and adverse events in relation to the treatment what can generate the therapy discontinuity. This following by the pharmaceutical allows us to observe which patients who continues with the initial scheme, or the ones who passed through changes on the first six months using, what hinders the adherence .Another word found that deserves to be noticed was the sexual HIV transmission, because the knowledge about the transmission of the disease and the increase of the life expectative with the adequacy treatment, are factors that turns possible the health services to work not only in a preventive way, but also on the caring perspective respecting the singularity of the subject .As for the factors that contributes to non adhesion of the antiretroviral therapy, was formed by a group with the words: Drugs user and Substance abuse, the finding of this research corroborates with the study conducted in Bahia that affirmed that the illicit drugs use is statistically related to the non adherence to the treatment .Another word remarked on the key-words of the researched articles, was the social isolation, this can occur due to a failure on the patient support network, what corroborates with the finding the qualitative study conducted with 10 patients living with HIV/AIDS, in which 08 reveals the difficulty on the support network construction, which can be composed by family, partners and friends, this fragile bound is related to the stigma, fear of the prejudice and the difficult to accept the living conditions of those patients .The social isolation is also referred during the medication taking moment, because due to the prejudice the patients who work aims to take the medication alone, due to the great quantity of medications throughout the day, what interferes to the daily life activities, besides causing the forgetfulness, facto that turns the adherence unfavorable .On the actual conceptual map was verified also as support network to the community intervention and the fixed-dose combinations as possibilities to improve the medication adherence.Giving the positive and negative factors that interfere on the TARV adherence, it is important to highlight the necessity of more Health services researches, aiming to spread the importance of the multi professional team and the familiar support network on the TARV adherence.Although that the therapy with antiretroviral is the world therapeutic model of choice to treatment of people living with HIV/AIDS, for almost two decades, it was observed that there are still few publications regarding the adherence to the anti-retroviral, besides the scientific production about this theme is in maturation phase, inferring that it is not about an obsolete theme, conducting, a certain concerning, bearing in mind the importance of the treatment adherence maintenance to the therapeutic success.It is evident that the adherence to the TARV has an aspect considered multi factorial and it implies on the necessity to assistance with multi disciplinary view. However, it was noticed that there is few interest by the health professionals who aren’t doctors in research about the thematic, suggesting that, at least on the scientific area, there isn’t yet a homogeneity regarding this professional integration.The theme is still being researched by renamed researching centers, as well as researchers from the highest lineage, in their majority, of North American origin. However, the adherence to the antiretroviral presented itself for being a research theme with more necessity of accurate results, bearing in mind the majority of the articles found have presented study design with a quantitative approach.It was also verified that the necessity of studies that present as objects the health services to the promotion of the adherence to TARV, and also the focus on the importance of the multi professional team and the familiar support network.It is noteworthy that the bibliometric was a statistic tool extremely relevant to generate information about the TARV publications. In relation to the authors who published about this thematic, the Lotka Law was efficient to list them. It was possible to identify the most used journals to the article publication about the TARV adherence through the Bradford law, finally, to identify the most used words on the articles abstracts, was applied the Zipf law.Given the above, it is noteworthy the importance to conduct studies evolving the TARV adherence, as well as the financing aiming to deepen the aspects and technologies related to this thematic bearing in mind to provide ways to promote health and avoid grievances coming from a low treatment adherence.


Overuse of antibiotics is a major public health problem, contributing to growing antibiotic resistance. Procalcitonin has been reported to be commonly elevated in bacterial, but not viral infection. Multiple European trials found procalcitonin-guided care reduced antibiotic use in lower respiratory tract infection, with no apparent harm. However, applicability to US practice is limited due to trial design features impractical in the US, between-country differences, and residual safety concerns.The Procalcitonin Antibiotic Consensus Trial (ProACT) is a multicenter randomized trial to determine the impact of a procalcitonin antibiotic prescribing guideline, implemented with basic reproducible strategies, in US patients with lower respiratory tract infection.We describe the trial methods using the Consolidated Standards of Reporting Trials (CONSORT) framework, and the rationale for key design decisions, including choice of eligibility criteria, choice of control arm, and approach to guideline implementation.NCT02130986. Registered May 1, 2014.ClinicalTrials.gov  Whether or not to administer antibiotics is a common and challenging clinical decision. Clinical presentations for infectious and non-infectious conditions overlap, and current diagnostic tests are inadequate. Given fears of untreated bacterial illness, clinicians often default to a decision to prescribe antibiotics. This pattern drives antibiotic overuse , 2 and rHost response to bacterial infection includes broad expression of procalcitonin from both immune and parenchymal cells, resulting in elevated serum concentration . Viral iHowever, applicability to US practice is limited due to trial design features impractical in the US, between-country differences, and residual safety concerns . For exaérieux, Marcy-l’Étoile, France), while noting the primary limitation of the meta-analysis was a lack of US clinical trial sites [Current guidelines for procalcitonin guided LRTI care vary from low to moderately strong recommendation  to recomal sites .In November 2014, ProACT  began enrollment in the United States. ProACT seeks to determine the effect of a procalcitonin guideline on antibiotic exposure and adverse outcomes in clinically diagnosed LRTI, using a study design generalizable to US healthcare. This manuscript provides the trial methodology using the Consolidated Standards of Reporting Trials (CONSORT) framework –36, and ProACT is a patient-level, 1:1 randomized, parallel group, 14-center US trial comparing a procalcitonin-guided antibiotic prescribing guideline  to usual care. We chose to test this guideline in a usual care environment where best practice exists and is promoted, in patient encounters with clinical uncertainty regarding antibiotic prescription, and with a design that embraces clinician autonomy. We summarize trial methods in Tables Study staff enroll adult ED patients with a primary clinical diagnosis of acute LRTI, where the treating clinician is willing to consider procalcitonin in antibiotic decision making Table . By targWe exclude patients with conditions where 1) physicians are unlikely to withhold antibiotics , (2) procalcitonin can be elevated without bacterial infection , and (3) follow-up would be difficult  . At study launch, no center routinely used procalcitonin, only 2 centers had procalcitonin clinically available, and no LRTI guidelines recommended routine clinical use of procalcitonin.To standardize study procedures, we provide standardized training and materials plus continuous coordinating center support. We conducted a group investigator and coordinator training meeting at study launch, and individual sessions for two centers that were added subsequently. Training materials are available on the study website. Regular center visits, newsletters, around-the-clock coordinating center access, center monitoring, protocol delivery and procalcitonin guideline adherence reports and feedback were used to further enhance standardization.To standardize procalcitonin measurement, bioMérieux provided the procalcitonin assay equipment, installation, and in-service training. We provided centers with a packet that outlined test result reporting procedures, troubleshooting procedures, frequently asked questions, and study contact information. Each center’s Clinical Laboratory Improvement Amendments (CLIA) certified laboratory measured procalcitonin from plasma  or serumOur overall adherence approach is similar to many quality improvement programs. This design balances enforcement strategies not reproducible in routine care with a completely hands-off strategy that risks trial failure due to study unawareness , 49.For each study procalcitonin blood draw, we track the times for sample collection, and times from sample collection to clinician notification of procalcitonin information. We promote adherence to the study intervention with regular feedback to each center, and identify solutions for rectifying non-adherence.We track clinician adherence to the procalcitonin antibiotic guideline. If antibiotics are prescribed or continued when procalcitonin is low, coordinators query the clinician and record the reasons for non-adherence. We promote adherence to the procalcitonin guideline with regular feedback and discussion with each center. To increase study awareness and guideline adherence, centers in-service trained all clinician groups with primary responsibility for antibiotic prescription for LRTI. Upon discharge from ED or hospital, participants receive a packet that includes a letter to their primary care physician with a study synopsis, their last procalcitonin result, and the procalcitonin guideline.Our primary outcome is total antibiotic exposure, defined as the total number of antibiotic days by Day 30 , mechanical ventilation via endotracheal tube, renal failure , lung aSecondary outcomes include antibiotic initiation by the initial ED clinician, hospital length of stay, 90 day and 1 year mortality, ICU admission and subsequent ED visits by Day 30, and quality of life at day 15 and day 30  analysis, for both hypotheses. ITT can bias towards no difference, which may lead to a false rejection of H2o, which uses a non-inferiority design. We therefore will also perform per-protocol analyses where the procalcitonin guideline was followed, as per CONSORT recommendations . We willp-values for significance. In the U.S., antibiotic use for LRTI is high, and our design excludes common conditions where procalcitonin can be high without infection. Given these two conditions, we believed procalcitonin would not increase antibiotic use over an already high baseline, and initially chose one-sided significance testing. To be conservative and allow for the possibility of increased antibiotic use in the intervention arm, we will conduct and report two-sided p-values. As sample size is driven by the larger requirements of noninferiority testing for H2o, we are well powered to test H1o.For H1o, we will compare the mean number of total antibiotic-days by Day 30 using two-sample t-test, or a nonparametric counterpart if data distribution is not normal, and report two-sided For H2o, we will compare the difference in proportions of the composite adverse outcomes endpoint, relative to a 4.5% non-inferiority margin, and construct a two-sided 95% confidence interval for the difference in proportions. We will declare non-inferiority if the upper limit of the confidence interval is below 4.5%. Non-inferiority hypothesis testing is one-sided. We will report results in accordance with the CONSORT statements.ProACT is the first multicenter U.S. randomized trial of procalcitonin. In designing the trial, we considered three key issues – choice of eligibility criteria, choice of control arm, and approach to guideline implementation.Tests should only be obtained if results may change management . We therTrials should test novel interventions on a background of “best care”. We chose centers with evidence of commitment to LRTI quality care, and disseminated national LRTI guidelines to promote best practice. This approach balances the control arm extremes of “wild type” usual care, versus an “active control” arm with interventional enforcement, consistent with the NIH conference on Considering Usual Medical Care in Clinical Trial Design recommendations .We chose a guideline implementation approach generalizable to U.S. clinical practice. A key difference between ProACT and the largest European LRTI trial is that the guideline recommendation is not deployed using coordinating center “enforcement methods” , 20. InsProACT will provide generalizable evidence on the impact of a procalcitonin guideline, implemented with basic reproducible strategies, on antibiotic exposure and safety in U.S. patients with lower respiratory tract infection.


P = 0.01) and 2–3 months . At 1.5-month follow-up, CSI was associated with improved VAS score compared with physical therapy (PT) . No significant differences in the VAS score reduction were observed between CSI and shock wave therapy within 3 months. In summary, CSI tends to be more effective for pain reduction than non-invasive treatments within 3 months. Moreover, CSI provides significant pain relief at 1.5 months after treatment compared with PT. This study provides important clinical information for selecting therapeutics.The first choice of treatment for patients with plantar fasciitis is non-invasive treatment, rather than corticosteroid injection (CSI). However, no comprehensive study has compared the effectiveness of CSI with non-invasive treatments for plantar fasciitis. We conducted a meta-analysis comparing CSI and non-invasive treatment effects on plantar fasciitis. The primary outcome was pain reduction. Nine randomized controlled trials comparing CSI with 4 non-invasive treatment types were included. A trend favoring CSI over non-invasive treatments was indicated regarding reduction in the visual analogue scale (VAS) score at 1–1.5 (mean difference (MD), 1.70; 95% confidence interval (CI) = 0.39–3.01;  Typical symptoms include pain with the first weight-bearing step in the morning, and the diagnosis can be made clinically. Some clinicians prefer to use the term plantar fasciopathy in lieu of plantar fasciitis to de-emphasise the inflammatory component because pathological examination of the fascia typically reveals degeneration over inflammation2.Plantar fasciitis is the most common cause of inferior heel pain3. Prolonged weight-bearing, obesity, limited ankle joint dorsiflexion, posterior muscle group tightness and maladaptive patterns of walking or running can produce biomechanical stress of the plantar fascia2.Although the cause of plantar fasciitis can be multifactorial, the most common etiology is biomechanical stress of the plantar fascia at its enthesis of the calcaneal tuberosity6, orthosis8, oral nonsteroidal anti-inflammatory drugs (NSAIDs)9, radiation therapy (RT)10 and shock wave (SW)11 and invasive treatments, such as corticosteroid injection (CSI)13, botulinum toxin injection14, platelet-rich plasma (PRP) injection15 and surgery16. PT for plantar fascia comprises stretching exercises and mobilization to improve lower extremity joint mobility and flexibility of the plantar fascia5. Therapeutic ultrasound, a type of PT modality, is applied to the posterior heel to increase tissue circulation and metabolism, and to soften the plantar fascia6. Orthosis includes splinting, enhancing the mechanical control of the foot and ankle7 or providing insoles for shock absorption along the inferior foot8. Oral NSAIDs are known to inhibit cyclooxygenase-2, thereby exerting an anti-inflammatory effect on the plantar fascia to relieve pain9. RT treatments expose the heel area to radiation to reduce inflammation over the treated area10. SW treatment applies high pulse SW energy to the insertion zone of the plantar fascia, potentially healing the degenerative tissue of the plantar fascia11.To date, there are various treatments for plantar fasciitis. Common treatments can be divided into non-invasive treatments, such as physical therapy (PT)13. Botulinum toxin, which is injected in the plantar fascia and gastrocnemius-soleus muscular complex, can reduce the tension in the plantar fascia and relax the muscles14. PRP stimulates the natural healing process by promoting platelet growth factors, thereby accelerating the physiological healing process of the plantar fascia15. Surgical procedures, such as fasciotomy for plantar fascia release16, are usually reserved as last-resort options for treating plantar fasciitis in patients with persistent recalcitrant heel pain after receiving other treatments.Corticosteroid can accelerate the process of pain relief through its strong anti-inflammatory effect. The mechanism of action of corticosteroid, which is administered via injection, involves the inhibition of fibroblast proliferation and ground substance protein expression, which are observed in the pathological features of plantar fasciitis17. Compared to botulinum toxin and PRP injection, CSI is cheaper, more easily prepared and performed and has an acceptable therapeutic effect. There has been no evidence showing that botulinum toxin and PRP injection provided a better therapeutic effect than CSI18. Currently, CSI is still one of the first-line treatments for plantar fasciitis19. Nevertheless, from the viewpoint of patients with plantar fasciitis, if non-invasive treatments could provide a therapeutic effect equal to that of CSI, these patients would choose non-invasive treatments over CSI as their first choice. However, a review of the literature yielded no comprehensive studies comparing the efficacy of CSI with that of non-invasive treatments for plantar fasciitis. Therefore, the present study aimed to conduct a meta-analysis that compared the therapeutic efficacy of CSI and that of non-invasive treatments for plantar fasciitis.A meta-analysis found that CSI provided better pain relief than placebo in treating plantar fasciitis20.This study was conducted in accordance with the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) StatementWe searched the PubMed, EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials, Scopus and Web of Science databases using the following terms: plantar fasciitis, plantar fasciopathy, corticosteroid, steroid and glucocorticoid in the title or abstract from the earliest records up to 22 June 2017. There were no language restrictions.21, has been widely used to quantify heel pain22. The VAS is self-reported, with 0 denoting no pain and 10 denoting the worst possible pain. The exclusion criteria of the present study were as follows: (1) the reporting of studies that combined another treatment with either CSI or non-invasive treatment during the entire treatment period; (2) the article was a case report, review, study protocol, or abstract; or (3) no pain score was reported. Two investigators (C.M.C. and M.L.) developed the selection criteria, and one of them (C.M.C.) conducted the literature search. Another investigator (C.H.L.) assessed these criteria and independently checked the enrolled trials. Discrepancies were resolved by discussion with a third investigator (C.H.L.) and by referencing the original report.The inclusion criteria of the present study were as follows: (1) a study that compared the efficacy of CSI and a non-invasive treatment for patients with plantar fasciitis or plantar fasciopathy, with a non-invasive treatment being defined as one not penetrating the body by incision or injection; (2) a randomized controlled trial (RCT); and (3) a full-text article reporting a pain score, e.g., visual analogue scale (VAS), both before and after the treatments, as well as a pain reduction score  that could be obtained. The VAS, directly reflecting subjective pain experienced at a particular body part23, in which the aggregate score ranged from 0 to 5 points.All data from eligible studies were extracted by 2 independent investigators according to a standard protocol. The extracted data included patient characteristics, treatment regimens, timing of treatment administration and details of outcome measurements. The quality of each RCT was evaluated using the Jadad scaleData were extracted from baseline measurements and at 1–1.5 and 2–3 months after the initial treatment. The mean change in pain reduction score from baseline is the primary outcome. Continuous variables were compared using the mean difference (MD) and accompanying 95% confidence intervals (CIs).I2 ≥ 50%), a random-effects analysis was applied. The Cochrane Collaboration’s Review Manager software package (RevMan 5.3) was used for this analysis. A P-value of <0.05 was considered statistically significant.Where significant heterogeneity existed  twice a day for 4 weeks.At the end of the article selection process, 10 RCTs were included in the qualitative synthesis . VAS score reduction was significantly greater in the CSI group than in the PT group at 1.5-month follow-up . VAS score reduction was significantly greater in the CSI group than in the NSAIDs group at 1-month follow-up . No significant differences were observed in VAS score reduction between CSI and SW at 1–1.5-month follow-up .The present study reported outcomes using VAS. Figure P = 0.003). The difference in VAS score reduction between CSI and NSAID groups at 2 months was significant . No significant differences in VAS score reduction between CSI and SW at 2–3-month follow-up were found .The differences between CSI and non-invasive treatments and the between-group differences in VAS score reduction at 2–3 months are shown in Fig. et al.22, the VAS score in patients who received CSI for plantar fasciitis decreased from 5.46 (pre-injection) to 1.50 (2 weeks post-injection) and 0.77 (2 months post-injection) and then went up to 2.46 (1 year post-injection). Another study12 found that, among patients receiving CSI for plantar fasciitis, VAS scores decreased from 6.44 (pre-injection) to 3.38 (3 weeks post-injection) and then ticked up slightly to 3.63 (3 months post-injection). The time of maximum therapeutic effect with CSI might be <3 months post-injection. We speculate this is the reason why the effect of CSI was not more significant than that of PT at 3 months post-treatment.The present meta-analysis compared the efficacy of CSI and that of non-invasive treatments in the treatment of plantar fasciitis. The major finding of the present study is that CSI resulted in better pain relief from plantar fasciitis than non-invasive treatments at 1–1.5 and 2–3 months after treatment. Another major finding is that CSI had better therapeutic effect in pain relief than PT at 1.5 months after treatment. Although the present study indicated that CSI had better result than did PT in terms of pain reduction at 3 months, no significant differences were observed between CSI and PT at 3 months. In the study by Tsai et al.5 and Ryan et al.4 were the 2 that compared the efficacy of CSI and PT for the treatment of plantar fasciitis in our present study. The PT interventions in the 2 studies were stretching exercises, and participants were individually instructed by a trained therapist initially and the therapist provided follow-ups and patient guidance in sessions thereafter. Celik et al.’s article5 illustrated that patients with plantar fasciitis received 11 times of stretching exercises and joint mobilization for 3 weeks, and significant improvement in pain reduction was detected not only at 3 months but also at 1 year after treatment. We considered the possibility that the effect could last up to 1 year because these patients were advised to repeat the same stretching exercises on their own; however, completion the these self-stretching exercises was not documented. Given the lack of sufficient evidence of the therapeutic effectiveness of PT for plantar fasciitis, more studies focusing on the outcomes, times and types of PT for plantar fasciitis should be conducted in the future.To the best of our knowledge, there have been only a few articles published that discuss the effect of PT on plantar fasciitis. The studies by Celik 25. Theoretically, SW could increase the proliferation of growth factors, peripheral blood circulation, angiogenesis and neovascularization in the degenerative tissue of the heel26, and SW is therefore believed to be effective in the treatment of plantar fasciitis. Moreover, several meta-analyses have documented the advantages of SW over placebo treatments28. Our present meta-analysis yielded no differences in the effectiveness of SW and CSI at 1–1.5 and 2–3 months after treatment. A study29 by Hsiao et al. also found similar results. Hsiao et al.29 reported a better therapeutic effect in CSI than in SW at 3 months after treatment; however, it also did not reach significant difference. Studies comparing SW with CSI for longer follow-up periods, such as 6 months or 1 year, are scarce. An RCT conducted by Porter et al.30, found that both SW and CSI to be effective in reducing pain in treating plantar fasciitis at 12 months after treatment, but the average VAS scores for SW and CSI at 12 months after treatment were similar. Still, more studies comparing the long-term therapeutic effect of the 2 treatments are needed.Currently, plantar fasciitis is considered not only an inflammatory condition but also a degenerative process31, which was published in 1996, mentioned the use of SW for plantar fasciitis treatment, and many studies35 comparing the effectiveness of SW and CSI for plantar fasciitis were published after that one. One meta-analysis27 suggested that setting the highest and mostly tolerable energy output within medium-intensity range (energy flux density 0.08–0.28 mJ/mm2) is the ideal alternative when applying focal SW therapy on plantar fasciitis. One of the 5 RCTs comparing the effectiveness of SW and CSI in the present study used low-intensity SW and 4 used medium-intensity SW in their SW groups. Of the 4 RCTs comparing SW and CSI at 3 months, all used medium-intensity SW in their SW groups. Thus, it seems that even in using the most effective SW therapeutic range, pain reduction in SW was not greater than that observed in CSI.The earliest article included in the literature review36 or splinting38, for plantar fasciitis treatment. However, only one study, by Yucel et al.8, has compared the therapeutic effect of insole use and CSI, and it showed that pain reduction was better in the CSI group than in the insole group 1 month after treatment. However, head-to-head comparison studies between orthosis and CSI for plantar fasciitis remain scarce. Wearing an orthosis for plantar fasciitis treatment usually takes long treatment period. Currently, no standard guideline exists on how many times a day and for how many days an orthosis should be worn to achieve the desired therapeutic effect in treating plantar fasciitis. The major problem that researchers encounter when they study this topic is that of measuring patient compliance.Previous studies have discussed the efficacy of orthosis, including insole39. Another head-to-head study, by Biswas et al.9, comparing oral NSAIDs and CSI showed that pain relief was significantly greater after CSI than after oral NSAIDs, and the recurrence of heel pain was significantly higher in the oral NSAID group9. This study9 was the only trial included in the meta-analysis that compared VAS score reduction in CSI and NSAIDs. Our results also favored CSI, although it was limited to a single trial comparison. Considering the side effects of oral NSAIDs and their limited therapeutic effect, NSAIDs as a treatment option for plantar fasciitis depend on the risk and benefits evaluation done by the clinician.Although oral NSAIDs are frequently prescribed to patients with acute or chronic musculoskeletal or soft tissue pain, current evidence does not support its efficacy in treating plantar fasciitis. A randomized, prospective, placebo-controlled study showed that there were no statistically significant differences between the placebo and oral NSAID groups in pain relief at 1, 2 or 6 months10. Head-to-head comparison studies between RT and CSI for plantar fasciitis are also rare. In a study by Canyilmaz et al.10, patients with plantar fasciitis randomly received either RT  or CSI (1 injection with 1 mL of 40 mg methylprednisolone and 0.5 mL of 1% lidocaine), and the results in the RT group were significantly superior to those in the CSI group  at 3 and 6 months after treatment. Although evidence suggests that the risk of cancer following low to intermediate RT for benign disease is small, caution must be exercised when considering RT use in younger adults40. Niewald et al.41 enrolled 127 patients to receive either a standard dose or a very low dose of RT for plantar fasciitis, in which 9 patients (7%) had to be excluded after randomization because they withdrew their informed consent to radiotherapy. Obtaining patients’ consent to RT in treating plantar fasciitis is still challenging.Because of its known anti-inflammatory effects, RT has been used for >60 years. However, its exact mechanism remains unknownet al.30 and Yucel et al.35 reported that 8 and 4 patients, respectively, required analgesia due to pain after CSI. In the study by Biswas et al.9, 60 patients received CSI, 6 reported injection site erythema, 2 reported injection site infection and 2 reported plantar fascia rupture. In total, 316 patients in the 9 RCTs received CSI, of which 2 patients (0.6%) reported plantar fascia rupture and 2 (0.6%) reported injection site infection. CSI provides some relief from pain, but can be associated with severe complications. A retrospective chart review showed that, after an average of 2.67 blind injections of steroid, 2.4% of patients with plantar fasciitis (3/123) experienced plantar fascia rupture42. However, some non-invasive treatments would also result in side effects or complications. In a study by Porter et al.30, 6 patients reported throbbing pain and erythema and 4 reported severe headache or migraine after SW. Yucel et al.35 also reported that 2 patients had a mild throbbing sensation that lasted for an average of 5 days and another 2 had mild erythema after SW. Biswas et al.9 reported that 40 patients had gastritis, 5 had esophagitis, 8 had pruritus and 5 experienced bloating after oral NSAIDs.Of the 9 RCTs, only a few articles mentioned the complications after treatments. Porter There are some limitations to our meta-analysis. First, due to the limited number of trials, not all non-invasive treatment options could be included. Therefore, the non-invasive treatments covered in the present study may not represent all types of non-invasive treatments, and the results of comparing CSI with certain non-invasive treatments other than SW, PT, insole and NSAIDs could not be obtained. Second, outcome measurements, other than VAS, were not universally used in all included trials. Without these data, we could not discern the comprehensive outcome of various treatment options in patients with plantar fasciitis. Third, because the included trials lack long-term data, we could provide only short-term (i.e. up to 3 months) comparison data. Despite these limitations, our study demonstrates a clear comparison of therapeutic outcome between CSI and non-invasive treatments for plantar fasciitis and provides important information to clinicians that could be useful in the selection of therapeutic options.In conclusion, compared with non-invasive treatments, CSI treatment for plantar fasciitis is associated with short-term (i.e. 3 months) pain reduction. CSI is superior to PT in relieving pain at 1.5 months. CSI and SW have similar probabilities of providing pain relief within 3 months of follow-up. Large-scale, well-designed RCTs comparing different non-invasive treatment options with CSI, with various objective outcome assessments and longer follow-up, are required in the future.


We studied non-response rates to antibiotics in the under-reported subgroup of adolescents aged 12 to 17 years old, using standardised criteria representing antibiotic treatment failure. Routine, primary care data from the UK Clinical Practice Research Datalink (CPRD) were used. Annual, non-response rates by antibiotics and by indication were determined. We identified 824,651 monotherapies in 415,468 adolescents: 368,900 (45%) episodes for upper respiratory tract infections (URTIs), 89,558 (11%) for lower respiratory tract infections (LRTIs), 286,969 (35%) for skin/soft tissue infections (SSTIs) and 79,224 (10%) for acute otitis media (AOM). The most frequently prescribed antibiotics were amoxicillin (27%), penicillin-V (24%), erythromycin (11%), flucloxacillin (11%) and oxytetracycline (6%). In 1991, the overall non-response rate was 9.3%: 11.9% for LRTIs, 9.5% for URTIs, 7.1% for SSTIs, 9.7% for AOM. In 2012, the overall non-response rate was 9.2%. Highest non-response rates were for AOM in 1991–1999 and for LRTIs in 2000–2012. Physicians generally prescribed antibiotics to adolescents according to recommendations. Evidence of antibiotic non-response was less common among adolescents during this 22-year study period compared with an all-age population, where the overall non-response rate was 12%. Microbial resistance in adults and children is increasing worldwide, posing a major threat to public health . NumerouIn order to address non-response to antibiotic treatment, it is essential that patterns of non-response are understood. Microbial resistance typically affects hospitalised patients, more so than in primary care settings, although antibiotics are routinely prescribed for respiratory tract infections in both primary and secondary care . ConsideConcern regarding the effectiveness of antibiotics in adolescents has emerged. During clinical development, this age group is often studied less thoroughly than children aged 12 years and younger. Failure to respond to antibiotics does not necessarily imply a causal association with antibiotic resistance . Many paIn our previous study  marking Data were extracted from the Clinical Practice Research Datalink (CPRD), a longitudinal anonymised research database drawn from nearly 700 primary care practices in the UK. This database contains demographic, diagnostic, treatment and referral information for approximately 8% of the UK population .The data used in this study was a subgroup of the dataset from our recent study  and consThe current study received ethical approval from CPRD’s Independent Scientific Advisory Committee on 31 October 2013, protocol number 13_168R.Prescriptions for antibiotics were selected for four relevant infection classes: upper respiratory tract infections (URTIs), which included tonsillitis, laryngitis, pharyngitis and sinusitis; lower respiratory tract infections (LRTIs), including pneumonia, whooping cough and bronchitis; skin and soft tissue infections (SSTIs), including acne, abscesses, impetigo and cellulitis; and acute otitis media (AOM). These categories were the same as in our previous study . The indAntibiotic monotherapy episodes were defined here as one or more consecutive prescriptions for a single antibiotic separated by no more than 30 days and uninterrupted by prescriptions for other antibiotic drug substances. Only first-line monotherapies, i.e. where there were no prescriptions for a different antibiotic in the 30 days prior to initiation, were included in this study. Monotherapy episodes were excluded if they began before 1991 or after 2012, or if the interval from the later of the patient’s registration date and the practice’s up-to-standard date to initiation was less than 365 days.In a separate procedure (not illustrated), we measured background infection rates over time for each infection class as the proportion of all GP consultations in which the GP recorded a diagnosis of that infection in adolescents. Additionally, we determined the proportion of these infection-related consultations in which an antibiotic was prescribed. The prescription pattern of the five most commonly prescribed antibiotics over the research period in each infection is presented. For each year of the studied period, we evaluated the proportion of antibiotic monotherapies that resulted in treatment non-response. We defined antibiotic treatment non-response as the earliest occurrence of any of five events: (1) prescription of a different antibiotic within 30 days of the initial antibiotic prescription; or (2) GP record of admission to hospital with a diagnosis of infection within 30 days of initial antibiotic prescription; or (3) GP referral to an infection-related specialist service within 30 days of initial antibiotic prescription; or (4) a GP record of emergency department visit within three days of antibiotic initiation; or (5) a GP record of death with an infection-related clinical code, within 30 days of initial antibiotic prescription.Treatment non-response rates are presented overall and for the five most frequently prescribed antibiotics within each infection class. Over the 22 years observed, the number of patients and participating practices increased, requiring treatment non-response rates to be averaged over the first five-year period (1991–1995) in order to create a more stable baseline for comparison with those in the last five-year period (2008–2012).Treatment non-response rates were presented as standardised ratios of observed rates to predicted rates for each year, using 1991 as the index year. Standardised ratios were adopted because of variations in antibiotic prescription patterns and age dispersion. Indexed treatment non-response rates were calculated using a matrix of infection subclass, antibiotic drug and gender; rates from 1991 were used to predict expected number of treatment non-responses, and, subsequently, to calculate the ratio.In this study 824,651 antibiotic monotherapies were prescribed to 415,468 adolescents. Of these, 368,900 (45%) therapies were for URTIs; 89,558 (11%) for LRTIs; 286,969 (35%) for SSTIs; and 79,224 (10%) for AOM . The mean age of the adolescents in 1991–1995 was 14.5 years (Standard deviation (SD) 1.7 years) and in 2008–2012, 14.8 years (SD 1.7 years) . Those wWithin the LRTI infection class, the proportion of co-medications increased from 1991–1995 to 2008–2012 from 2.8% to 8.0% for systemic corticosteroids, 22.3% to 29.4% for bronchodilators and 9.8% to 16.3% for inhaled corticosteroids. The proportion of co-medications in the other three infection classes remained generally constant from the first to the latter five-year period. The proportion of adolescent smokers was high (20%–27%) in the 1991–1995 period, but decreased to 5%–12% in the period 2008–2012 .p < 0.01). The change in consultation rates varied by type of infection. Rates of consultations per 1000 patients per year decreased from 251 to 110 (p < 0.01) for URTIs, from 46 to 16 (p < 0.01) for AOM, and from 50 to 20 (p < 0.01) for LRTIs. Consultation rates for SSTI increased from 129 to 137 consultations per 1000 patients per year (p < 0.01).GP consultation rates for the four infection classes, with or without antibiotic treatment, decreased over time . The allThe five most frequently prescribed antibiotics were amoxicillin (27.3%), penicillin-V (24.2%), erythromycin (11.3%), flucloxacillin (10.5%) and oxytetracycline (5.9%). Lymecycline (4.1%), co-amoxiclav (1.5%), doxycycline (1.4%) and clarithromycin (1.3%) were less frequently prescribed; the remaining antibiotics were prescribed in even lower quantities and they are reported together in a combined group termed “Others” (12.5%).The prescription pattern of the most frequently prescribed antibiotics in each infection class, for each year between 1991 and 2012 is illustrated in In adolescents, skin and soft tissue infection prescriptions were more prominent than in the original, all-age study (35% vs. 23%), with therapies associated with acne comprising more than half of the antibiotic therapies in the adolescent study . By contA consistent prescription rate over the 22 years was generally observed in the five most frequently prescribed antibiotics for URTIs. However, antibiotics prescribed for SSTIs showed a varying pattern over time . For exaThe most frequently prescribed antibiotics in each infection class remained the same from the first five-year period to the last five-year period, albeit with changes in their ranking of relative frequency . PenicilThe overall antibiotic non-response rate for the four infection classes was 9.5%, with a non-linear increase from 9.3% in 1991, peaking at 11.0% in 1995, and then declining to 9.2% in 2012. In 1991, the treatment non-response rates were 11.9% for LRTIs, 9.5% for URTIs, 7.1% for SSTIs and 9.7% for AOM. In 2012, treatment non-response rates were 11.4% for LRTIs, 9.4% for URTIs, 8.4% for SSTIs and 9.8% for AOM . SSTIs hThe two most frequently prescribed antibiotics for URTIs, penicillin-V and amoxicillin, both had stable non-response rates, ranging from 7% to 11% over the study period . Within For AOM, the treatment non-response rates of amoxicillin, erythromycin and co-amoxiclav remained stable over time . In contAfter adjusting for antibiotic, index year and infection class, the rate of LRTI treatment non-response initially increased by 9% from 1991 to 1992 and then decreased from 1992 to 2012 by 28.3%. For SSTIs, URTIs and AOM, rates of antibiotic treatment non-response decreased from 1991 to 2012 by 40.5%, 10.2% and 19.6%, respectively. The overall adjusted treatment non-response rate decreased by 21.5% over the study period .This study examined non-response, in adolescents, to antibiotics prescribed for four common infection classes. We found that primary care physicians prescribe antibiotics to adolescents as they do for adults, rarely prescribing non-recommended compounds. In general, response to antibiotic treatment in adolescents was better than that in the all-age population.We selected data for patients aged from 12 to 17 years from the dataset created for our original CPRD study  and analThe most frequently prescribed antibiotics for upper respiratory tract infections in adolescents—penicillin-V, amoxicillin, erythromycin, co-amoxiclav and clarithromycin—were also frequent choices in the original cohort, and these are also listed in the guidelines as primary choices for bacterial infections . HoweverLower respiratory tract infections were uncommon in adolescents (only 2.6% of the infections). The antibiotics most frequently prescribed for lower respiratory tract infections: amoxicillin, erythromycin, co-amoxiclav, clarithromycin and doxycycline, were also the most frequently prescribed in the original cohort. Non-response rates for amoxicillin and the macrolides erythromycin and clarithromycin in adolescents were stable and at or below 10% throughout the study period, whilst in the original cohort, the respective non-response rates were between 15% and 20%, probably reflecting the large proportion of older and frailer patients.During the first five years of the study period, many different antibiotics were prescribed for the treatment of skin infections in adolescence. Over time and with the introduction of lymecycline in the UK in 1996, the pattern of prescription for this infection class became more defined, with flucloxacillin and lymecycline together being prescribed in more than half of the cases.In acute otitis media in adolescents, the top five antibiotics were amoxicillin, erythromycin, co-amoxiclav, penicillin-V and clarithromycin. In these adolescents as well as in the original study cohort, the majority of cases of AOM in the last five years of the study were treated with amoxicillin (80%). Amoxicillin, erythromycin and clarithromycin had the lowest average treatment non-response rates, between 8% and 11%, over the last five years of the study; these rates were lower than those reported for the original cohort. Most respiratory tract infections managed in UK primary care are viral in origin, therefore a large proportion of the infections included in our study would not have responded to antibiotic treatment. Surveillance linked to clinical findings and outcomes was not carried out on a systematic basis during this time period in the UK. We do not therefore know whether changing pathogens and antibiotic sensitivities could have accounted for in the trends described. Point-of-care tests are not used in UK primary care for respiratory tract infections. The numbers consulting with coughs and colds as well as the proportion of coughs and colds treated with antibiotics in primary care increased between 2004 and 2011 .The adolescents formed a small subgroup of the original, all-age population and they were not excluded from the overall population values reported here. Had we compared the adolescent subgroup with the original population minus adolescent patients, the comparisons might have been more distinct. Differences observed here may therefore be somewhat underestimated but are still valid. For infections requiring long-term antibiotic use, our algorithm may be overestimating rates of non-response because the prescription of different antibiotics in ongoing therapy would have been taken to signify non-response. Similarly, some infection episodes may have been misclassified as non-responsive because the initial therapy was followed within 30 days by the prescription of another antibiotic for a different indication.Adolescents prescribed antibiotics are usually clinically managed as adults, and research on antibiotic non-response in this age group is scarce. In this study, we evaluated antibiotic prescription patterns and non-response rates for the treatment of four common infection classes in adolescents. Our data suggest that primary care physicians prescribe antibiotics to adolescents in line with current guidelines regarding initial prescriptions and, using our definition of antibiotic non-response, that adolescents respond generally better to these antibiotics compared with the general population as a whole. Non-response to antibiotics does not imply a causal link with antibiotic resistance, as many of the infections for which antibiotics are prescribed are viral. However, antibiotic resistance may be relevant in a minority of infections, and knowledge of non-response rates may be useful to inform discussion with patients about potential risks and benefits of antibiotic treatment for common infections.