Antibiotic resistance (AR) continues to be a serious problem. Many factors contribute to AR, including inappropriate use of antibiotics, in which both healthcare professionals and patients play a contributing role. This study aimed to assess the awareness and knowledge of antibiotic usage and AR among the general public (in affluent and deprived areas) and community pharmacists’ (CPs’) in Greater London.N = 384) residing in affluent areas of London. The second stage targeted public (N = 384) in deprived areas of London. In addition, CPs (N = 240) across the same areas were also surveyed. Data analysis was performed using Microsoft Excel and SPSS Software packages.A cross-sectional survey involving members of the public was conducted between July 2014 and February 2015. Stage one involved members of the public (n = 139/384) and 57% (n = 220/384) and 25% (n = 60/240) of public residing in affluent areas, deprived areas and of CPs respectively was achieved. Definitive trends in knowledge of how antibiotics work could not be drawn to distinguish between affluent and deprived areas. However, public respondents residing in affluent areas possessed better understanding of AR and prudent use of antibiotics, and this was statistically significant in both cases (p < 0.05). Exposure to an antibiotic campaign  did not raise public respondents’ knowledge on AR and only partially raised their general knowledge on antibiotics usage. Only 20% of public residing in deprived areas received counselling from a CP, among them 74% had an antibiotic prescribed on at least one previous occasion. Those who received counselling displayed better knowledge about concordance/adherence with respect to antibiotic usage (p < 0.05) whereas exposure to an antibiotic campaign made no significant impact on knowledge about concordance/adherence.Response rate: 36% (The study highlights that there has been no change in the status quo with respect to awareness of antibiotic usage and AR even after the implementation of several awareness campaigns in England. Those who benefited from CP counselling showed a significant better knowledge towards prudent antibiotic usage which stresses the importance of CPs’ counselling on antibiotic prescription. Alexander Fleming, the man who discovered penicillin in 1928, and who subsequently received his Nobel Prize in 1945 for this work, predicted in his then winning speech that the world would one day be facing antibiotic resistance (AR) .Several factors play a contributing role in the development of AR. While inappropriate use of antibiotics has been identified as the main cause behind AR , 8; therBoth healthcare professionals (HCPs) and patients are responsible for AR; there is a direct correlation between use and overuse of antibiotics and the emergence of AR , 11, 12.The threat of AR is increasing at an alarming rate , making AR would not be such a great concern if there were a continuous supply of new novel antibiotics. Since pharmaceutical companies have not been forthcoming with development of any new antibiotics with novel mechanisms of action in recent years –27, effoAndybiotic – Don’t wear me out’ [p < 0.0005) of the people still believed that antibiotics work on viruses [n = 1888) and after (n = 1830) the EAAD campaign to evaluate its success. No improvement was seen in the respondents’ understanding of correct antibiotics usage. Furthermore, the results detected a significant rise in the number of respondents keeping leftover antibiotics and thus casting doubt over the evidence that the campaign was effective [Global collaboration to encourage the prudent use of antibiotics and raise awareness of AR has been promoted through awareness-raising activities/ campaigns in Australia, USA,Canada and most European countries , 28. In  me out’  in which viruses . Campaig viruses . McNulty viruses  comparedffective .This demonstrates the fact that one campaign at a point in time does not sufficiently promote the awareness amongst the general public. There is a need for continual public awareness campaigns covering large percentages of the public. As part of the EAAD, in September 2014, the Antibiotic Guardian Campaign was launched in England where all members of the society, including HCPs are asked to make a pledge that encourages the individual to take on measures that combat antimicrobial resistance .HCPs such as community pharmacists (CPs) are in the best position to help in reducing AR due to their level of antibiotic knowledge and accessibility to the community , 35. ThiThis study aimed to assess the awareness and knowledge of antibiotic usage and AR among the general public and to assess CPs’ knowledge about AR in London. The study was conducted among public residing in affluent and deprived areas, with a hypothesis that such a socio-demographic factor can be related to awareness and knowledge of AR, with public in affluent areas having more awareness and knowledge of AR, since the incidence of infectious diseases tends to be higher in groups with lower socioeconomic status and outcomes tend to be poorer .This is a cross-sectional survey study that was conducted in two stages. Stage one involved members of the public in affluent areas, whereas stage two involved members of the public in deprived areas, in addition to CPs in both affluent and deprived areas.Members of the public were approached in person by two researchers in affluent public areas of London , and another two researchers in deprived public areas or in areas with diverse ethnicities . Affluent and deprived areas were determined based on the latest published index of multiple deprivations (IMD) score  and wereA sample size of 384 members of the public in affluent areas and 384 in deprived areas were approached at random in public places and handed the questionnaire. The total adult population in the included boroughs was 327,078 and 1,196,845 for affluent and deprived areas respectively. The sample size calculation was done using Raosoft sample size calculator  providinThe questionnaire was structured to facilitate self-administration by the public, and was partially based on a previous survey related to the topic  and aime240 Pharmacies were selected by convenience sampling in the same areas through which public were approached. The sample size was also calculated using the Raosoft sample size calculator . The totCPs were sent a postal survey with a prepaid envelope for returning the questionnaire in January 2015. The questionnaire was posted with an information sheet detailing the aims of the study, maintenance of confidentiality and the importance of participation. Only one response was received from each pharmacy. To maximise response rate, a follow-up questionnaire package was sent to CPs who didn’t provide an initial response, after one month in February 2015. Only fully completed questionnaires that were returned up until end of February 2015 were considered for the final analysis.The questionnaire for this phase was designed by the researchers and focused on the role CPs played in increasing awareness about AR and whether they feel there is a need to do more for the community in this regard.A pilot study was done to validate both CPs and public questionnaires after obtaining ethical approval and prior data collection.For CP survey, the pilot phase aimed to test content and face validity of the questionnaire used. The researchers discussed the questionnaire topics informally with 5 CPs in South London. Afterwards, the CPs were asked to fill the questionnaire and provide any comments about the questions on the chosen topics. The content was deemed satisfactory by the CPs; however, minor changes were required, which involved changing the wording of some questions.Whereas the public survey was piloted on a sample of 30 members of the public in South London to test for face and content validity. People were asked to fill the questionnaire, to indicate whether the questions were clear in relation to the topic and to provide any comments to improve the questionnaire. Minor amendments were required which involved changing the wording of some questions in order to facilitate self-administration. The results obtained in the pilot study were not included in the final analysis to avoid any type of bias.p value of < 0.05 was considered to be statistically significant.All responses were coded before analysis. Simple statistical analyses (Chi square test) were employed to determine whether a relationship exists between responses to questions on knowledge, behaviour and respondents’ demographics. A Ethical approval for both stages of the study was obtained from the Delegated Research Ethics Committee at Kingston University London (Ref: 1213/045).A total of 384 members of the public were approached in affluent areas and 139 agreed to participate giving a response rate of 36%. Whereas, in deprived areas, 384 were approached and 220 agreed to participate, giving a response rate of 57%. As for CPs, 240 questionnaires were mailed; however only 60 completed the questionnaire, providing a response rate of 25%.n = 112/139) of respondents in affluent areas displayed better understanding by disagreeing with the statement ‘antibiotics help cure the common cold, cough and flu’ compared with 45% (n = 98/220) in deprived areas (p < 0.05). Whereas, 68% (n = 149/220) of respondents in deprived areas displayed better understanding by disagreeing with the statement ‘antibiotics are effective against fungi’ compared with 43% (60/139) in affluent areas (p < 0.05). Both sets of respondents possessed comparatively poor knowledge as only 55% (n = 77/139) in affluent areas and 46% (n = 101/220) in deprived areas knew that antibiotics are not effective against virus.Table n = 112/139) correctly agreed that ‘antibiotic resistance is when antibiotics no longer work to treat infections’, compared to 57% (n = 126/220) in deprived areas, (p < 0.05) and 88% (n = 123/139) agreed that ‘if taken too often or unnecessarily, antibiotics are less likely to work in the future’, compared to 61% (n = 135/220) in deprived areas, (p < 0.05).As for knowledge on issues surrounding AR, Table ‘taking antibiotics as prescribed’ and 85% never ‘stopped taking antibiotics when symptoms have improved’, compared to 58% (n = 95/163) and 34% (n = 55/163) respectively in deprived areas (p < 0.05).Respondents in affluent areas showed a much better understanding on prudent antibiotics usage compared to those in deprived areas Table , with 99The responses provided by respondents in deprived areas were further analysed.Ethnicity and language did not influence their general knowledge on antibiotic usage whereas education (at a degree level or above), being in a healthcare profession or having a family member working in healthcare partly enhanced but not always significantly, their general knowledge on antibiotic usage Table .Table 4In = 45/139) of respondents have been exposed to an antibiotic awareness campaign compared to an even lower 17% (n = 37/220) of respondents in deprived areas. Exposure to an antibiotic awareness campaigns in deprived areas partially raised public respondents’ general knowledge on antibiotics usage but not on AR  were further analysed to investigate the impact of counselling and antibiotic campaigns on their antibiotic consumption behaviour (Table n = 32/163) stated that they always received counselling on antibiotic usage. Respondents who received counselling on antibiotic usage displayed better knowledge about concordance/adherence behaviour with respect to antibiotic usage than those who did not always receive counselling (p < 0.05) (Table The responses of public in deprived areas who have had an antibiotic prescribed to them on at least one previous occasion (ur Table . However5) Table . Exposur5) Table .n = 134/139) participants recalled that they have had an antibiotic on at least one previous occasion, 92% (n = 123/134) confirmed the antibiotics were prescribed to them on a prescription. However, 5% (n = 7/134) of respondents admitted they had some antibiotics left over from a previous supply and 1% (n = 1/134) indicated the supply was purchased over the counter (OTC). None of the respondents indicated that friends/family had given them antibiotics, however 3% (n = 4/134) specifically requested their doctor to prescribe an antibiotic but were refused.In affluent areas, 96% (n = 163/220) of respondents recalled that they have had antibiotics on at least one previous occasion. 90% (n = 146/163) confirmed the antibiotics were prescribed to them on a prescription. However, some participants also admitted that they had obtained antibiotics from various other means. Notably 12% (n = 19/163) from family/friends, 7% (n = 12/163) from abroad, 9% (n = 14/163) from a ‘previous supply’, and 7% (n = 11/163) from the internet.In deprived areas, 74% (n = 45/60) of pharmacist respondents indicated they had been requested to supply an antibiotic without a prescription. The main requests for antibiotics were for cold/flu  followed by for sore throat .Interestingly, 75% (n = 101/139) of participants indicated they would never insist on having an antibiotic prescribed to them. However, only 33% (n = 46/139) said they would trust their doctor if an antibiotic was ever refused to be prescribed to them. Whereas, in deprived areas, 66% (n = 108/163) of participants who had an antibiotic on at least one previous occasion indicated they hadn’t insisted on having an antibiotic prescribed to them. When asked whether they would trust their doctor even if they did not prescribe them an antibiotic, although 36% (58/163) remained neutral, 21% (35/163) indicated that they would strongly distrust their doctor if an antibiotic is not prescribed.In affluent areas, 73% (n = 48/60) of CPs admitted to not ever initiate a campaign to raise awareness on AR although 81% (n = 49/60) agreed with the importance of running the campaigns. The reported low uptake of pharmacist respondents in running the antibiotic awareness campaign was due to several factors. Notably lack of engagement was cited to be due to lack of funding , high workload/time constraints , followed by language barrier with patients/communication problems .80% (The current findings shed light on the existing situation pertaining to antibiotic usage and awareness of AR among the public in affluent and deprived areas of London.p < 0.05), which in return supports our hypothesis. In addition, public respondents in deprived areas possessed much poorer knowledge on prudent antibiotic usage compared to those in affluent areas (p < 0.05). In the current study, 88% in affluent areas agreed that antibiotics become ineffective if used unnecessarily compared to 61% in deprived areas. In this regard, a recent report by the European commission demonstrated that knowledge of antibiotics among the public has remained constant since 2013 with 84% of participants knew that antibiotics would become ineffective if used unnecessarily [Overall, public respondents residing in affluent areas possessed much better knowledge and understanding on AR problems and antibiotic usage and this was statistically significant  that antibiotics are effective against bacteria, they could not differentiate between bacteria and viruses and hence, believed that antibiotics would work against diseases caused by viruses also. Our results showed that 45 and 54% in affluent and deprived areas respectively believed that antibiotics are effective against viruses. Unfortunately, this is again comparable to the results of the survey study that was conducted in Britain10 years ago by McNulty et al.  after thIn deprived areas, 55% of respondents incorrectly believed that antibiotics can treat sore throat, cure common cold, cough and flu; 34% also admitted that they had insisted that an antibiotic be prescribed to them. In addition, CPs in the current study indicated that cold/flu and sore throat were the main conditions for which people request antibiotics from a pharmacy without prescription. Patients demand antibiotics perhaps because they often misunderstand the antibiotic action against microbes and the different models of prudent usage. In a UK study, 55% of 1000 GPs surveyed admitted that they felt under pressure from patients demanding an antibiotic. Importantly, 44% revealed that although they felt an antibiotic was neither appropriate nor necessary, they prescribed it anyway to close the consultation with the patient . In anotn = 32/163) in deprived areas actually received counselling on antibiotic usage from a CP, given that counselling on safe use of medicines is a part of the dispensing service which is provided by all pharmacy contractors with NHS England [antibiotic guardians” as one way to halt the spread of AR [Considering that 80% of prescribed antibiotics occur in primary care , 36, 48, England . On the ad of AR .In the current study, although 81% of CPs indicated that AR awareness campaigns are important to educate members of the public, yet their motivation in running such campaigns is lacking, with 80% not ever initiating an antibiotic awareness campaign. This was reflected with the small percentages of the public who were exposed to an antibiotics awareness campaign (32 and 17% in affluent and deprived areas respectively). However, this highlights/suggests lack of CPs’ efforts for curtailing the global crisis of AR, and stresses the importance to have joint efforts by all HCPs and members of the public to address the issue of AR .A small percentage of respondents admitted to taking antibiotics that were not prescribed for them by a qualified HCP. The revelation by some respondents that they have leftover antibiotics (5% in affluent areas and 9% in deprived areas) was similar to the 10% of those surveyed in other studies , 50. In Communication between HCPs and their patients should play an important part in conveying correct usage of antibiotics to reduce AR. Horne  highlighThe current study has several limitations that should be taken into consideration when interpreting the findings. The study was conducted only within some regions in London which limits the generalisability of the results on a national scale. Furthermore, the effect of counselling on knowledge regarding antibiotic behaviour was only studied from the responses acquired from the public in deprived areas of London. The sample size of those responses was rather small, thus limiting the generalisation of the influence of demographic factors, campaign exposure and counselling on antibiotic knowledge and adherence. On the other hand, although two attempts were made to boost response rate for CPs’ survey, yet the response rate obtained was small to be generalizable. In general, studies employing a self-administered questionnaire have other potential limitations including non-response bias, recall bias and social desirability bias due to the nature of the data being self-reported , 56. TheThe public surveyed still had deficiencies in antibiotic knowledge, which highlights that there has been no change in the status quo with respect to awareness of antibiotic usage and AR even after the implementation of several awareness campaigns in England, although respondents from affluent areas performed better overall compared to those in deprived areas. On the other hand, those who benefited from CP counselling showed a significant better knowledge towards prudent antibiotic usage which highlights the importance of CPs’ counselling on every antibiotic prescription. In an era where AR is a ticking time bomb, stringent measures in prescribing and dispensing antibiotics should be followed, with a view to making pharmacist counselling on every antibiotic prescription compulsory.


Deutsches Ärzteblatt (DÄ).Media frequently draws inappropriate causal statements from observational studies. We analyzed the reporting of study results in the Medical News section of the German medical journal Study design: Retrospective quantitative content analysis of randomly selected news reports and related original journal articles and press releases.A medical news report was selected if headlines comprised at least two linked variables. Two raters independently categorized the headline and text of each news report, conclusions of the abstract and full text of the related journal article, and the press release. The assessment instrument comprised five categories from ‘neutral’ to ‘unconditionally causal’.Outcome measures: degree of matching between 1) news headlines and conclusions of the journal article, 2) headlines and text of news reports, 3) text and conclusions, and 4) headlines and press releases. We analyzed whether news headlines rated as unconditionally causal based on randomized controlled trials (RCTs).One-thousand eighty-seven medical news reports were published between April 2015 and May 2016. The final random sample comprised 176 news reports and 100 related press releases.Degree of matching: 1) 45% (79/176) for news headlines and journal article conclusions, 2) 55% (97/176) for headlines and text, 3) 53% (93/176) for text and conclusions, and 4) 41% (41/100) for headlines and press releases. Exaggerations were found in 45% (80/176) of the headlines compared to the conclusions of the related journal article. Sixty-five of 137 unconditionally causal statements of the news headlines were phrased more weakly in the subsequent news text body. Only 52 of 137 headlines (38%) categorized as unconditionally causal reported RCTs.Reporting of medical news in the DÄ medical journal is misleading. Most headlines that imply causal associations were not based on RCTs. Medical journalists should follow standards of reporting scientific study results. Media regularly report on health research results. Since randomized controlled trials (RCTs) are the gold standard for questions about benefits and harms of medical interventions, it would be expected that results from RCTs with patient-relevant endpoints would be reported in the media more frequently than observational studies. However, studies with lower methodological quality are cited just as frequently –3. The mThe causal interpretation of observational studies can lead to wrong medical decisions. For example, hormone replacement therapy was recommended based on observational studies of postmenopausal women .In a press release in 2012, the German Network for Evidence-based Medicine (DNEbM) denounced the distorted representations and causal interpretations of association studies in the German media coverage, and called for critical assessment of scientific results by medical journalists .In Germany, the Deutsches Ärzteblatt (DÄ) is the official journal of the German Medical Association and the medical journal with the largest circulation. In addition to its weekly journal, medical news reports about current study results are regularly published on the DÄ website . News reA part of this work was carried out within the framework of a master thesis by the coauthor MB. The methodological approach was defined a priori .A retrospective quantitative content analysis of randomly selected medical news from the DÄ website, as well as of the corresponding original studies and press releases, was carried out.Bundesärztekammer) and the National Association of Statutory Health Insurance Physicians (Kassenärztliche Bundesvereinigung [KBV]). In 2016, the DÄ journal published 44 issues with a total circulation of 357,102 printed journals. DÄ is targeted to all physicians and medical disciplines: employed, non-employed, and retired, as well as physicians who work in non-medical areas. DÄ is one of the most widely read German medical journals, and the DÄ website had about 1.6 million visitors per month between June 2015 and May 2016 [DÄ is the official publication of the German Medical Association  and news announcements (from the starting date until 15 May 2016). We planned to analyze about 20% percent of the included reports. All medical news reports were saved along with their corresponding studies and press releases. Random sampling was performed using a computer-assisted random generator. Reports about interventions or epidemiological evaluations and their links to health were included. For this, the news report headline was required to have at least two linked variables, such as "Vitamin C could protect against cataracts” . News abA systematic literature search identified a tool that has been used to evaluate causality statements in peer reviewed papers, press releases, and health-related news stories , 7. It iThe endpoint was the degree of matching between: a) the categorized headline of the medical news reports and the conclusions of the original study publication; b) the headline and the text body of the medical news report; c) the text body and the conclusions of the original studies; and d) the headline and the press release. In addition, whether the news report headlines rated as causal, based on RCTs, was analyzed.A master student (MB) and a health scientist (SB) independently categorized the headline and text body of each news report, the conclusions  of the original study publication, and the related full press releases (headline plus text). In some cases, statements within the text body of news reports as well as within the press releases were inconsistent, i.e. the text started with a causal statement, which was subsequently phrased more weakly. In this case, the text was classified within the weaker category. We used a similar procedure for statement inconsistencies between conclusions of the abstract and the full text of the study publications. We compared the ratings from the first 15 datasets to discuss possible discrepancies arising from the evaluation tool at an early stage. As a 100% degree of matching was obtained for these 15 datasets, the remaining datasets were categorized without any further intermediate adjustments.To classify the study design, three categories were defined: 1) non-identifiable study design; 2) studies that allow causal interpretations ; and 3) studies that at the most allow associations (such as cohort studies and case-control studies). If the study design was not reported in the abstract, the full text of the study publication was considered.Headlines were additionally categorized by a third rater (AR). Discussions about rating differences were held to reach a consensus; if no consensus was reached by the raters, members of the pilot group were consulted. At the request of the journal, we additionally categorized the press release headlines and the first two sentences separately from the full press releases.The inter-rater reliability (IRR) between the three raters for the headlines is given by Fleiss' kappa, and the IRR between two of the raters of the remaining entire datasets, by Cohen’s kappa. The IRR for the headlines was very good for the two raters who analyzed the entire dataset (κ = 0.95). A substantial agreement for headlines was also shown with the third rater (κ = 0.69). The lower IRR resulted from a misunderstanding about an item in the evaluation tool, which could be resolved by consensus discussions. The mean IRR for the news text bodies, study conclusions, and press releases was κ = 0.97.The analysis of the categorized datasets with respect to the result parameters was descriptive. Absolute numbers and percentages are reported.From April 2015 to May 2016, 1087 medical news reports were published by DÄ. We randomly selected 302 headlines to test for inclusion criteria, of which 202 met the criteria. However, as some news reports either were not based on original studies or reported pathophysiological analyses, we included an additional 25 headlines that were randomly chosen from the remaining 785 medical news reports. Thus, we analyzed a total of 176 headlines (16%) and their related original studies. Of these studies, 100 had a corresponding press release .In total, 79 of 176 headlines and related original study publications were assigned to the same category. In other words, the news headline statements were consistent with the conclusions of the related study in 45% of the cases. Eight of the 176 news headlines were worded neutrally . ExaggerThe categorized headlines and the corresponding text body of the medical news matched in 97 of 176 cases (55%). Two headlines and the corresponding texts were formulated neutrally. In a relevant proportion, the statements of the remaining headlines were weakened in the text body (68/176). Of the 137 headlines that were clearly stated in a causal manner, the corresponding text likewise contained a causal statement in 72 cases and contained a weaker formulated statement in 65 cases .The text of the news reports and the original study conclusions received the same rating in 93 out of 176 cases (53%). Four news reports were rated as neutral. A total of 76 news reports were identified as unconditionally causal . From thThe categories of headlines and full press releases matched in 41% of the cases (41/100). Of the 100 news headlines that had a corresponding press release, 78 were rated as unconditionally causal. Likewise, 32 press releases (41%) were rated as unconditionally causal, 11 as neutral, 18 as association, 14 as "could" statements, and 3 as "can" statements .The degree of matching between the text body of the medical news and the press release was 46% (data not shown).The additional comparisons of DÄ headlines with press release headlines showed a matching of 49% (49/100); DÄ headlines and press release headlines plus the first two sentences matched in 43% (43/100) of the cases .A total of 137 out of 176 headlines were rated as unconditionally causal . HoweverOnly about half of the medical news reports on the DÄ website agree with the conclusions of the original study publications. The news headlines often contain causal statements, even though the majority of them only describe observational studies. This leads to study results being presented in the medical news reports in an exaggerated and therefore misleading manner.A representative sample from the medical news reports of DÄ was analyzed. The randomly selected news reports contained publications with a broad range of health topics, ranging over a year. To categorize the medical news reports as well as the original study publications, a previously developed tool was used that has already been applied several times , 7. For As we did not present the news reports to the target group of DÄ, we do not know how physicians interpret the headlines.We did not carry out a critical evaluation of RCTs. In fact, RCTs with a poor methodological quality might not allow a causal interpretation of the results. Therefore, the proportion of headlines with causal statements that were correctly based on valid RCTs might be still too high in our analysis. Furthermore, we did not check the correctness of the conclusions of the original study publications. Study conclusions often do not correspond to the study results. For instance, one study of articles reporting RCTs with non-significant results found that the conclusions given in both the abstract and in the text body distorted the results in more than a third of the cases . In ordeThis work confirms the results of previous investigations. Similar to media reports and press releases –3, the met al. found that 40% of university press releases contain recommendations that are not confirmed in the original publication [The rate of exaggeration through causal interpretation of association studies is also confirmed in the literature. In their analysis, Sumner lication . This walication . In anotlication . In thislication .Qualitatively better press releases seem to be linked with more transparent media reports . If a prThe medical news reports of DÄ showed only a weak correlation with the corresponding press releases. In contrast to Sumner et al. , 7, we cAn investigation of press releases, media reports, and RCTs showed that media reports mainly contain the same misinterpretations as press releases . The samet al. first correctly reformulated 30 abstracts from RCTs for which the original publication exaggerated a non-significant primary endpoint [Such distortions have an influence on the interpretations of study results. For instance, in an RCT performed with clinicians, Boutron endpoint . For theendpoint .The extent to which the type of coverage in the medical news reports of DÄ determines whether a physician would like to read the corresponding original study publication has so far not been investigated. The influence on professional activity thus remains unclear.However, media can influence the health-related behavior of both physicians and citizens –22. The Our results show that standards for reporting results from scientific work are not taken sufficiently into account in the medical news reports of DÄ. The main focus of the news section should not be to draw attention but rather to send the correct message. A neutral phrasing / wording of the headlines could prevent misinterpretations, which possibly also result from translation . Further, mentioning the study design in the headline would be preferable, similar to the required reporting standards for titles of study publications , 26. ForFor readers, it is not clear who is writing the medical news reports. Thus, crediting the authors of the reports, as a basic prerequisite for transparency and responsibility, should be standard in the DÄ news section.Medical journalists have a difficult role, especially when press releases and abstracts of the studies are distorted. Critical evaluation of studies requires a corresponding competence. The German Network for Evidence-based Medicine (DNEbM) regularly offers workshops for journalists.S1 Text(DOCX)Click here for additional data file.S1 Table(PDF)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.


The Grover quantum search algorithm is a hallmark application of a quantum computer with a well-known speedup over classical searches of an unsorted database. Here, we report results for a complete three-qubit Grover search algorithm using the scalable quantum computing technology of trapped atomic ions, with better-than-classical performance. Two methods of state marking are used for the oracles: a phase-flip method employed by other experimental demonstrations, and a Boolean method requiring an ancilla qubit that is directly equivalent to the state marking scheme required to perform a classical search. We also report the deterministic implementation of a Toffoli-4 gate, which is used along with Toffoli-3 gates to construct the algorithms; these gates have process fidelities of 70.5% and 89.6%, respectively. Grover’s algorithm provides a quantum speedup when searching through an unsorted database. Here, the authors perform it on 3 qubits using trapped ions, demonstrating two methods for marking the correct result in the algorithm’s oracle and providing data for searches yielding 1 or 2 solutions. It is an optimal search algorithm for a quantum computer3, and has further applications as a subroutine for other quantum algorithms5. Searches with two qubits have been demonstrated on a variety of platforms12 and proposed for others13, but larger search spaces have only been demonstrated on a non-scalable NMR system14.Searching large databases is an important problem with broad applications. The Grover search algorithmN, the single-shot probability of measuring the correct answer is maximized to near-unity by repeating the oracle and amplification stages O((N)1/2) times2. By comparison, a classical search algorithm will get the correct answer after an average of N/2 queries of the oracle. For large databases, this quadratic speedup represents a significant advantage for quantum computers.The Grover search algorithm has four stages: initialization, oracle, amplification, and measurement, as shown in Fig. 15 on n = 3 qubits, which corresponds to a search database of size N = 2n = 8. The algorithm is executed for all eight possible single-result oracles and all 28 possible two-result oracles. All searches are performed with a single iteration. For a single-solution algorithm (t = 1), the algorithmic probability of measuring the correct state after one iteration is 2, compared to t = 2), where two states are marked as correct answers during the oracle stage and both states’ amplitudes are amplified in the algorithm’s amplification stage, the probability of measuring one of the two correct answers is 100% for the quantum case, as compared to Here, we implement the Grover search algorithm using a scalable trapped atomic ion system16, only one is directly comparable to a classical search. The Boolean method requires the use of an ancilla qubit initialized to |1〉, as shown in Fig. NOT and Ck(NOT) (k ≤ n) gates such that, were the oracle circuit to be implemented classically, the ancilla bit would flip if and only if the input to the circuit is one of the marked states. By using classically available gates, this oracle formulation is directly equivalent to the classical search algorithm, and therefore can most convincingly demonstrate the quantum algorithm’s superiority. On a quantum computer, because the initialization sets up an equal superposition of all possible input states, the Cn(NOT) gate targeted on the ancilla provides a phase kickback that flips the phase of the marked state(s) in the data qubits. An example oracle is shown in Fig. Z and Ck(Z) (k ≤ n − 1) gates that directly flip the phase(s) of the state(s) to be marked ) as well as gates between arbitrary pairs of ions (XX(χ)) (see Methods for details). State-dependent fluorescence detection with each ion mapped to a separate photomultiplier tube (PMT) channel allows for individual ion readout15.The experiments presented here were performed on a programmable quantum computer consisting of a linear chain of five trapped CNOT) gates constructed from an 15. Here, we show results for a controlled-controlled-NOT (C2(NOT)), or Toffoli-3, gate, with a process fidelity of 89.6(2)% % Fig. . Toffolimentclass2pt{minimmentclass2pt{minim14. Any doubly-controlled unitary C2(U) operation can be performed with five two-qubit interactions s, and one C(V†)) if a controlled-V operation is available such that V2 = U27. Since CNOT  and C2(Z) gates, which can be constructed by adding a few single-qubit rotations to a CNOT or Toffoli-3 gate, respectively (see Methods for circuits). For all circuits, the single-qubit rotations are further optimized to minimize total rotation time28.Our Toffoli-3 gate is constructed from five two-qubit gates . By again using both CNOT gates29.We use a related strategy to construct a Toffoli-4 gate, and report an average process fidelity of 70.5(3)% Fig. . Using tej is the expected population and mj is the measured population for each state j30. Additionally, all of the data shown in this paper is corrected to account for state preparation and measurement (SPAM) errors , similar to the method proposed in ref. 31 while also accounting for multi-ion crosstalk15. All uncertainties given are statistical uncertainties based on the number of experiments performed.Figures XX(χ) gates and 3 qubits for phase oracles compared to 16 XX(χ) gates and 5 qubits for Boolean oracles) results in better performance, as expected. These results compare favorably with the classical ASP of 25%.The single iteration, single-solution Grover search algorithm shown in Fig. XX(χ) gates and three qubits for phase oracles compared to 10–14 XX(χ) gates and four qubits for Boolean oracles) results in better performance, as expected. For all oracles in both cases, the two states with the highest measurement probability are also the two marked states. These results compare favorably with the classical ASP of 46.4%.The two-solution Grover search algorithm shown in Fig. n, and for a constant number of solutions t. For a database of size N = 2n stored on n qubits, the amplification stage requires one Toffoli-n gate, and the t-solution oracle stage requires at worst t Toffoli-n (for a phase oracle) or Toffoli-(n + 1) (for a Boolean oracle) gates; optimal oracles for particular sets of marked states may require even fewer two-qubit gates. The method used here to construct the Toffoli-4 circuit scales to Toffoli-n gates as 6n − 13 in the two-qubit gate count and as 29. This paves the way for more extensive use of the Grover search algorithm in solving larger problems on quantum computers, including using the circuit as a subroutine for other quantum algorithms.We note that this implementation of the Grover search algorithm scales linearly in the two-qubit gate count and ancilla count for increasing search database size as a function of the number of qubits R and XX(χ) gates directly implemented by the experiment. The single-qubit rotation is defined asX-axis (Rx(θ)) are achieved by setting ϕ = 0, and rotations about the Y-axis (Ry(θ)) are achieved by setting Z-axis (Rz(θ)) are comprised of three rotations about axes in the XY plane, as demonstrated in Fig. Here we present detailed circuit diagrams for all of the operations presented in the paper above, shown in terms of the χ can be varied continuously by adjusting the overall power applied to the gate, but the gates used here require only The two-qubit entangling gate isXX gates are combined with rotation R gates to construct the composite gates needed for the Grover search algorithm implementation. The parameter χ can be positive or negative, depending on what ion pair is chosen and the particulars of the pulse segmentation solution chosen for the ion pair in question; the sign of χ (sgn(χ)) is determined experimentally for each ion pair. Consequently, some composite gate circuits include rotations with parameters that depend on sgn(χ). Composite gates were constructed by starting with known circuits, converting constituent parts into R and XX gates using lower-level constructions, and then optimizing the circuit. First, the number of XX gates was minimized . Second, the single-qubit gates were optimized by minimizing the sum of all rotation angles θ, as this minimizes the total time for the experiment. Additional details can be found in refs. 29.Two-qubit CNOT and controlled-Z gates are shown in Fig. XX gate and several rotations. The three-qubit gates used here are the Toffoli-3 and controlled-controlled-Z (CCZ) gates, shown in Fig. q1 and q2) and one target qubit (qt). Finally, the four-qubit Toffoli-4 gate is shown in Fig. q1, q2, and q3) and one target qubit (qt), and it additionally requires an ancilla qubit (qa).The two-qubit qa is simply omitted. To preserve the modularity of the algorithm, the initialization stage and amplification stage were each optimized without regard to the contents of the oracle, so each possible oracle can simply be inserted into the algorithm without making any changes to the other stages.The Grover search algorithm is implemented using circuits that are equivalent to those shown in Fig. X, CN(NOT) gates that marked the desired state(s) for each oracle. For phase oracles, EXOR polynomial synthesis was used to find a set of Z, CN(Z) gates that marked the desired state(s) for each oracle. For example, for Boolean oracles, the selection was limited to the classically available X (or NOT) and CN(NOT) gates, and a reversible circuit was constructed such that the output bit (corresponding to the ancilla qubit in the quantum oracle) would be flipped if and only if a marked state was used as the input to the circuit. While there are many possible circuit constructions for each oracle, the oracle chosen for implementation was one that first minimized the number of two-qubit interactions required, and then minimized the number of single-qubit interactions needed. The synthesis techniques used are scalable and can be applied to oracles of any size. The oracles used here were implemented as per the circuit diagrams shown in Table Oracles for the Grover search algorithm were constructed using a combination of reversible and classical logic synthesis techniques. For Boolean oracles, reversible logic synthesis was employed to find a set of R and XX gates. Finally, perform further optimizations to first minimize the number of two-qubit XX gates required, and then to minimize the total rotation time  across all R gates. However, since the optimization of quantum circuits is QMA-Hard, we anticipate that future improvements in algorithm design, circuit synthesis, and circuit optimization techniques may result in more efficient circuit implementations, facilitating increased experimental performance.Other quantum algorithms may be implemented on this system in a similar fashion. First, decompose the algorithm’s subroutines into high-level circuits. Second, optimize those circuits to minimize the number of two-qubit interactions required. Third, decompose the high-level circuits into physical-level All relevant data are available from the corresponding author upon request.Supplementary Information


RD) is a recently defined fibro‐inflammatory condition. We describe a novel association between reactive IgG4+ plasma cells and cystic lymphangioma in a young woman who had a dramatic clinical response to steroids.Lymphangiomas are benign tumors of the lymphatic vessels, which can be inflammatory and occasionally steroid‐responsive. IgG4‐related disease (IgG4‐ A previously healthy 29‐year‐old Caucasian woman presented with a six‐month history of bilateral leg edema and weight loss (65–52 kg) associated with anorexia and nonbloody diarrhea. She denied any constitutional or infectious symptoms and had no history to suggest heart failure, liver cirrhosis, pulmonary or renal disease, such as dyspnea, frothy urine, abdominal pain, or jaundice. She was not on any prescription medications or recreational drugs. Her complete blood count, renal, and liver profiles were normal. C‐reactive protein was 57 mg/L (<3.1), albumin 7 g/L (34–50), and urinary protein 0.23 g/day. Antinuclear and antitissue transglutaminase antibodies, blood, urine, stool cultures, parasite examination, and viral serologies were all negative. Echocardiogram was normal. Computed tomography of the neck, chest, abdomen, and pelvis showed extensive retroperitoneal cystic lesions extending from the subdiaphragmatic region to the pelvic inlet, two discrete cysts in the left supraclavicular fossa, and mediastinum which appeared continuous via the thoracic duct suggestive of multiple lymphoceles. Upper and lower endoscopies and small bowel capsule studies were normal. Needle biopsies of the retroperitoneal and neck lesion were nondiagnostic.She developed anasarca and chylous ascites; after multiple inconclusive lymphangiographies, she underwent exploratory laparotomy with resection of the pelvic cysts. Pathology showed abundant plasma cells with >100IgG4+ cells/HPF and IgG4: IgG ratio 99% Fig. . Other fHer ascites failed to improve with repeated drainage and total parenteral nutrition for 4 weeks. Although she did not meet diagnostic criteria for IgG4‐RD, the finding of IgG+ plasma cells led to a trial of systemic therapy with intravenous methylprednisolone 500 mg/day × 3 days Lymphangiomas are rare cystic malformation arising from sequestration of lymphatic tissue that fails to communicate with the lymphatic system. Ninety‐five percent cases are found in the neck and axilla. Retroperitoneal involvement constitutes only 1% Immunoglobulin G4‐related disease (IgG4‐RD) is a systemic disease characterized by tumefactive lesions, particularly in glandular tissues  and fibrosis. Nearly any organ or tissue can be involved, and the histology is remarkably similar in most tissues. Biopsies of affected organs demonstrate a lymphoplasmacytic infiltrate enriched with IgG4 + plasma cells , storiform fibrosis, and obliterative phlebitis. Notable exceptions are bone marrow and lymph nodes, where fibrosis and obliterative phlebitis are not seen AAAZ: was the first author, wrote the main body of the manuscript, and performed thorough literature search to enrich the discussion part. SLM: was the second author, gathered information, medical history, and physical examination, and contributed to the literature search and manuscript editing. MNC: was the third author, contributed with rheumatology investigation of the case and management of IgG4‐related inflammatory infiltrate with steroid, and contributed to manuscript editing and IgG4 RD discussion. GWS: was the fourth author, provided high‐quality microscopic images of the biopsy with the histopathological description, and contributed to manuscript editing. LYCC: was the fifth author and main treating physician of the patient, supervised manuscript writing and editing, and contributed in writing the discussion part. All authors had access to the data and participated in the writing of the manuscript.None of the authors have any conflict of interest or financial disclosures related to this manuscript.


Structural variants (SVs) in human genomes are implicated in a variety of human diseases. Long-read sequencing delivers much longer read lengths than short-read sequencing and may greatly improve SV detection. However, due to the relatively high cost of long-read sequencing, it is unclear what coverage is needed and how to optimally use the aligners and SV callers.In this study, we developed NextSV, a meta-caller to perform SV calling from low coverage long-read sequencing data. NextSV integrates three aligners and three SV callers and generates two integrated call sets (sensitive/stringent) for different analysis purposes. We evaluated SV calling performance of NextSV under different PacBio coverages on two personal genomes, NA12878 and HX1. Our results showed that, compared with running any single SV caller, NextSV stringent call set had higher precision and balanced accuracy (F1 score) while NextSV sensitive call set had a higher recall. At 10X coverage, the recall of NextSV sensitive call set was 93.5 to 94.1% for deletions and 87.9 to 93.2% for insertions, indicating that ~10X coverage might be an optimal coverage to use in practice, considering the balance between the sequencing costs and the recall rates. We further evaluated the Mendelian errors on an Ashkenazi Jewish trio dataset.Our results provide useful guidelines for SV detection from low coverage whole-genome PacBio data and we expect that NextSV will facilitate the analysis of SVs on long-read sequencing data.The online version of this article (10.1186/s12859-018-2207-1) contains supplementary material, which is available to authorized users. Structural variants (SVs) represent genomic rearrangements , and SVs may play important roles in human diversity and disease susceptibility –3. Many Two popular SV software tools have been developed specifically for long-read sequencing: PBHoney  and SnifTo address these challenges, we developed NextSV, an automated SV detection pipeline integrating multiple tools. NextSV automatically execute these software tools with optimized parameters for user-specified coverage, then integrates results of each caller and generates a sensitive call set and a stringent call set, for different analysis purposes.Recently, the Genome in a Bottle (GIAB) consortium and the 1000 Genome Project Consortium released high-confidence SV calls for the NA12878 genome, an extensively sequenced genome by different platforms, enabling benchmarking of SV callers , 18. TheFive whole-genome PacBio sequencing data sets were used to test the performance of SV calling pipelines Table . Data sePacBio subreads were iteratively aligned to the human reference genome  using the BLASR aligner (parameter: -bestn 1). Each read’s single best alignment was stored in the SAM output. Unmapped portions of each read were extracted from the alignments and remapped to the reference genome. The alignments in SAM format were converted to BAM format and sorted by SAMtools. PBHoney-Tails and PBHoney-Spots (from PBSuite-15.8.24) were run with slightly modified parameters  to increase sensitivity and to discover SVs under low coverages (2-15X). The reference FASTA files used in this study were downloaded from the FTP sites of 1000 Genome Project  (GRCh37)PacBio subreads were aligned to the reference genome, using BWA-MEM (bwa mem -M -x pacbio) or NGMLR (default parameters) to generate the BAM file. The BAM file was sorted by SAMtools, then used as input of Sniffles (version 1.0.5). Sniffles was run with slightly modified parameters  to increase sensitivity and discover SVs under low fold of coverages (2-15X).As shown in Fig. Users can choose to run any of the four aligner/SV caller combination. By default, NextSV will enable BLASR/PBHoney-Spots, BLASR/PBHoney-Tails and NGMLR/Sniffles and integrate the results to generate the sensitive calls and stringent calls. We do not enable BWA/Sniffles by default because Sniffles works better with NGMLR in our evaluation and alignment is a time consuming step. SVs that are shorter than reads may result in intra-read discordances while larger SVs may result in soft-clipped tails of long reads. We suggest running both PBHoney-Spots and PBHoney-Tails because they are two complementary algorithms designed to detect intra-read discordances and soft-clipped tails, respectively. Sniffles uses multiple evidences to detect SV so it should be suitable for both types of SVs.NextSV sensitive call set is generated as:SNIF ∪ (SPOT ∪ TAIL),and NextSV stringent call set is generated as:SNIF ∩ (SPOT ∪ TAIL),where SNIF denotes the call set of Sniffles , SPOT denotes the call set of BLASR / PBHoney-Spots and TAIL denotes the call set of BLASR / PBHoney-Tails.delta. Delta used by NIST/GIAB analysis team was 1000 bp and used by Pendleton et al.  was 100The high-confidence deletion call set of the NA12878 genome was release by the Genome In A Bottle (GIAB) consortium , in whicThe SV calls of each caller were compared with the high-confidence SV set. Precision, recall, and F1 score were used to evaluate the performance of the callers. Precision, recall, and F1 were calculated asTo determine the optimal coverage for SV detection on PacBio data, we evaluated the performance of NextSV under several different coverages. We downloaded a recently published PacBio data set of NA12878  and downFirst, we examined how many calls in the high-confidence set can be discovered. As shown in Fig. Second, we examined the precision and balanced accuracy F1 scores) under different coverages Fig. . The pre scores uTo verify the performance of SV detection on different individuals, we also performed evaluation on a Chinese genome HX1, which was sequenced by us recently  at 103X As the de novo mutation rate is very low , 28, MenTo evaluate the computational resources consumed by NextSV, we used the whole genome sequencing data set of HX1 (10X coverage) for benchmarking. All aligners and SV callers in NextSV were tested using a machine equipped with 12-core Intel Xeon 2.66 GHz CPU and 48 Gigabytes of memory. As shown in Table Long-read sequencing such as PacBio sequencing has clear advantages over short-read sequencing on SV discovery . HoweverThe high-confidence call set of HX1 genome was generated using two steps. First, we used a call set from a previously validated local assembly-based approach , 20, 31 There is often a trade-off between recall and precision. NextSV generates a sensitive call set and a stringent call set, for different purposes. NextSV sensitive call set is suitable for users who consider recall more important than precision and who can afford extensive downstream analysis (such as Sanger sequencing) to validate the candidate variants. This is often the case when doing disease-casual variant discovery on personal genomes. NextSV stringent call set has the highest precision, F1 score. It is suitable for users who aim to perform genome-wide analysis of SVs on a collection of samples, with limited downstream validation.The performance of SV callers are affected by the parameter settings. The number of supporting reads is a key parameter that affect the trade-off between recall and precision. By default, PBHoney requires a minimal read support of 3 for an SV event and Sniffles requires a minimal read support of 10 for an SV event. However, this may be too high for low coverage data set. In our evaluation of recall and precision, we changed this setting to require a minimal read support of 2. This allows detection of SVs from very low coverage regions, with an acceptable precision. Thus, substantially higher number of true positives would be detected and less variants of interest would be missed. For users who consider precision to be more important than recall, they can either use the NextSV stringent call set or specify a stricter parameter (e.g. requiring more supporting reads) when running the NextSV pipeline. The F1 score is a balance between recall and precision. Therefore, its correlation with coverage is affected by the two aspects. In general, as the coverage increases, the recall increases but the precision decreases. Therefore, the F1 score may either increase or decrease as the coverage increases.In addition to test recalls and precisions, we examined the allele drop-in (ADI) errors, which represent the SV calls that in the offspring but not appear in either parent. Since the de novo mutation rate is very low, the ADI errors may mainly come from errors of sequencing and subsequent SV detection. In our results, the ADI rates of insertions are higher than those of deletion calls, which is consistent with the fact that PacBio sequencing has higher per-base insertion errors than deletion errors. Another source of ADI may come from the SV callers. SV detection from PacBio data set is still in its early stage. The currently available SV callers are not carefully designed for low-coverage data sets. For example, Sniffles requires 10 reads to support a SV under default settings, which means at least 20X coverage is required to detect a heterozygous SV. We expect the improvement of SV callers in the future.NextSV currently supports four aligner / SV caller combinations: BLASR / PBHoney-Spots, BLASR / PBHoney-Tails, BWA / Sniffles, NGMLR / Sniffles, but we expect to continuously expand the support for other aligner / caller combinations. In the future, if more aligners/SV callers are supported, we will evaluate the performance of each combination and find the best aligner for each SV caller. The NextSV sensitive call will be the union call set of all SV callers; the NextSV stringent calls will be the calls that are detected by at least two SV callers. If one SV caller can work with multiple aligners, only the call set of its best aligner will be used.In this study, we only evaluated the performance for insertions and deletions because we only have the high-confidence calls of insertions and deletions. This is another limitation of the study. We will evaluate the performance on other types of SVs in the future when more high-confidence SV calls are available. Nonetheless, NextSV generates SV calls of all types. The output of NextSV is in ANNOVAR-compatible format. Users can easily perform downstream annotation using ANNOVAR and disease gene discovery using Phenolyzer . NextSV In this study, we proposed NextSV, a comprehensive, user-friendly and efficient meta-caller to perform SV calling from low coverage long-read sequencing data. NextSV integrates multiple aligners and SV callers and performs better than running a single SV caller. We also showed that ~10X PacBio coverage can be an optimal coverage to use in practice, considering the balance between the sequencing costs and the recall rates. Our results provide useful guidelines for SV detection from low coverage whole-genome PacBio data and we expect that NextSV will facilitate the analysis of SVs on long-read sequencing data.Additional file 1:Tables S1-S24. Performances of BLASR/PBHoney-Spots, BLASR/PBHoney-Tails, BWA/Sniffles, NGMLR/Sniffles and NextSV on the NA12878 genome and the HX1 genome. (PDF 472 kb)


Background. Antibiotic prophylaxis for surgical site infections (SSIs) for breast surgery is widespread, but the benefit in clean surgical cases is not well defined. Methods. A retrospective analysis of 855 patients undergoing elective, nonreconstructive breast operations was performed, with 401 patients receiving no antibiotics and 454 patients receiving a single dose of preoperative antibiotic. Results. Administration of a preoperative antibiotic did not decrease the SSI rate. In this community-based study, antibiotic use practices varied considerably by surgeon. In univariate analyses, SSI rates appeared to increase with prophylactic antibiotic use , likely because the use of underdosed antibiotics was associated with higher rates of SSI . Methicillin-resistant Staphylococcus aureus was the most common isolate from SSI cultures, 31.8% (7 of 22). In multivariable analyses, increased risk of SSI was associated with BMI > 25 kg/m2 . Conclusion. The administration of a single dose of preoperative antibiotic did not decrease the rate of SSI in this large series of patients undergoing clean breast operations. BMI >25 kg/m2 and the use of an inadequate dose of antibiotics for prophylaxis may increase risk of SSI. Surgical site infection (SSI) is a commonly reported source of postsurgical morbidity. In breast surgery, three separate reviews of the National Surgical Quality Improvement Program (NSQIP) database demonstrated SSI rates of 1.4%–3.2% –11. The A large RCT published by Hall et al. in 2006 evaluated the use of antibiotics in nonreconstructive breast surgery for both benign and malignant pathologies. It failed to show a difference in SSI rates with the use of a preoperative antibiotic not available in the USA, flucloxacillin . In contA retrospective records analysis was performed for patients who underwent elective, nonreconstructive breast surgery between 2008 and 2012 at the National Accreditation Program for Breast Centers (NAPBC) accredited institutions: the Marshfield Clinic Ambulatory Surgery Center or Ministry Saint Joseph's Hospital, a tertiary referral hospital in Marshfield, Wisconsin. Marshfield Clinic Institutional Review Board approval was obtained. Current Procedural Terminology (CPT) codes were used to identify patients who had elective breast surgery not involving simultaneous placement of an implant or tissue expander. The procedures were performed by surgical oncologists or plastic surgeons. Operative indications included benign and malignant disease. Patients undergoing a concurrent sentinel lymph node biopsy or lymphadenectomy were included. Selection of antibiotic was at the discretion of the surgeon.Procedures were classified as small and large surface area because procedures involving larger surface areas alone have been shown to increase the risk of SSI . Small sExclusion criteria included placement of a breast implant or tissue expander, evidence of preoperative infection, improper timing of antibiotic administration (administration after incision or more than 1 hour earlier or timing not clearly recorded), treatment with an antibiotic within 30 days for an unrelated infectious process, a concurrent major operation at a secondary site, or absence of surgical follow-up within 30 days.Data was gathered by clinical chart review. Initial abstraction was done by the primary author and verified by the second. The operative reports were reviewed to ensure that the procedures were properly coded. Patients who underwent bilateral procedures were considered as a single subject. If one side of a bilateral procedure was a large surface area procedure, the patient was included in the large surface area analysis. Timing of antibiotic administration, dose, and time of incision were gathered from perioperative nursing, pharmacy, and anesthesia records. All Marshfield Clinic and Saint Joseph's Hospital documentation within at least 30 days of the procedure was reviewed. The diagnosis of an SSI was documented by the surgeon of record based on postoperative clinical examination and/or the presence of positive bacterial cultures from wound drainage within 30 days of the procedure.Z-/t-test was used for normally distributed data, Wilcoxon Rank-Sum test for skewed data, and Fisher's Exact or Chi-square test for categorical data. Controls were chosen as the referent group in order to derive the odds ratio, 95% confidence interval, and corresponding p value for antibiotic use in association with the SSI outcome. Similarly, analyses were performed for the following clinical variables: wire localization, body mass index (BMI), diabetes mellitus, sex, prior operation within 30 days, surgeon, small or large surface area, BMI > 25 or ≤ 25 kg/m2, and age > 50 or ≤ 50 years, as well as whether the procedure was a reduction mammaplasty or mastopexy. Age and BMI were assessed as both binary and continuous variables. A cross-tab analysis comparing antibiotic use and resulting SSI rate was conducted to determine whether certain subgroups of patients benefited from preoperative antibiotic use. These groups were stratified by age > 50 or ≤ 50 years, sex, BMI > 25 or ≤ 25 kg/m2, large surface area, small surface area, diabetes, wire localization, previous ipsilateral breast operation within 30 days, and whether or not the operation was a reduction mammaplasty or mastopexy. Antibiotic dosages were also analyzed for significant associations with SSI between patients with similar BMI.Assuming a 5% absolute difference in SSI rates between patients who received a single preoperative dose of antibiotic and those who did not, a minimum of 400 cases and 400 controls were necessary to attain 80% statistical power. This was based on an expected difference of SSI rates from 8% for the patients who did not receive any antibiotics to 3% for those who received a single dose of preoperative antibiotic , 14–16. p value of <0.05 is considered statistically significant. All data analyses were carried out using the commercially available statistical software package, SAS, version 9.3, English .In the multivariable analysis, stepwise logistic regression modeling was applied to determine the set of statistically significant clinical risk factors in association with the SSI outcome. A Records of 1,461 patients were reviewed. Of these patients, 606 were excluded: 120 received implants or expanders within 30 days, 6 had a documented breast infection prior to operation, 145 had improper timing of antibiotics, 249 were given postoperative antibiotics prophylactically or for unrelated conditions, and 18 had no follow-up within 30 days, leaving 855 qualifying patients. The study contained 454 patients who received a single dose of preoperative prophylactic antibiotic within 60 minutes of incision and 401 patients who did not receive antibiotics.Patient demographics and rate of antibiotic administration are displayed in p value < 0.0001). There was an increase in SSI rates for patients with a previous ipsilateral breast operation within 30 days, a large surface area procedure, or a BMI > 25 kg/m2. Elevated BMI was associated with an increased SSI rate. Reduction mammaplasty and mastopexy were independently associated with a higher SSI rate. Localizing wire placement was associated with a lower SSI rate. Staphylococcus aureus (MRSA), 31.8% (7 of 22). This was followed by coagulase negative Staphylococcus, methicillin-susceptible Staphylococcus aureus (MSSA), and Escherichia coli: 22.7%, 13.6%, and 9.1%, respectively. Five patients had no growth from their cultures but were still felt to have an SSI clinically.Twenty-two of the 71 patients with a surgical site infection had cultures at the time of clinical diagnosis. The most common bacterium cultured was methicillin-resistantp < 0.0001, OR: 3.7, 95% CI: 2.03–6.65) . In contrast, patients who received antibiotic prophylaxis with 2 grams of cefazolin or more than 300 mg of clindamycin did not have a significantly different SSI rate from those that did not have prophylactic antibiotics.The antibiotic agent used in 87.7% of cases was cefazolin. The remaining patients received clindamycin (7.3%), vancomycin (3.7%), or ciprofloxacin (1.3%). Underdosing of antibiotics was common in those patients who did receive antibiotics. Of those who were treated with cefazolin, 325 (81%) received only 1 gram and none of the patients who weighed ≥120 kg received the currently recommended 3 grams . In fact03–6.65) . Similar2, and a procedure other than reduction mammaplasty or mastopexy. In all of these groups, use of an antibiotic was associated with an increased SSI rate.To compare antibiotic use and SSI rate in subgroups, a cross-tab analysis was performed . The sub2, age > 50 or ≤ 50 years, and patients with reduction mammaplasty or mastopexy (p < 0.0001) and BMI >25 kg/m2 was associated with an increased SSI rate .To better understand the effect of antibiotics on SSI, a multivariable stepwise logistic regression analysis was performed using the following variables: antibiotic use, diabetes, sex, prior operation, surgeon, small or large surface area, BMI > or ≤ 25 kg/mastopexy . In the Modern healthcare is accompanied by increased monitoring of individual and institutional outcomes. Pay-for-performance reimbursement models and CMS “never events” take into consideration postoperative complications. This affects all surgeons that operate on the breast for benign or malignant indications, not to mention the wellbeing of their patients. In some disciplines, SSI rates can be reduced with a single dose of preoperative antibiotic and a recent Cochrane review suggests that this may be the case in the context of breast cancer surgery . HoweverThree separate NSQIP database reviews showed that the SSI rates in breast surgery range from 1.4% to 3.2% –11. ThisIn fact, the use of prophylactic antibiotics with dosages below current recommended dosing guidelines may increase the risk of SSI as seen in our study  17]. Th. Th17]. Staphylococci species were the most common bacteria isolated from the subset of patients with SSIs that were cultured. This compares similarly to a previous study which found 60% of cultures from SSIs complicating breast surgery isolated staphylococci species . Also, iAnother finding in the study was that preoperative localizing wire placement was associated with a lower SSI rate than in procedures with no wire placement. However, preoperative instrumentation has been shown to increase the rate of SSI . Our obs2. The median BMI of patients who did receive an antibiotic was 30.0 kg/m2  of drugs, increasing Vd of lipophilic drugs and decreasing Vd of hydrophilic drugs [The other significant risk factor for SSI identified in multivariable analysis was a BMI indicative of being overweight or obese, supporting previous studies , 18, 24..0003, 2 , the useic drugs .p < 0.0001), particularly if it was a reduction mammaplasty or mastopexy . There were increased SSI rates in both large surface area  and reduction mammaplasty and mastopexy procedures (14%, p = 0.0003, Studies evaluating the use of antibiotics in reduction mammaplasty or mastopexy have conflicting results as to the role of antibiotics in preventing SSI , 16, 27.Inherent limitations with our study include its retrospective design, variability in the patient population among surgeons, and variability in the rates of antibiotic administration among patient groups. These introduce the potential for selection bias.The classification of large surface area and small surface area procedures is subjective. A woman with large breasts undergoing a lumpectomy may actually have an operation involving more surface area than a woman with small breasts undergoing a mastectomy. The results must be interpreted with this limitation in mind. Volume of resection or specimen weight would likely be a more accurate measure but may not be known preoperatively during the decision of prophylactic antibiotic use or not.Additionally, in an attempt to make our study generalizable, we included both benign and malignant disease. Malignancy has been associated with immunosuppression and Angarita et al. found advanced tumors of the breast associated with increased SSI . We did Again, in an attempt to have general applicability, both male and female patients were included. Obviously, far less data is available on male breast operations and there is the possibility of a gender difference in SSI. However, a small number of male patients included in our study were nearly equally divided between receiving antibiotics and not and none developed an SSI, so including them did not change the main findings of the study.Given the increased surgical site infection rate in breast surgery compared to clean cases overall, our study aimed to determine whether the SSI rate was decreased by prophylactic antibiotic administration in a community-based clinical practice. While certain patient groups are more prone to developing SSI, such as those with elevated BMI, we found that a timely single dose of preoperative antibiotic did not lower the SSI rate overall or in at-risk groups. Inadequately dosed antibiotics may actually increase the risk of SSI. Our data suggests that when prescribed, antibiotics should at least follow current dosing recommendations. Of note, the most common organism identified in our SSIs was MRSA, which lends favor to the practice of obtaining cultures with susceptibilities in suspected postoperative wound infections following breast surgery. We also observed significant variability in antibiotic prescribing practices from surgeon to surgeon. Despite the perceived low cost and relative low morbidity, antibiotics without benefit should not be prescribed. This study, which included both benign and malignant conditions, challenges the routine practice of preoperative antibiotic use for elective, nonreconstructive breast surgery.


How to cite this article: Yilmaz B, Kiziltas S, Yildiz S, Gümüs B, Çevik H. Simultaneous Immunoglobulin G4-associated Autoimmune Hepatitis and Autoimmune Pancreatitis. Euroasian J Hepato-Gastroenterol 2017;7(1):95-96. Dear Editor,The case of a patient with immunoglobulin G4 (IgG4)-associated autoimmune hepatitis (AIH) and autoimmune pancreatitis (AIP) is presented. With increased levels of serum IgG4 and abundant IgG4 positive plasma cell infiltration, AIH was reported and proposed to be called "IgG4-associated AIH." However, the clinical course of this new disease entity remains unclear. A 57-year-old woman presented at our institution with weakness, sickness, darkening of urine color. Patient was admitted to our hospital due to elevated levels of serum aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, bilirubin levels, CA 19-9, amylase, and lipase. Prothrombin time was prolonged. Alfa-fetoprotein levels were normal. The IgG4 level of 5,050 mg/dL was detected. Antinuclear antibody was positive; antismooth muscle antibody and antimitochondrial antibody were negative. Hepatitis B virus deoxyribonucleic acid (-), Hepatitis C virus ribonucleic acid (-), and anti-hepatitis A virus IgG (+) were detected. Patients had never used alcohol. In conclusion, except for high serum IgG4 levels and IgG4 positive plasma cell infiltration, the findings in patients with IgG4-associated AIH are consistent with the findings in patients with classical AIH. Therefore, there may be many more patients than formerly thought who are diagnosed as having classical AIH, but who actually have IgG4-associated AIH. Further cases need to be evaluated to clarify the clinical course and the standard treatment for IgG4-associated simultaneous AIH and AIP.1 The IgG4-associated diseases include pancreatitis and cholangitis. The IgG4-associated AIH has also been proposed, but whether it represents a distinct entity is not yet clearly defined.2 Autoimmune pancreatitis is described by high serum IgG4 levels and lymphoplasmacytic inflammation.3A rare case with immunoglobulin G4 (IgG4)-associated autoimmune hepatitis (AIH) and autoimmune pancreatitis (AIP) is presented. Autoimmune hepatitis is characterized by increased levels of serum (IgG4) and abundant IgG4-positive plasma cell infiltration and proposed to be called "IgG4-associated AIH."A 57-year-old woman presented at our institution with weakness, sickness, darkening of urine color. Patient was hospitalized with increased levels of liver transaminases, gamma-glutamyltransferase, bilirubin, amylase, and lipase. Aspartate aminotransferase levels were 1,369 U/L and alanine aminotransferase levels were 1,120 U/L. Gamma-glutamyltranspeptidase of 596 U/L, amylase 363 U/L, lipase 622 U/L, CA 19-9: 715 IU/mL, and IgG4 5050 mg/dL were detected. Antinuclear antibody was high titer at 1:320. Hepatitis markers were negative. The patient provided a written consent form. Granula echogenicity in the liver, increase in the wall thickness of gallbladder, peripancreatic lymphadenopathy were detected on abdominal ultrasound examination. Computerized tomography demonstrated the same findings as ultrasound examination  and 2.Magnetic resonance cholangiopancreatography was normal. Liver biopsy findings are not specifically diagnostic. In general, the biopsy proved the presence of chronic hepatitis and demonstrated no clue for the discrimination of other causes of chronic hepatitis. Typically, the biopsy shows an irregularly distributed relatively heavy portal infiltrate, with periportal or paraseptal interface hepatitis with increased numbers of plasma cells and eosinophils in addition to lymphocytes. In liver biopsy interphase activity, confluent necrosis, hepatic duct proliferation, and biliary stasis were detected . PancreaOur case clearly demonstrates that IgG4-associated AIH and AIP can be simultaneously present as part of a clinical spectrum. This clinical situation should be considered as a possible diagnosis in patients with classically diagnosed AIH. The publication of more cases of IgG4-associated simultaneous AIH and AIP will determine the clinical importance and prevalence of this uncommon entity.


A patient with a prior diagnosis of IgG4-related autoimmune pancreatitis (AIP) presented four years later with severe prednisone resistant immune thrombocytopenia (ITP). Her case is reported and the scant literature of the very unusual possible association of IgG4-related AIP and ITP is reviewed. It is suggested that investigation for IgG4-related disease be part of the work-up of ITP. IgG4-related disease (IgG4-RD) is a rare and recently recognized immune-mediated disorder characterized by tissue infiltration by IgG4-positive plasma cells. Most patients also have elevated serum IgG4. The commonest clinical manifestations are lymphadenopathy, submandibular gland enlargement, and autoimmune pancreatitis (AIP) but IgG4-RD is a systemic disease and can affect almost any organ -3. We reA 76-year-old Japanese woman presented with spontaneous bruising and a headache. Four years previously she was diagnosed with IgG4-related autoimmune pancreatitis (AIP) following a Whipple procedure for a presumed malignancy of the common bile duct. Histopathology was negative for malignancy, instead showing IgG4 autoimmune disease with large numbers of IgG4 secreting plasma cells in the pancreas, common bile duct, and gallbladder. She did not receive specific treatment for IgG4-RD following surgery and had no indication of disease progression. She had a several year history of dry eyes and enlarged submandibular salivary glands which had been biopsied and attributed to Sjögren’s syndrome. Her medical history included mild cognitive impairment secondary to a traumatic brain injury in her distant past and hypertension for which she was taking felodipine 5 mg/day. Four weeks before her presentation with bruising she had started pantoprazole 40 mg/day for postprandial epigastric pain.On presentation with bruising and headache, she denied mucocutaneous, gastrointestinal, or genitourinary bleeding and her medications did not include antiplatelet or anticoagulant drugs. Her headache had persisted for over a day and was not associated with a history of trauma or signs or symptoms of increased intracranial pressure. She denied constitutional symptoms or abdominal pain. On examination, she had diffuse ecchymoses on her abdomen and all four limbs as well as petechiae on the lower limbs and small purpuric lesions in the oropharynx. The submandibular salivary glands were firm and enlarged. There was no lymphadenopathy. Neurological and abdominal examinations were normal.Her platelet count was 3 x 109/L , hemoglobin 77 gm/L  and WBC of 5.2 x 109/L . Serum iron and transferrin saturation were low, 4 umol/L  and 8%  respectively. Ferritin was low-normal 33 ug/L  and vitamin B12 was normal. INR and PTT were 1  and 24 sec , respectively. Liver biochemistry revealed total bilirubin 25 umol/L , alkaline phosphatase 140 U/L  and ALT 17 U/L . Total gammaglobulin was 26.1 g/L . IgG subclasses were measured. IgG4 was very high at 15.4 g/L . IgG1 was 15.5 g/L , IgG2 was 16.2 g/L  and IgG3 was normal at 0.85 g/L . The pathologist noted this to be strongly suggestive of IgG4-RD. Serology for Helicobacter pylori, hepatitis B and C, and HIV was negative. A non-contrast computed tomography (CT) scan of the head showed an acute right subdural hematoma 0.7 cm in maximum thickness and a small, subacute, left subdural hematoma measuring 2-3 mm Figure . CT of tThe patient was initially thought to have pantoprazole induced ITP  complicaIgG4-RD is a pleomorphic disease with involvement described in over 40 tissues and organs -3. AutoiIf ITP is part of the spectrum of IgG4-RD, what is the role of IgG4 in its genesis? IgG4 is not the usual subclass of IgG associated with ITP . Only onH. pylori has become.Our case adds to the scant literature on ITP occurring with AIP and with IgG4-RD. It is the second patient reported thus far in whom the ITP was resistant to first-line treatment with prednisone and IVIG; although it is well recognized that not all cases of ITP respond to standard therapy, nor are they all "idiopathic". Perhaps the measurement of serum IgG4 should be part of the "routine" investigation of ITP just as checking for Finally, our report and others remind us that those caring for patients with an IgG4-related disease should be vigilant for the development of synchronous and metachronous complications in other organ systems.