Widespread antimicrobial use and concomitant resistance have led to a significant threat to public health. Because inappropriate use and overuse of antibiotics based on insufficient knowledge are one of the major drivers of antibiotic resistance, education about prudent antibiotic use aimed at both the prescribers and the public is important. This review investigates recent studies on the effect of interventions for promoting prudent antibiotics prescribing. Up to now, most educational efforts have been targeted to medical professionals, and many studies showed that these educational efforts are significantly effective in reducing antibiotic prescribing. Recently, the development of educational programs to reduce antibiotic use is expanding into other groups, such as the adult public and children. The investigation of the contents of educational programs for prescribers and the public demonstrates that it is important to develop effective educational programs suitable for each group. In particular, it seems now to be crucial to develop appropriate curricula for teaching medical and nonmedical  undergraduate students about general medicine, microbial virulence, mechanism of antibiotic resistance, and judicious antibiotic prescribing. Immunologist Frank Macfarlane Burnet in 1953 predicted the “virtual elimination of infectious disease as a significant factor in social life” . HoweverHowever, misuse or overuse of antimicrobial agents is still prevalent and acts as a significant contributor to the emergence of antibiotic resistance . AntimicAntibiotic resistance is no longer just a hospital problem . The comTherefore, the multifaceted approach that combines education of children, campaigns for the adult public, and antibiotic stewardship programs for medical professionals should be conducted. In this review, we will examine the importance of educating prescribers and the public (adults and children) and discuss some relevant aspects, including the content of teaching programs, training the trainer, and evaluation of program effectiveness.http://www.nice.org.uk), Canadian Agency for Drugs and Technologies in Health (http://www.cadth.ca), Current Controlled Trials , and BioMed Central . We used keywords as search terms. We combined terms for selected indications . The literature search included all studies published in English between 1983 and 2014. We identified 28 randomized controlled trial (RCT) studies containing clinician education. In addition, recent articles pertaining to educational programs for teaching prudent antibiotic use were also examined.To assess the effectiveness of clinician education, we used the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA)  in our rTo examine the effectiveness of educational strategies, we searched a variety of studies assessing the effectiveness of education programs that currently work. Because most educational efforts were focused on clinician education, we first searched RCT studies assessing the effectiveness of clinician education programs alone or combined with other strategies, using the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA). We identified 28 RCT studies containing clinician education. Most studies showed that reduction in antibiotic prescribing was achieved through interventions focused on clinician education programs, such as interactive seminars , mailingIt is hard to compare effectiveness between educational strategies and to conclude definitely which educational intervention shows better outcome, because of the differences between the participants' characteristics. Nevertheless, when effectiveness between educational interventions was compared, reduction rates of antibiotic prescribing through educational programs are as follows: interactive seminars, 25%; mailing campaigns, 9%; small-group education, 52%; educational outreach visit, 30%; guidelines and leaflets, 42%; combination, 23%. Therefore, the intervention containing small-group education seems to be most often effective. Despite these results, the effectiveness of clinician education without combining with other strategies remains controversial, because several studies have shown no significant effect on antibiotic prescription after education , 34.To minimize misuse or overuse of antibiotics in hospital, besides clinician education, there are a number of intervention programs, such as patient education, delayed prescriptions, audit and feedback, clinician reminder and decision support system, and financial and regulatory incentives or disincentives. Various studies to evaluate the effect of multifaceted interventions combined with other strategies such as audit and feedback intervention have also been published. The effectiveness rates of combined education intervention were tested in combination with other strategies, including patient education , 36, delBecause human behaviors are affected by complex factors, such as attitudes and beliefs, a close collaboration with behavioral and social sciences is required when developing an educational intervention program . FurtherIn contrast to extensive studies about the effectiveness of clinician education, there were only several studies about the effect of educational programs for undergraduate medical students, the public, or children. Unfortunately, there is no RCT study assessing the effectiveness of educational programs for these groups. Furthermore, as far as we know, there is no study measuring the effectiveness of an educational program on prudent antibiotic prescribing for medical students. There have been several formal evaluations of public campaigns aimed at improving antibiotic prescribing. Some successful campaigns directed to the general population have led to a substantial reduction in prescribing in Australia , 44, theSeveral studies aimed to evaluate the effectiveness of school educational programs in improving student's knowledge of judicious antibiotic use. In the Czech Republic, France, and England, the study to evaluate the efficacy of the e-Big teaching pack showed that the junior e-Bug teaching pack demonstrated a significant improvement in student's knowledge in all sections, and this knowledge was retained 6 weeks later . HoweverIn conclusion, many RCT studies demonstrated that clinician education to reduce antibiotic prescribing is fairly effective, regardless of the type of educational programs. However, there is no RCT study assessing the effectiveness of educational programs for the public or children. This may be caused by the fact that up to now most of the effort has been put into the development and assessment of educational programs for physicians in hospitals. Therefore, for the development of effective educational programs for other groups as well as physicians, we will summarize current educational programs and investigate the missing aspect of educational programs for prudent antibiotic use.A lack of knowledge about antibiotics may significantly affect the quality of prescribing . NeverthA recent WHO report emphasizes the importance of undergraduate training courses in prudent prescribing of antibiotics . In someβ-lactamase- (ESBL-) producing and carbapenemase-positive Enterobacteriaceae strains in food animals [We must also consider the antibiotic prescriptions for animals and agriculture. Antibiotics have also been used in veterinary medicine since the first commercial antibiotic became available for the treatment of human disease . Althoug animals , 64. TheBecause perceived patients have an increasingly participative role in the decision to prescribe in general practice , 66, eduBecause children have relatively more creative inquiry-based activities to promote active learning, all junior (7–11 years) and senior 12–15 years) groups who need to undergo compulsory education are the most appropriate target group for education about prudent antibiotic use. Although most countries have the curricula covering the topic of human health and hygiene, limited information about prudent antibiotic use and limitations of antibiotics were provided within compulsory education. However, many recent programs in Europe and the United States have been directed to the education of children , 12, 61.–15 yearsUp to now, considerable effort has been put into education of physicians in hospitals. To optimize antimicrobial therapy and reduce antimicrobial resistance, many institutions conduct antimicrobial stewardship programs (ASPs) which are executed by multidisciplinary antimicrobial utilization teams comprising physicians, epidemiologists, pharmacists, microbiologists, and infectious disease specialists . ASPs ar European Antibiotic Awareness Day and provided the toolkit containing template materials and evidence-based educational key messages (http://ecdc.europa.eu/en/eaad/Pages/Home.aspx).In view of educational postgraduate course, training the prescribers of antibiotics in the community is also important. Internship/foundation training or close collaboration between local healthcare providers and academicians can give the opportunity for educating the prescribers in the community. For example, an open-access curriculum containing a series of postgraduate courses and workshops has been developed in the context of the European Union funded research project “Genomics to combat resistance against antibiotics in community-acquired lower respiratory tract infections in Europe (GRACE)” . The webSome studies suggest that educational outreach visits using an academic detailer to meet face-to-face with the health professional in the community can be effective , 71. TheUntil now, little attention has been given to the education of medical students. Recently, some reports evaluating medical students' perceptions, attitudes, and knowledge about antimicrobial prescribing and resistance have been published. In the United States, 92% of 317 medical students agreed that strong knowledge of antimicrobials is important in their careers, and 90% said that they would like more education about appropriate prescribing of antibiotics . Similarhttp://www.pause-online.org.uk), a website of shared standardized teaching materials for prudent antimicrobial prescribing, was developed for the undergraduate medical curriculum [Rather than formal lectures, interactive learning in the format of problem-based learning with case vignettes can be suitable for this topic. For example, the University of Nijmegen (Netherlands) offers a program-based module on antibiotic policy for third year students, treating the history of infectious diseases, hygiene and infection control, antibiotic guidelines, and principles of prophylaxis . In addirriculum .A number of research reports investigated the level of knowledge, attitude, and behavior regarding antibiotic of the general public around the world –79. In I European Antibiotic Awareness Day since 2008 (http://ecdc.europa.eu/en/eaad/Pages/Home.aspx). In the United States, the CDC's Get Smart: Know When Antibiotics Work has been conducted (http://www.cdc.gov/getsmart/) as well. These public campaigns can contribute to the habit of more careful use of antibiotics in outpatients, at least in high-income countries [In last decade, to improve the public's knowledge of antibiotics, various national campaigns through several media  have been directed to educate the public. For example, the ECDC has annually conducted theountries . Severalountries , 54. In ountries , 54. Howountries .β-lactam antibiotic [In many countries, antibiotic prescribing rates for children are the highest . A reportibiotic . In the tibiotic . The majtibiotic  and the tibiotic .Programs directed to children education have been developed as follows: e-Bug in Europe, Do Bugs Need Drugs? in Canada, and the Microbes en question in French. The e-Bug, the European commission-funded antibiotic teaching resource , is a reThe e-Bug resource aims not only to educate children about prudent antibiotic use, but also to educate them about hygiene and the spread of infection, thereby allowing them to protect themselves from many common childhood illness through appropriate hand and respiratory hygiene . This teTo reinforce learning, many of the core messages in the senior school pack are the same as in the junior school pack, but the senior school pack also incorporates different activities and explores the issues in much greater depth. Furthermore, to allow for a range of abilities within a school, or in home-based work, extension activities are always included in each lesson plan . To provhttp://www.e-Bug.eu). This website also contains video clips of pack activities, student computer games, and presentations for teacher use. The junior game was developed as a platform game and the senior game was developed as a story-based detective game [To distribute free e-Bug packs to all schools across Europe and beyond, all the pack materials can be downloaded directly at the e-Bug website . ESGAP has published its effort in making an inventory of easily accessible available websites, which may be helpful to anyone who is willing either to implement or to improve hospital-based antimicrobial stewardship programs or to educate hospital professionals about better antimicrobial practices [In hospitals, a multidisciplinary core group, including infectious-disease's specialists, microbiologists, pharmacists, and antibiotic stewardship team, must be involved in the development and implementation of a local educational program on prudent antibiotic prescribing . A multiractices , 95. ESGSchool teachers and nurses delivering the educational sessions on prudent antibiotic use must also be trained. On a national level, a policy for educating school teachers and nurses should be required. For example, Public Health England is currently producing a series of “train the trainer” materials aimed at informing school nurses and others about how to educate school children about hygiene, the spread of infection, and prudent antibiotic use . ParticiUntil now, most educational efforts have been targeted at medical professionals  after their training and at the adult public . In the  Clostridium difficile infection and the spectrum of activity of commonly used antibiotics. These results suggest that there are deficiencies in the medical school's curricula and addressing these deficiencies by standardization of medical school's curricula is required [A 24-item electronic survey of fourth year medical students at the three medical schools  in the United States showed that the majority of students did not know the appropriate management of complicated urinary tract infections or antimicrobial-resistant infections . Only harequired . Developrequired .http://www.wakehealth.edu/AS-Curriculum). This curriculum contains materials for the preclinical and clinical years of instruction. For the clinical years, the curriculum contains five small-group activities that highlight antibiotic stewardship principles through case-based scenarios and management of common infections where antibiotics are often misused [Basically, the main educational elements for prescribers described in  misused .To manage antibiotic resistance, continuous efforts to educate people about judicious antibiotic use are important. Up to now, most educational efforts have been targeted to medical professionals and to the adult public. However, because medical professionals and adults have already established their knowledge, attitudes, and behaviours about antibiotic use, it is difficult to change their deeply established views and behaviours. Thus, in the past few years, a variety of programs to educate children has been made. Many studies showed that these educational efforts targeted to medical professionals, the adult public, and children are fairly effective in improving serious misunderstandings about antibiotics and reducing its use. However, novel antibiotics introduced in the market are still rare and pathogenic bacteria are adapting quickly to existing antibiotics, particularly to antibiotics acting on the Gram-negative bacteria . Therefo


Primary care providers were familiar with recommendations for antibiotic drug selection for common infections, but do not always comply with them. Appropriate selection of antibiotic drugs is critical to optimize treatment of infections and limit the spread of antibiotic resistance. To better inform public health efforts to improve prescribing of antibiotic drugs, we conducted in-depth interviews with 36 primary care providers in the United States  to explore knowledge, attitudes, and self-reported practices regarding antibiotic drug resistance and antibiotic drug selection for common infections. Participants were generally familiar with guideline recommendations for antibiotic drug selection for common infections, but did not always comply with them. Reasons for nonadherence included the belief that nonrecommended agents are more likely to cure an infection, concern for patient or parent satisfaction, and fear of infectious complications. Providers inconsistently defined broad- and narrow-spectrum antibiotic agents. There was widespread concern for antibiotic resistance; however, it was not commonly considered when selecting therapy. Strategies to encourage use of first-line agents are needed in addition to limiting unnecessary prescribing of antibiotic drugs. Antibiotic prescribing guidelines establish standards of care, help focus efforts on quality improvement, and have been shown to improve patient outcomes  are outdated and focus on non-US–based physicians; they do not include nurse practitioners or physician assistants, who together comprise >25% of the US primary care workforce , and physician assistants (PAs) from a nationwide marketing database in the United States. We initially contacted and screened potential participants , family medicine (n = 9), and internal medicine (n = 9). Among PAs (n = 4) and NPs (n = 5), 6 practiced in family medicine setting and 3 practiced in pediatrics. Provider specialty, years in practice, and demographic information are described in Interviews were conducted during May 2013. One professional moderator who had >25 years of moderating experience conducted all interviews. Based on a discussion guide prepared by our research team (data not shown), participants were first informed of the sponsoring organization , the planned use of data, and presence of listeners; they were then asked “warm-up” questions about the practice setting in which the participant worked and the patient populations whom they served. Next, each interview proceeded through an ordered list of open-ended questions on self-reported antibiotic prescribing practices, perceived prescribing practices of their peers, attitudes toward clinical practice guidelines for common bacterial infections, knowledge of narrow- versus broad-spectrum antibiotic agents, preferred resources and methods for medical education and antibiotic treatment, and attitudes toward antibiotic resistance.Participants were provided a worksheet before the interview . This study was reviewed and approved for exemption status by the Human Research Protection Office of the Centers for Disease Control and Prevention.We conducted 36 interviews, each lasting ≈45 minutes. Through analysis of provider in-depth interviews, several common themes regarding antibiotic prescribing and antibiotic resistance were identified .PCPs generally cited little difficulty selecting antibiotic treatments for common infections, but indicated that allergies, complicated medical histories, and recurrent infections regularly make antibiotic selection more challenging. Previous experience and familiarity with an agent were frequently cited as influential factors when choosing antibiotic therapy. Results from the ranking exercise suggest that illness severity, medical history, and clinical practice guidelines were important considerations across all specialties.When asked why their peers made inappropriate choices regarding antibiotic selection, responses varied. The most common perceived reasons for inappropriate antibiotic prescribing were pressure from patients or parents; desire to prevent litigation as a result of complications of infections; concern for patient or parent satisfaction with the visit; and perceived decreases in visit length. Illnesses for which participants believed appropriate antibiotic selection was more difficult for their peers included sinus infections and recurrent urinary tract infections.Broad-spectrum agents were widely thought to be more successful for curing an infection than narrow-spectrum antibiotics. One participant noted that broad-spectrum antibiotics are often chosen because less uncertainty exists regarding the adequacy of antimicrobial activity, which is why they may be commonly selected even if a narrow-spectrum agent is indicated. When asked whether antibiotic spectrum was a consideration when prescribing an antibiotic, participants indicated that it was generally not as important as choosing a drug known to successfully treat the infection. Choosing a narrow-spectrum agent was perceived to be a more attractive option when the diagnosis was more certain or when a patient was perceived to have a benign clinical condition.PCPs commonly perceived that patients expect an antibiotic for clinical visits, contributing to a shared feeling of pressure among PCPs to satisfy patients. Concern was further expressed that patient satisfaction scores are a common method by which providers are evaluated by hospital administration and insurance companies and that this may inadvertently contribute to more frequent antibiotic prescribing. Some participants believed that such evaluation methods could be a barrier to appropriate antibiotic use. PCPs in private practice said they were particularly sensitive to patient desires and were concerned that their patients might leave their practice in favor of another physician if their expectations were not met.Several participants believed other health care providers’ prescribing behaviors negatively affected their own. For example, if a patient sees a PCP and receives a course of antibiotics, and later visits another PCP for a separate infection with the same symptoms, they have the established expectation to receive another course of antibiotics. As a result, the new provider feels pressured by such expectations to prescribe antibiotics even if they may be inappropriate.Responses to the clinical vignettes were generally in line with the recommended first-line therapies. Among 9 participants given a case describing acute bacterial sinusitis, 7 appropriately chose amoxicillin or amoxicillin/clavulanate. One participant chose to treat the patient with moxifloxacin, and another chose azithromycin. Sixteen of 18 PCPs given clinical vignettes of either AOM or group A streptococcal pharyngitis selected the recommended first-line treatments amoxicillin or penicillin. In response to the clinical vignette for acute cystitis, only 4 of 9 family practitioners selected the first-line agent nitrofurantoin; 4 others chose to treat the patient with a fluoroquinolone, and 1 chose to prescribe trimethoprim-sulfamethoxazole.Participants had no shared definition of “broad-spectrum antibiotic” or “narrow-spectrum antibiotic” regardless of specialty or number of years in practice. When asked to define broad- versus narrow-spectrum antibiotics, responses varied . AlthougAlthough some participants correctly identified amoxicillin as a narrow-spectrum agent, and azithromycin as a broad-spectrum agent, many participants were uncertain of the spectrum of antimicrobial activity for these 2 widely used antibiotics. In general, participants were able to correctly identify fluoroquinolones and later-generation cephalosporins as broad-spectrum agents, especially in relation to other antibiotics. Many participants agreed that broad- and narrow-spectrum antibiotics were not uniformly defined among their colleagues.Respondents believed that changing prescribing behaviors is a difficult task. When asked why some health care providers are reluctant to change their prescribing practices, many participants believed that health care providers are used to the way they have been practicing medicine for years. They believed that even when providers are familiar with established clinical practice guidelines, it may not matter because they seldom change their prescribing behaviors. Several respondents believed the best way to change antibiotic prescribing behavior is to change the expectations of patients so the pressure to prescribe antibiotics is reduced.Respondents’ preference of how they would like to receive information regarding antibiotic selection varied. Some participants suggested incorporating information in the electronic medical record to improve prescribing . One frequent suggestion to improve antibiotic prescribing was to have a quick reference guide for each major diagnosis, including antibiotic indications and causative pathogens. Another suggestion was to have a mobile telephone application available without Internet access. Several respondents saw value in having easy access to antibiotic resistance data for their local area.Participants generally agreed that antibiotic resistance is a concern for their patients and for public health; however, it was not commonly mentioned as a factor when considering which antibiotic to prescribe. Several participants expressed serious concerns about the availability of effective antibiotic therapies in the future related to increases in antibiotic resistance. Respondents also noted an increasing frequency of patients who were reluctant to begin antibiotics or complete their course of antibiotics because of concerns about antibiotic resistance.Streptococcus pneumoniae, a pathogen frequently implicated in bacterial respiratory infections, has a much higher prevalence of resistance to macrolides than it does to amoxicillin  have shown the most promise in changing prescribing behaviors in ambulatory care settings  are critical to addressing the growing threat of antibiotic resistance.Worksheet and case scenario interview for primary care providers participating in the study on antibiotic selection and screening instrument used to select participants.


Noun/verb dissociations in the literature defy interpretation due to the confound between lexical category and semantic meaning; nouns and verbs typically describe concrete objects and actions. Abstract words, pertaining to neither, are a critical test case: dissociations along lexical-grammatical lines would support models purporting lexical category as the principle governing brain organisation, whilst semantic models predict dissociation between concrete words but not abstract items. During fMRI scanning, participants read orthogonalised word categories of nouns and verbs, with or without concrete, sensorimotor meaning. Analysis of inferior frontal/insula, precentral and central areas revealed an interaction between lexical class and semantic factors with clear category differences between concrete nouns and verbs but not abstract ones. Though the brain stores the combinatorial and lexical-grammatical properties of words, our data show that topographical differences in brain activation, especially in the motor system and inferior frontal cortex, are driven by semantics and not by lexical class. A range of neuropsychological  and braiadvocatus diaboli, one might still argue that the phrase “to wug” suggests an action  whereas the context “the wug” is more compatible with an object (a rug) interpretation and, therefore, these pseudowords were not truly stripped of semantic associations, but were, in fact, semantically biased by the contexts in which they were presented: as the authors did not explore this possibility empirically, this interpretation  and semantic (action/object relationship) differences in brain activation would vary these factors independently. Earlier work explored this strategy using EEG  and fMRIThe debate concerning lexical vs. semantic differences as the primary factor for neural differentiation might be addressed with the exploration of well-matched word categories orthogonalised for semantic and lexical factors, such that the contribution of these factors to brain activation in specific cortical areas can be clarified. Whilst nouns and verbs have generally been investigated in the context of concrete items which refer respectively to objects and actions in the world (e.g. “door” and “speak”), they are also highly typical as abstract items generally used to speak about abstract concepts or feelings  and therefore possessing few, if any, sensorimotor associations. Using typical nouns and verbs of a concrete or abstract semantic nature, we here tested predictions of theories of lexical and semantic category representation in the human brain. The lexical–grammatical approach to category-specific local brain processes postulates that the differences in word-elicited cortical activation landscapes are best described in terms of the lexical  categories of nouns and verbs . This poIn contrast, a semantic approach postulates a difference in brain activation topographies only for concrete nouns and verbs semantically related to objects and actions respectively, but not for abstract nouns and verbs, which lack such clear differences in semantic links with action and perception information. The grounded semantics position views semantic representations as circuits tying together symbolic word form information with action and perception schemas . In thisnot between abstract and concrete items of the same lexical category, reflected in a main effect of lexical category, would imply that the differential topographies for nouns and verbs are driven by the grammatical categories that these items belong to, rather than their varying semantic associations.With tight matching of stimuli and the use of event-related functional resonance imaging (fMRI), we here address the debate around the question as to whether brain activation topographies elicited by words are driven by lexical or semantic factors, or by both. In an orthogonalised design, we presented participants with concrete nouns, concrete verbs, abstract nouns and abstract verbs, hypothesising that differential brain activation between concrete items but not between abstract ones would support a view of semantics driving brain differences between nouns and verbs . Divisions between nouns and verbs but 22.1n = 18) were right-handed, monolingual native speakers of English all of whom had no history of psychiatric or neurological illness and were free of psychotropic medication. They had normal or corrected-to-normal vision as suitable for a task within the visual modality. The mean age of participants was 29 (SE = 2.8), all were strongly right-handed  = 4.574, p < .000 l; concrete nouns: t(39) = 7.891, p < .0001), and the reverse was true for the verbs (concrete verbs: t(39) = −10.950, p < .0001; abstract verbs: t(39) = −24.240, p < .0001). As can be seen in In order to disentangle the effects of lexical category from semantic-abstractness, four word categories of 40 words each were employed  = 1.006, p > .436), bigram  = 1.679, p > .084) and trigram frequency  = .868, p > .560). 120 hash marks, matched to word stimuli in length, acted as a low level visual baseline in contrasts.The experimental word categories were dispersed among 200 filler words during presentation, with which they were matched in length  with a head coil attached was employed during data collection. The functional scans consisted of 32 slices which covered the whole brain in descending order , and echo-planar sequence parameters were TR = 2000 ms TE = 30 ms and flip angle = 78 degrees.SPM5  was employed for all processing stages. Images were corrected for slice timing and re-aligned to the first image using sinc interpolation. The EPI images were co-registered to the structural T1 images, which were normalised to the 152-subject T1 template of the Montreal Neurological Institute (MNI), and the resulting transformation parameters applied to the co-registered EPI images. During this pre-processing, images were resampled with a spatial resolution of 2 × 2 × 2 mm and spatially smoothed with an 8-mm full-width half-maximum Gaussian kernel. Single-subject and second level statistical contrasts were computed using the canonical Haemodynamic Response Function (HRF) of the general linear model, a measure for the amplitude of brain response. Low-frequency noise was removed by applying a high-pass filter of 128s. Onset times for each stimulus were extracted from Eprime output files and integrated into a model for each block in which each stimulus group was modelled as a separate event. Group data were then analysed with a random-effects analysis. Activation to each of the experimental word categories was compared statistically against baseline (the hash mark condition) and subsequently between critical stimulus conditions . Stereotaxic coordinates for voxels are reported in the Montreal Neurological Institute (MNI) standard space.In addition to whole brain analysis, a regions of interest (ROI) analysis was undertaken in which 2 mm-radius regions were defined using the MarsBar function of SPM5 . This ant-values) was found in the contrast of all experimental words pooled together against the baseline, plotted at an FDR-corrected significance level of p < .05. The criteria for ROI selection was based on t/Z-values-obtained in this contrast: we selected the three “most significant voxels”, i.e. those with the highest t/Z values for the words vs. baseline contrast. As this comparison (words vs. baseline) is orthogonal to both of the variables investigated , the strategy applied for selecting ROIs follows recent recommendations to avoid “double dipping”  = −14.028, p < .001), less concrete (t(78) = −16.812, p < .001), less related to visual objects (t(78) = −15.145, p < .001), and less form/shape-related (t(78) = −10.443, p < .001) than concrete nouns. Likewise, abstract verbs were significantly less imageable (t(78) = −8.613, p < .001), less concrete (t(78), and less action-related (t(78) = −3.018, p < .005) than concrete verbs. There were no significant differences between the two abstract categories in imageability (t(78) = .809, p > .421), visual- (t(78) = 1.364, p > .175) or form-relatedness (t(78) = 8.54, p > .395), though abstract verbs were significantly less concrete than abstract nouns (t(78) = 2.206, p < .031). As expected, the most highly imageable category, concrete nouns, significantly outperformed concrete verbs in imageability (t(78) = 8.988, p < .001), concreteness (t(78) = 18.307, p < .001), and visual- (t(78) = 9.814, p < .001) and form-relatedness (t(78) = 4.861, p < .001).Statistical tests for word groups, including interactions and main effects, are displayed in t-tests revealed that the d’prime of each word category was significantly above 0 . A two-way ANOVA  revealed no significant main effects or interactions between the d’primes of different word categories, such that there was no behavioural evidence for processing differences between word categories.On the surprise word recognition test performed after scanning, performance was above chance (average hit rate: 76.2% (SE = 4.2%), false positive rate: 56.8% (SE = 5.2%), d’prime rate: 0.53). Although these results only document moderate recognition of stimulus words, possibly due to the large number of the stimuli presented and the long delay between experiment and later testing outside the scanner (∼23 min average), they document that subjects had been attentive during passive reading. In order to check that concrete items were not processed any more thoroughly than abstract ones, d’prime values were calculated for each word category. The average d’primes for each category were as follows: concrete nouns = .024; concrete verbs = 0.59; abstract nouns = 0.52; abstract verbs = 0.56. One-sample 3.2p < .05 in Examination of the contrast of all experimental words against the hashmark baseline, presented at an FDR-corrected significance level of 3.3p- and high t-values  = 4.002, p < .028), demonstrated that the four word categories evoked significantly different topographic activation patterns across these three frontocentral regions.  = 4.38, p < 0.020). Planned comparison tests failed to reveal a category difference in the inferior frontal and precentral ROIs, but documented stronger haemodynamic activity in central motor cortex for concrete action-related verbs than for object-related nouns  = 5.66, p < 0.029) and a tendency in the opposite direction for the inferior frontal ROI  = 2.227, p > .15). When grouping together premotor and motor ROIs , significantly stronger responses to concrete verbs than to concrete nouns were re-confirmed  = 5.74, p < 0.028). The same two-way analysis of variance carried out for abstract nouns and verbs failed to reveal a significance interaction effect of the ROI and Lexical category factors  = 0.79, p > 0.46, n.s.). There was no indication of word category differences in motor, premotor or prefrontal areas of interest. This pattern of results shows that only concrete action-/object-related nouns and verbs, but not abstract ones, activate the frontocentral areas differentially.To further investigate this complex interaction, separate analyses of variance were carried out for concrete and abstract words . For concrete nouns and verbs, there was a significant interaction of the ROI factor with Lexical category . The precentral region indicated the same trend but without reaching significance. The inferior frontal ROI showed a trend towards stronger responses to concrete nouns compared with the other three categories, though this did not reach significance (t(17) = 1.351, p > .195).Further inspection of activation patterns to abstract and concrete nouns and verbs in the three ROIs suggested that, over and above the statistically confirmed category-difference for concrete but not abstract items, the abstract items seemed to group with action verbs. Pooling haemodynamic responses to abstract words with those to concrete action verbs did indeed confirm significantly greater activity in the central motor ROI than that evoked by concrete nouns . Their left STS ROI revealed a trend towards a lexical category difference which, though weak and far below significance  = .422, p > .525), somewhat resembled that reported by Bedny, with numerically greater activity for verbs  = .400, p > .536) or the left anterior superior temporal sulcus ROI  = .105, p > .750); in these cases, any numerical differences in favour of verbs were also absent in our data, in favour of a numerical contrast in the opposite direction. The combination of all three Bedny et al. regions  also failed to reveal a significant effect of lexical category or semantics. Although, in our present analysis, activation maxima did not arise in the left STS in the contrast of all experimental words against baseline, we chose two coordinates located in the cluster of STS activation which were closest to Bedny et al.’s original anterior and posterior STS regions  and semantic dissociations  was exploited in defining ROIs . Bedny eerbs see , Part A.ions see B. These F = 6.280, p < .025). Of more important note, though, was the significant interaction between this lexical category factor and the semantics variable  = 9.319, p = .007). This interaction was driven by significantly greater activation for concrete nouns (see t(17) = 2.301, p < .035) and posterior (t(17) = 3.046, p < .01) frontal regions. Whilst nouns generally evoked greater average activation than verbs in these regions, the difference between abstract nouns and verbs did not reach significance in the present study. Comparison of brain responses to concrete nouns to the pooled response to all three other word types confirmed the relatively enhanced signal to the former in the anterior ROI (t(17) = 2.611, p = .018) and a trend in this direction in the posterior (t(17) = 1.672, p = .113). Note, furthermore, the similarity between the activation advantage for concrete nouns in this ROI defined by So far, analysis of all ROIs from the previous literature failed to reveal effects of lexical category. We did, however, observe a main effect of lexical category in analysis of two left frontal-insula regions  suggested by ouns see  compared4In a study of abstract and concrete noun and verb processing, we found a significant interaction effect of orthogonalized semantic (abstract vs. concrete) and lexical (noun vs. verb) factors in the frontocentral motor system. In central and precentral motor cortex, activation to concrete verbs was generally enhanced compared with concrete nouns and, crucially, a similar difference for abstract word groups was absent. Inferior frontal regions suggested the opposite contrast, activation greater for concrete nouns than for concrete verbs, but, once again, the contrast of nouns vs. verbs was not significant for abstract items. As statistically significant effects of lexical category appeared in interaction with semantic differences between abstract and concrete words, our results argue against a distinction between topographical patterns of brain activation in terms of the lexical categories of nouns and verbs. Rather, our data show that brain activation patterns to nouns and verbs depend on the semantic nature of these items. The most prominent brain distinctions include enhanced activity in central motor cortex to verbs typically used to speak about actions relative to object-related nouns, and relatively stronger activation in inferior frontal cortex to object nouns as compared with action verbs.not for abstract items. These results show that noun/verb differences in brain activation patterns are specific to concrete items and therefore depend on semantics.Our neurometabolic data reveals a pattern of activation across frontal and temporal cortices typical of that generally seen in visual word processing . It is aA search for effects of lexical category in temporal regions implicated in previous literature was unfruitful, though a lexical category effect did appear in two frontal regions previously implicated by 4.1The proposition that lexical  categories are differentially represented in the brain would seem plausible given that nouns and verbs are suggested by many to be linguistic universals , even prBased on previous evidence from neuropsychological, neurophysiological and neurometabolic investigation, a range of authors have suggested that the lexical/grammatical category of words might be the primary dimension by which neural segregation is driven . This idProblematically, as mentioned in the introduction, nouns and verbs differ on a range of dimensions uncontrolled for in many of the studies mentioned in the previous paragraph. These features are either semantic in nature (as many nouns relate to objects whereas most verbs are used to speak about actions) or immanent to psycholinguistics measures (for example word frequency) or more general linguistic features   are reflected at brain-level by a topographical distinction between motor systems and inferior-temporal activations. The current work can therefore corroborate some of the statements made by studies above which, due to their methodological flaws, could not be strongly defended the findings reported here suggest that previously reported noun/verb differences in the brain were driven by semantics. This position seems consistent with an EEG study, where A lack of neurophysiological and neurometabolic differences in brain activation patterns elicited by the lexical categories might lead some to suggest that lexical categories are illusory, lacking a brain basis – an argument that would of course be flawed. Apart from their semantic differences, nouns and verbs are distinct in their combinatorial properties: English nouns combine with articles and adjectives, and verbs combine with nouns, pronouns and specific prepositions or complementizers. It is necessary to neurally represent the different combinatorial properties of these words in the brain, and the imprinting of different combinatorial patterns of nouns and verbs in a neurocomputational model induces fine-grained connection differences at the neuronal circuit level which provide a neuromechanistic correlate of combinatorial lexical categories . However4.3Differential activation was found for concrete nouns and verbs, whereby the latter activated motor and premotor areas more strongly than the former and the opposite contrast was significant in inferior frontal cortex. These results are consistent with and explained by a neuromechanistic model rooted in Hebb’s concept of distributed cell assemblies. Because knowledge about the form and meaning of a word are normally active together such that neuronal connections between the respective neuronal circuits are strengthened, these meaning- and form-related circuits are joined together into one higher-order semantic network – to the degree that one circuit part typically does not activate without the other becoming active too. There is room for flexibility in this mechanism, especially if attentional resources are limited, overt motor action is being prepared for, or context puts a focus on grammatical processing . However. Pre-existing work reported that form-related words activate inferior frontal areas , because their semantic manifestation in action and perception is quite variable and therefore correlation learning predicts relatively weak links between sign and concept. We did not find a general difference in activation between our strongly action-related verbs and the abstract categories here, but, as mentioned, this may be due to the stimulus selection, especially a low proportion of abstract terms with variable semantics in the present stimulus set. In this context, it is noteworthy that Abstract nouns and verbs can, of course, differ semantically both between 5This study investigated whether topographical patterns of brain activation to nouns and verbs are driven by lexical  class or rather by semantics and word meaning. We found that concrete nouns and verbs activate frontocentral cortex to different degrees. Whereas motor and premotor areas are relatively more strongly activated by action verbs, concrete nouns activated more anterior prefrontal areas. At the cognitive level, these differential activations appear to relate to the processing of action schemas that are part of the semantic representation of action verbs and of form knowledge semantically linked to object words. Abstract nouns and verbs fail to elicit similar activation differences, thus calling into question previous claims about genuine brain loci for the major lexical categories. Systematic investigation of other areas, especially temporal cortex, also failed to reveal a genuine distinction between noun and verb processing loci. We suggest that topographical brain activation differences elicited by words are driven by semantic factors and that the lexical category distinction is mechanistically implemented at a level beyond the grain size of neurometabolic imaging.This work was supported by the MRC , EPSRC and BBSRC (BABEL grant), DFG (Center of Excellence “Languages of Emotion”) and Freie Universität Berlin.


IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS), so-called Mikulicz’s disease, is characterized by elevated serum IgG4 and infiltration of IgG4-positive plasma cells in glandular tissues. Recently, several studies reported both malignant lymphoma developed on the background of IgG4-associated conditions and IgG4-producing malignant lymphoma (non-IgG4-related disease).We report on the case of a 70-year-old man who was strongly suspected IgG4-DS because of high serum IgG4 concentration (215 mg/dl) and bilateral swelling of parotid and submandibular glands. Biopsies of cervical lymph node and a portion of submandibular gland were performed. These histopathological findings subsequently confirmed a diagnosis of marginal zone B cell lymphoma.Differential diagnosis of IgG4-DS is necessary from other disorders, including Sjögren’s syndrome, sarcoidosis, Castleman’s disease, Wegener’s granulomatosis, lymphoma, and cancer. We suggest that biopsy of swollen lesions is important for a definitive diagnosis of IgG4-DS and discuss the mechanism of development in this case. IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS), also known as Mikulicz’s disease (MD), is a unique condition characterized by enlargement of the lacrimal and salivary glands caused by infiltration of lymphocytes. IgG4-DS has been considered a subtype of Sjögren’s syndrome (SS) because of certain histopathological similarities, particularly lymphocytic infiltration . HoweverA 70-year-old man was referred to our institution with bilateral continuous painless swelling of the parotid glands (PGs) and submandibular glands (SMGs) in March 2013. He had previously attended another hospital with chief complaints of dry mouth and bilateral swelling of SMGs, which were diagnosed as chronic sialoadenitis by computed tomography (CT) in January 2013. However, he did not receive any treatment at that time and ignored the swelling. He had no medical history of allergic diseases such as bronchial asthma, atopic dermatitis, or allergic rhinitis.Physical findings showed no fever , a blood pressure of 124/68 mmHg, a pulse rate of 64 beats per min, and arterial oxygen saturation of 98% in room air. He had a dry mouth and stomatitis with reduced unstimulated salivary flow rate (0.9 ml/15 min). Bilateral PGs, SMGs, and sublingual glands were elastic, hard, and swollen, but not painful. Several cervical lymph nodes were enlarged. F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) demonstrated abnormal multiple accumulations in the SMGs  and in several systemic lymph nodes  , and platelet count of 12.6 × 104/mm3. Serum chemistry data were all within normal limits. His C-reactive protein concentration was 0.07 mg/dl. Immunological tests were negative for anti-nuclear antibody, anti-SS-A antibody, and rheumatoid factor. Serum levels of IgG, IgA, IgM, and IgE were within normal limits , but his serum IgG4 concentration was elevated (215 mg/dl). The proportion of total IgG molecules that were subclass IgG4 was 18%. The serum soluble interelukin-2 receptor (sIL-2R) concentration was abnormally high .Laboratory findings are indicated in Table IgG4-DS was initially suspected because of the enlarged glandular tissues and high serum IgG4 concentration. Open biopsies of the cervical lymph node and a portion of the left SMG were therefore performed for definitive diagnosis. Histologically, all sections showed severe lymphoplasmacytic infiltration with hyperplastic lymphoid follicles, so-called follicular colonization. Furthermore, the plasmacytoid cells showed nuclear pleomorphism. Immunohistochemical staining showed mild infiltration of IgG4-positive plasma cells  and monotypic predominance of kappa-light chain. The infiltrating lymphocytes were positive for B cell markers (CD20 and CD79a) and bcl-2, but negative for T-cell markers , CD10 and cyclinD1 (Figure These histopathological findings and clinical features confirmed a diagnosis of MZL. The patient was treated with 600 mg rituximab for six times as currently recommended regimen -11. SwelIgG4-DS is now recognized as a new emerging disorder, characterized by high serum IgG4, marked infiltration of IgG4-positive plasma cells and severe fibrosis with hyperplastic ectopic germinal centers in lacrimal and salivary glands. We recently proposed ‘Comprehensive diagnostic criteria for IgG4-RD’ . IgG4-RDIsabel et al.  reportedSingle-agent therapy of rituximab is not effective for MZL but for IgG4-RD . In thisWritten informed consent was obtained from the patient for the publication of this report and any accompanying images.


Lactobacillus rhamnosus GG intake on preschool children’s antibiotic use, and antibiotic-associated gastrointestinal complaints in a double blind, randomized placebo-controlled trial with 231 children aged 2–7. In addition, we analysed the effect of L. rhanmosus GG on the intestinal microbiota in a subset of 88 children. The results show that long-term L. rhamnosus GG supplementation has an influence on the composition of the intestinal microbiota in children, causing an increase in the abundance of Prevotella, Lactococcus, and Ruminococcus, and a decrease in Escherichia. The treatment appeared to prevent some of the changes in the microbiota associated with penicillin use, but not those associated with macrolide use. The treatment, however, did reduce the frequency of gastrointestinal complaints after a macrolide course. Finally, the treatment appeared to prevent certain bacterial infections for up to 3 years after the trial, as indicated by reduced antibiotic use.Antibiotic use is considered among the most severe causes of disturbance to children’s developing intestinal microbiota, and frequently causes adverse gastrointestinal effects ranging from mild and transient diarrhoea to life-threatening infections. Probiotics are commonly advocated to help in preventing antibiotic-associated gastrointestinal symptoms. However, it is currently unknown whether probiotics alleviate the antibiotic-associated changes in children’s microbiota. Furthermore, it is not known how long-term probiotic consumption influences the developing microbiota of children. We analysed the influence of long-term Trial Registration: ClinicalTrials.gov NCT01014676 Clostridium difficile [Antibiotics account for the majority of prescription medication used by children in western countries  and relaifficile . Severalifficile –8 and inifficile –11: the ifficile . Bile acAnimal experiments have demonstrated that early-life antibiotic use disrupts the microbiota and consequently immune function and metabolism, predisposing to the development of obesity ,14 and aLactobacillus rhamnosus GG is one of the best studied probiotics [Clostridium difficile -associated diarrhoea [L. rhamnosus GG produces pili decorated with the mucus-binding protein SpaC [Probiotics have been recently redefined as live microorganisms that when administered in adequate amounts confer a health benefit on the host . Lactic obiotics  and metaobiotics , Clostriiarrhoea , hospitaiarrhoea , antibioiarrhoea , and theiarrhoea . Short-tiarrhoea ,32. Thisiarrhoea . L. rhamein SpaC . The pilein SpaC ,34. Therein SpaC ,36.L. rhamnosus GG is available in various food products and pharmaceutical formulations, making the continuous consumption of this strain very common. In this study we address the effect of long-term consumption of L. rhamnosus GG on the health outcome and microbiota of a cohort of preschool children by utilizing antibiotic purchase records and culture-independent microarray analysis of the faecal microbiota.The long-term effects of continuous probiotic use on the developing intestinal microbiota of children, and its potential to protect from antibiotic-associated changes in the microbiota, are not well documented. L. rhamnosus GG supplementation on the occurrence of viral respiratory infections in children aged 2–6 years [http://clinicaltrials.gov with the identifier NCT01014676. The parents provided written informed consent. The participants were randomly assigned into probiotic and placebo treatment groups, both receiving three ad libitum doses of milk daily, on average 400 ml per day. The probiotic treatment group received milk containing L. rhamnosus GG , and the placebo group received similar milk  without the probiotic. The participants were guided not to use probiotic products during the intervention and three weeks prior to the intervention. The intervention continued for seven months (October 2009–April 2010). All participants attended a health check and were asked to provide a faecal sample at the beginning and end of the intervention period. Compliance with the milk intake in both groups was monitored by the day care staff and parents, who recorded the daily intake. Moreover, parents kept daily symptom diaries throughout the intervention, marking-down various gastrointestinal and respiratory complaints. For the current study, the frequency of gastrointestinal complaints  per day was calculated before, during and after antibiotic treatment for the children who used antibiotics during the intervention to assess the ability of the probiotic to reduce antibiotic-associated gastrointestinal complaints.The study is based on a double-blind placebo-controlled trial, conducted during the winter 2009–2010, investigating the effect of –6 years . The stust generation cephalosporins, macrolides (azithromycin and clarithromycin), and sulphonamide-trimethoprim. Antibiotics in Finland are only available by prescription by a medical doctor, but prescriptions can be made without a positive bacterial culture. Therefore, the antibiotic purchases reflect bacterial infections, but the correlation may not be perfect. It is possible that viral infection are sometimes incorrectly diagnosed as bacterial and treated with antibiotics.Originally a total of 501 children completed the study. Exclusion criteria in the original study were milk allergy, lactose intolerance, congenital heart disease requiring regular medication, malignant diseases, cytostatic treatment, use of biological rheumatic medication, continuous microbial medication, regular use of oral corticosteroids, diabetes and simultaneous participation in other clinical trials. Written informed consent (by the parents) to access the antibiotic purchase records was provided by 231 children. The national individual-based drug purchase registry of the Finnish Social Insurance Institute was utilized to obtain information on antibiotic purchases during the intervention and for three years after the intervention (until the end of 2012). The collection of antibiotic purchase records was approved by the ethical boards of the Helsinki and Uusimaa Hospital Region, and the Social Insurance Institute. We categorized the antibiotics into penicillins, , 1L. rhamnosus GG in the samples  of  samples . The PCR samples . Further samples  and 2. NL. rhamnosus GG group), Pen+LGG (L. rhamnosus GG + penicillin), and Mac+LGG (L. rhamnosus GG + macrolide). The use of sulfonamide-trimethoprim (N = 7) and cephalosporins (N = 4) were so uncommon during the intervention that their association with the microbiota could not be assessed.For the microbiota analysis, the 88 children were categorized into 6 treatment groups based on their antibiotic purchases during the 7-month intervention : ControlL. rhamnosus GG strain [in situ hybridization) -based quantitation of bacterial genera [The faecal samples were collected at home and transported immediately to the study centre for storage in -70°C, or were initially stored in the home freezer for 0.5–78 hours (on average 19 hours) before being transported to the study center. DNA was extracted from the faecal samples with the Promega Genomic Wizard DNA Purification Kit , using a modified protocol developed for bacterial DNA extraction from faecal samples . CompliaG strain . Only coG strain . The micG strain . The sigG strain . The genl genera . The groL. rhamnosus GG treatment and antibiotic purchases  from the beginning of the intervention in 2009 until the end of 2012 we included 231 children . Survival analysis  was conducted to test if the treatment groups differed in their persistence without antibiotics. The end outcome in the models was the first antibiotic purchase. Negative binomial models were used to analyse the cumulative number of courses purchased by different time points.To investigate the associations between L. rhamnosus GG group N = 49). Using a paired-sample Wilcoxon-test, we tested whether the frequency of GI complaints (average number of complaints/day) was higher after an antibiotic course than before in the groups Pen, Mac, Pen+LGG, and Mac+LGG. Using the Kruskal-Wallis test, we tested whether the difference in the GI complaint frequency before and after an antibiotic course was different between the Pen and Pen+LGG groups, and between the Mac and Mac+LGG groups.The number of gastrointestinal (GI) complaints before, during and after antibiotic courses was analysed in a sub-cohort including 96 cases that had purchased antibiotics during the intervention , only the false discovery rate—corrected p-values <0.05 were considered as significant and were reported. The genus-level bacterial groups significantly associated with the treatments were clustered based on their response profiles  to visualize, which bacterial groups respond to the treatments similarly.All statistical analyses were conducted with the program R , using tUsing the Finnish drug purchase registry, we were able to accurately follow the antibiotic use of the study children during and for nearly 3 years after the intervention. The treatment groups did not differ in prior antibiotic use or prevalence of asthma or allergies Tables  and 2.L. rhamnosus GG group received antibiotics. However, the prevalence of sulfonamide-trimethoprim use was significantly reduced in the L. rhamnosus GG group . There was a borderline significant increase in the frequency of complaints during the week before a course compared to the previous month in the placebo group (p = 0.04) and in the L. rhamnosus GG group (p = 0.11). Neither penicillin nor macrolide courses were associated with an immediate increase in the frequency of symptoms during the course in either treatment group. However, during the month after a macrolide course, there was a significantly higher frequency of complaints in the placebo group as compared to the probiotic group (p = 0.03).There frequency of gastrointestinal complaints in the children that received antibiotics during the intervention (number of complaints per day per child) was on average highest during the week before the start of an antibiotic course , with noL. rhamnosus GG treatment caused microbial changes . In both groups, the microbiota of the macrolide-treated children deviated most strongly from the non-antibiotic treated children. Macrolide use was associated with reduced diversity and stability of the microbiota . The effBacteroides spp. , and the relatives of Clostridium difficile, uncultured Mollicutes, and Haemophilus spp.  among the bacteria residing in the small intestine: species related to Lactococcus and Lactobacillus gasseri increased in abundance by 4.5-fold (p<0.0001) and 1.9-fold (p = 0.005), respectively, while the relatives of Escherichia coli decreased by 2.5-fold (p<0.0001). The daily consumption of L. rhamnosus GG is likely to increase the concentration of its main metabolic product, lactic acid, in the small intestine, which may promote other lactic acid bacteria and conversely reduce the abundance of competing Proteobacteria that are less acid-tolerant. This may be a beneficial change, as many species and strains related to E. coli are potentially pathogenic and produce the inflammatory lipopolysaccharide (LPS) [Several genus-level bacterial groups were significantly associated with the treatment, indicating that the regular consumption of de (LPS) . Howeverde (LPS) ,32, indiL. rhamnosus GG intervention appeared to have some beneficial effects on the microbiota and was associated with reduced frequency of GI complaints after a macrolide course, it failed to prevent most of the macrolide-associated changes in the microbiota. This indicates that the protective effect of L. rhamnosus GG during antibiotic treatment is not caused by stabilization or a faster recovery of the overall microbiota. Macrolide use in both the L. rhamnosus GG and the placebo group was associated with a clear and consistent pattern of low abundance of the Actinobacterial genera Bifidobacterium and Collinsella, and a high abundance of Bacteroides species related to B. fragilis, B. ovatus, B. stercoris, and B. uniformis and many groups of Proteobacteria. The only clear benefit of the L. rhamnosus GG intervention was observed on the relatives of Eubacterium hallii, a butyrate-producer [L. rhamnosus GG—treated ones. Whether the protective effect of L. rhamnosus GG on E. hallii or other butyrate producers during macrolide treatment is general and results in a reduction of gastrointestinal disturbance remains to be verified.Although the producer , which dBacteroides spp. Many Bacteroides species are often macrolide-resistant [Bacteroides spp. in children has been associated with increased serum IgE levels [B. fragilis and B. ovatus, the two groups that were strongly increased in the macrolide-users, have been associated with childhood overweight [Nearly all children using macrolides had increased levels of esistant , which mE levels  and withE levels ,51. Specerweight , aberranerweight ,54 and ierweight ,56.Clostridium difficile, uncultured Mollicutes, and Haemophilus spp. were all significantly increased in the placebo-treated penicillin-users. However, these changes did not occur in the probiotic group, indicating that the probiotic may be effective in protecting the microbiota against penicillin-associated disturbance and increase in potential pathogens.Pencillin use was associated with a weaker shift in the microbiota composition than macrolide use. The abundance of Clostridium cluster I, relatives of Lactobacillus-Bifidobacterium supplementation in adults during H. pylori eradication therapy (amoxicillin-clarithromycin-lansopratzole) and during amoxicillin treatment has been shown to enable a quicker recovery of the microbiota [L. rhamnosus GG administration may have similar effects in children, enabling a faster recovery from or increased resilience against penicillin-associated disturbance. However, the treatment was ineffective against macrolide-associated disturbance, with Bifidobacterium even more strongly depressed by the macrolide in the L. rhamnosus GG group than in the placebo group. These results suggest that the combination of Lactobacillus and Bifidobacterium strains may be more effective in preventing antibiotic-associated changes in the microbiota than Lactobacillus alone.Previously, crobiota . Our resL. rhamnosus GG treatment, or that beta-lactam purchases are not a good proxy for infections. The latter would be the case if beta-lactam antibiotics were prescribed more leniently than the other antibiotic types, even when a bacterial infection has not been verified. The reduction of antibiotic use is an encouraging result, in terms of the threat of antibiotic resistance and in terms of the impact antibiotic exert on the microbiota. L. rhamnosus GG intake may prevent antibiotic-associated changes in the microbiota and the potential metabolic and immunological consequences indirectly by preventing infections and thus reducing antibiotic use.Perhaps the most important finding was that the use of macrolide and sulphonamide-trimethoprim antibiotics was significantly and persistently reduced after the intervention for up to 3 years. However, beta-lactam  use was unaffected by the treatment. This suggests that either a type of infection that is treated with macrolide and sulphonamide-trimethoprim, but not with beta-lactam antibiotics, was prevented by the L. rhamnosus GG supplementation has no clear adverse effects on the microbiota or overall health of 2–7 year old children. It appears to have a beneficial influence on the microbiota composition, to prevent penicillin-associated changes in the microbiota, and to confer a long-term protection against certain infections.The results confirm that long-term S1 TableThe Fold changes and p-values refer to comparison between the treatment groups and the control group which did not receive any treatments. The bold values indicate a significant  difference from the control group.(XLSX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.


Objective. We measured some anthropometric dimensions of Iranian guidance school students selected from different ethnicities. Background. Anthropometric dimensions are used for design of equipment, furniture, and clothing. Furniture with inappropriate design not fulfilling the users' anthropometric dimensions may have a negative effect on health. Method. A total of 7400 Iranian guidance school students aged 12–14 years entered the study and their static anthropometric dimensions were measured. Descriptive statistics such as mean, standard deviation, and key percentiles were calculated. All dimensions were compared among different ethnicities and different genders. Results. This study showed significant differences in a set of 22 anthropometric dimensions regarding gender, age, and ethnicity. Conclusion. According to the results of this study, difference between genders and among different ethnicities should be taken into account by designers and manufacturers of guidance school furniture. Application. This study has prepared a data bank of anthropometric dimensions of 12–14-year-old students which can be used as basic information to find appropriate dimensions of school furniture. In order to properly design different products, it is important to have access to anthropometric dimensions of the potential users –7.Inappropriate dimensions of furniture and other products which do not match the users' body dimensions may lead to many adverse effects , 5, 8–12Appropriate design according to the target user groups and identification of the most important body dimensions are key issues in the design process . There iSeveral researches have worked on anthropometric dimensions of people in different ages in many countries with different races or ethnicities , 14–20.It is documented that such factors as age, gender, race, ethnicity, nutrition, and geographic area will affect anthropometric dimensions , 21–24.Race refers to grouping of people according to biological characteristics, while ethnicity also encompasses additional cultural factors . Some raThere are six ethnicities in different parts of Iran  with different cultural, economic, nutritional, and geographical characteristics. Turk and Kurd population live in a naturally rich area with cold and damp weather in west and northwest of Iran, and Baluch population live in a deprived area with a hot and dry weather in southeast of Iran. It is said that Kurd and Turk population are naturally larger in body size than other ethnicities. The authors have found these differences in their previous study on primary school children in different Iranian ethnicities .Anthropometric studies on Iranian population are few and most of them with small sample size , 32. To Lack of national anthropometric data leads to the design of clothing, shoes, and furniture based upon anthropometric dimensions of other populations, which may not represent the body sizes of the real population. This study was designed to measure some static anthropometric dimensions in Iranian guidance school children considering ethnic differences. Anno Persico (between 21.3.1998 and 20.3.1999 AD).This was a cross-sectional study conducted on 7400 guidance school students aged 12–14 years from different ethnicities in Iran. The students were assigned in each age category according to the information of their identity card; for example, a student was considered to be 12 years old when he (she) was born in the year 1377The dimensions which were measured included the following: weight, standing vertical dimensions , sitting vertical dimensions , horizontal dimensions , depths (chest and abdomen), and thicknesses (one-thigh and two-thigh) .  FigureThe subjects stood and sat in standard postures for measurement of standing and sitting dimensions . Six groups of technicians who were trained for measurements in a planned course performed the measurements using similar techniques. The groups consisted of an observer and two recorders. The dimensions were repeated for 7% of subjects by two other observers blinded to the previous measurements. Subjects entered the study wearing home clothing without shoes .The study sample included 7400 subjects (3560 boys and 3840 girls) from six ethnicities . The details of the number of subjects are presented in We obtained an informed written consent from parents and oral consent from students after explanation of the procedure.t-test and one-way ANOVA were used for the comparison of means between two genders and among six ethnicities, respectively.Descriptive statistics  were measured for each dimension regarding gender, age, and ethnicity. The dimensions were compared between two genders and among six ethnicities in each age group. Student's In this study, 7400 subjects (3560 boys and 3840 girls) aged 12 to 14 years in six ethnicities were assessed. There was a significant difference between males and females in most dimensions. p values for difference among ethnicities were less than 0.001 for all dimensions except for height in 12-year-old girls (p = 0.260), sitting height in 12-year-old girls (p = 0.519), and sitting eye height in 13-year-old girls (p = 0.030).There was a significant difference between ethnicities in all anthropometric dimensions. Today, it is important to measure anthropometric dimensions as a key step for design process. Such variables as age, gender, and ethnicity affect these dimensions, so it is critical to consider these variables for preparation of anthropometric databases.In this study we measured the anthropometric dimensions of students aged 12 to 14 years from different ethnicities in Iran. The results showed a significant difference between two genders in all age groups and among all ethnicities for most of the dimensions.In this study, 12- and 13-year-old girls' weight was significantly more than boys which was opposite in 14-year-old subjects. In 12-year-old subjects, girls had larger heights and upper extremity lengths, although boys showed larger lower extremity heights and lengths. In 13- and 14-year-old subjects, most anthropometric dimensions were significantly larger in boys except for depths and dimensions related to buttocks which is explainable by the size of breasts and buttocks in girls due to puberty.In this study, Turk boys had the largest dimensions in most of the measured dimensions except for abdominal depth, upper extremity distances and widths, lower extremity, and sitting heights which were larger in Fars ethnicity, although in some of them such as forearm-forearm distance the difference was negligible. Most dimensions were smaller in Baluch boys than other ethnicities except for most upper extremity dimensions and some lower extremity heights.In about one-third of dimensions Arab girls had the largest measures and in other dimensions Kurds and Turks showed larger dimensions.There is a considerable difference among different Iranian ethnicities regarding genetic characteristics, climate, geographical area, and socioeconomic characteristics which may affect anthropometric dimensions. For example, Turks and Kurds live in a naturally rich area, but Baluchis live in a province which is naturally deprived, so some differences are probably due to these issues.There are some studies in different populations for measurement of anthropometric dimensions. Mokdad and Al-Ansari measured 44 anthropometric dimensions of Bahraini children aged 6–12 years. They found significant difference between two genders in many dimensions . A totalThe difference between races or ethnicities regarding anthropometric dimensions has also been identified in some studies. Rosnah et al. found a significant difference between Malays and non-Malays which is in agreement with the results of current study . JahanshAlthough climatic, nutritional, and economic factors are significantly different in different populations and countries, one of the important factors contributing to anthropometric differences is race or ethnicity.Anthropometric dimensions of the study children were different from other populations. Anthropometric dimensions of Greek, American, and Mexican children were more than Iranian children , 17, 19 The anthropometric dimensions we measured in this study can be used to design school furniture matched to our population. It is recommended that the number of anthropometric dimensions be increased to create databases used to design clothing, shoes, and other products. It is also recommended that these measurements be repeated to seek for temporal trends.This study had some limitations. We tried to select real native students in each ethnicity, but some hybrid students may have entered the study and we might not have detected these subjects.In this study we found significantly different anthropometric dimensions in different Iranian ethnicities. This makes it necessary to pay attention to these differences when school furniture is designed. The results of this study showed that students need furniture specifically designed and manufactured considering their ethnicity, gender, and age. It is obvious that designing school furniture separately for each ethnicity is very difficult, so a practical approach is to design adjustable furniture using the anthropometric dimension measured in this study.Anthropometric dimensions of the users should be put in mind when determining the dimensions of school furniture.This study showed a significant gender difference in all anthropometric dimensions.This study showed a significant difference among different ethnicities in most anthropometric dimensions.


Streptococcus pneumoniae (Pnc) serotype distribution led to a modification in pneumococcal antibiotic susceptibility. In 2011, the pattern of antibiotic prescription in France for acute otitis media in infants was greatly modified, with decreased use of third-generation cephalosporins and amoxicillin–clavulanate replaced by amoxicillin alone. To assess antibiotic strategies, here we measured the antibiotic susceptibility of Pnc and Haemophilus influenzae (Hi) isolated from nasopharyngeal flora in infants with acute otitis media in the 13-valent PCV (PCV13) era in France.After the implementation of pneumococcal conjugate vaccines (PCVs), the marked shift in From November 2006 to June 2013, 77 pediatricians obtained nasopharyngeal swabs from infants (6 to 24 months old) with acute otitis media. The swabs were sent for analysis to the national reference centre for pneumococci in France. Demographics, medical history, and physical examination findings were recorded.We examined data for 7200 children, 3498 in the pre-PCV13 period (2006–2009) and 3702 in the post-PCV13 period (2010–2013). The Pnc carriage rate decreased from 57.9 % to 54.2 % between the 2 periods, and the proportion of pneumococcal strains with reduced susceptibility to penicillin or resistant to penicillin decreased from 47.1 % to 39 % (P < 0.0001). The Hi carriage rate increased from 48.2 % to 52.4 %, with the proportion of ß-lactamase–producing strains decreasing from 17.1 % to 11.9 % and the proportion of ß-lactamase–nonproducing, ampicillin-resistant strains remaining stable, from 7.7 % to 8.2 %. We did not identify any risk factor associated with carriage of ß-lactamase–producing Hi strains .In France, the nasopharyngeal carriage rate of reduced-susceptibility pneumococcal strains and ß-lactamase–producing Hi strains decreased in children with acute otitis media after 2010, the year the PCV13 was introduced. Accordingly, amoxicillin as the first-line drug for acute otitis media requiring antibiotics remains a valid choice. Streptococcus pneumoniae (Pnc) and Haemophilus influenzae (Hi) are the leading bacterial species implicated in AOM, followed by Moraxella catarrhalis (Mc) and, to a lesser extent, group A β-hemolytic streptococci [Acute otitis media (AOM) is the most frequent bacterial infection in childhood and one of the major indications for antibiotics in many countries . Streptoptococci . For AOMptococci , 4. Deteptococci .Few medical centers in Europe or the United States continue to routinely perform tympanocentesis , 7. The For these reasons, NP culture has not been considered a useful predictor of AOM etiology in clinical practice. However, if NP cultures are not useful for treatment for specific patients with AOM, they may be useful on a population basis for formulating recommendations in one country or in different regions .In France, 7 valent pneumococcal conjugate vaccine (PCV7) was introduced for high risk children < 2 years old in 2002, then for all children < 2 years old in 2006. PCV7 coverage reached 86 % in 2008. In June 2010, the French authorities recommended routine vaccination with PCV13 of infants at 2, 4 and 12 months old to replace PCV7. During a one-year transition period, switching from PCV7 to PCV13 was recommended at any point in the schedule to complete the immunization series. The PCV vaccination coverage for children younger than 2 years after changing from PCV7 to PCV13 is greater than 92 % [Since the implementation of PCV7 and PCV13, two major and related changes have occurred: the Pnc serotype distribution has shifted, which has led to a modification in pneumococcal antibiotic susceptibility. The changes in antibiotic susceptibility could also result from other factors such as variations in antibiotic consumption (volume and type of compound used) or rate of children cared for outside the home , 11Since 2000, to follow the changes induced by PCV implementation, our research group has analyzed several hundred NP samples from children with AOM all over France each year . The datA rapid change in resistance of Pnc and Hi to the commonly used antimicrobials prompts a reevaluation of the treatment strategies . To asseFrom November 2006 to June 2013, 77 French pediatricians throughout France took part in a cross-sectional study. An NP swab was obtained from children aged 6 to 24 months with a diagnosis of purulent AOM . We exclThe study was approved by the Saint Germain en Laye Ethics Committee , and written informed consent was obtained from parents or guardians.NP specimens were obtained with use of cotton-tipped wire swabs. The swabs were inserted into the anterior nares, gently rubbed on the NP wall and immediately placed in transport medium . The samples were transferred within 48 h to Robert Debré Hospital and to the national reference center for pneumococci in France.http://www.eucast.org/clinical_breakpoints/).Pnc culture, identification, serotyping and antibiotic susceptibility testing were performed as previously described . SusceptH. influenzae strains were further classified as ampicillin susceptible (MIC ≤ 1 mg/L), or resistant (MIC > 1 mg/L). ß-lactamase negative ampicillin resistance (BLNAR) was determined according to the CLSI break points [Isolates of Hi were identified by colony morphology assay and conventional methods of determination. Hi isolates underwent capsular serotyping by the slide agglutination method with specific antisera . The production of ß-lactamase was assessed by a chromogenic cephalosporin test . k points . If the k points .Data were double-entered by using 4D software 6.4 and analyzed by using Stata SE 13.1  for univariate analysis and multivariate logistic regression . Chi-square test was used to compare NP carriage of pneumococci and Hi before and after PCV13 implementation. Factors related to NP carriage were identified on univariate analysis . Multivariate logistic regression analysis was performed to identify the main factors associated with carriage of Pnc, Pnc strains with reduced susceptibility to penicillin (RSP), Hi carriage, and ß-lactamase–producing Hi strains. For these models, factors had to be determined by the physician during the visits. When different factors were highly correlated, such as recent antibiotic use, history of AOM and otitis-prone children, we retained the most relevant factor. The following variables were included in multivariate logistic regression models: daycare attendance, siblings, recent antibiotic treatment (within 3 months before enrolment), otalgia + fever ≥38.5 °C, conjunctivitis, and bilateral AOM. All models were adjusted for age. Age was dichotomized as <1 and ≥ 1 year. The cut-off of 1 year was chosen because the vaccination schedules differ before and after this age (reflecting the immunity maturation); in many studies, the NP carriage is higher after 1 year; and in one of our studies, young age (<1 year) predicted penicillin non-susceptible pneumococci carriage [During the 7 years, we assessed samples for 7200 patients (3498 in the pre-PCV13 period and 3702 in the post-PCV13 period). Table The Pnc carriage rate decreased from 57.9 % to 54.2 % between the pre- and post-PCV13 period, and the proportion of Pnc strains with reduced susceptibility to penicillin or resistant to penicillin decreased from 47.1 % to 39 % (P < 0.0001) (Table n = 289) to 11.9 % (n = 230) and that of ß-lactamase–nonproducing, ampicillin-resistant (BLNAR) strains remained stable, < 10 %, with 7.7 % and 8.2 % in the pre- and post-PCV13 periods  Hi isolates were serotype b. The proportion of ß-lactamase–producing Hi strains decreased from 17.1 % (On multivariate logistic regression analysis Table , the maiS. pneumoniae and H. influenzae are the cornerstones of the rationale for antimicrobial recommendations for AOM [The levels of resistance to antibiotic for  for AOM , 8. In 2 for AOM . These g for AOM . Complyi for AOM , 15. Con for AOM , 15.Since 2011 (Fig. S. pneumoniae was expected [The decrease in antibiotic resistance to expected . As in oexpected , 22. Desexpected . SeveralIn contrast, the decrease in ß-lactamase–producing Hi strains was not expected. Two explanations could be raised. The first is the reduced antibiotic use for children in France. Since 2001, following a national campaign promoting a judicious use of antibiotics in France, antibiotic use in children has been sharply reduced, particularly for children < 2 years . FurtherPCV13 impact in our population was expected since we have already showed the impact of PCV7 on carriage and antibiotic resistance . We haveS. pneumoniae, which are resistant to penicillin, may, similar to serotype 19A, become more prevalent. This possibility underscores the importance of the continuous availability of current data that reflects local and national microbiologic trends.This situation of infection and antibiotic resistance is very dynamic and the few non-vaccine strains of The NP carriage rate of RSP-Pnc strains and ß-lactamase–producing Hi strains has decreased in children with AOM in France since 2010, the year of PCV13 implementation in France. Accordingly, amoxicillin as the first-line drug for AOM requiring antibiotics remains a valid recommendation. However, the AOM microbiology is evolving and requires continuous monitoring and adjustments of policy for antibiotics.