Timely administration of appropriate antibiotic therapy has been shown to improve outcome in hospital-acquired pneumonia (HAP). Empirical treatment guidelines tailored to local ecology have been advocated in antibiotic stewardship programs. We compared a local ecology based algorithm (LEBA) to a surveillance culture based algorithm (SCBA) in terms of appropriate coverage and spectrum of antimicrobial activity.We retrospectively assessed 2 hypothetical empirical antibiotic treatment algorithms for HAP on an existing high-quality prospectively collected database in a mixed 36-bed tertiary intensive care unit (ICU). Data on consecutive episodes of microbiologically confirmed HAP were collected over a period of 40 months and divided in a derivation (1 July 2009 to 31 October 2010) and validation (1 November 2010 until 31 October 2012) cohort. On the derivation cohort we constructed a LEBA, based on overall observed bacterial resistance patterns, and a SCBA, which targeted therapy to surveillance culture (SC) in the individual patient. Therapy was directed against pathogens found in respiratory SC collected two to five days before HAP, and in the absence of these, presence or absence of multi-drug resistant (MDR) pathogens in other SC dictated broad-spectrum, respectively narrow spectrum antibiotic therapy. Subsequently, LEBA and SCBA were retrospectively reviewed and compared with actually prescribed antibiotics in the validation cohort.P <0.001). SCBA recommended significantly less combination therapy and carbapenems compared to LEBA (P <0.001). SCBA targeted antibiotics to recent respiratory SC in 38.1% (43 out of 113 episodes) of HAP; in these cases adequacy was 93% (40 out of 43).The first 100 HAP episodes made up the derivation cohort and the subsequent 113 HAP episodes the validation cohort. Appropriate antibiotic coverage rates by applying LEBA and SCBA were 88.5% and 87.6%, respectively, and did not differ significantly with respect to appropriateness of the actually prescribed initial therapy (84.1%). SCBA proposed more narrow spectrum therapy as compared to LEBA and the actually prescribed antimicrobials (Rates of appropriate antimicrobial coverage were identical in LEBA and SCBA. However, in this setting of moderate MDR prevalence, the use of SCBA would result in a significant reduction of the use of broad-spectrum drugs and may be a preferential strategy when implementing antibiotic stewardship programs. As honeumonia-5. As atneumonia,7. In adneumonia-11. WithIn this study, we developed two algorithms for initial antibiotic prescription in ICU patients with suspected HAP. We aimed a) to assess the potential of an algorithm to aid in antibiotic stewardship in our setting and b) quantify the contribution of SC to antibiotic stewardship as compared to empirical therapy based upon local epidemiology.This retrospective analysis was conducted at the 14-bed Medical ICU and the 22-bed Surgical ICU of the Ghent University Hospital . With the aid of the software application, Computer-based Surveillance and Alerting of infections, Antimicrobial Resistance and Antibiotic consumption in the ICU (COSARA), all episodes of pneumonia were registered prospectively from 1 July 2009 to 31 October 2012. COSARA assists the attending ICU-physician in acquiring an overview of the various daily collected data related to infection diagnosis  and treatment. This includes a graphical display of current and past antibiotic treatments as a timeline and provides direct links to a real-time copy of the various source records. The graphical interface allows the user to label infectious episodes during daily clinical rounds and interdisciplinary staff meetings to a predefined list of diagnoses in all patients admitted to the ICU. As such, the program facilitates the build-up of an extensive data-warehouse on antibiotic use and infection in the ICU[4 colony-forming units (CFU)/ml in BAL were 81% and 87%, respectively[Pneumonia was defined to be hospital-acquired if it occurred 48 h or more after admission to the hospital. HAP was defined clinically as the presence of new and/or progressive and persistent pulmonary infiltrates on the chest radiograph, in combination with two or more of the following criteria: worsening of oxygenation, increase in purulent tracheobronchial secretions, presence of fever (≥38.5°C) or hypothermia (≤36°C). Only microbiologically confirmed HAP was included: confirmation consisted of the isolation of a respiratory pathogen with at least 1+ semiquantitative growth of a good quality respiratory sample  obtained within one calendar day prior or after clinical diagnosis of HAP. In our hospital, microbiological analysis of respiratory samples routinely consists of semiquantitative culture of endotracheal aspirate (ETA) in the ventilated patient or sputum in the non-intubated patient. For logistic reasons, broncho-alveolar lavage (BAL) is not systematically performed, similarly to current practice in the majority of European ICUs. We prevectively. HAP wasThe collected data were divided into a derivation and a validation cohort. The first 100 HAP episodes (1 July 2009 to 31 October 2010) made up the derivation cohort for the development of the local ecology-based algorithm (LEBA) and the surveillance culture-based algorithm (SCBA), both aiming to achieve a minimum of 85% appropriate coverage rate. For LEBA [Stenotrophomonas spp. and Pseudomonas aeruginosa. In case of appropriate therapy, the antimicrobial spectrum was expressed as x steps in excess to the most narrow-spectrum therapy possible covering all causative pathogens isolated in the HAP episodes.We compared rates of appropriateness and spectrum between LEBA, SCBA and actually prescribed antimicrobial therapy by the treating physician. Therapy was considered appropriate when all pathogens involved in the HAP episode were covered by the antibiotic, or by at least one component of the antibiotic combination. To quantify the antimicrobial spectrum, we constructed a scale ranging from 1 - the most narrow-spectrum of empirical therapy, lacking antipseudomonal activity - to 5 - a combination therapy of two or more antibiotic agents (Table s (MRSA), and wits (MRSA), and by P <0.05.Continuous variables are described as mean (±standard deviation) or median (interquartile range) for normal or non-normal distribution, respectively. To compare paired proportions the McNemar test for related samples was used. Differences in medians were checked using the Wilcoxon signed-rank test. All statistical analyses were performed with SPSS® software . Statistical significance was defined as P = 0.10). The overall ICU mortality was 30.1% and did not differ between patients with or without appropriate antimicrobial therapy .All data reported apply to the validation cohort of 113 episodes of HAP, including 52 (46%) episodes of VAP, registered between 1 November 2010 and 31 October 2012 in 104 patients. There was need for subsequent mechanical ventilation in 39/61 (64%) of the non-VAP patients. The median age of the patients was 64 years (54 to 74), and 74% were male. In 99 (87.6%) of the HAP episodes, clinical risk factors for MDR pathogens were present: prior antibiotics in 81%, current hospitalization for 5 days or more or hospitalization in the previous 6 months in 82%. Septic shock was present in 23% of the HAP episodes. The length of ICU stay following diagnosis of HAP was 10 days (6 to 22) when appropriate antibiotics were administered, 7 days (2 to 16) if the prescribed antibiotics were inappropriate . Pathogens associated with inadequate empirical therapy are detailed in Table Appropriate antibiotic therapy was prescribed in 95 (84.1%) HAP episodes. Antimicrobial choices proposed by LEBA and SCBA were appropriate in 88.5% and 87.6%, respectively. Paired analysis showed no significant difference in adequacy for the different strategies (prescribed therapy versus LEBA: P <0.001) . SCBA recommended carbapenems in significantly fewer episodes than LEBA (24 (21.2%) versus 92 (81.4%), respectively (P <0.001)).In significantly more episodes, SCBA proposed antibiotics of a narrower spectrum as compared to both the prescribed therapy and the regimen suggested by LEBA , S. pneumonia (1/53), Enterobactereaceae (29/53), P. aeruginosa (10/53), other Gram-negative bacteria (7/53). Recent respiratory SC accurately predicted all causative pathogens in 81.4% (35/43) of HAP; SCBA-targeted antimicrobial therapy would appropriately cover all causative pathogens (including those not predicted by SC) in 93% (40/43) of cases.Respiratory SC sampled 2 to 5 days before HAP onset were available in 63 episodes (55.8%) of HAP, of which 43 (68%) grew at least one pathogen. As such, SCBA suggested targeted antimicrobial therapy in 43/113 (38.1%) of HAP episodes: HAP for which targeted therapy was suggested was ventilator-associated in 72% (31/43), occurred more than 5 days after ICU admission in 77% (33/43) and was caused by the following pathogens (n = 53): In the case of negative or absent respiratory SC 2 to 5 days before start of HAP , SCBA took into account both respiratory SC more than 5 days prior to infection and non-respiratory SC. In 28/70 (40%) of these HAP episodes positive SC were available, leading to upgrading of the proposed empirical therapy in 13/70 HAP (19%) and a switch from inappropriate to appropriate antibiotic proposals in 10 episodes. By not upgrading our therapy in these cases our rate of appropriate antibiotic therapy would have dropped from 87.6% to 78.8%.Both guidance by SC as well as the use of ICU-specific empirical schemes that incorporate local microbiology data have been shown to increase appropriate empirical prescription and reduce the use of broad-spectrum antimicrobials as compared to general guidelines,8,17-19.Two observations underlie the construction of SCBA. First, previously we found high negative predictive values of negative SC for the presence of MDR pathogens in HAP, allowinIn hospital-acquired infection, narrowing the spectrum of antibiotic therapy is usually done as de-escalation following an initially broad-spectrum therapy aimed at maximal chance for appropriate coverage. However, limiting antimicrobial therapy upfront may offer several advantages. First, aminoglycosides and glycopeptides, which carry an important toxicity profile,22, wereRestricting the number of empirical combination therapies will reduce direct antibiotic costs. On the other hand one fulltime-equivalent microbiology laboratory technician is assigned to process SC of all patients admitted to our 36-bed ICU and the cost for the laboratory material is estimated at 33 euro per week. However, not all of this cost is exclusively for surveillance purposes, as few additional respiratory cultures for diagnostic purposes are required under this SC regime. Additionally, it can be argued that SC are a cornerstone in infection control in settings where MDR pathogens are endemic and that their guidance of antibiotic therapy is only an added benefit,29.A number of limitations have to be addressed. First, our study is evidently monocentric and our SCBA is site-specific. However, the concept of SCBA may be more universally applicable, as the predictive values of SC as reported in several recent studies are fairly consistent, provided that SC are regularly and at least twice weekly sampled. Our SCBAs compared to an algorithm based upon clinical risk factors for MDR and adapted to local susceptibility results, an algorithm with additional guidance from SC could achieve comparably high rates of appropriate coverage with the use of fewer broad-spectrum antibiotics. Antibiotic therapy specifically targeted to respiratory pathogens identified in recent SC would be possible in 38% of HAP episodes. SC-guided algorithms may constitute a component of antibiotic stewardship programs. Additional studies should be performed in ICU settings with higher levels of antibiotic resistance.• Addition of surveillance culture results in empirical antibiotic treatment algorithms for hospital-acquired pneumonia could restrict the use of broad-spectrum antimicrobial drugs.• Targeting empirical treatment to recent respiratory surveillance cultures could be achieved in more than one third of hospital-acquired pneumonia.Staphylococcus aureus; MRSA: methicillin-resistant Staphylococcus aureus; SC: surveillance cultures; SCBA: surveillance culture-based algorithm; VAP: ventilator-associated pneumonia.ATS-IDSA: American Thoracic Society-Infectious Diseases Society of America; BAL: broncho-alveolar lavage; CFU: colony forming units; COSARA: Computer-based Surveillance and Alerting of infections, Antimicrobial Resistance and Antibiotic consumption in the ICU; ETA: endotracheal aspirate; HAP: hospital-acquired pneumonia; LEBA: local ecology-based algorithm; MDR: multi-drug resistant; MSSA: methicillin-susceptible The authors declare that they have no competing interests.LDB conceived, designed and coordinated the study, performed data acquisition and analyses and drafted the manuscript, LS performed data acquisition and analyses and critically revised the manuscript for important intellectual content, BG contributed to data acquisition and analyses and critically revised the manuscript for important intellectual content, JB contributed to data acquisition and analyses and critically revised the manuscript for important intellectual content, GC contributed to data acquisition and analyses and critically revised the manuscript for important intellectual content, JDW contributed to data acquisition and analyses and critically revised the manuscript for important intellectual content, DB contributed to data acquisition and analyses and critically revised the manuscript for important intellectual content, JD contributed to data acquisition and analyses and critically revised the manuscript for important intellectual content, PD conceived, designed and coordinated the study, performed data acquisition and analyses and drafted the manuscript. All authors read and approved the final manuscript. All authors agree to be fully accountable for the content of this work.


Providing heroin to people with heroin addiction taking part in medical trials assessing the effectiveness of the drug as a treatment alternative breaches ethical research standards, some ethicists maintain. Heroin addicts, they say, are unable to consent voluntarily to taking part in these trials. Other ethicists disagree. In our view, both sides of the debate have an inadequate understanding of ‘voluntariness’. In this article we therefore offer a fuller definition of the concept, one which allows for a more flexible, case-to-case approach in which some heroin addicts are considered capable of consenting voluntarily, others not. An advantage of this approach, it is argued, is that it provides a safety net to minimise the risk of inflicting harm on trial participants. Several studies show that financial concerns, fear of arrest, values regarding parenthood and many other factors influencing decisions in general often persuade a person addicted to heroin to cease their drug-oriented behaviour.2 That heroin addicts frequently respond to such incentives means that they cannot have lost the ability to resist their desire for heroin. We can presume, therefore, that heroin addicts have the competence to give voluntary consent to take part in trials involving the drug.In the bioethics literature, there has been considerable debate as to whether giving heroin addicts legal access to free heroin in connection with research on the effectiveness of heroin prescription as a treatment alternative constitutes a breach of ethical research standards. The ethical issue here is that the researcher must obtain the informed consent of the study participants. For their consent to be valid, individuals must give it voluntarily. The question is whether consent can be said to have been given voluntarily if the person has heroin addiction . Those who claim that it cannot argue that it is in the nature of heroin addiction for individuals to lose their ability to resist their desire for heroin. Since a loss of ability means heroin addicts cannot refuse offers of free heroin, neither can we presume that they can give voluntary consent to take part in research that involves giving them a choice of free heroin.We want to argue that both sides in this debate are mistaken. Although it is plausible that many – perhaps even most or all – heroin addicts have the ability to resist their desire to take heroin, the degree to which their consent is voluntarily given greatly depends on the wider social and psychological circumstances under which they choose whether to consent or not. Focusing on these circumstances rather than universal and hard-to-verify claims about abilities of resistance allows for a more flexible, case-to-case approach, one that does not rule out the possibility that while some heroin addicts might be competent to give voluntary consent, some might not. One advantage of this approach compared with the alternatives is that it provides a safety net to minimise the risk of inflicting harm on the individuals who participate in these kinds of studies.1 Whether prescribing heroin therapeutically is an effective way of treating heroin users needs to be determined empirically and will not be discussed here.Before presenting our argument, a note of caution is in order: we do not want to claim that the answer to the ethical question raised by research on heroin prescription as a treatment alternative is alone sufficient to determine whether or not such research should be carried out. Even if the issue of voluntary consent in heroin trials was problematic, it does not follow that prescribing heroin as a treatment alternative should necessarily be banned. If, for example, the risks to the participants were small or non-existent while the benefits outweighed such risks, strategies that circumvent the normal standards of consent should indeed be considered. One such strategy could be to appoint some surrogate authority who is not involved in the study (e.g. a family member) to ensure the best interests of the participant, or perhaps to relax competence-defining criteria.3 Controlling influences are divided into ‘external’ and ‘internal’ depending on whether they are caused by the intentional actions of other persons (such as different forms of coercion or manipulation) or lack of internal self-control, an incapacity typically associated with mental illness. Although this characterisation of voluntary action is both plausible and, no doubt, helpful in many situations in which clinicians have to assess a person’s capacity, we believe it is ill suited to explaining how certain social circumstances and the beliefs they inform might sometimes constrain choices. This is because the circumstances and beliefs might exert a controlling influence on the person, causing them to feel pressured into performing certain actions , without necessarily removing their internal capacity for self-control. In fact, we believe research on the effectiveness of heroin prescription as a treatment alternative provides an illustration of this, as we try to show in this article. First, however, we need to introduce another concept of ‘voluntariness’ that comes from political and legal philosophy.4 This will allow us to explain how social circumstances and the beliefs they inform could deprive a person of their voluntariness without removing their internal capacity for self-control. We introduce it here with a view to suggesting an alternative – and, we believe, important – perspective on the effects addiction might be thought to have on the voluntariness of heroin addicts’ consent that has been largely ignored in the debate about this issue. It is worth noting that it relies on a consequentialist ethical theory, which some readers may have objections about. We cannot provide a full conceptual defence of this notion or its ethical foundations here. Consequentialism, however, is a widely used approach in much ethical analysis in the field of healthcare.What does it mean to say that a consent is voluntary? In the bioethics literature it is widely agreed that a person acts voluntarily if he or she wills the action  without being under the controlling influence of another person or condition.beliefs about her options and hence actual motivation for making the choice. As we argue in the next section, we cannot rule out that the social circumstances typical of many chronic heroin addicts affect their beliefs about their options in a way that undermine the voluntariness of their consent even if they retain their capacity for self-control .5Very briefly, this alternative concept of voluntariness begins by distinguishing between three types of options in terms of ‘acceptability’, where the standard for the acceptability of options is an objective standard of well-being. First, there are options that one strongly dislikes, which one holds to be ‘unacceptable’ in the sense that they bring one’s well-being below a certain threshold. These are options that are thoroughly bad because they involve losses it would be unreasonable to expect anyone to bear. Second, there are options that are undesirable but not thoroughly bad, which one holds to be ‘acceptable’ in the sense that they bring one’s well-being above a certain threshold. These are options that have sufficient value to be choiceworthy. Finally, there are options that bring one’s well-being up to a high level and that one likes so much that one chooses them. Consider then the following plausible definition of voluntary choice: a choice is voluntary if it is not made because no other acceptable alternative options are available. This negative definition implies the existence of two types of situations in which a person makes a voluntary choice. First, there are situations in which she has at least two acceptable options and chooses one of them because, all things considered, she prefers one option to the other. Second, there are situations in which she has at least one option that she likes so much that she chooses it because of that, whether or not there are any acceptable alternative options. In neither of these cases is her reason for making her choice not having other acceptable alternative options. One implication of this concept of voluntariness is that whether a choice is voluntary or not depends not just on the person’s internal capacity for self-control, but crucially also on her 6 Thus, heroin trials have essentially sought to determine the therapeutic value of prescribing heroin to high-risk heroin users for whom such benefits cannot be expected or achieved by existing treatment options.7 When discussing the competence of heroin addicts to consent to participation in heroin trials we should therefore focus primarily on chronic addicts with a history of repeated treatment failure. The prevalence of health and social problems in this group of addicts is widely acknowledged.7 Major psychopathological studies of heroin users report rates of comorbidity that far exceed those of general population estimates. In addition to having high rates of comorbidity, it is well known that many individuals with chronic heroin addiction lead marginalised, impoverished lives, often associated with criminal activity, anxiety and high levels of risk. Can it be ruled out that such circumstances might create situations of constrained choice? We believe that it cannot. To see how such a situation could arise, consider first the option of obtaining heroin from the street. Many individuals reach a point in their chronic heroin addiction history in which their current lifestyles do not seem to them to be sustainable any longer; evidence of this is that many eventually seek help for their addiction. Presumably the costs of maintaining this lifestyle begin to exceed the benefits. Put in the terminology introduced in the last section, we might say that they come to consider a life centred on the procurement of heroin to be ‘unacceptable’ in the sense of no longer bringing their well-being above a certain threshold. Consider next the option of abstaining from heroin. For an action to be an acceptable option, it is not sufficient to have the ability or power to perform it. One must also believe one has that ability or power. There are many studies showing that mood disorders such as depression and anxiety lower belief in the person’s capabilities or perceived self-efficacy.8 Since there is a strong correlation between mood disorders and chronic heroin addiction, it is reasonable to assume that many heroin addicts harbour a low sense of self-efficacy and lack confidence in their ability to abstain from heroin.9 Chronic heroin addiction is associated with hopelessness about the future and a sense of powerlessness to influence the direction one’s life is going – reinforced by a history of failed attempts to abstain. Now, a lack of belief in one’s own ability is clearly detrimental to one’s will. Thus, according to a standard philosophical view, intentions involve plans of action and such plans, in order to be rational, require the belief that one has an acceptable chance of changing the world in ways one believes are for the better.10 Given this view, it would not be rational to form intentions one believes one is not going to carry out. The implication is that individuals with heroin addiction who have little belief in their capacity to abstain are likely to find it extremely difficult to form the intention to abstain. That is, since they believe they are going to fail if they try, they are likely to lack the will to abstain. Consequently, their commitment to changing their way of life may be low. Since believing one has reasons not to make an effort to exercise an ability (since one thinks it is futile) is not equivalent to lacking the ability, the problem here is not a lack of ability. The problem rather is an impairment of rational will due to a lack of belief in self-efficacy. It cannot be ruled out that such impairments of the will may lead some chronic heroin addicts to falsely believe abstinence is a non-option.To determine whether heroin addicts are able to give voluntary consent, assuming the understanding of voluntariness just outlined, we need to know something about their beliefs about their options. Of course, one difficulty is that heroin addicts are not all alike. Their individual circumstances including social and personal resources are likely to differ, and their beliefs about their options are therefore likely to differ as well. That being said, there is widespread consensus that heroin treatment is suited to a minority of heroin users as a second-line treatment for those individuals who do not respond to methadone or buprenorphine treatment delivered under optimal conditions.because of that? In fact, there appears to be little reason to think so. Many heroin addicts actually refuse to take part in these studies. In heroin trials in Switzerland, only a third of participants decided to take part when given the choice.11 One reason, presumably, is that they find the costs of keeping regular appointments with healthcare professionals too high. Chronic heroin addicts who do consent must judge these costs as less important than the benefits associated with obtaining free heroin. Presumably, they consider the value of obtaining free heroin to be sufficient to make participation in research acceptable, even if they do not consider the combined value of obtaining free heroin and taking part in research to be very high.If this is correct, everything depends on the option of taking part in research. Will a person with chronic heroin addiction consider this option to have a high value, not just as an acceptable way of avoiding the hassle on the street or to get free heroin from a legal source, but as a way of improving their well-being so much that they choose it To sum up, it cannot be ruled out that many chronic heroin addicts for whom the problems of procuring the drug on the street are unacceptable, but for whom abstinence is not an option, believe they have only one option, which is to consent to research involving the medical provision of heroin. Since there is evidence to suggest that they might choose this option not because they like it very much, but because they have no acceptable alternative options, their consent could be construed as non-voluntary. What constrains their choice is not their desire for heroin, but the wider social and psychological circumstances of their heroin addiction and the beliefs about the options these circumstances create.Our reasoning here is, of course, hypothetical. We have no empirical evidence of the contents of the decision-making processes in individuals with heroin addiction (nor do we know whether any such evidence exists). However, if it is a plausible reconstruction of what these processes might look like given the situational constraints and our current state of knowledge, it suffices, we believe, for our current purpose, to provide a reason why we should not take the voluntariness of their consent for granted.As we have argued, given a certain plausible conception of voluntariness, we cannot rule out that the beliefs held by individuals with heroin addiction about their options and hence their motivation for action might undermine the voluntariness of their consent even if they have the ability to resist their desire for heroin. One important reason for this is that the wider social circumstances typical of many such individuals may shape their beliefs about their capacity to make choices (such as making abstinence seem impossible) and these beliefs  could then impair their will to abstain from heroin use. This suggests that paying special attention to these circumstances should form an integral part of the assessment of whether or not the person’s consent is voluntary. However, the argument may perhaps strike some as overly philosophical. On what basis can we decide between different conceptions of voluntariness? Let us end with some more general considerations in favour of the view we have presented.www.wma.net/en/30publications/10policies/b3/). What makes it so ethically challenging to assess whether, in the case of heroin research, a person is competent to give their consent voluntarily is, of course, that we have no uncontroversial concept of voluntariness that applies to the specific circumstances of heroin addicts, and we have no direct access to the mental processes of the consenting individual to accurately appraise whatever conception we lean towards. This means that judgements about voluntary consent will always involve uncertainty. How can we best deal with this uncertainty? An ethical way of justifying why one approach is chosen over another might be to compare the potential harm these approaches may inflict on the research participants. Such an overall account of harm will have to reflect the inherent uncertainty of the assessment and also include considerations of harm potentially caused by a flawed assessment.According to the World Medical Association’s declaration on ethical principles for medical research involving human subjects (the Helsinki Declaration), the participation of human subjects in research requires the voluntary consent of individuals who are considered competent to give their consent . There may be circumstances in which it might be better for some individuals with heroin addiction to receive free heroin under medical supervision than getting it on the street. That is, the harm inflicted on these addicts by obtaining heroin on the street might greatly exceed the potential harm resulting from participation in heroin trials, because of mistaken assumptions about valid consent. Thus, these addicts might end up worse off than if (a) had not been used as the basis for an assessment of voluntary consent. Ironically, the protective safety net of the ethical standard of valid consent breaks down in this case, and in fact inflicts more harm than if the standard were ignored. Next, consider (b). The circumstances of many individuals addicted to heroin might suggest that they have some chance of succeeding in abstinence-based drug treatment programmes. However, this option of trying to achieve a life free of heroin is effectively ruled out if they receive heroin medication on a regular basis. Consequently, the harm these individuals may suffer could be considerable if their consent is accepted as valid without further questioning. Again, they could end up worse off than if we had not used (b) as the basis of the assessment of voluntary consent. Finally, consider (c). This approach differs from (a) and (b) by focusing on the particular person’s social and psychological circumstances (including motivating beliefs) as the basis of the assessment, rather than on universal and hard-to-verify claims about abilities of resistance of persons with heroin addiction. It therefore allows for a more flexible, case-to-case approach, one that neither rules out competence to consent voluntarily nor rules it in. This option would minimise the risk of inflicting more harm than if (c) had not been applied. Consequently, the potential of inflicting harm by assuming this approach is smaller compared with (a) and (b).a priori and uncertainty will always be involved whenever attempts are made to confirm or reject their appropriateness a posteriori, philosophy offers a means of identifying the most apt conceptualisation according to a risk-minimising ethical analysis. An assessment of capacity for voluntary consent in individuals with heroin addiction should be based on an approach that minimises the risk of harming them more than if the approach were not applied. According to our argument, focusing on addicts’ social and psychological circumstances (including motivating beliefs) as the basis of an assessment rather than their abilities of resistance is the most apt approach in this regard. We therefore suggest that this approach to the assessment of participant consent should guide and inform an ethical practice of including and excluding heroin addicts in research on heroin provision.Philosophy and medicine are inherent to mental healthcare. Clinical assessments of mental non-observable categories rely on adequate philosophical conceptualisations. Since the adequacy of these conceptualisations cannot be settled


Objective. A meta-analysis was conducted to analyze c-Met expression in cervical cancer. Methods. Articles related to our study were retrieved from PubMed, Elsevier, and China National Knowledge Infrastructure. State 12.0 was used for literature review, data extraction, and meta-analysis. The random-effects model and fixed-effects model were utilized to pool the relative ratio based on the heterogeneity test in the meta-analysis. Results. Nine studies that include data of 685 cervical carcinoma tissues were analyzed. However, three studies did not thoroughly discuss c-Met expression in nonneoplastic cervical tissue; thus, only six studies involving 364 patients and 228 nonneoplastic cervical tissues were included in the review. c-Met expression was higher in cervical cancer (60.99%) than in nonneoplastic cervical tissue (19.74%). Cervical carcinoma, cervical intraepithelial neoplasm, and normal cervical tissue were also examined. Results showed that increasing malignancy resulted in elevated c-Met expression. The relationship between c-Met expression and clinicopathologic features was also evaluated. c-Met expression correlated with disease-free survival, lymph node involvement, and lymphovascular space invasion. No statistical difference was observed between c-Met expression and other clinicopathological factors. Conclusions. c-Met is a potential diagnostic and prognostic indicator of cervical cancer. Cervical cancer, with an estimated death number of 265,700, was the fourth most commonly diagnosed cancer and was the fourth leading cause of cancer death among women worldwide in 2012. Approximately 87% of cervical cancer deaths occurred in developing countries . Cervicac-Met is a hepatocyte growth factor (HGF) receptor and a protooncogene that encodes c-Met gene production. c-Met is also a transmembrane receptor demonstrating independent phosphorylation , 5. HGF Moreover, c-Met overexpression is detected in cervical and endometrial cancers , 15. In PubMed, Elsevier, and China National Knowledge Infrastructure were searched using the key words “c-Met,” “Met,” “HGF/c-met,” and “HGF,” with “cervical cancer,” “diagnosis,” and “prognosis.” The most recent research update was published on August 10, 2015. Each article was manually screened. The related articles were read in full text, excluding those that evidently did not comply with the requirements of our meta-analysis.The inclusion criteria were as follows: (1) direct immunohistochemical detection of cervical cancer without any restriction on publication year or language; (2) no limitation on age and race; and (3) outcome indicators including clinical parameters, such as age (≥35 years old/<35 years old), histological grade (poor expression versus well and moderate expression), clinical stage , lymph node metastasis, lymphovascular space invasion (LVSI), parametrial involvement, tumor size, and stromal invasion (≥50% invasion versus 50% invasion), and cancer cell type (squamous carcinoma/nonsquamous carcinoma).The exclusion criteria were as follows: (1) nondetection of c-Met expression in cervical cancer; (2) no clear positive and negative expression of cervical cancer; and (3) failure to acquire valid data required for relevant clinical parameters, such as age, histological grade, clinical stage, lymph node metastasis, stromal invasion, LVSI, parametrial involvement, tumor size, and cancer cell type.Data were carefully and independently extracted from all eligible publications by following the inclusion and exclusion criteria. A study was included in the meta-analysis if investigators have reached a consensus. The data extracted from each study included the name of the first author, year of publication, number of cases, supplier of antibody, clinicopathological parameters, experimental methods, and case collection period.P < 0.05. Univariate analysis was performed to examine the differences in c-Met expression between cancer and noncarcinoma tissue. Risk ratios (RRs) or odds ratios (ORs) estimated at 95% confidence intervals (CIs) were used to analyze dichotomous variables. The random-effects model was utilized to calculate the pooled effect. In addition, chi-square test, I2 index, and P value were used to evaluate the studies. I2 index and P value were consistent in terms of heterogeneity. The fixed-effects model was employed when I2 < 50% and P > 0.1, whereas the random-effects model was used when I2 > 50% and P < 0.1. However, several inconsistencies, such as when I2 > 50% and P > 0.1, were found between the two models because the I2 index takes the degree of freedom into account. As such, I2 is recommended as a reference, and the random-effects model was selected. When I2 < 50% and P < 0.1, I2 was recommended as a reference, and the fixed-effects model was selected for statistical analysis.State 12.0 was used in the meta-analysis. c-Met expression was considered significant when A total of 727 out of 777 potentially relevant studies were irrelevant to this meta-analysis . The 50 All of the nine articles immunohistochemically detected c-Met protein, and a summary of their basic information is presented in P = 0.002). Statistical heterogeneity was also significant   . The ranP = 0.025) and demonstrated moderate heterogeneity  (P = 0.052), with P > 0.05, indicating the absence of a statistical significance.Articles that investigated the correlation of c-Met protein expression with disease-free survival (DFS) or overall survival (OS) were examined for this meta-analysis . Results= 0.083) . A poor P = 0.044) and moderate heterogeneity  compared with the neoplasia group (P = 0.003). The random-effects model was used to detect moderate heterogeneity  , and nonneoplastic cervical groups were compared in five articles reporting on c-Met expression . The ceria group . The res= 0.711) .Z = 2.78, P = 0.005; I2 = 57.5%, P = 0.028). Moreover, three studies that investigated LVSI were examined. A high c-Met overexpression correlated with a high percentage of LVSI. The pooled RR was 1.16 . Clinical stage, deep cervical stromal invasion, histological differentiation, patient age, presence or absence of parametrial involvement, tumor size, and histological cell type were not correlated with c-Met expression (P > 0.05).Clinical parameters, including tumor stage, lymph node involvement, depth of cervical stromal invasion, tumor differentiation (grade), patient age, presence of parametrial involvement, LVSI, tumor size, and cancer cell histologic type, were examined . Seven sState 12.0 was used to detect publication bias, and most of the points were within the 95% CI, indicating a moderate publication bias.Cervical cancer is a common gynecological cancer worldwide. Early detection greatly increases the success of patient treatment and prolongs patient survival. Lymph node metastasis and local or regional relapse are the primary causes of death in these patients –33. TherThe protooncogene c-Met encodes a growth factor receptor encoding HGF receptor and demonstrates tyrosine kinase activity. c-Met induces the proliferation, movement, and invasion of epithelial cells. Several experimental studies have shown that the activation of HGF/c-Met signal transduction is related to the occurrence and development of human tumors.c-Met is overexpressed in human tumors, such as thyroid, gastric, pancreatic, breast, and prostate cancers. HGF/c-Met is associated with the occurrence, development, and prognosis of cervical cancer. Manavi et al.  used a dc-Met is a receptor tyrosine kinase that plays a vital role in cancer growth by activating mitotic signaling pathways. Interference with c-Met activation may provide an effective approach for cervical cancer treatment . This meHowever, the greatest challenge is that only few studies investigated c-Met expression in cervical cancer, and most of the articles that are eligible for meta-analysis reported on data obtained from the same country. Thus, heterogeneity may be observed among data reported in these articles. We did not obtain further clinical follow-up data on c-Met expression in cervical cancer because this factor is relatively a new one. Thus, more robust clinical data are needed to confirm the conclusion of this meta-analysis.In this meta-analysis, nine articles reporting on c-Met expression in cervical cancer were analyzed. We evaluated the data from nine articles reporting on c-Met expression in 543 cervical cancer and 868 nonneoplastic cervix tissues. The expression of c-Met was significantly lower in nonneoplastic cervical tissue than in cervical cancer. DFS and OS were also examined. The c-Met overexpression in primary tumor correlated with poor DFS. Although c-Met overexpression in primary tumor correlated with OS has no meaning, there was a trend with poor OS about cervical cancer patients. Comparison of clinical parameters showed that cases demonstrating a high c-Met expression in their primary tumors are prone to exhibit lymph node metastasis and LVSI, although this phenomenon is not associated (or correlated) with clinical stage, percentage of cervical stromal invasion, histopathological differentiation, patient age, presence of parametrial involvement, tumor size, and histological cell type. In conclusion, c-Met, as an important factor in tumorigenesis, is a potential diagnostic and prognostic indicator of cervical cancer.


Since social media started getting more attention from users on the Internet, social media has been one of the most important information source in the world. Especially, with the increasing popularity of social media, data posted on social media sites are rapidly becoming collective intelligence, which is a term used to refer to new media that is displacing traditional media. In this paper, we focus on geotagged tweets on the Twitter site. These geotagged tweets are referred to as georeferenced documents because they include not only a short text message, but also the documents’ posting time and location. Many researchers have been tackling the development of new data mining techniques for georeferenced documents to identify and analyze emergency topics, such as natural disasters, weather, diseases, and other incidents. In particular, the utilization of geotagged tweets to identify and analyze natural disasters has received much attention from administrative agencies recently because some case studies have achieved compelling results. In this paper, we propose a novel real-time analysis application for identifying bursty local areas related to emergency topics. The aim of our new application is to provide new platforms that can identify and analyze the localities of emergency topics. The proposed application is composed of three core computational intelligence techniques: the Naive Bayes classifier technique, the spatiotemporal clustering technique, and the burst detection technique. Moreover, we have implemented two types of application interface: a Web application interface and an android application interface. To evaluate the proposed application, we have implemented a real-time weather observation system embedded the proposed application. we used actual crawling geotagged tweets posted on the Twitter site. The weather observation system successfully detected bursty local areas related to observed emergency weather topics.The online version of this article (doi:10.1186/s40064-015-0817-x) contains supplementary material, which is available to authorized users.The online version of this article (doi:10.1186/s40064-015-0817-x) contains supplementary material, which is available to authorized users. In recent years, social media has played a significant role as an alternative source of information -density-based spatiotemporal clustering algorithm; the experimental results indicate that their proposed algorithm can extract bursty local areas in a set of geotagged tweets, including keywords related to a topic related to weather topics.It is of value to people interested in a certain topic to observe dense areas where many georeferenced documents related to the topic are located. In this paper, these dense areas are referred to as bursty local areas related to the topic. For example, ε,τ)-density-based spatiotemporal clustering algorithm is a useful algorithm for extracting bursty local areas; however, two functional issues remain unresolved. One issue is that the -density-based spatiotemporal clustering algorithm does not support real-time extraction. In In this paper, we propose a novel real-time analysis application for identifying bursty local areas related to emergency topics. The aim of our new application is to provide new platforms that can identify and analyze the localities of emergency topics. The proposed application is composed of three core computational intelligence techniques: the Naive Bayes classifier technique, the spatiotemporal clustering technique, and the burst detection technique. The -density-based spatiotemporal clusters in real time, an incremental algorithm for -density-based spatiotemporal clustering is used. The target topics of this study are emergency topics; therefore we need to identify local bursty areas in real time. In ε,τ)-density-based spatiotemporal clusters on the arrival of each relevant georeferenced document.To identify -density-based spatiotemporal clustering algorithm are reviewed. In Section The rest of this paper is organized as follows. In Section In the era of big data, we are witnessing the rapid growth of a new type of information source. Social media has been noticed by a significant number of people; today, we obtain information instantaneously about emergency topics that surround us. In particular, tweets from one of the most widely used micro-blogging services have been involved in many different application domains Recently, a huge amount of geotagged tweets are posted because of the popularity of geomobile applications on smartphones. These geotagged tweets are useful for extracting local topics and events -density-based spatiotemporal clustering algorithm proposed in ε,τ)-density-based spatiotemporal clustering algorithm is the improved version of DBSCAN algorithm This section reviews the density-based clustering framework and the -density-based spatiotemporal clustering algorithm is based on the density-based spatial clustering algorithm The -density-based spatiotemporal clustering algorithm ε-neighborhood density and recognizes areas in which densities are higher than in other areas. However, it does not consider temporal changes. By contrast, the -density-based spatiotemporal clustering algorithm extracts -density-based spatiotemporal clusters that are both temporally and spatially-separated from other spatial clusters.The algorithm that has affected the density-based spatial clustering algorithm is the DBSCAN algorithm, which was first introduced by Ester et al. . The -density-based spatiotemporal clustering algorithm, areas with high spatial-/temporal-densities of data points can be considered spatiotemporal clusters, whereas those with low spatial-/temporal-densities cannot. To extract spatiotemporal clusters, we extend the definitions of density in DBSCAN. Suppose that a emergency topic is getting more attention in a local area. Users in the local area starts posting geotagged tweets related to the emergency topic; therefore, if we detect high dense regions in which there are many geotagged tweets, we can analyze local bursty areas where emergency topic is getting more attention from local people.In the -density-based neighborhood, which indicates the density of the neighborhood of a georeferenced document, is defined as follows.The -density-based neighborhood of a georeferenced document gdp, which is denoted by Nε,τ)((gdp), is defined asThe -density-based neighborhood. In DBSCAN, the neighborhood of document gdp is a set of documents that exist within ε from gdp. In the left-hand side of Figure gdp. Conversely, the -density-based neighborhood of gdp is a set of documents that exist within ε from gdp, where each document in the -density-based neighborhood is posted in τ before or after the posted time of document gdp. The right-hand side of Figure ε,τ)-density-based neighborhood. In this example, there are three documents, Nε,τ)((gdp)={gd2,gd3,gd4}. Document gd1 is within ε from document gdp; however, it is not in Nε,τ)((gdp), because it is not posted in τ before or after the posted time of document gdp.Figure gdp is called a core georeferenced document if there is at least a minimum number of georeferenced documents, MinGDoc, in the -density-based neighborhood Nε,τ)((dp) of that georeferenced document ((gdp)|≥MinGDoc). Otherwise, ((gdp)|≤MinGDoc), a georeferenced document gdp is called a border georeferenced document.A georeferenced document MinGDoc is set to three. In the left-hand side of Figure gdp is a core georeferenced document, because |Nε,τ)((gdp)| is three. In the right-hand side of Figure gdp is not a core georeferenced document, because |Nε,τ)((gdp)| is three.Suppose that gdq is in the -density-based neighborhood of georeferenced document gdp. If the number of georeferenced documents in the -density-based neighborhood of georeferenced document gdp is greater than or equal to MinGDoc, i.e., is |Nε,τ)((gdp)|≥MinGDoc, document gdq is -density-based directly reachable from gdp. In other words, georeferenced documents in the -density-based neighborhood of a core georeferenced document are -density-based directly reachable from the core georeferenced document.Suppose that the georeferenced document gdp is a core georeferenced document, because Nε,τ)((dp)≥MinGDoc. Then, gd1, gd2 and gd4 are in the -density-based neighborhood of document gdp. These three georeferenced documents are -density-based directly reachable from gdp.On the left-hand side of Figure gdp1,gdp2,⋯,gdpn) and the i+1-th georeferenced document gdpi+1 is -density-based directly reachable from the i-th georeferenced document gdpi. Georeferenced document gdpn is -density-based reachable from georeferenced document gdp1.Suppose that there is a georeferenced document sequence , the i+1-th georeferenced document gdpi+1 is -density-based directly reachable from gdpi. Therefore, dp5 is -density-based reachable from gdp1.Figure gdp and gdq are -density-based reachable from a georeferenced document gdo, which is an arbitrary georeferenced document. If |Nε,τ)((gdo)|≥MinGDoc, we denote that gdp is -density-based connected to gdq.Suppose that georeferenced documents gdp6 is -density-based connected to gdp5, because gdp5 is -density-based reachable from gdp2 and gdp6 is -density-based reachable from gdp2.Figure ε,τ)-density-based spatiotemporal cluster consists of two types of georeferenced document: core georeferenced documents, which are mutually -density-based reachable; and border georeferenced documents, which are -density-based directly reachable from the core georeferenced documents. An -density-based spatiotemporal cluster is defined as follows.An -density-based spatiotemporal cluster (DSC) in a georeferenced document set GD satisfies the following restrictions: (1) ∀gdp, gdq∈GD, if and only if gdp∈DSC and gdq is -density-based reachable from gdp, and gdq is also in DSC. (2) ∀gdp, gdq∈DSC, gdp is -density-based connected to gdq.An -density-based spatiotemporal cluster if gdp is -density-based connected to document gdq.Even if ε,τ)-density-based spatiotemporal clustering. In this algorithm, for each georeferenced document gdp in GD, the function IsClustered checks whether document gdp is already assigned to a spatiotemporal cluster. Then, the -density-based neighborhood of document gdp is obtained using the function GetNeighborhood. If georeferenced document gdp is a core document according to Definition 2, it is assigned to a new spatiotemporal cluster, and all the neighbors are queued to Q for further processing. The processing and assignment of georeferenced documents to the current spatiotemporal cluster continues until the queue is empty. The next georeferenced document is dequeued from queue Q. If the dequeued georeferenced document is not already assigned to the current spatiotemporal cluster, it is assigned to the current spatiotemporal cluster. Then, if the dequeued document is a core document, the georeferenced documents in the -density-based neighborhood of the dequeued georeferenced document are queued in queue Q using the function EnNniqueQueue, which places the input georeferenced documents into queue Q if they are not already in queue Q.Algorithm 1 describes the batch algorithm for , pti, which is the time when the georeferenced document was posted, and pli, which is the location where gdi was posted or is located .Our system has a georeferenced document database that contains geotagged tweets crawled by the Twitter site. Let DocumentExtractionManager fetches a georeferenced document, which is newly inserted in the georeferenced document database.DocumentExtractionManager classifies the fetched georeferenced document gdi using a Naive Bayes classifier. If and only if gdi is classified to “positive” class, which means gdi is related to an observed emergency topic, go to the next step.DocumentClusteringManager executes the incremental algorithm for extracting -density-based spatiotemporal clustering, for which there are two input data: gdi and a set of current extracted -density-based spatiotemporal clusters.ε,τ)-density-based spatiotemporal cluster, the burstiness of the cluster is calculated.For each  is the prior probability of class and P(gd|class) is the likelihood.where CLASS. Let a training data set TDS be TDS={,,⋯,}, where ci∈CLASS. A set of all words in class is denoted by Wclass={word1,word2,⋯,wordl}.The Naive Bayes classifier requires a training data set including multiple georeferenced documents that are classified in one class in gd represents a bag-of-words word1,word2,⋯,wordnumw(gd), where let numw(gd) be the number of words in gd. The georeferenced P(wordi|class) is the probability that wordi occurs in class. P(wordi|class) is defined as where, OW is the number of occurrence of wordi in class.where gd denoted by cgd∈CLASS is determined by finding the maximum posterior probability. The assigned class of ε,τ)-density-based spatiotemporal clustering algorithm, which extracts -density-based spatiotemporal clusters based on every georeferenced document that arrives for real-time extraction. There are two features in the incremental -density-based spatiotemporal clustering algorithm: limited re-clustering and merging.In the incremental algorithm, the algorithm updates the states of the extracted spatiotemporal clusters and extracts new spatiotemporal clusters every time a georeferenced document is added. Algorithm 2 describes the incremental -density-based spatiotemporal clusters must be updated; but the added georeferenced document affects only its -density-based neighborhood within τ directly. Function GetRecentData(gd) returns gd’s -density-based neighborhood within τ. After the -density-based neighborhood is extracted to generate seeds and these seed georeferenced documents are re-clustered again.When a georeferenced document is added to the georeferenced documents, existing -density-based spatiotemporal clusters need to be appended to other -density-based spatiotemporal clusters. Suppose that -density-based spatiotemporal cluster stc is expanding. If a core georeferenced document in stc includes a georeferenced document, which is clustered in stc′, stc′ is appended to stc. Function AppendClusters appends two spatiotemporal clusters and return a appended spatiotemporal cluster.In the incremental algorithm, during re-clustering, some -density-based spatiotemporal clusters. In the location-based burst detection algorithm, there are two sequences, that of the number of georeferenced documents and that of the number of relevant georeferenced documents.To identify the burstiness of extracted areas, we integrate location-based burst detection techniques ε,τ)-density-based spatiotemporal cluster is referred to as the sequence of relevant georeferenced documents. Moreover, the influence rates of georeferenced documents gradually decrease according to distance from the center of each cluster.In this study, a sequence of the number of all the relevant georeferenced documents is referred to as the sequence of georeferenced documents and a sequence of the number of relevant georeferenced documents in each , and number of detected heavily snowy and rainy areas (B), sorted by date. The value of (B/A×100) indicates the detection rates of the identification. The detection rates are less than 50% for 8 out of 12 days and 8 out of 16 days respectively, because there are many country areas that had heavily where no geotagged tweets were posted.As mentioned above, the number of heavily snowy and rainy areas were 106 and 131 respectively. Tables B/C×100) that indicate another detection rates. The detection rates are larger than 50% for 8 out of 12 days and 12 out of 16 days respectively. The average of detection rates are 83.7% and 73.0%. Threfore, areas where there are geotagged tweets, the proposed framework can identifly heavily rainy areas with high detection rates. However, some areas are low detection rates because time interval posted geotagged tweets of those areas are long. Those areas was raining all day on the observed day, for example “Saeki Oita”, “Nobeoka Miyazaki” and “Tsuno Miyazaki” on June 4.We also evaluated another type of detection rates; Tables Figure To discuss potential extension of the proposed application, we observed local heavy rain called “Guerrilla Rainstorm”. through the system. Figure In this paper, we proposed a novel real-time analysis application for identifying bursty local areas related emergency topics. The aim of our new application is to provide a new platform that can identify and analyze the localities of emergency topics. Three core computational intelligence techniques are applied in our applications: the Naive Bayes classifier technique, the spatiotemporal clustering technique, and the burst detection technique. Moreover, we developed two types of application interface: a Web-based interface and an android application interface. We have implemented a real-time weather observation system embedded the proposed application framework. To evaluate the implemented system, which is embedded the proposed application, actual crawling geotagged tweets posted on the Twitter site were used. We observed real time weather topics and our system could successfully detect bursty areas of observed emergency topics that is related to weather topics. In the future work, we are planning to develop an alert system that provides the details of detected bursty areas for users located near the bursty areas. We will also extend our proposed method to support multi-languages. Moreover, to improve the usability of our system, we have to develop an automatic method for making train set because making train sets is difficult for end users.


The project “Capacity building to implement state of the art surveillance systems for antibiotic consumption and resistance in Kosovo” was financed by the European Union and implemented by the National Institute of Public Health of Kosovo in collaboration with the University of Antwerp during 2012-2014.The main objectives of this project were to monitor volumes and patterns of antibiotic use and to establish a comprehensive surveillance system of antibiotic resistant bacteria.Total antimicrobial use data were analysed according to the WHO ATC/DDD methodology and expressed in DDD/1000inhabitants/day (DID). Data on antimicrobial use in hospitals were collected in all seven hospitals of Kosovo using the methodology of a point prevalence survey based on ESAC. Survey of consumption in primary care was retrospective and involved 12 Family Medicine Centres covering all 6 regions of Kosova.Total antibacterial use in Kosovo was 26.3 DID. The top antibacterial subgroups were penicillins  and other beta-lactam antibacterials . Kosovo had the highest proportional total parenteral use of cefriaxone in Europe (53.9) and lowest use of systemic antimycotics and antifungals (0.08 DID). Of total number of 1579 enrolled patients in Kosovo hospitals, 769 (48.7%) of them received antibiotics. The most prescribed antibiotic was ceftriaxone (41.5%), followed by gentamycin (12.1%). Antibiotics were administered mainly through parenteral route (73.3%). Empiric antibiotic prescription was higher than etiological (88.28% vs. 11.72%). Of all patients who attended primary care level, 33% received antibiotics. Administration through the parenteral route was 43%. Antibiotic prescription with generic names was noticed only in 31% of cases. The most prescribed antibiotic in primary care level was also ceftriaxone.Gathered data will serve as a tool for quality improvement in Kosovo and will support the preparation of guidelines and protocols for prudent use of antibiotics.None declared.


T1 maps of the liver. The balanced steady‐state free precession (bSSFP) sequence causes water and fat signals to have opposite phase when repetition time (TR) = 2.3 msec at 3T. In voxels that contain both fat and water, the MOLLI T1 measurement is influenced by the choice of TR.To characterize the effect of fat on modified Look–Locker inversion recovery (MOLLI) T1 measurements of the liver were simulated using the Bloch equations while varying the hepatic lipid content (HLC). Phantom scans were performed on margarine phantoms, using both MOLLI and spin echo inversion recovery sequences. MOLLI T1 at 3T and HLC were determined in patients (n = 8) before and after bariatric surgery.MOLLI T1 values when TR = 2.3 msec. Patients were found to have higher MOLLI T1 at elevated HLC (T1 = 929 ± 97 msec) than at low HLC (T1 = 870 ± 44 msec).At 3T, with HLC in the 0–35% range, higher fat fraction values lead to longer MOLLI T1 values are affected by HLC, substantially changing MOLLI T1 in a clinically relevant range of fat content. J. Magn. Reson. Imaging 2016;44:105–111.At 3T, MOLLI  T1 mapping technique and variants of it have been gaining interest in cardiovascular magnetic resonance imaging (MRI)T1 map within a breath‐hold. It has also been demonstrated that MOLLI T1 maps provide diagnostic information in the heartTHE MODIFIED LOOK–LOCKER INVERSION RECOVERY (MOLLI)T1, and in regions of visceral fat the MOLLI T1 method measures this short T1 with high reproducibility.T1 method detects long T1 regions of the blood pool with high reproducibility.T1 would be the weighted sum of the T1 of the fat and the T1 of the hepatic tissue. The measured T1 of the liver would thus be expected to be reduced in fatty liver due to this partial volume effect. Phantom scans and previous work have demonstrated that T1 decreases with increasing fat concentration when using conventional imaging methods, ie, spin echo inversion recovery (SE‐IR).Fat is known to have a short T1 values have been shown to be influenced by fat and off‐resonance frequencies at 1.5T in the calf muscleT1 is often measured in patients with fatty liversT1 of the water component which appears to be of diagnostic significance when using T1 mapping in the liver,T1 of the fat is constantT1 to assess liver disease is the clarification and quantification of the extent to which the presence of fat can mask or exaggerate changes in MOLLI T1 due to disease.MOLLI T1 maps at 3T with a bSSFP TR = 2.3 msec and to explain the mechanisms for this behavior.The aim of this study was thus to investigate the effect of different fat concentrations and off‐resonance frequencies on MOLLI T1 mapping method. It uses several inversion pulses and acquires images synchronized to the cardiac cycle using a snapshot bSSFPMOLLI is an electrocardiogram (ECG)‐gated inversion recovery The bSSFP readout results in images that are sensitive to the off‐resonance frequency of the protons being imaged Fig. .17 The cT1 would lie somewhere between the individual T1s of the fat and the water. However, in the situation described in this work the water and fat are exactly out of phase, and so the signal recovery is the difference of two exponentials weighted by the relative contributions of fat and water. In practice, for relatively small fat concentrations this results in a measured value for T1 that is longer than the T1 value of either the fat or water component.The signal in a voxel containing both fat and water with no exchange of magnetization between them would be determined by the well‐known partial volume effect. If the fat and water were in phase then the recovery would follow the sum of these two recovering exponentials; in practice, if this were fit to a single exponential then the measured T1 with the MOLLI method.A Bloch equationT1 values lie in the 700–1400 msec interval,T1.A single inversion followed by five image readouts was simulated, providing a good approximation to the MOLLI acquisition but eliminating the complexity that is due to the multitude of possible sampling schemes that have been described.1 = 750 Hz and β = 3.45.The following simulation parameters were used: 3T field strength, 192 × 144 matrix, 84 phase encode lines, 24 phase encode lines before the central line, flip angle (FA) = 35°, TR/TE = 2.3/1.15 msec, TI = 100, 1000, 1900, 2800, 3700 msec, adiabatic hyperbolic secant 1 inversion pulse of 10.24 msec duration, time‐bandwidth product of R = 5.48, peak BT1 and T2 values for fat and liver components were: T1fat = 382 msec, T2fat = 68 msec,T1hepatic = 812 msec,T2hepatic = 34 msec.F, being defined using Eq. f and ρw denote the proton densities of fat and water.T1* is the apparent T1 and A and B are additional fit parameters.T1 values were computed by using the imperfect,T1 caused by repetition times other than 2.3 msec, the variation of MOLLI T1 with off‐resonance frequency was simulated for two repetition times found in the literature: TR = 2.14 msec3 and TR = 2.6 msec.T1 values, the TR was varied in a simulation comprising a water and a multiple‐peak fat component with 30% fat fraction. The spectral model of the fat was based on the 1H spectrum of the margarine phantom described below. The same imaging protocol was simulated as described in the previous section, with the following differences: TI = 200, 1200, 2200, 3200, 4200 msec, RR = 1000 msec, and 31 bSSFP TR values in the range 1.93 to 5.75 msec. T1 and T2 values for fat and water components corresponded to those of a margarine phantom and were T1fat = 325 msec, T2fat = 120 msec, T1water = 2448 msec, and T2water = 207 msec. The measurements leading to these values are described in the next section.To further explore the effects of fat on MOLLI Phantom experiments were carried out using a margarine phantom  with 30% fat content. First, the margarine phantom was scanned using a 5‐point MOLLI sequence. Imaging parameters followed a standardized MOLLI acquisition protocol : 192 × 144 matrix, FA = 35°, TR/TE = 2.3/0.99 msec, TI = 100, 1100, 2100, 3100, 4100 msec, simulated ECG with RR = 1000 msec. Then the same margarine phantom was scanned using the SE‐IR sequence. Imaging parameters followed a standardized acquisition protocol: 128 × 128 matrix, TR = 10000 msec, TI = 50, 150, 250, 400, 600, 900, 1300, 2000, 3000, 4500, 6500 msec, TE = 7.4 msec. In both cases images were acquired using a Siemens 3T Verio scanner using a 32‐channel head RF coil.Following the margarine scans, a sample of the margarine was heated and then spun with a centrifuge  at 4000 rpm for 5 minutes. After spinning the sample, separate layers of fat and water were obtained that were scanned using the MOLLI acquisition and the SE‐IR acquisition using the same scanner and same protocols as described above.T1 of the whole margarine and the water component only over a range of repetition times. The previously described 5‐point MOLLI acquisition protocol was used with the following changes: TI = 200, 1200, 2200, 3200, 4200 msec, RR = 1000 msec, and 31 bSSFP TR values ranging from 1.93 to 5.75 msec.A subsequent experiment was carried out in order to determine MOLLI T1 values were determined by fitting the signal intensity of a circular region of interest on the bSSFP images following the inversion pulse to Eq. T1. T1 values for images acquired using the SE‐IR sequence were computed by fitting Eq. MOLLI 2, mean waist circumference: 120.25 ± 10.35 cm, and mean hip circumference: 134.5 ± 11.2 cm. Four of the patients suffered from diabetes. Postoperative parameters were: mean BMI: 36.4 ± 4.8 kg/m2, mean waist circumference: 107.7 ± 10.6 cm, and mean hip circumference: 120.6 ± 8.6 cm.In order to compare the results of the simulations to results obtained in vivo, data from eight patients  were processed retrospectively. Patients were scanned before weight reduction surgery and 6 months postoperatively. Relevant parameters of the patients before surgery included mean body mass index (BMI): 45.8 ± 5.5 kg/mThe study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki, and was approved by the institutional research departments and the National Research Ethics Service (13/SC/0243). All patients gave written informed consent.T1 maps (5‐point MOLLI was employed). T2* maps were collected for hepatic iron quantification and 1H MRS for the quantification of liver fat using the stimulated echo acquisition mode (STEAM) sequence. Imaging parameters for the MOLLI scan were: 192 × 134–160 matrix (depending on patient), field of view (FOV) 280–348 × 350–500 mm (depending on patient), slice thickness of 8 mm, GRAPPA acceleration factor 2, pixel bandwidth 898 Hz/px, TR/TE = 2.14/1.07 msec, FA = 35°, TI = 110, 110+RR, 110+2RR, 110+3RR, 110+4RR msec. MOLLI T1 maps were acquired in transverse scan planes.At each timepoint, patients had liver MOLLI T2* maps were determined using a multiecho acquisition with RF spoiling. Imaging parameters for this acquisition were as follows: same FOV as for the 5‐point MOLLI sequence, 192 × 128–160 matrix (depending on patient), slice thickness of 3 mm, GRAPPA acceleration factor 2, TR/TE = 26.5/2.46, 7.38, 12.30, 17.22, 22.14 msec, FA = 20°. Fat saturation and double‐inversion black blood preparation were used.3. The voxel of interest was placed in the lateral part of the right lobe of the liver, avoiding vessels, bile ducts, and the edge of the liver. Spectra were processed using AMARES in jMRUIThe STEAM spectroscopy experiment usedT1 and HLC. At low HLC (0–16% range) the measured MOLLI T1 increases with increasing fat, and can be approximated by:T1 is expressed in milliseconds and F is the percent HLC. This trend ends at approximately F = 40%, where fitting becomes impossible owing to the water signal and fat signal canceling each other out. For F > 50% the MOLLI T1 values change rapidly, eventually reaching the T1 of the fat at 100% fat fraction. The increase of MOLLI T1 is explained by the simultaneous increase of both the B/A ratio and the apparent T1 (T1*) in Eq. Figure T1 variation in the case of off‐resonance. Although the bSSFP readout leads to a symmetric MOLLI T1 variation around the central water frequency for 0% HLC, using a multiple‐peak spectral model of the lipid leads to asymmetric off‐resonance frequency dependence.Figure T1 on off‐resonance frequency when using repetition times from the literatureT1 values were found to be higher at lower repetition times for most fat fractions and off‐resonance frequencies. In addition, MOLLI T1–off‐resonance frequency dependence is both larger and increasingly asymmetric with respect to frequency in the presence of higher fat.In simulations the dependence of MOLLI T1 values determined from MOLLI and SE‐IR experiments in the margarine phantom are presented in Table Figure T1 on repetition times is shown in Fig. T1 values of the margarine phantom with 30% fat were higher than those of water over the 1.8 to 3.5 msec range and lower over the 3.5 to 5.75 msec range due to the relative position of the bSSFP profiles of the fat and water. However, the simulated and measured data did not agree perfectly. A possible explanation for the mismatch could be the missing information on the different T1 and T2 values of the individual fat peaks in the margarine phantom. A similar difference between simulation and phantom experiments can be seen in Thiesson et al's work.The results of the simulation and phantom experiment exploring the dependence of MOLLI T1 fit to the MOLLI data failed at the first visit. The measured HLC for this patient was 39.7%, which is in the regime where the Bloch simulated data could also not be fitted to an inversion recovery model.One patient was excluded from the comparison because the T2* values larger than 19 msec and one had T2* = 15 msec, indicating elevated iron but all within the normal range for T2* at 3T.Six patients had normal T1 measurements for seven patients are shown in Fig. T1 and HLC are also included for three different levels of liver fibrosis, characterized by the Ishak score.T1 values at 0% HLC for the three curves were taken from Banerjee et al, as shown in their fig. 2 of Ref. T1 that occur in these patients are consistent with the hypothesis that the water in the livers of these patients is elevated but stable between exams and that the fat concentration has changed. These patients are expected to have some level of inflammation or fibrosis, which has previously been shown to elevate MOLLI T1.Pre‐ and postoperative MOLLI T1 at 3T increases with fat concentration in simulation and phantoms when using TR = 2.3 msec. This also applies when TR lies in the range 2.1 to 2.6 msec. The MOLLI T1 elevation is seen in vivo with the caveat that there may be other changes in the livers of the patients over 6 months after bariatric surgery that would be expected to modify the T1.In a physiological range of HLC from 0% to 45%Due to a chemical shift difference of 447 Hz between fat and water at 3T, the two tissue components are exactly out of phase with their passbands overlapping when using TR = 2.3 msec. Thus, combined signals from tissue containing fat and water are less dependent on off‐resonance frequency than reported previously using TR = 2.7 msec at 1.5T.T1 measurements within a single subject and between subjects.These simulations suggest that careful shimming, in addition to the use of a TR of 2.3 msec or less, is useful to maximize the consistency of MOLLI T1 measurements is close to the minimum TR available with existing hardware, at 1.5T longer TR values would have to be used to produce a similar overlapping of the two bSSFP passbands due to the smaller chemical shift difference between fat and water.In contrast to 3T, where the optimal TR for reducing the frequency dependence of MOLLI T1 evolution in a 6‐month interval after bariatric surgery follows our model describing the influence of fat on MOLLI T1 values. We expect that, while the amount of fat changes in these patients, other parameters known to affect the T1 (such as fibrosis and inflammation) remain fairly constant. In general terms, the change in measured MOLLI T1 is consistent with the behavior that is predicted by the simulation for changes in liver fat in five of the seven patients; in one patient the change in liver fat is very small and the MOLLI T1 change is small, and in one patient the liver fat change is small, but the MOLLI T1 change is ∼100 msec, not following the model. We believe that this supports the applicability of the model in vivo.Patient MOLLI T1 in two of the patients was not explained by change in fat fractions, suggesting the existence of other mechanisms responsible for having an influence on hepatic MOLLI T1 values.A limitation of this study is the small size of the patient cohort. A change in MOLLI T1 mapping method is used extensively in cardiac imaging and so it is important to briefly consider the effect of myocardial fat on MOLLI T1 maps at 3T. Since global lipid fractions in the myocardium are in the 0.2–2% interval,T1 values. An exception is in focal lipid accumulations, which can be as high as 35% in the case of lipomatous metaplasia,The MOLLI T1 measurements in the liver. This effect is in addition to the previously known effects of T2, magnetization transfer, off‐resonance frequency, and iron concentration. Simulation has shown that fat fractions up to 40% will have an additive effect on the measured MOLLI T1 value at 3T when using a bSSFP readout with TR = 2.3 msec. This behavior has been confirmed in the livers of patients undergoing weight‐reduction surgery.In conclusion, this study has shown that the presence of fat influences MOLLI T1 measurements, as fat fraction values measured in the liver can be large enough to cause severe MOLLI T1 alterations.The influence of fat should be considered in the assessment of hepatic diseases using MOLLI


Nseir and colleagues presented data from a large multicenter study of patients with ventilator-associated tracheobronchitis (VAT), demonstrating that appropriate antibiotic therapy for VAT was an independent predictor for reducing transition to pneumonia . These data added to the growing evidence supporting the use of appropriate antibiotic therapy for VAT as a standard of care to prevent VAP and improve patient outcomes. Critical Care, Nseir and colleagues [Pseudomonas aeruginosa, Staphylococcus aureus, and Acinetobacter baumannii were the most common pathogens isolated. In the multivariable analysis, appropriate antibiotic therapy was the only risk factor independently associated with reduced risk of transition to VAP (P =0.009).In a previous issue of lleagues  presente5) organisms per milliliter of a bacterial pathogen [Previous studies have demonstrated that patients diagnosed with VAT or VAP (or both) have increased ventilator days, length of ICU stay, and associated health-care costs -6. Patiepathogen . Howeverpathogen ,8. Intrapathogen ,4,9,10.P <0.03), and a longer time to the first episode of VAT/VAP .Bouza and colleagues  comparedRecently, there has been increased interest in the use of adjunctive aerosolized antibiotic therapy for VAT and VAP, administered by an improved nebulizer delivery system to increase weaning from the ventilator and shorten ICU stay ,9,10. A Interestingly, different approaches exist for antibiotic treatment of urinary tract infections (UTI) due to cystitis or pyelonephritis versus respiratory tract infections due to VAT and VAP Figure A. PatienVentilated ICU patients developing VAT or VAP or both are at increased risk for chronic co-morbidities that include debility, tracheostomy, acute and chronic lung damage, delirium, post-traumatic stress disorder, and short- or long-term cognitive impairment that increase the need for rehabilitation, chronic care, hospital readmission, and increased health-care costs ,14. UnroS. aureus, P. aeruginosa, Acinetobacter species, or other multi-drug-resistant Gram-negative pathogens [In a recent survey of VAT involving medical staff in 288 ICUs in 16 different countries worldwide, 50.3% of respondents recommended antibiotic therapy for VAT, 93% thought VAT increased length of ICU stay, and 50% believed that VAT increased patient mortality ,6,8. Assathogens . Conside


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