The public health concerns over the long-term exposure to antibiotics have risen in different parts of the world. The purpose of this study was to investigate the antibiotic consumption pattern in livestock and poultry and to estimate the quantity of antibiotic active ingredient (mg) consumed per unit weight (Kg) of red meat, milk and egg production in Iran in 2010. A cross-sectional study was designed in charmahal - bakhtiary province-Iran. A questioner has been developed by naming 110 types of antibiotics. Twenty two veterinary clinicians and three livestock pharmaceutical distributor companies were included in the survey to determine the antibiotic prescription and distribution pattern in the farms. Veterinary organization of Iran supplied the information of the total antibiotic consumption in different dosage forms. National and international data on the livestock and poultry production were obtained from the relevant official web sites. Tetracycline class of antibiotics was the most common types of antibacterial prescribed and sold to both livestock and poultry farms. Amino glycoside, penicillin and macrolide in the cattle farms and furofenocole in broiler farms were the second most used groups of antibiotics. The quantity of antibiotic active ingredients consumed per unit weight of animal-originated food products was counted as 107.4 mg/kg for both milk and red meat and 249.5 mg/kg for broiler meat and egg. Totally, it was estimated that 133 mg antibiotic substances was used per kg of milk, meat and egg produced in 2010. In comparison to available data for other countries, consumption of antibiotics in livestock and poultry in Iran is higher than developed countries with an exception of South Korea. The findings of the present study could be alarming for the legislative authorities in food security and safety. More clear evaluation should be carried out as well as implementation of national monitoring and inspective programs in order to reach an added safety regarding animal-originated foods. Antibiotics are the most important group of anti-microbial drugs, widely prescribed for human, and animals. It is estimated that 100–200 thousand tons of antibiotic substances are annually produced in the world. VeterinExposure evaluation may also been performed using a deterministic approach where, in a certain society, the weight ratio of the total consumed antibiotics to the produced animal-originated foods is defined as an antibiotic consumption index,11. For In Iran, there is some evidence of violation in antibiotic residues among the tested food samples-16.However, no study has been conducted to demonstrate the exposure to antibiotics through food consumption. Moreover, there is no recorded report on the diversity of antibiotics consumption in livestock and poultry farms in Iran.The objectives of this study were to characterize the antibiotic utilization pattern in Iran livestock and poultry farms. In addition, the antibiotic consumption index concerning animal-originated food produced in the year of 2010 was also investigated.This survey was a cross-sectional descriptive study conducted in the Charmahal- Bakhtiary province in Iran. This province is considered as one of the major livestock production regions in Iran. The study was designed in three parts as following: Firstly, the prescription rate of antibiotics for livestock and broiler farms surveyed through a face-to-face interview by veterinary clinicians. Secondly, the distribution pattern of the sold antibiotics in the tested area was determined by some interviews with animal pharmaceutical distributors. Finally, the antibiotic consumption index was calculated by using the data obtained from official veterinary and agriculture authorities in Iran.Two types of questionnaire were prepared in order to determine the prescription rate and distribution pattern of antibiotics, each contained 110 antibiotics in 10 major class including penicillins, tetracyclines, cephalosporins, macrolides, amino-glycosides, aminocyclitol, sulfonamides, nitrofourans, fluoroquinolones and fungicides, all are usable in veterinary practicing,18. The The Veterinary Organization of Iran was requested to provide the data on the total amount of antibiotics used on anmals in 2010 in the country. Since the given information was presented as the number of unit packages in four different dosage forms of antibiotics , the amount of active ingredient for each dosage form was calculated using the following equation.E: The total amount of antibiotic active ingredient for each dosage form (kg), n: the number of each packaged antibiotic dosage form presented by the veterinary Organization of Iran C: the concentration of antibiotic active ingredient (%) for each type of antibiotic, included in each dosage form, V: the net weight or volume of the package (g or ml), N: the number of antibiotic types that were offered through the given dosage form and 103 is a conversion coefficient of g to kg.Where :The total amount of utilized antibiotic active ingredient supplied by four dosage forms was calculated using the Equation no. 2Et is the total amount of antibiotic active ingredient consumed in Iran in 2010 (kg).Where Information on the animal originated food production was obtained from the ministry of agriculture’s official website. Data onAntibiotic consumption index was considered as an exposure calculated as proportion of the quantity of the total antibiotic active ingredient (mg) consumed per unit weight (Kg) of animal originated food produced in 2010 index which waData analysis was performed using Microsoft Office Excel version 2003.In Table The results of the questionnaires filled out by pharmaceutical distributor companies showed that 48 out of 110 questioned types of antibiotics have been frequently sold to the animal farms in 2010.The distribution pattern of antibiotics sold out by interviewed veterinary pharmaceutical companies is illustrated in Figure Figure Table In Table According to Tables Using the official representative data, the overall production of meat, milk and egg in France, United state of America and Europe in 2007 was counted to be 2.2, 8.8 and 16.2 times more than that of Iran in 2010, respectively.Table Studying the antibiotic consumption pattern in animals in the present work, revealed that tetracyclines had the highest rate of consumption in the investigated Iranian farms. Furthermore, oxytetracyclin was intensively prescribed for both livestock and poultry followed by gentamycin and tylosin in livestock and furofenocole and sulfodiazin in poultry.Tetracyclines are broad-spectrum and the most commonly used antibiotics in many countries mainly for prophylactic and growth promotion purpose. It was reported that in Britain, tetracycline, sulfonamides and macrolids formed 90% of the total used livestock antibiotics by 61%, 19% and 9%, respectability, whilst the corresponding figure in South Korea was reported to be 45%, 15% and 4%, respectively. The finExposure evaluation of a food contaminant is usually carried out by measuring the residues in food samples. When antibiotic residue in animal originated food comes in to consideration as a potential human hazard, it needs to perform a study in a very large size. In addition, elaborated laboratory techniques are required. Alternatively, estimation of per capita exposure to antibiotics using a representative national data is applicable. However, in Iran, official reports do not cover the antibiotics utilized in the animal husbandry. Therefore, in the presented study, such information was provided via correspondence from the veterinary organization. Determination of the type and the quantity of antibiotic consumption at the farm level is not mainly feasible due to farmers’ economic problems. Antibiotic consumption factor is considered as a general index for risk assessment of exposure to antibiotic residues. Based oIn line with the results of present study, recent experimental studies in this country, carried out on the antibiotic residues in the food animals highlighted a high violation rate among the tested samples; in a couple of studies 14 to 24% of the raw milk samples were detected to be positive in terms of antibiotic residues,14. In aBased on the information presented in Table It has been reported that annually thousands ton of antibiotics were used in the world. The United States of America with the annual consumption of 11148 tons is the highest consumer of livestock antibiotic worldwide. AccordiEscherichia coli and Streptococcus strains involved in mastitis infection were positive for antibiotic resistance; 52-84% of E. coli isolates and 13-20% of Streptococcus strains were found to be resistant to penicillin, oxy-tetracycline, streptomycin, erythromycin and colistin[Previous studies have shown that a direct relation exists between the long-term antibiotic consumption in a society and the prevalence of antibiotic resistant bacteria,11. Accocolistin. Moreovecolistin,35. ThisFocusing on the farms located in a specific geographical area could be regarded as a limitation in this study and it is necessary to perform a more comprehensive study in future. The heterogeneous nature of previous research works on the exposure assessment of antibiotics through foods in Iran makes it difficult to reach to a precise conclusion in the current situation of public exposure to antibiotics in Iran.The present study shows that in Iran, antibiotic consumption in veterinary is noticeable and the consumption index is more than the developed countries. The qualitative pattern of antibiotic consumption in both cattle and poultry farms almost resembled that of other countries in which bacteriostatic antibiotics such as tetracycline has the highest share. However, their consumption found to be good among other countries. It seemed that the risk assessment of exposure to this class of antibiotics is an urgent need in Iran.The authors declare that they have no competing interests.FA carried out the present survey as the first part of his MSc thesis dissertation in Food Safety and drafted the manuscript. MM supervised the project and participated in review and correction of the manuscript. MJ contributed in the correction of the final draft of the manuscript. All authors read and approved the final manuscript.


With the introduction of HAART in many HIV treatment centers in Nigeria, there has been a decreased incidence of AIDS-related mortality and growing concern about the incidence of AIDS specific and non-AIDS specific cancers. This study thus sought to investigate patterns and incidence of cervical and anal warts among patients in a Special Treatment Center (SPC) before being diagnosed of having HIV and after starting ARVs.We linked results from a population-based HIV registry in our SPC with that of two cancer registries and evaluated the risk of developing anal or cervical warts a year prior to onset of ARV and a year after commencement of HAART. Standardized incidence ratios (SIRs) were calculated to relate presence of cervical and anal warts in people with AIDS to that in the general population. We also used logistic regression with 95% confidential interval to compare risk according to demographic factors and CD4 count.The study involved 542 patients diagnosed with HIV within the two years of the study. Persons with AIDS had elevated risks of cervical warts  and anal warts . Risk for cervical warts increased with increasing time relative to AIDS onset (p=0.02), this trend was not significant for anal warts (p=0.12). Risk of developing both warts was unrelated to CD4 count at onset of treatment (p=0.43).There is a modest excess risk of developing cervical and anal warts among this group of patients. The risk seems to increase with increasing years on ARVs. This is not related to the immune state of the patients. There is a need to pay attention to patients on ARV therapy as they advance in years with ARV medication.


In Taiwan, the policy of catastrophic illness certificates has benefited some populations with specific diseases, but its effect on the use of medical services and the sequence of public health has not been examined. As a pilot of a series of studies, focused on emergency department (ED) visits, the present study aimed to compare medical utilization and various diagnostic categories at EDs between the elderly with an identified catastrophic illness and the elderly without.A cross-sectional study, based on a large-sample nationwide database ), was performed in Taiwan. The 2008 insurance records of ambulatory medical services for subjects aged 65 years or more among the above one million of the population were further selected and analyzed. Taiwan’s registered catastrophic illness dataset for 2008 was linked in order to identify the target subgroup.p < 0.001). The three most common medical problems diagnosed when visiting EDs were injury/poisoning (14.22%), genitourinary disorders (11.26%) and neoplasm-related morbidity (10.77%) for the elderly population with a catastrophic illness, which differed from those for the elderly without a catastrophic illness.The prevalence of certificated catastrophic illness in Taiwan’s elderly utilizing ambulatory medical services was 10.16%. On average, 61.62 emergency department (ED) visits/1,000 persons (95% CI: 59.22–64.01) per month was estimated for the elderly Taiwanese with catastrophic illness, which was significantly greater than that for the elderly without a catastrophic illness . A significantly greater total medical expenditure for emergency care was observed in the catastrophic illness subgroup (US$145.6 ± 193.5) as compared with the non-catastrophic illness group (US$108.7 ± 338.0) (In Taiwan, the elderly with any certificated catastrophic illness had significantly more ED visits and a higher ED medical cost due to untypical medical complaints. A nationwide health insurance system improves the quality of life and promotes the health of residents, especially when the insurance tax is low, and when many medical facilities are provided. A study evaluating medical utilization based on the Taiwan NHI system in 2002 revealed that on average, a person had 13.4 physician consultations and consulted 3.4 specialties, 5.2 physicians, and 3.9 healthcare facilities in a year; 17.3% of the studied cohort had visited different healthcare facilities on the same day; and 23.5% had visited physicians of the same specialty at different healthcare facilities within 7 days [In Taiwan, the aging society has become an important issue. Owing to progress in the economy as well as in preventive medicine, the life span of Taiwanese people has increased markedly in recent years. This phenomenon has been combined with an unprecedented decline in the overall fertility rate to create a rapidly aging society. As a result, some chronic medical conditions have become major public health problems. Promoting health among the elderly is an important medical issue; in fact, the elderly population has been identified as one of the target populations in the "Healthy People 2020 in Taiwan" program . TherefoTo understand the effect of catastrophic illness certification on the use of medical services and the sequence of public health in Taiwan, a simple descriptive, sampled population-based survey maybe is valuable and can be processed as a pilot of a series of studies. Designed as a cross-sectional, randomly-sampled study, the present study was focused on emergency department (ED) visits and aimed to compare medical utilization and various diagnostic categories at EDs between the elderly with an identified catastrophic illness and the elderly without.Taiwan launched a single-payer National Health Insurance (NHI) Program on March 1, 1995. As of 2007, 22.60 million of Taiwan’s total population of 22.96 million were enrolled in this program; foreigners in Taiwan are also eligible for inclusion. This universal national health insurance, financed jointly by payroll taxes, subsidies, and individual premiums, commenced in Taiwan, and its coverage expanded from 57% of the population  to more than 98% (after the year 2005). All enrollees enjoy almost free access to healthcare with a small co-payment by most clinics and hospitals [Data in the NHIRD that could be used to identify patients or care providers, including medical institutions and physicians, is scrambled before being sent to the NHRI for database inclusion, and is further scrambled before being released to each researcher. Theoretically, it is impossible to query the data alone to identify individuals at any level using this database. All researchers who wish to use the NHIRD and its data subsets are required to sign a written agreement declaring that they have no intention of attempting to obtain information that could potentially violate the privacy of patients or care providers. This study protocol was evaluated by the NHRI, who gave their agreement to the planned analysis of the NHIRD. This study was also approved by the Institutional Review Board (IRB) of Taoyuan General Hospital, which has been certificated by the Department of Health, Taiwan .vs. 50.4%, respectively). There were no significant differences in the gender distribution, age distribution or average insured payroll-related amount between the claimants in the 2005 sampled data and the original NHIRD [A retrospective fixed cohort population was used as the original study population. Every claimant of the NHI Program at any time during 2005 was included in the population  selected for random sampling. Using a random number generator to produce 1,073,891 random numbers, the original claims data of 1,000,000 randomly-sampled beneficiaries from the year 2005 was the original study population of the present study. The majority of the sample population of 1,000,000 subjects were aged from 20 to 65 years, and the male and female subpopulations were of a similar size  were used to evaluate the significance of differences between the catastrophic and non-catastrophic illnesses and the psychiatric and non-psychiatric disorders among these catastrophic illnesses. All statistical calculations were performed using the Statistical Package for Social Sciences for Windows (SPSS for Windows 15.0).Descriptive statistics are represented as numbers of cases, percentages, and means with standard deviation (SD). The independent Table According to the Taiwan health authority’s classification, there were 30 categories of catastrophic illnesses and, the studied population comprised 10,217 catastrophic illness cases (Table p < 0.001). Meanwhile, the majority of the medical expenditure was used for treatment-associated costs , which differed significantly between the two groups.The monthly ED visits of the catastrophic illness group and the non-catastrophic illness group are illustrated in Figure p < 0.001)  Table .Additionally, the diagnostic categories of the ED visits were compared between the two studied subgroups. With the exception of ill-defined symptoms or signs, the three most definite medical problems when visiting EDs were injury/poisoning (19.43%), circulatory disorders 12.15%) and digestive disorders (9.49%) for the non-catastrophic illness elderly population; these differed from those for the catastrophic illness elderly subjects, which were injury/poisoning (14.22%), genitourinary disorders (11.26%) and neoplasm-related morbidity (10.77%) . In addition, the average treatment-associated expenditure and drug-associated expenditure in Taiwan EDs were 64.5% and 10.6% of the total ED-associated cost, respectively. In particular, treatment-associated cost markedly increased with age  [Based on randomly-sampled cases from Taiwan’s NHI data, the direct medical cost of one ED visit in Taiwan averaged NT$1,792 (US$54.3) for insurers in 2004, and the annual increase of expenditure for emergency medicine was estimated to be 4.9% (< 0.001) . CompareOtherwise, the frequency of major medical problems diagnosed at ED visits varied by age: the subjects aged 65 years or older had the highest percentage of multiple diagnoses (43%), and the most common diagnostic category among this elderly subgroup was ill-defined symptoms/signs (32.2%), which was noted in 55.9% of cases with multiple diagnoses . In the The present study is a descriptive epidemiological survey to evaluate the ED utilization of the elderly Taiwanese population, and some limitations exist. Possible sources of uncontrolled confounding in the present study, for example, social-economic influences, family support, complex co-morbidity or pharmacological management strategies, were not evaluated. Further investigations using data from a community-based interview survey will be performed.Some limitations exist in the present study. First, a certificate of any catastrophic illness was confirmed based on the definitions announced by the Taiwan’s Health authority but according to the patients’ application. A misclassification bias could be happen when analyzing the present data because some lowly socio-ecological leveled or educated people didn’t know and use the welfare of the health insurance system. Second, the resent study was a cross-sectional study merely to describe the differences in EDs utilization and direct medical expenditure between the catastrophic and non-catastrophic illnesses. Much more interesting comparisons between the two groups, such as consequent lifespan, quality of life et al., could not be obtained. That needs other prospective surveys in future.In Taiwan, the elderly with an officially certificated catastrophic illness had significantly more ED visits and a higher ED medical cost; they also used greater emergency medical resources owing to different medical complaints as compared to those without a catastrophic illness.All authors declare that they have no conflicts of interest, including directorships, stock holding or contracts.The study was designed by NPY and YHL; data were gathered and analyzed by CYC and JCH; the initial draft of the manuscript was written by NPY and ILY; and the accuracy of the data and analyses was assured by NTC and CLC. All authors participated in the preparation of the manuscript and approved the final version.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6963/13/152/prepub


To evaluate therapeutic education delivered in a pediatric emergency department to improve parents’ satisfaction and attitudes about judicious antibiotic use.In an emergency department of a tertiary pediatric hospital, children aged 1 month to 6 years and discharged with an oral antibiotic prescription for an acute respiratory or urinary tract infection were randomized to a patient therapeutic education on antibiotic use (intervention group) or fever control (control group) delivered to the parents (in the presence of the children) by a pharmacist trained in therapeutic education. Education consisted in a 30-minute face-to-face session with four components: educational diagnosis, educational contract, education, and evaluation. The main outcome measure was parent satisfaction about information on antibiotics received at the hospital, as assessed by a telephone interview on day 14. The secondary outcome was attitudes about antibiotic use evaluated on day 14 and at month 6.P=0.002, exact Fisher test). Of the 300 randomized children, 150 per arm, 259 were evaluated on day 14. Parent satisfaction with information on antibiotics was higher in the intervention group .Group parents had higher proportions of correct answers on day 14 to questions on attitudes about judicious antibiotic use than did control-group parents (Therapeutic education delivered by a clinical pharmacist in the pediatric emergency department holds promise for improving the use of antibiotics prescribed to pediatric outpatients.ClinicalTrials.gov NCT00948779 http://clinicaltrials.gov/show/NCT00948779 Infections caused by antibiotic-resistant microorganisms are associated with high morbidity, mortality, and healthcare costs . AntibioAcute respiratory tract infections (ARTIs) are common reasons for antibiotic prescription . The numDecreasing antibiotic overuse and misuse is a crucial objective in the fight against antibiotic resistance ,14. InteVisits to the PED provide an opportunity for health-promotion and family-education interventions ,27. To oWe evaluated a therapeutic education intervention designed to improve skills useful for a better adherence to prescribed antibiotics and delivered by clinical pharmacists to parents and children seen in a PED in Paris, France. We then conducted a randomized controlled trial to assess the effect of this intervention on parent satisfaction and attitudes about antibiotic use in children prescribed antibiotics for an ARTI or urinary tract infection.The protocol for this trial and supporting CONSORT checklist are available as supporting information; see This study was approved by the appropriate biomedical research ethics committee in February 2009 . No incentives to participation were offered. Oral informed consent was obtained from at least one of the parents or legal guardian; hereafter, the term “parents” is used for both. The study was registered on Clinicaltrial.gov (NCT00948779) on July 28, 2009. The education sessions were delivered to the parents accompanying the children.Patients meeting study criteria were enrolled from Monday to Friday between 9 a.m. and 6 p.m., from February 2, 2009 to September 26, 2011.Children between 1 month and 6 years of age were eligible if they were discharged from the PED with a prescription for 5 to 10 days of an oral liquid antibiotic to treat an ARTI  or an urinary tract infection (pyelonephritis or cystitis). The criteria regarding diagnoses and treatment duration were chosen to produce a homogeneous population. No specific instructions were given to the physicians, who delivered the usual information about fever control and antibiotic treatment to the parents. Exclusion criteria were chronic conditions affecting drug dosing, suspected or known allergy to the prescribed antibiotics, and no telephone number for contacting the parents. No patient could be included more than once. Parents having poor knowledge of French were excluded because we did not have the resources needed to deliver education sessions in other languages. The parents of eligible patients were informed about the study orally and via a printed information sheet. To ensure blinding of the parents, the existence of two groups was not disclosed. Once informed consent was obtained, patients were enrolled by the PED physicians and referred to a clinical pharmacist on site. The children were allocated at random in a 1:1 ratio to therapeutic education on antibiotic use (the intervention group) or on fever control (the control group). A block randomization scheme with variable block length was previously generated using a computer. To ensure concealment, the clinical pharmacist used an Intranet connection to obtain the group assignment of each included patient.The intervention and control sessions were designed by a clinical pharmacist trained in therapeutic education, in compliance with 1998 World Health Organization (WHO) and 2007 French National Authority for Health (HAS) recommendations ,29. FiveThe contents of the intervention and control sessions were similar in terms of the teaching tools and methods but differed regarding the topic discussed, which was antibiotic use or fever control. The teaching goals for the families in the intervention group were as follows: good understanding of antibiotic therapy effects on the diagnosed disease, good understanding of treatment modalities, correct preparation and administration of the antibiotic , awareness of potential undesirable effects and ability to manage these effects, ability to explain the importance of the antibiotic treatment to all the child’s caregivers, familiarity with the concept of generic antibiotics, and ability to specify to the pharmacist filling the prescription which flavor is desirable. The control session had the following teaching goals: good understanding of the pharmacological and physical means available for controlling fever, ability to use these means appropriately, ability to administer antipyretic medications to the child, and ability to explain the importance and modalities of pharmacological and physical fever-control measures to all the child’s caregivers.The pharmacists delivering the education used an interview grid to ensure standardization of the sessions. As the intention-to-treat approach was used, they could answer all the parents’ questions, even those on fever control in the intervention group and those on antibiotics in the control group. Sessions were organized according to the four stages recommended by the WHO: educational diagnosis, educational contract, education, and evaluation . The eduThe impact of the education sessions was assessed by administering a questionnaire over the telephone 14 days and 6 months after the PED visit. Pharmacists blinded to group allocation and trained to administer the questionnaire conducted the assessments. For the first assessment, at least three attempts to contact each family were made between day 14 and day 17 inclusive. The questionnaire consisted of 11 standardized structured questions on satisfaction and attitudes 2. The iFor each patient, we recorded demographic data, the current diagnosis, name(s) of prescribed antibiotics, dose (mg/kg/day) and duration prescribed, and best telephone number for subsequently contacting the parents. If possible, two phone numbers were collected. Use of the best telephone number has been shown to improve contact rates compared to use of the number in the medical record ,34.The primary outcome measure was the percentage of parents satisfied with information on antibiotic therapy received in the PED, during the physician visit and the educational session ,23-25. TAt least 136 patients were required in each group to detect a 15% difference in the proportions of satisfied parents between the two groups (80% versus 65%) with 80% power and a two-tailed α value of 0.05. The value in the control group was estimated from the literature and the value in the intervention group was the smallest improvement deemed relevant . We did ® . Qualitative variables were described as frequencies (percentages) and quantitative variables as means (SD) when distribution was normal and as medians (quartiles 1 and 3) otherwise. The Likert-scale replies on satisfaction were dichotomized as dissatisfied or satisfied with the neutral response classified as dissatisfied [P values of 0.05 or less were considered significant. No interim analyses were planned or performed.Statistical analyses were performed using SASatisfied ; similaratisfied . For queAcute otitis media was the leading reason for antibiotic prescription and amoxicillin+clavulanate was the most often prescribed antibiotic 3. In 7 P=0.002) (The proportion of parents satisfied with the information on antibiotics received in the PED (primary outcome measure) was significantly higher in the intervention group than in the control group  4.Among secondary outcome measures, the proportion of parents satisfied with information on fever control was significantly higher in the control group, where the session dealt with this topic, than in the intervention group.P=0.017, Mann-Whitney U test). The proportions of parents who gave correct answers to 5 and 6 of these questions were 44% (57/129) and 36% (46/129), respectively, in the intervention group and 37% (48/130) and 28% (36/130), respectively, in the control group (Leftover antibiotics can be saved for later use” (P=0.04) and “If my child does not take all the antibiotic prescribed, some of the germs may survive” (P=0.02) (Parents in the intervention group gave significantly higher numbers of correct answers on day 14 to the questions on attitudes about judicious antibiotic use than did parents in the control group (ol group 2. This (P=0.02) 5. No diP=0.018. Baseline characteristics did not differ between intervention and control group . The parent who completed the first assessment had attended the education session in 232 (89.6%) cases. We found no difference between the subgroups with one versus both parents having attended the educational session in terms of satisfaction with information about antibiotic use  or about fever control . Neither did we find any significant difference in the number of correct answers to the questions on attitudes about judicious antibiotic use . For one family, the first assessment was conducted during a face-to-face interview because the child was admitted to the PED 14 days after the first visit.The number of phone calls made for the first assessment ranged from 1 to 9. The median time needed to administer the questionnaire over the telephone was 10 minutes. The mothers completed the first assessment in 103 (79.8%) cases in the intervention group versus 101 (77.7%) cases in the control group . The proportions of parents who gave correct answers to 5 and 6 questions on attitudes were 42% (51/122) and 39% (48/122), respectively, in the intervention group, and 47% (56/118) and 36% (42/118), respectively, in the control group (P<10-3).After 6 months, the proportions of parents who gave correct answers to questions on attitudes about judicious antibiotic use were not significantly different in the two groups   7. The pThe number of phone calls per family for the second assessment ranged from 1 to 8. The mother completed the second assessment in 188 (78%) cases. The person interviewed for the second assessment was the same as for the first assessment in 89.1% of cases and had attended the education session in 89.4% of cases.Our results demonstrate that a therapeutic education session on antibiotic use delivered in the PED improves parent satisfaction with information about antibiotic use and parent attitudes concerning judicious antibiotic use, compared to a control session on fever control. The effect of the session on antibiotic use might increase the likelihood of children receiving antibiotic therapy at home as prescribed by the physician.The improved satisfaction about information on antibiotics received in the PED is encouraging, since dissatisfaction with explanations of medical problems or with treatment instructions given by the healthcare staff has a major influence on prescription filling by parents of children seen in PEDs ,23,36. ILeftover antibiotics can be saved for later use”. In a global survey of treatment non-adherence, awareness of the need to complete antibiotic courses and to discard any leftover antibiotics was associated with better adherence [Failure to fill prescriptions given in the PED remains a major challenge . Accordidherence , a key fAntibiotic treatments for acute infectious diseases are brief. Decreasing their misuse requires an improvement in behavior at the time of prescription, during the acute illness of the child, which is likely to induce anxiety in the parents. The interview performed 6 months later gave us an indication of parent attitudes at a distance from the acute episode, when they may have recovered from any initial anxiety. Therefore, the second interview consisted only in the 6 questions on attitudes of antibiotic use.The improved attitudes about antibiotic use in the control group at the second assessment after 6 months compared to the first assessment after 14 days may suggest that the anxiety associated with the acute illness in the child adversely affected performance on the attitudes questionnaire. This possibility would support the provision of education at the time of the acute illness. A study involving a third assessment at the time of a subsequent ARTI or urinary tract infection would further support this hypothesis if attitudes was again found to differ between the two groups.Another hypothesis is that during the 6-month interval the families may have received further information on the proper use of antibiotics. However, no educational intervention targeting the public was conducted in France during the period extending from inclusion of the first patient to study completion (February 2009 to September 2011). However, we did not investigate the effect of the first assessment, which may have increased parent awareness about proper antibiotic use.Leftover antibiotics can be saved for later use”). One possible explanation may be the nationwide public education campaign on antibiotic use conducted in France shortly before our study [Interestingly, the overall proportion of correct answers to questions on attitudes about antibiotic use was high in both groups compared to that in the adherent group studied by Pechere et al.   intervention-group and 18 (12%) control-group patients may have affected our results. However, the intent-to-treat analysis of the primary outcome, in which missing data were replaced by unfavorable results, still showed better results in the intervention group. Although the trial was randomized, important predictors of attitude about antibiotic use were not measured such as parent educational level, previous exposure to antibiotic use, parent age, and socioeconomic status . The effWe included only children discharged with an antibiotic prescription. The objective of our intervention was not to decrease antibiotic use but, instead, to prevent the misuse of antibiotics by families, which can have a profound negative impact not only on the community, but also on individuals . FinallyIn summary, educational interventions delivered by clinical pharmacists in the PED were well accepted by families. An education session on antibiotic use was associated with high parent satisfaction and improved attitudes about judicious antibiotics use on day 14. However, no difference was found between the groups after 6 months. Our data suggest that educational interventions in PEDs may hold promise for decreasing the misuse of antibiotics.Protocol S1Trial Protocol.(PDF)Click here for additional data file.Checklist S1CONSORT Checklist.(DOC)Click here for additional data file.


Undoped self-assembled GaN quantum dots (QD) stacked in superlattices (SL) with AlN spacer layers were submitted to thermal annealing treatments. Changes in the balance between the quantum confinement, strain state of the stacked heterostructures and quantum confined Stark effect lead to the observation of GaN QD excitonic recombination above and below the bulk GaN bandgap. In Eu-implanted SL structures, the GaN QD recombination was found to be dependent on the implantation fluence. For samples implanted with high fluence, a broad emission band at 2.7 eV was tentatively assigned to the emission of large blurred GaN QD present in the damage region of the implanted SL. This emission band is absent in the SL structures implanted with lower fluence and hence lower defect level. In both cases, high energy emission bands at approx. 3.9 eV suggest the presence of smaller dots for which the photoluminescence intensity was seen to be constant with increasing temperatures. Despite the fact that different deexcitation processes occur in undoped and Eu-implanted SL structures, the excitation population mechanisms were seen to be sample-independent. Two main absorption bands with maxima at approx. 4.1 and 4.7 to 4.9 eV are responsible for the population of the optically active centres in the SL samples. I(14 K)/I(RT), exhibits a sample dependent behaviour  direction, while lower fluence does not change the XRD characteristics of the sample [3+ luminescence, additional broad emission bands can be identified on the high energy side, as shown in Figure Two other sets of 20 periods GaN QD/AlN SL (#987 and #989) with larger quantum dots /I(RT)~4). On the contrary, the high energy emission peak at 3.9 eV is seen to have an intensity which is nearly constant up to 200 K. A slight increase of the PL intensity was seen for higher temperatures accompanied with a small energy shift of the peak position, commonly observed in small GaN QDs [Figure  GaN QDs . For theI(14 K)/I(RT) of the high energy GaN QD emission is practically constant up to RT while for the 3.0 eV PL band a ratio of 1.3 was found. The small thermal quenching of the luminescence observed for the SL implanted with lower fluence suggests that the competing non-radiative processes are less important as expected for the lower damaged SL structure.For samples implanted with lower fluence (#989(a)--Figures In Eu-implanted SL structures, the GaN QD recombination was found to be dependent on the implantation fluence. For samples implanted with high fluence, a broad emission band at 2.7 eV was tentatively assigned to the emission occurring at large blurred GaN QD. The temperature-dependent PL analysis in this sample evidences a fast decrease of the luminescence, consistent with the competing non-radiative relaxation processes expected for a large defective SL. This emission band is absent in the lower fluence implanted SL structure, which has high structural quality. In this case, the GaN QD PL at approx. 3.0 eV evidences a smaller thermal quenching with increasing temperatures from 14 K to RT. Additionally, the peak position of the emission shifts to higher energy when compared with the one of the as-grown sample. This blue shift was also observed in undoped and annealed SL showing that a change in the balance between the QC and QCSE occur with thermal annealing treatments.Despite the fact that different de-excitation processes occur in as-grown, annealed and Eu-implanted SL, the optically active centres in the GaN QD/AlN SL are excited via the same paths: two main absorption bands with maxima at approx. 4.1 and 4.7 to 4.9 eV.MBE: molecular beam epitaxy; PL: photoluminescence; PLE: photoluminescence excitation; QCSE: quantum confined Stark effect; QD: quantum dots; RT: room temperature; SL: superlattice; XRR: X-ray reflection.The authors declare that they have no competing interests.All the authors have made substantial intellectual contributions to the presented study. VF and BD were responsible for the growth of the analysed samples, SM, EA and KL performed the implantation and annealing treatments and carried the experiments and data analysis of the structural samples characterization, MP, AJN and TM carried out the acquisition of the optical data and their interpretation. All the authors have together discussed and interpreted the results. All the authors read and approved the final manuscript.


Financial relationships between physicians and industry are extensive and public reporting of industry payments to physicians is now occurring. Our objectives were to describe physician recipients of large total payments from these seven companies, and to examine discrepancies between these payments and conflict of interest (COI) disclosures in authors’ concurrent publications.The investigative journalism organization, ProPublica, compiled the Dollars for Docs database of payments to individuals from publically available data from seven US pharmaceutical companies during the period 2009 to 2010. We examined the cohort of 373 physicians in this database who each received USD $100,000 or more in the reporting period 2009 to 2010.These physicians received a total of $52,600,624 during this period . The predominant specialties were internal medicine and psychiatry. 147 of these physicians authored a total of 134 publications in the first quarter of 2011 and 77% (103) of these publications provided a COI disclosure. 69% of the 103 publications did not contain disclosures of the payment listed in the Dollars for Docs database.With increased public reporting of industry payments to physicians, it is apparent that large sums are being paid for services such as consulting and peer education. In over two-thirds of publications where COI disclosures were provided, the disclosures by physician authors did not include industry payments that were documented in the Dollars for Docs database. Financial relationships between physicians and industry are extensive in the U.S.,2, encomConcern over COI and resultant risk of bias has engendered a variety of approaches and policies by biomedical journals, academic institutions, medical and continuing education institutions, healthcare delivery systems, professional organizations, and public sector policy makers. Central to COI policies is disclosure, and recent efforts to address COI have focused on disclosure and increased transparency. One such policy in the US is the Physician Payments Sunshine Act, signed into law in the US in 2010 as part of the Patient Protection and Affordable Care Act. This policy requires that pharmaceutical, medical device, biological, and medical supply manufacturers report to the U.S. Department of Health and Human Services payments that are more than $10 to physicians and teaching hospitals[To date, drug companies have rarely disclosed payments to their speakers. Recently, however, a number of companies have begun posting doctors’ names and compensation on their web sites, some in anticipation of the Sunshine Act, others a result of legal settlements with the US government for illegal marketing of pharmaceuticals.The objectives of this study were to describe the physician recipients of large total payments from pharmaceutical companies and to examine discrepancies between those payments and payee disclosures in concurrent publications. This study explores the feasibility, utility, and limitations of using publically available payment data to examine these discrepancies.The source of our payment data was the Dollars for Docs database, developed by ProPublica, an investigative journalism organization. The DolProPublica obtained these data from open-access websites for each of the seven companies and aggregated them into a single database. The original data were available in a variety of formats, including unsortable PDFs. ProPublica programming staff used a variety of programs to scrape and clean the data, including Google Refine, FirebugFor each recipient of a payment from one of the seven companies, the database includes the recipient’s name, city and state, reason for the payment, company making the payment, and the quarter(s) when the payment was made. Companies varied in their categorization of the reasons for payments, for example AstraZeneca and Merck only reported payments to speakers, whereas Eli Lilly, Cephalon and Pfizer reported payments for a variety of services, including meals, travel, and consulting. The exact date for the payments was not provided, and companies varied in their aggregation of calendar quarters. The database has been continuously updated since its first release with the addition of more companies, individuals, and payments. For this study, we used payment data from the initial database, released in October, 2010.We selected as our study cohort individuals who received more than USD $100,000 in the period 2009 to 2010. We chose this cohort of payees because the large amounts of funds that these individuals received should likely be remembered and disclosed in concurrent publications, and we felt that these payees may have characteristics that make them somewhat homogeneous in their behaviors. Among these individuals, we examined only physicians, excluding other healthcare providers. We obtained demographic information on the cohort, including age, sex, years since medical school graduation, primary affiliation, specialty, and state of medical board certification. These demographic data were obtained from institutional websites, HealthGrades© and a general Internet search. All data were entered into Microsoft Access .In order to examine whether physicians disclose these payments, we identified publications by physicians in our cohort in any authorship position by searching Medline from January 1, 2011 through March 31, 2011 using the Ovid search engine. We included all types of publications , and confined our search to English language publications. Results were imported into an EndNote library . If we identified publications by authors with similar names, we reviewed the full text to further examine the institutional affiliation, credentials, and subject matter of the article to determine if the individual in our cohort authored the publication. If there was any uncertainty about whether a physician in our cohort authored a specific publication, a second member of our research team independently examined the publications and if there was disagreement, consensus was achieved.We then compared the COI disclosures to payments made to those individuals as indicated in the Dollars for Docs database. Because the lag time between completion of the COI disclosure and the date of publication (both electronic and print) is variable and unknown, and the database does not contain exact payment dates, we compared disclosures in 2011 publications to payments received in 2009 and 2010. This should produce a conservative (low) estimate of discrepancies, as COI disclosures in publications in 2011 should in all likelihood include payments to those authors in the prior 2 years.Since this is an observational, exploratory study, we did not perform sample size calculations. Descriptive statistics were used to summarize physician characteristics, total payments, and discrepancies in disclosures. An analysis of variance model was used to compare the mean total payments among specialties with adequate sample size (n > 20) and a linear regression model was used to assess the association between total payments and physician characteristics (age and sex). All analyses were conducted using SAS 9.3 .Of the 18,297 individuals listed in the database, 384 were identified by ProPublica as earning $100,000 or more during the time period 2009 to 2010  (TableP < 0.0001). In particular, the mean total payment to physicians in internal medicine was significantly higher than to physicians in family medicine  $1,533 to $41,482) and to psychiatrists . The mean total payment to surgeons was also significantly higher than to psychiatrists . The mean total payment to surgeons was not significantly different from that to physicians in internal medicine . Based on results from the linear regression, the total payment per physician per quarter was not associated with sex (P = 0.1730) or age (P = 0.4908).For specialties with five or more physicians represented in our cohort, mean payments ranged from $125,733 for psychiatry to $174,666 for anesthesiology. Four specialties  had 20 or more physicians represented in our cohort and the mean total payments per physician per quarter were significantly different among these specialties . Of the 134 publications by physicians in the first quarter of 2011, 103 (77%) provided author disclosures of COI in the publication while the remaining 23% did not. Among publications with disclosures, 42 (41%) reported that the index author had nothing to disclose, while in 29 publications (28%) the author disclosed a conflict other than the payment in the Dollars for Docs database. In the remaining 32 publications (31%), the payment in the database was disclosed. The percentage of publications with the payer in the Dollars for Docs database disclosed, stratified by the 7 companies, is displayed in FigureIn summary, among a cohort of physicians who were known recipients of large total payments from a select group of 7 pharmaceutical companies, nearly one-quarter of their concurrent publications do not report any COI disclosures. Furthermore, of the publications with disclosure statements, over two-thirds do not report payments listed in the Dollars for Docs database.Several prior studies have examined the accuracy of COI disclosures in journal publications, with similar results. Two recent studies compared disclosures in publications to payment information from an orthopedic device company. Chimonas and colleagues reportedOur study has important strengths. Our data originated with payer databases, which were placed in the public domain either voluntarily or by mandate of legal settlements. The use of physician payment data from pharmaceutical companies is novel, to our knowledge, and our study provides insights into the methods, feasibility, and limitations of using such datasets for studies of discrepancies between payments known to have occurred and disclosure in peer-reviewed journals. When datasets are more complete and journal policies more uniform, these approaches can be used to determine the accuracy and completeness of disclosures.Our study findings have important implications. Journal editors and readers rely on accurate disclosures by authors in order to assess the credibility and risk of bias in journal publications, and our findings suggest that the accuracy and completeness of disclosures cannot be assumed at present. As industry payment data increasingly become publically available, however, journal staff and readers will be able to verify the accuracy of author disclosures. Though in the US, until the Sunshine Act is implemented and there is a unified public reporting system for industry payments to physicians, it may not be feasible for journal editors and staff to check author disclosures. For authors, the increasing availability of payment data may promote more accurate disclosures or may discourage physicians from accepting industry payments, although there is as yet no evidence to support these possibilities. It is hoped that the standardized reporting form of the International Committee of Medical Journal Editors will impThere are a number of limitations to this pilot work. First, these are exploratory analyses on a small cohort of American physicians, whose characteristics and behaviors are likely not representative of US physicians in general, including those who receive much smaller total payments or those who do not receive funds from industry. Second, the database that we examined was limited to the payments of only 7 pharmaceutical companies during variable intervals in 2009 and 2010. The exact dates for payments were not available, and the categorization of types of payments varied across companies, making comparisons of the reasons for payments difficult.Third, we faced challenges identifying publications by our physician cohort: exact author names vary  and can resemble names of non-cohort authors. If we failed to identify all of the author’s publications, we may bias our assessment of rates of discrepancies if missing publications have a different disclosure rate than the rate in the publications that we identified. There is a delay in indexing publications in Medline thus more recent publications may have been missed.Fourth, our assessment of rates of discrepancies cannot be equated with inaccurate disclosures because of several assumptions that we made. We did not examine journal COI policies, but rather assumed that all journals required disclosures. We also did not examine how journal COI policies address relevance of the topic of the publication to the disclosure. We assumed that all payments in the database should have been disclosed in the identified publications.It was difficult to determine the relationship between the time of disclosure and payments as it was not possible to know exactly when authors completed disclosures relative to the time of publication, as this varies widely across journals. Although some journals request an update of disclosures at the time of publication, it is unknown how frequently authors comply and how accurate those updates are. In addition, we only had information on the quarter or group of quarters when payments occurred, and not the exact dates. Although unlikely, we could have overestimated rates of discrepancies if disclosure occurred well prior to publication and prior to drug company payment, or if a disclosure was close to the publication date and the required time period of disclosure was short, with payment preceding the disclosure period. We feel that our approach of examining 2011 publications should minimize these biases, as disclosures in publications likely encompass payments in the prior 2 years. Chimonas and colleagues used a sFinally, we were unable to determine the reasons for discrepancies, which are undoubtedly multifactorial, including forgetting, carelessness, misreading or misinterpreting COI policies, lack of clarity in disclosure forms, or purposeful nonreporting. From these retrospective, observational data we clearly cannot determine causality or impute motive.Future research can build on this work. Studies could further describe the characteristics of physicians and other healthcare professionals who accept payments across a broad range of values and payment types. The effectiveness of specific COI policies and disclosure forms for achieving accurate and complete disclosures should be explored for journals, institutional review boards, academic institutions, and other organizations. Predictors of the accuracy of COI disclosures can be examined when more complete payment data are available with implementation of the Sunshine Act. The effLittle is known about the effect of disclosure policies and practices on the intended outcomes of improving transparency and aiding in the interpretation of journal articles. The dominant opinions in the literature are that disclosures are essential because they enable the “readers to form their own opinions on whether a conflict exists and what relevance it has for the study”. HoweverTransparency of industry payments to US physicians is increasing because of new and anticipated government policies and practices. Large amounts of money are going to physicians from industry for non-research-related services. In a small and select cohort of physicians receiving large total payments from pharmaceutical companies, there are discrepancies between payments known to have occurred and disclosures in publications. Journal editors need to continue to develop policies and approaches that lead to accurate and complete disclosures. Failure to accurately report financial relationships with industry inhibits the ability of readers to assess the credibility and risk of bias of publications.AHRQ: Agency for healthcare and research quality; AZ: AstraZeneca; COI: Conflict of interest; CPG: Clinical practice guideline; GSK: GlaxoSmithKline; J&J: Johnson & Johnson; USD: United States dollar.SLN has received funding from the US Agency for Healthcare Research and Quality to study conflict of interest in clinical practice guideline development. HKH, LAO, BUB and RF received salary support from the Agency for Healthcare Research and Quality under grant number 1R01HS018500, to study conflict of interest in clinical practice guideline development. All authors declare that they have no other competing interests.SLN, HKH and LAO conceived of the study and participated in the design. SLN, HKH, BUB and LAO participated in the collection and management of the data. All authors contributed to the analysis and interpretation of the data and assisted in the preparation, review, and approval of the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6939/13/24/prepub


Patients with IgG4-related disease (IgG4-RD) share histopathological characteristics that are similar across affected organs. The finding of infiltration with IgG4+ plasma cells in the proper clinical and histopathological contexts connects a large number of clinical entities that were viewed previously as separate conditions. The renal involvement in IgG4-RD is usually characterized by tubulointerstitial nephritis, but membranous nephropathy has also been reported to be one of the renal complications of IgG4-RD. The recent discovery that a high proportion of patients with idiopathic membranous nephropathy (IMN) have IgG4 autoantibodies to the M-type phospholipase A2 receptor (PLA2R) in the circulation and glomerular immune deposits, together with the profound IgG4 hypergammaglobulinemia and occasional reports of membranous nephropathy in IgG4-RD, raised the question of a common antigen. To assess the presence of anti-PLA2R antibody in patients with IgG4-RD, we screened sera from 28 IgG4-RD patients by immunoblot. None of the patients in this cohort had detectable circulating anti-PLA2R antibodies. This study suggests that despite some clinical and serological overlaps between IgG4-RD and IMN,anti-PLA2R antibodies do not play a role in the pathogenesis of IgG4-RD. Additional studies of IgG4-RD with evidence of membranous nephropathy are important to exclude any definite relationship. IgG4-related disease (IgG4-RD) is a multiorgan system fibroinflammatory condition defined by a tendency to form tumorous lesions in various organs including the pancreas, salivary and lacrimal glands, biliary tract, liver, lung, and kidney, aorta . The hisIdiopathic membranous nephropathy (IMN) is an organ-specific autoimmune disorder and a leading cause of nephrotic syndrome in adults. Until recently, the etiology of this condition was unknown, but studies in experimental MN had established that circulating antibodies bind to a target antigen on glomerular podocytes and form antigen-antibody complexes that cause podocyte injury and proteinuria . In 2009IgG4-RD and IMN both appear to respond well to B cell depletion treatment with rituximab , 12, 13.Membranous nephropathy has been reported in some patients with IgG4-RD –18, but Because of certainclinical and pathological features of IgG4-RD and IMN overlap, the shared association with antibodies of the IgG4 subclass, and the ostensible improvement that both diseases demonstrate in response to B cell depletion, we assayed sera from patients in our longitudinal IgG4-RD registry for antibodies directed against PLA2R.Between July 2009 and September 2011, we obtained serum samples from 28 patients with IgG4-RD. All patients were enrolled in the Massachusetts General Hospital IgG4-RD Registry. The screening of human sera for anti-PLA2R antibodies was approved by the Institutional Review Boards at both the Massachusetts General Hospital and Boston University Medical Center.Patients were eligible to participate in the study if they had a biopsy-confirmed diagnosis of IgG4-RD. Histopathologic features considered to be highly suggestive of IgG4-RD diagnosis included lymphoplasmacytic infiltrates and storiform fibrosis within involved organs. Obliterative phlebitis and mild-to-moderate tissue eosinophilia were observed frequently but were not required for the diagnosis . In addiImmunohistochemical staining was performed as previously described . FormaliSerum IgG4 concentrations were measured by nephelometry .Patients' sera were tested for the presence of anti-PLA2R antibodies by immunoblot, under nonreducing conditions, as previously described . RecombiSera from 28 patients were tested for the presence of anti-PLA2R antibodies. The patients' baseline characteristics are shown in n = 9), salivary glands (n = 8), and orbital regions (n = 7). Five patients had IgG4-related pancreatitis (type 1 AIP), and four had IgG4-related sclerosing cholangitis. The other sites involved were the retroperitoneum (n = 4), aorta (n = 3), and the skin, pericardium, lung, thyroid gland, and tonsils (1 patient each).The patients' manifestations of IgG4-RD covered the full range of disease expression , includiTwo patients had evidence of kidney dysfunction, characterized by renal masses and proteinuria. Patient 16  was founPatient 14 was diagnosed with IgG4-related retroperitoneal fibrosis. Acute renal failure and proteinuria emerged a year after the diagnosis of IgG4-RD and resolved with glucocorticoid treatment. Kidney biopsy showed tubular injury, periglomerular fibrosis, interstitial inflammation, and the presence of IgG4+ plasma cells. Immunofluorescence microscopy showed no tubular basement membrane or glomerular basement membrane deposits. There were prominent mesangial granular deposits of IgG, IgA, IgM, and C3.Most of the patients were entered into the IgG4-RD Registry after the initiation of prednisone treatment. Twenty-one (75%) of the 28 patients were receiving glucocorticoids at the time their serum IgG4 was measured for the first time. Fifteen (54%) of the 28 patients had elevated serum IgG4. Among those patients with elevated serum IgG4 concentrations at baseline, the mean IgG4 was 640 mg/dL . The mean serum IgG4 concentration for all patients in the cohort was 342 mg/dL. Among the seven patients who were not treated with glucocorticoids before the diagnosis of IgG4-RD and serum sampling, the mean IgG4 level was 230 mg/dL.Patients were tested for rheumatoid factor by nephelometry, which was positive in 2 patients (7%). Antinuclear antibody (ANA) testing by immunofluorescence using the HEp-2 substrate was positive in 24 patients (85%). Patient 4 had a strongly positive ANA in an anticentromere pattern but had no clinical features of limited systemic sclerosis or Sjögren's syndrome, and salivary gland histopathology disclosed findings diagnostic of IgG4-RD, not Sjögren's syndrome. Enzyme-linked immunoabsorbent assays for antibodies against Ro, La, Sm, and RNP antigens were negative in all 28 patients.The sera from these 28 patients with IgG4-RD were tested for the presence of autoantibodies reactive with PLA2R. None of the serum samples contained detectable anti-PLA2R antibodies when screened at a dilution of 1 : 25 .IgG4-RD and IMN have significant overlap in their renal manifestations. Although membranous nephropathy is most often a renal limited autoimmune disease , membranous lesions and nephrotic syndrome have also been reported in IgG4-RD  and may There are a variety of potential explanations for this finding. The first is that anti-PLA2R antibodies do not play a role in IgG4-RD and that a different antigen-antibody system is at play in those few cases that develop membranous nephropathy . This isn = 7).A second possible explanation for our inability to detect the anti-PLA2R antibodies in this IgG4-RD patient cohort is that 75% of the patients received glucocorticoids prior to their entry to the study. Although glucocorticoids may have reduced the level of anti-PLA2R antibodies below the level of detection by the immunoblot assay used in this study, they are generally ineffective when used alone for treatment of IMN. Moreover, we did not detect these antibodies even in patients who had not been treated with glucocorticoids prior to serum sampling (A third potential explanation for our failure to find any relationship between the presence of anti-PLA2R antibodies and IgG4-RD is that IgG4-RD is not a single disease but rather a pathologic syndrome in which certain mechanisms operate across organ systems. If this explanation were true, then anti-PLA2R antibodies might play a role in some disease subsets of IgG4-RD, particularly the renal disease subset. The renal disease subset of IgG4-RD is underrepresented in our Registry as only two patients had overt renal disease, and none had biopsy-proven membranous glomerulonephropathy or nephrotic range proteinuria. An expanded study that includes a larger number of IgG4-RD patients with renal involvement of this nature is important to exclude definitively any relationship between IgG4-RD and antibodies to the PLA2R.Given the consistency of pathological features across involved organs in IgG4-RD, we believe that our findings likely represent the true nature of the relationship between IgG4-RD and antibodies to the PLA2-R, namely, that there is none. The significance of IgG4 hypergammaglobulinemia and IgG4+ plasma cell infiltration into involved organs in patients with IgG4-RD—whether they are pathogenic or just “innocent bystanders”—remains to be clarified.


Guidelines and performance measures recommend avoiding antibiotics for acute cough/acute bronchitis and presume visits are straightforward with simple diagnostic decision-making. We evaluated clinician-assigned diagnoses, diagnostic uncertainty, and antibiotic prescribing for acute cough visits in primary care.We conducted a retrospective analysis of acute cough visits – cough lasting ≤21 days in adults 18–64 years old without chronic lung disease – in a primary care practice from March 2011 through June 2012.Of 56,301 visits, 962 (2%) were for acute cough. Clinicians diagnosed patients with 1, 2, or ≥ 3 cough-related diagnoses in 54%, 35%, and 11% of visits, respectively. The most common principal diagnoses were upper respiratory infection (46%), sinusitis (10%), acute bronchitis (9%), and pneumonia (8%). Clinicians prescribed antibiotics in 22% of all visits: 65% of visits with antibiotic-appropriate diagnoses and 4% of visits with non-antibiotic-appropriate diagnoses. Clinicians expressed diagnostic uncertainty in 16% of all visits: 43% of visits with antibiotic-appropriate diagnoses and 5% of visits with non-antibiotic-appropriate diagnoses. Clinicians expressed uncertainty more often when prescribing antibiotics than when not prescribing antibiotics . As the number of visit diagnoses increased from 1 to 2 to ≥ 3, clinicians were more likely to express diagnostic uncertainty  and prescribe antibiotics .Acute cough may be more complex and have more diagnostic uncertainty than guidelines and performance measures presume. Efforts to reduce antibiotic prescribing for acute cough should address diagnostic complexity and uncertainty that clinicians face. Guidelines and performance measures recommend avoiding routine antibiotic prescribing for patients with acute cough/acute bronchitis –3]. The. The3]. Part of the gap between recommendations and actual practice may be that guidelines and performance measures presume visits are straightforward with simple diagnostic decision-making, when, in fact, they are more complex. The American College of Physicians/Centers for Disease Control and Prevention guideline, “Principles of appropriate antibiotic use for treatment of acute bronchitis in adults” does not apply to patients with cardiopulmonary disease and focuses on excluding the diagnosis of pneumonia, but does not mention the possibility of other concomitant, cough-related diagnoses ,7. The HWe conducted a retrospective chart review to measure the antibiotic prescribing rate and measure the prevalence of diagnostic complexity and diagnostic uncertainty that clinicians face when treating patients with acute cough.We performed a retrospective analysis to identify acute cough visits to a single primary care practice. We included visits by patients aged 18 to 64 years old, with a cough lasting up to 21 days, and without chronic lung disease. This analysis was part of an evaluation to inform an intervention targeted at reducing antibiotic prescribing for acute cough/acute bronchitis throughout our Practice Based Research Network.The Phyllis Jen Center for Primary Care is a teaching practice in the Brigham and Women’s Primary Care Practice Based Research Network. The practice has over 40 faculty physicians and 80 internal medicine residents with continuity clinics each academic year. About 40 additional internal medicine residents rotate through the practice for urgent care visits. There are also 3 Nurse Practitioners, 2 Registered Nurses, 2 Pharmacy Technicians, 2 Pharmacists, and 1 Social Worker. The practice serves a socioeconomically, racially, and ethnically diverse patient population.The practice uses the Longitudinal Medical Record as the official electronic health record (EHR) . The EHRUsing the EHR schedule, we identified all visits made to the practice between March 1, 2011 and June 30, 2012. We included only patients aged 18 to 64 years old to match the age range of the HEDIS performance measure. We excluded patients who had made a visit to the practice in the prior 30 days, and patients with chronic lung disease on their problem list. Our list of chronic lung disease diagnoses included, but was not limited to, asthma, asthmatic bronchitis, chronic obstructive pulmonary disease, interstitial lung disease, and chronic bronchitis.For patient visits that met our inclusion criteria, we reviewed the EHR note to identify patients with acute cough. We verified that patients met a guideline-consistent definition of acute cough/acute bronchitis: a cough lasting 21 or fewer days in a patient age 18 to 64 years old without chronic lung disease or immunosuppression [To assess inclusion and exclusion criteria and to record information about acute cough visits, we imported and manually extracted acute cough visit data into a study-specific database (Microsoft Access 2003). We imported data including date, provider name, patient identification number, age, sex, race/ethnicity (from registration data) and vital signs. We extracted clinical documentation data about the patient’s chief complaint or reason for visit, symptoms, physical exam findings, diagnoses, and treatments. For symptoms, we also noted whether the following eight symptoms were present, not present, or not mentioned: sore throat, phlegm/sputum, shortness of breath, headache, fevers, nasal symptoms, myalgias, and chest pain.For the physical exam, we extracted information on the normality, abnormality, or lack of mention about general appearance, tympanic membranes, external auditory canals, oropharynx, lymphadenopathy, lung sounds, or wheezing. Finally, we recorded the presence or absence of a chest x-ray, and whether the results were normal or abnormal.We extracted up to three clinician-assigned diagnoses as documented in the assessment and plan section of the visit note. For each visit, we assigned one of 16 common diagnoses associated with an acute cough. We considered sinusitis, pneumonia, streptococcal pharyngitis, otitis media, bacterial infection, and pertussis “antibiotic-appropriate diagnoses”. We use the term “antibiotic-appropriate diagnoses” for diagnoses for which some patients may require antibiotics according to guidelines  even though the majority of patients with “antibiotic-appropriate diagnoses” may not require antibiotics. We considered upper respiratory infection (URI), acute bronchitis, viral syndrome, post-nasal drip, non-streptococcal pharyngitis, allergies, reactive airway disease, gastroesophageal reflux disease, conjunctivitis, and influenza “non-antibiotic-appropriate diagnoses”. For diagnoses not in one of these 16 categories, we classified them as “other” and considered “other” a non-antibiotic-appropriate diagnosis. Even though some of these diagnoses might more rightly be considered symptoms , these were the diagnoses assigned by the treating clinician.We noted when the clinician expressed uncertainty when assigning the diagnosis, such as when providers used words like “maybe,” “unclear,” or used question marks in association with the diagnosis. As examples, we considered notes to express diagnostic uncertainty if they included text such as the patient “had a cough and sore throat with unclear etiology” or “presenting with ?acute bronchitis”. We also considered clinicians’ weighing of multiple possible diagnoses an expression of uncertainty . We did not consider clinicians documenting two distinct diagnoses an expression of uncertainty (e.g. “pneumonia with acute bronchitis” or “URI with sinusitis”).We collected and documented up to four prescribed medications as recorded in the electronic health record, giving preference to antibiotics and cough-related treatments. We did not abstract information about non-cough-related diagnoses or associated antibiotics (e.g. amoxicillin given to a patient with a urinary tract infection). We did not distinguish between immediate antibiotic prescribing and “delayed antibiotic prescribing”. Delayed antibiotic prescribing was very rare and guidelines and performance measures make no distinction or allowance for delayed antibiotic prescribing -3.We extracted information about whether patients made any follow-up visits to an affiliated site or received any antibiotic prescriptions within the 30 days following their initial visit. For each follow-up visit made, we noted where the care was delivered , the subject of the visit note, and whether the visit was related to acute bronchitis and/or antibiotic prescribing. If the follow-up visit was cough-related, we extracted up to three diagnoses, whether the clinicians expressed diagnostic uncertainty, and/or prescribed antibiotics.For each visit, we assigned a principal diagnosis. We prioritized the principal diagnosis by giving preference to the most antibiotic-appropriate diagnosis mentioned in a given visit in the following order: pneumonia, sinusitis, streptococcal pharyngitis, otitis media, pertussis, non-streptococcal pharyngitis, acute bronchitis, upper respiratory infection, post nasal drip, allergies, and other. For example, if a visit was given both URI and pneumonia diagnoses, the visit was assigned a principal diagnosis of pneumonia.We used standard descriptive statistics to describe and compare baseline characteristics of physicians and patients. We compared continuous variables using Student’s t test and categorical variables using the ×  test. WeThe Partners HealthCare Human Research Committee approved the study protocol.During the study period, there were 56,301 visits to the practice. We excluded 31,017 (54%) visits due to age, the presence of chronic lung disease, and having had a visit in the previous 30 days , post-nasal drip (9%), acute bronchitis (8%), and sinusitis (7%). After prioritizing cough-related diagnoses from most antibiotic-appropriate to least, the most common principal cough-related diagnoses were URI (46%), sinusitis (10%), acute bronchitis (9%), and pneumonia . Clinicians expressed diagnostic uncertainty more often for antibiotic-appropriate diagnoses 43%) than for non-antibiotic-appropriate diagnoses . Clinicians were more likely to express diagnostic uncertainty with increasing number of diagnoses: 5% for 1 diagnosis, 25% for 2 diagnoses, and 40% for 3 or more diagnoses , antitussives or expectorants (17%), decongestants (16%), analgesic/antipyretics (8%), and bronchodilators (7%). The most common classes of antibiotics were macrolides 53%), penicillins (28%), and fluoroquinolones (10%). Clinicians prescribed antibiotics in 65% (180/277) of visits with antibiotic-appropriate diagnoses, and 4% (29/685) of visits with non-antibiotic-appropriate diagnoses  of antibiotic prescribing.Residents were less likely to prescribe antibiotics overall . Residents did not prescribe antibiotics at different rates for antibiotic-appropriate diagnoses  or for non-antibiotic-appropriate diagnoses .As the number of diagnoses increased, clinicians were more likely to prescribe antibiotics: 16% for 1 diagnosis, 25% for 2 diagnoses, 41% for 3 or more diagnoses, respectively  initial visits resulted in 205 cough-related follow-up visits. These visits were to the same clinic as their initial visit (76%); to a specialist (12%); to an emergency department (10%); or to a different primary care practice (3%). Initial visits with a follow-up visit were more likely to have had an antibiotic-appropriate diagnosis (40%) compared to initial visits without a follow-up visit . Initial visits with a follow-up visit were also more likely to have had an antibiotic prescription (21%) compared to initial visits without a follow-up visit . There was no significant difference in diagnostic uncertainty between visits that did (19%) and did not have a follow-up visit .When comparing initial visit and follow-up diagnoses, 62% of follow-up visits had a different primary diagnosis than in the original visit note; 18% of visits changed from an antibiotic-appropriate diagnosis to a non-antibiotic-appropriate diagnosis; and 17% changed from non-antibiotic-appropriate to antibiotic-appropriate. Of all initial visits, 76 (8%) patients received an antibiotic prescription within 30 days. There was no difference in antibiotic prescribing at follow-up visits at the study clinic (29%) versus other sites .Guidelines and performance measures for antibiotic prescribing for acute cough/acute bronchitis presume that visits are simple and decision-making is straightforward. In this retrospective chart review, 46% of visits had more than one cough-related diagnosis and clinicians expressed diagnostic uncertainty in 16% of visits. Clinicians prescribed antibiotics more commonly for visits with antibiotic-appropriate diagnoses, with an increasing number of cough-related diagnoses, and at which the clinician expressed diagnostic uncertainty.Clinicians prescribed antibiotics at 65% of visits with antibiotic-appropriate diagnoses and 4% with non-antibiotic-appropriate diagnoses. Although we use the term “antibiotic-appropriate diagnosis”, not all of these visits require antibiotics, like mild sinusitis of short duration ,10, suspClinicians were more likely to prescribe antibiotics at visits with more cough-related diagnoses. Logically, the more diagnoses, the more likely one diagnosis would be antibiotic-appropriate. Beyond the presence of antibiotic-appropriate diagnoses, having more than one cough-related diagnosis may indicate greater patient complexity or an implicit expression of diagnostic uncertainty.not prescribed. More directly stated, when there is uncertainty, the treatment is less likely to match the diagnosis. Clinicians were more likely to express diagnostic uncertainty when they gave more than one diagnosis for the visit, and suggest diagnostic ambiguity when listing symptoms such as “cough” as a diagnosis. These associations point to a confluence between diagnostic uncertainty, increasing number of diagnoses, antibiotic-appropriate diagnoses, and antibiotic prescribing.Explicit expressions of diagnostic uncertainty were associated with antibiotic prescribing. In addition, clinicians seemed to express diagnostic uncertainty even more when there was a mismatch between the diagnosis and antibiotic treatment: clinicians expressed diagnostic uncertainty in 43% of antibiotic-appropriate diagnosis visits and 65% of antibiotic-appropriate diagnosis visits at which an antibiotic was Although clinicians may assuage their uncertainty with an antibiotic-appropriate diagnosis or an antibiotic prescription, patients do not do better. Initial visits with an antibiotic-appropriate primary diagnosis or with an antibiotic prescription were more likely to have a follow-up visit. Our analysis cannot answer whether these patients would not have had follow-up visits if the patients had been given non-antibiotic-appropriate diagnoses or had not been given antibiotics. A qualitative, European study suggests that clinicians decrease their antibiotic prescribing with an increase in clinical experience and diagnostic confidence .Our analysis has limitations that should be considered. First, the analysis was conducted in an academically-affiliated primary care teaching practice staffed mainly by general internists, some of whom were residents. However, we did not find any major diagnostic or prescribing differences between residents and non-residents. The presence of residents, researchers interested in judicious antibiotic use, and antibiotic-related quality improvement activities over the years may account for the relatively low antibiotic prescribing rate. Second, the analysis was dependent upon clinicians’ diagnoses and the accuracy and completeness of clinician documentation. However, as we were interested in clinician thinking about patients’ presentation and illness, the visit note provided insight into clinicians’ considerations. Third, our assignment of the most antibiotic-appropriate diagnosis as the principal diagnosis is forgiving to the treating clinicians and partially accounts for the very low apparent antibiotic prescribing rate for non-antibiotic-appropriate diagnoses. Fourth, expression of diagnostic uncertainty was varied and its interpretation somewhat subjective. Fifth, when assessing follow-up visits, we were limited to documentation within our healthcare system.Despite these limitations, our analysis shows that acute cough visits are more complicated than guidelines and performance measures presume. Even in a practice in which the antibiotic prescribing rate is much lower than the national average, clinicians gave patients more than one diagnosis in nearly half of visits and explicitly expressed uncertainty in 16% of visits. Both diagnosis number and explicit uncertainty were positively associated with antibiotic prescribing. Such complexity and uncertainty is not reflected in guidelines or performance measures.In addition to not capturing the complexity of actual clinical care – or perhaps because of it – the HEDIS acute bronchitis measure may cause unintended consequences. Roth and colleagues found that implementation of and improvement on the HEDIS measure led to a marked increase in a previously unused diagnosis code, which had a higher antibiotic prescribing rate . If the In conclusion, we found that 46% of acute cough visits had more than one cough-related diagnosis and clinicians expressed diagnostic uncertainty in 16% of visits. Antibiotic prescribing was associated with multiple diagnoses and diagnostic uncertainty. Revised guidelines that focus on the complaint of cough rather than on the diagnosis of “acute bronchitis”, and associated performance measures that include a broader range and number of diagnoses may more accurately reflect the complexity of the treatment of patients with acute cough.Beyond use of broader measures and more realistic guidelines, we also need better interventions to improve care of patients with acute cough/acute bronchitis . Most inEHR: Electronic health record; HEDIS: The healthcare effectiveness data and information set; URI: Upper respiratory infection.The authors have no financial or non-financial competing interests related to this manuscript. No sponsor had a role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; and preparation, review, or approval of the manuscript.JAL conceived of the study and oversaw its implementation with ACB. LEW and PPD contributed to the data extraction, cleaning, and analysis. LEW and JAL participated in the statistical analysis. LEW drafted the manuscript and all authors contributed to the writing, editing, and final approval of this manuscript. All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2296/14/120/prepub