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BACKGROUND:Current medical scores have limited efficiency and safety profiles to enable assignment to the most appropriate treatment site in patients with lower respiratory tract infections (LRTIs). We describe our current triage practice and assess the potential of a combination of CURB65 with proadrenomedullin (ProADM) levels for triage decisions. METHODS:Consecutive patients with LRTIs presenting to our emergency department were prospectively followed and retrospectively classified according to CURB65 and ProADM levels (CURB65-A). Low medical risk patients were further subgrouped according to biopsychosocial and functional risks. We compared the proportion of patients virtually allocated to triage sites with actual triage decisions and assessed the added impact of ProADM in a subgroup. RESULTS:Overall, 93% of 146 patients were hospitalised. Among the 138 patients with available CURB65-A, 17.4% had a low medical risk indicating possible treatment in an outpatient or non-acute medical setting; 34.1% had an intermediate medical risk (short-hospitalisation); and 48.6% had a high medical risk (hospitalisation). Fewer patients were in a low CURB65-A class (I) than a low CURB65 class (0,1) (17.4% vs. 46.3%, p

Objective: To assess the level of child and adolescent psychiatric staff's knowledge regarding pain management, to determine group differences between the medically more educated (physicians, nurses) and the less educated (psychologists, educators, special therapists) and to investigate the influence of gender, age, or professional experience as well as staff's own pain experiences., Methods: A total of 193 staff members from different professional backgrounds from three independent child and adolescent psychiatry clinics in Northern Germany were tested using the German version of the Pediatric Nurses' Knowledge and Attitudes Survey Regarding Pain Shriner's revision (PNKAS-Sr)., Results: In total, the staff scored correctly 66% of the inventory questions. There was no difference between medically more educated and less educated staff members regarding the knowledge of pain management. The main factors influencing PNKAS score were age, profession, and pain education training., Conclusions: Although chronic pain is not one of the main aspects of continuing education in child and adolescent psychiatry, the resulting level of knowledge was comparable to results of similar surveys with paediatric staffs. Nevertheless, further education is needed to enhance knowledge and understanding of children's pain in child psychiatry staff in order to professionally treat patients with chronic somatic and mental illnesses.

Work with the looking-while-listening (LWL-) paradigm suggested that 6-month-old English-learning infants associated several labels for common nouns with pictures of their referents: While one distractor picture was present, infants systematically fixated the named target picture. However, recent work revealed constraints of infants' noun comprehension. The age at which these abilities can be obtained appears to relate to the infants' familiarity with the talker, the target language, and word frequency differences in target-distractor pairs. Here, we present further data to this newly established field of research. We tested 42 monolingual German-learning infants aged 6-14 months by means of the LWL-paradigm. Infants saw two pictures side-by-side on a screen, whilst an unfamiliar male talker named one of both. Overall, infants did not fixate the target picture more than the distractor picture. In line with previous results, infants' performance on the task was higher when target and distractor differed within their word frequency-as operationalized by the parental rating of word exposure. Together, our results add further evidence for constraints on early word learning. They point to cross-linguistic differences in early word learning and strengthen the view that infants might use extra-linguistic cues within the stimulus pairing, such as frequency imbalance, to disambiguate between two potential referents., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Steil, Friedrich and Schild.)

Phonemic awareness and rudimentary grapheme knowledge concurrently develop in pre-school age. In a training study, we tried to disentangle the role of both precursor functions of reading for spoken word recognition. Two groups of children exercised with phonemic materials, but only one of both groups learnt corresponding letters to trained phonemes. A control group exercised finger-number associations (non-linguistic training). After the training, we tested how sensitive children were to prime-target variation in word onset priming. A group of young adults took part in the same experiment to provide data from experienced readers. While decision latencies to the targets suggested fine-grained spoken word processing in all groups, event-related potentials (ERPs) indicated that both phonemic training groups processed phonemic variation in more detail than the non-linguistic training group and young adults at early stages of speech processing. Our results indicate temporal plasticity of implicit speech processing in pre-school age as a function of explicit phonemic training., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bauch, Friedrich and Schild.)

It is widely accepted that finger and number representations are associated: many correlations (including longitudinal ones) between finger gnosis/counting and numerical/arithmetical abilities have been reported. However, such correlations do not necessarily imply causal influence of early finger-number training; even in longitudinal designs, mediating variables may be underlying such correlations. Therefore, we investigated whether there may be a causal relation by means of an extensive experimental intervention in which the impact of finger-number training on initial arithmetic skills was tested in kindergarteners to see whether they benefit from the intervention even before they start formal schooling. The experimental group received 50 training sessions altogether for 10 weeks on a daily basis. A control group received phonology training of a similar duration and intensity. All children improved in the arithmetic tasks. To our surprise and contrary to most accounts in the literature, the improvement shown by the experimental training group was not superior to that of the active control group. We discuss conceptual and methodological reasons why the finger-number training employed in this study did not increase the initial arithmetic skills beyond the unspecific effects of the control intervention., (Copyright © 2020 Schild, Bauch and Nuerk.)

Background: A comprehensive in-hospital patient management with reasonable and economic resource allocation is arguably the major challenge of health-care systems worldwide, especially in elderly, frail, and polymorbid patients. The need for patient management tools to improve the transition process and allocation of health care resources in routine clinical care particularly for the inpatient setting is obvious. To address these issues, a large prospective trial is warranted., Methods: The "Integrative Hospital Treatment in Older patients to benchmark and improve Outcome and Length of stay" (In-HospiTOOL) study is an investigator-initiated, multicenter effectiveness trial to compare the effects of a novel in-hospital management tool on length of hospital stay, readmission rate, quality of care, and other clinical outcomes using a time-series model. The study aims to include approximately 35`000 polymorbid medical patients over an 18-month period, divided in an observation, implementation, and intervention phase. Detailed data on treatment and outcome of polymorbid medical patients during the in-hospital stay and after 30 days will be gathered to investigate differences in resource use, inter-professional collaborations and to establish representative benchmarking data to promote measurement and display of quality of care data across seven Swiss hospitals. The trial will inform whether the "In-HospiTOOL" optimizes inter-professional collaboration and thereby reduces length of hospital stay without harming subjective and objective patient-oriented outcome markers., Discussion: Many of the current quality-mirroring tools do not reflect the real need and use of resources, especially in polymorbid and elderly patients. In addition, a validated tool for optimization of patient transition and discharge processes is still missing. The proposed multicenter effectiveness trial has potential to improve interprofessional collaboration and optimizes resource allocation from hospital admission to discharge. The results will enable inter-hospital comparison of transition processes and accomplish a benchmarking for inpatient care quality.

Navigation crucially depends on the capability to estimate time elapsed and distance covered during movement. From adults it is known that magnitude estimation is subject to characteristic biases. Most intriguing is the regression effect (central tendency), whose strength depends on the stimulus distribution (i.e. stimulus range), a second characteristic of magnitude estimation known as range effect. We examined regression and range effects for time and distance estimation in eleven-year-olds and young adults, using an egocentric virtual navigation task. Regression effects were stronger for distance compared to time and depended on stimulus range. These effects were more pronounced in children compared to adults due to a more heterogeneous performance among the children. Few children showed veridical estimations similar to adults; most children, however, performed less accurate displaying stronger regression effects. Our findings suggest that children use magnitude processing strategies similar to adults, but it seems that these are not yet fully developed in all eleven-year-olds and are further refined throughout adolescence.

Languages with contrastive stress, such as English or German, distinguish some words only via the stress status of their syllables, such as "CONtent" and "conTENT" (capitals indicate a stressed syllable). Listeners with a fixed-stress native language, such as Hungarian, have difficulties in explicitly discriminating variation of the stress position in a second language (L2). However, Event-Related Potentials (ERPs) indicate that Hungarian listeners implicitly notice variation from their native fixed-stress pattern. Here we used ERPs to investigate Hungarian listeners' implicit L2 processing. In a cross-modal word fragment priming experiment, we presented spoken stressed and unstressed German word onsets (primes) followed by printed versions of initially stressed and initially unstressed German words (targets). ERPs reflected stress priming exerted by both prime types. This indicates that Hungarian listeners implicitly linked German words with the stress status of the primes. Thus, the formerly described explicit stress discrimination difficulty associated with a fixed-stress native language does not generalize to implicit aspects of L2 word stress processing., (Copyright © 2018 Elsevier B.V. All rights reserved.)

It is a matter of debate, whether and how improved auditory discrimination abilities enable speeded speech comprehension in congenitally blind adults. Previous research has concentrated on semantic and syntactic aspects of processing. Here we investigated phonologically mediated spoken word access processes by means of word onset priming. Blind adults and age- and gender-matched sighted adults listened to spoken word onsets (primes) followed by complete words (targets). Phonological overlap between primes and targets varied. Blind participants made faster lexical decision responses than sighted participants, yet their speeded responses were not restricted to phonologically overlapping trials. Furthermore, timing of Event Related Potential (ERP) results did not differ between blind and sighted participants. Together these results suggest that blind and sighted listeners are equally fast in implicit phonological encoding and lexical matching mechanisms. It appears that blind adults' speeded speech processing emerges when phonological analysis makes promising word candidates available for further processing. As one possible interpretation, we speculate that lexical selection processes in blind adults do not need to wait for information from the visual domain, while auditory-visual integration mechanisms are mandatorily implemented in speech recognition routines of sighted adults., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Recent evidence suggests division of labor in phonological analysis underlying speech recognition. Adults and children appear to decompose the speech stream into phoneme-relevant information and into syllable stress. Here we investigate whether both speech processing streams develop from a common path in infancy, or whether there are two separate streams from early on. We presented stressed and unstressed syllables (spoken primes) followed by initially stressed early learned disyllabic German words (spoken targets). Stress overlap and phoneme overlap between the primes and the initial syllable of the targets varied orthogonally. We tested infants 3, 6 and 9 months after birth. Event-related potentials (ERPs) revealed stress priming without phoneme priming in the 3-month-olds; phoneme priming without stress priming in the 6-month-olds; and phoneme priming, stress priming as well as an interaction of both in 9-month-olds. In general the present findings reveal that infants start with separate processing streams related to syllable stress and to phoneme-relevant information; and that they need to learn to merge both aspects of speech processing. In particular the present results suggest (i) that phoneme-free prosodic processing dominates in early infancy; (ii) that prosody-free phoneme processing dominates in middle infancy; and (iii) that both types of processing are operating in parallel and can be merged in late infancy., (© 2017 John Wiley & Sons Ltd.)

Background: Early identification of patients requiring transfer to post-acute care (PAC) facilities shortens hospital stays. With a focus on interprofessional assessment of biopsychosocial risk, this study's aim was to assess medical and neurological patients' post-acute care discharge (PACD) scores on days 1 and 3 after hospital admission regarding diagnostic accuracy and effectiveness as an early screening tool. The transfer to PAC facilities served as the outcome ("gold standard")., Methods: In this prospective cohort study, registered at ClinicalTrial.gov (NCT01768494) on January 2013, 1432 medical and 464 neurological patients (total n = 1896) were included consecutively between February and October 2013. PACD scores and other relevant data were extracted from electronic records of patient admissions, hospital stays, and interviews at day 30 post-hospital admission. To gauge the scores' accuracy, we plotted receiver operating characteristic (ROC) curves, calculated area under the curve (AUC), and determined sensitivity and specificity at various cut-off levels., Results: Medical patients' day 1 and day 3 PACD scores accurately predicted discharge to PAC facilities, with respective discriminating powers (AUC) of 0.77 and 0.82. With a PACD cut-off of ≥8 points, day 1 and 3 sensitivities were respectively 72.6% and 83.6%, with respective specificities of 66.5% and 70.0%. Neurological patients' scores showed lower accuracy both days: using the same cut-off, respective day 1 and day 3 AUCs were 0.68 and 0.78, sensitivities 41.4% and 68.7% and specificities 81.4% and 83.4%., Conclusion: PACD scores at days 1 and 3 accurately predicted transfer to PAC facilities, especially in medical patients on day 3. To confirm and refine these results, PACD scores' value to guide discharge planning interventions and subsequent impact on hospital stay warrants further investigation., Trial Registration: ClinialTrials.gov Identifier, NCT01768494 .

Background: Urinary tract infections (UTIs) are common drivers of antibiotic use. The minimal effective duration of antibiotic therapy for UTIs is unknown, but any reduction is important to diminish selection pressure for antibiotic resistance, costs, and drug-related side-effects. The aim of this study was to investigate whether an algorithm based on procalcitonin (PCT) and quantitative pyuria reduces antibiotic exposure., Methods: From April 2012 to March 2014, we conducted a factorial design randomized controlled open-label trial. Immunocompetent adults with community-acquired non-catheter-related UTI were enrolled in the emergency department of a tertiary-care 600-bed hospital in northwestern Switzerland. Clinical presentation was used to guide initiation and duration of antibiotic therapy according to current guidelines (control group) or with a PCT-pyuria-based algorithm (PCT-pyuria group). The primary endpoint was overall antibiotic exposure within 90 days. Secondary endpoints included duration of the initial antibiotic therapy, persistent infection 7 days after end of therapy and 30 days after enrollment, recurrence and rehospitalizations within 90 days., Results: Overall, 394 patients were screened, 228 met predefined exclusion criteria, 30 declined to participate, and 11 were not eligible. Of these, 125 (76% women) were enrolled in the intention-to-treat (ITT) analysis and 96 patients with microbiologically confirmed UTI constituted the per protocol group; 84 of 125 (67%) patients had a febrile UTI, 28 (22%) had bacteremia, 5 (4%) died, and 3 (2%) were lost to follow-up. Overall antibiotic exposure within 90 days was shorter in the PCT-pyuria group than in the control group (median 7.0 [IQR, 5.0-14.0] vs. 10.0 [IQR, 7.0-16.0] days, P = 0.011) in the ITT analysis. Mortality, rates of persistent infections, recurrences, and rehospitalizations were not different., Conclusions: A PCT-pyuria-based algorithm reduced antibiotic exposure by 30% when compared to current guidelines without apparent negative effects on clinical outcomes.

The directionality of space-number association (SNA) is shaped by cultural experiences. It usually follows the culturally dominant reading direction. Smaller numbers are generally associated with the starting side for reading (left side in Western cultures), while larger numbers are associated with the right endpoint side. However, SNAs consistent with cultural reading directions are present before children can actually read and write. Therefore, these SNAs cannot only be shaped by the direction of children's own reading/writing behavior. We propose six distinct processes - one biological and five cultural/educational - underlying directional SNAs before formal reading acquisition: (i) Brain lateralization, (ii) Monitoring adult reading behavior, (iii) Pretend reading and writing, and rudimentary reading and writing skills, (iv) Dominant attentional directional preferences in a society, not directly related to reading direction, (v) Direct spatial-numerical learning, (vi) Other spatial-directional processes independent of reading direction. In this mini-review, we will differentiate between these processes, elaborate when in development they might emerge, discuss how they may create the SNAs observed in preliterate children and propose how they can be studied in the future.

Recently we reported that spoken stressed and unstressed primes differently modulate Event Related Potentials (ERPs) of spoken initially stressed targets. ERP stress priming was independent of prime-target phoneme overlap. Here we test whether phoneme-free ERP stress priming involves the lexicon. We used German target words with the same onset phonemes but different onset stress, such as MANdel ("almond") and manDAT ("mandate"; capital letters indicate stress). First syllables of those words served as primes. We orthogonally varied prime-target overlap in stress and phonemes. ERP stress priming did neither interact with phoneme priming nor with the stress pattern of the targets. However, polarity of ERP stress priming was reversed to that previously obtained. The present results are evidence for phoneme-free prosodic processing at the lexical level. Together with the previous results they reveal that phoneme-free prosodic representations at the pre-lexical and lexical level are recruited by neurobiological spoken word recognition., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Using word onset priming with early learned words, we tracked access to phonological representations and predictive phonological processing at 6, 12, 18, and 24 months after birth. Event-Related Potentials (ERPs) were recorded while participants heard German word onsets (primes) followed by disyllabic spoken words (targets). Primes and target onsets were either congruent or incongruent (ma - Mama vs. so - Mama [Engl. 'mommy']). For an adult control group, ERP differences were found for the N100 complex, which has been related to abstract auditory analysis; and for the P350 deflection, which has been related to lexical access. A combined analysis of all infants and young children revealed an immature instance of an N100 effect, suggesting adult-like abstract speech sound processing. A central negativity effect, which had formerly been obtained when adults or older children were engaged in a lexical decision task, suggests that adult-like predictive phonological processing is available early in infancy. However, the absence of a P350-like effect in the infant data suggests that adult-like access to phonological forms is not established in the first two years of life. Taken together, ERPs recorded in word onset priming proved useful in investigating early phonological processing without an explicit behavioral measure., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Speech is characterized by phonemes and prosody. Neurocognitive evidence supports the separate processing of each type of information. Therefore, one might suggest individual development of both pathways. In this study, we examine literacy acquisition in middle childhood. Children become aware of the phonemes in speech at that time and refine phoneme processing when they acquire an alphabetic writing system. We test whether an enhanced sensitivity to phonemes in middle childhood extends to other aspects of the speech signal, such as prosody. To investigate prosodic processing, we used stress priming. Spoken stressed and unstressed syllables (primes) preceded spoken German words with stress on the first syllable (targets). We orthogonally varied stress overlap and phoneme overlap between the primes and onsets of the targets. Lexical decisions and Event-Related Potentials (ERPs) for the targets were obtained for pre-reading preschoolers, reading pupils and adults. The behavioral and ERP results were largely comparable across all groups. The fastest responses were observed when the first syllable of the target word shared stress and phonemes with the preceding prime. ERP stress priming and ERP phoneme priming started 200 ms after the target word onset. Bilateral ERP stress priming was characterized by enhanced ERP amplitudes for stress overlap. Left-lateralized ERP phoneme priming replicates previously observed reduced ERP amplitudes for phoneme overlap. Groups differed in the strength of the behavioral phoneme priming and in the late ERP phoneme priming effect. The present results show that enhanced phonological processing in middle childhood is restricted to phonemes and does not extend to prosody. These results are indicative of two parallel processing systems for phonemes and prosody that might follow different developmental trajectories in middle childhood as a function of alphabetic literacy.

Background: An intervention trial found a trend for shorter length of stay (LOS) in patients with community-acquired pneumonia (CAP) when the CURB65 score was combined with the prognostic biomarker proadrenomedullin (ProADM) (CURB65-A). However, the efficacy and safety of CURB65-A in real life situations remains unclear., Methods: From September, 2011, until April, 2012, we performed a post-study prospective observational quality control survey at the cantonal Hospital of Aarau, Switzerland of consecutive adults with CAP. The primary endpoint was length of stay (LOS) during the index hospitalization and within 30 days. We compared the results with two well-defined historic cohorts of CAP patients hospitalized in the same hospital with the use of multivariate regression, namely 83 patients in the observation study without ProADM (OPTIMA I) and the 169 patients in the intervention study (OPTIMA II RCT)., Results: A total of 89 patients with confirmed CAP were included. As compared to patients with CURB65 only observed in the OPTIMA I study, adjusted regression analysis showed a significant shorter initial LOS (7.5 vs. 10.4 days; -2.32; 95% CI, -4.51 to -0.13; p = 0.04) when CURB65-A was used in clinical routine. No significant differences were found for LOS within 30 days. There were no significant differences in safety outcomes in regard to mortality and ICU admission between the cohorts., Conclusion: This post-study survey provides evidence that the use of ProADM in combination with CURB65 (CURB65-A) in "real life" situations reduces initial LOS compared to the CURB65 score alone without apparent negative effects on patient safety.

Concerns about inadequate performance and complexity limit routine use of clinical risk scores in lower respiratory tract infections. Our aim was to study feasibility and effects of adding the biomarker proadrenomedullin (proADM) to the confusion, urea>7 mmol·L(-1), respiratory rate≥30 breaths·min(-1), blood pressure<90 mmHg (systolic) or ≤60 mmHg (diastolic), age≥65 years (CURB-65) score on triage decisions and length of stay. In a randomised controlled proof-of-concept intervention trial, triage and discharge decisions were made for adults with lower respiratory tract infection according to interprofessional assessment using medical and nursing risk scores either without (control group) or with (proADM group) knowledge of proADM values, measured on admission, and on days 3 and 6. An adjusted generalised linear model was calculated to investigate the effect of our intervention. On initial presentation the algorithms were overruled in 123 (39.3%) of the cases. Mean length of stay tended to be shorter in the proADM (n=154, 6.3 days) compared with the control group (n=159, 6.8 days; adjusted regression coefficient -0.19, 95% CI -0.41-0.04; p=0.1). This trend was robust in subgroup analyses and for overall length of stay within 90 days (7.2 versus 7.9 days; adjusted regression coefficient -0.18, 95% CI -0.40-0.05; p=0.13). There were no differences in adverse outcomes or readmission. Logistic obstacles and overruling are major challenges to implement biomarker-enhanced algorithms in clinical settings and need to be addressed to shorten length of stay.

Objectives: Current guidelines provide limited evidence as to which patients with urinary tract infection (UTI) require hospitalisation. We evaluated the currently used triage routine and tested whether a set of criteria including biomarkers like proadrenomedullin (proADM) and urea have the potential to improve triage decisions., Methods: Consecutive adults with UTI presenting to our emergency department (ED) were recruited and followed for 30 days. We defined three virtual triage algorithms, which included either guideline-based clinical criteria, optimised admission proADM or urea levels in addition to a set of clinical criteria. We compared actual treatment sites and observed adverse events based on the physician judgment with the proportion of patients assigned to treatment sites according to the three virtual algorithms. Adverse outcome was defined as transfer to the intensive care unit (ICU), death, recurrence of UTI or rehospitalisation for any reason., Results: We recruited 127 patients (age 61.8 ± 20.8 years; 73.2 % females) and analysed the data of 123 patients with a final diagnosis of UTI. Of these 123 patients, 27 (22.0 %) were treated as outpatients. Virtual triage based only on clinical signs would have treated only 22 (17.9 %) patients as outpatients, with higher proportions of outpatients equally in both biomarker groups (29.3 %; p = 0.02). There were no significant differences in adverse events between outpatients according to the clinical (4.5 %), proADM (2.8 %) or urea groups (2.8 %). The mean length of stay was 6.6 days, including 2.2 days after reaching medical stability., Conclusions: Adding biomarkers to clinical criteria has the potential to improve risk-based triage without impairing safety. Current rates of admission and length of stay could be shortened in patients with UTI.

Background: Patients presenting to the emergency department (ED) currently face inacceptable delays in initial treatment, and long, costly hospital stays due to suboptimal initial triage and site-of-care decisions. Accurate ED triage should focus not only on initial treatment priority, but also on prediction of medical risk and nursing needs to improve site-of-care decisions and to simplify early discharge management. Different triage scores have been proposed, such as the Manchester triage system (MTS). Yet, these scores focus only on treatment priority, have suboptimal performance and lack validation in the Swiss health care system. Because the MTS will be introduced into clinical routine at the Kantonsspital Aarau, we propose a large prospective cohort study to optimize initial patient triage. Specifically, the aim of this trial is to derive a three-part triage algorithm to better predict (a) treatment priority; (b) medical risk and thus need for in-hospital treatment; (c) post-acute care needs of patients at the most proximal time point of ED admission., Methods/design: Prospective, observational, multicenter, multi-national cohort study. We will include all consecutive medical patients seeking ED care into this observational registry. There will be no exclusions except for non-adult and non-medical patients. Vital signs will be recorded and left over blood samples will be stored for later batch analysis of blood markers. Upon ED admission, the post-acute care discharge score (PACD) will be recorded. Attending ED physicians will adjudicate triage priority based on all available results at the time of ED discharge to the medical ward. Patients will be reassessed daily during the hospital course for medical stability and readiness for discharge from the nurses and if involved social workers perspective. To assess outcomes, data from electronic medical records will be used and all patients will be contacted 30 days after hospital admission to assess vital and functional status, re-hospitalization, satisfaction with care and quality of life measures. We aim to include between 5000 and 7000 patients over one year of recruitment to derive the three-part triage algorithm. The respective main endpoints were defined as (a) initial triage priority (high vs. low priority) adjudicated by the attending ED physician at ED discharge, (b) adverse 30 day outcome (death or intensive care unit admission) within 30 days following ED admission to assess patients risk and thus need for in-hospital treatment and (c) post acute care needs after hospital discharge, defined as transfer of patients to a post-acute care institution, for early recognition and planning of post-acute care needs. Other outcomes are time to first physician contact, time to initiation of adequate medical therapy, time to social worker involvement, length of hospital stay, reasons for discharge delays, patient's satisfaction with care, overall hospital costs and patients care needs after returning home., Discussion: Using a reliable initial triage system for estimating initial treatment priority, need for in-hospital treatment and post-acute care needs is an innovative and persuasive approach for a more targeted and efficient management of medical patients in the ED. The proposed interdisciplinary , multi-national project has unprecedented potential to improve initial triage decisions and optimize resource allocation to the sickest patients from admission to discharge. The algorithms derived in this study will be compared in a later randomized controlled trial against a usual care control group in terms of resource use, length of hospital stay, overall costs and patient's outcomes in terms of mortality, re-hospitalization, quality of life and satisfaction with care., Trial Registration: ClinicalTrials.gov Identifier, NCT01768494.

Background: Urinary tract infections (UTIs) are among the most common infectious diseases and drivers of antibiotic use and in-hospital days. A reduction of antibiotic use potentially lowers the risk of antibiotic resistance. An early and adequate risk assessment combining medical, biopsychosocial and functional risk scores has the potential to optimize site-of-care decisions and thus allocation of limited health-care resources. The aim of this factorial design study is twofold: first, for Intervention A, it investigates antibiotic exposure of patients treated with a protocol based on the type of UTI, procalcitonin (PCT) and pyuria. Second, for Intervention B, it investigates the usefulness of the prognostic biomarker proadrenomedullin (ProADM) integrated into an interdisciplinary assessment bundle for site-of-care decisions., Methods and Design: This randomized controlled open-label trial has a factorial design (2 × 2). Randomization of patients will be based on a pre-specified computer-generated randomization list and independent for the two interventions. Adults with UTI presenting to the emergency department (ED) will be screened and enrolled after providing informed consent. For our first Intervention (A), we developed a protocol based on previous observational research to recommend initiation and duration of antibiotic use based on the clinical presentation of UTI, pyuria and PCT levels. For our second intervention (B), an algorithm was developed to support site-of care decisions based on the prognostic marker ProADM and distinct nursing factors on days 1 and 3. Both interventions will be compared with a control group conforming to the guidelines. The primary endpoints for the two interventions will be: (A) overall exposure to antibiotics and (B) length of physician-led hospitalization within a follow-up of 30 days. Endpoints are assessed at discharge from hospital, and 30 and 90 days after admission. We plan to screen 300 patients and enroll 250 for an anticipated estimated loss of follow-up of 20%. This will provide adequate power for the two interventions., Discussion: This trial investigates two strategies for improved individualized medical care in patients with UTI. The minimally effective duration of antibiotic therapy is not known for UTIs, which is important for reducing the selection pressure for antibiotic resistance, costs and drug-related side effects. Triage decisions must be improved to reflect the true medical, biopsychosocial and functional risks in order to allocate patients to the most appropriate care setting and reduce hospital-acquired disability., Trial Registration Number: ISRCTN13663741.

Procalcitonin (PCT)-guided antibiotic stewardship is a successful strategy to decrease antibiotic use. We assessed if clinical judgement affected compliance with a PCT-algorithm for antibiotic prescribing in a multicenter surveillance of patients with lower respiratory tract infections (LRTI). Initiation and duration of antibiotic therapy, adherence to a PCT algorithm and outcome were monitored in consecutive adults with LRTI who were enrolled in a prospective observational quality control. We correlated initial clinical judgment of the treating physician with algorithm compliance and assessed the influence of PCT on the final decision to initiate antibiotic therapy. PCT levels correlated with physicians' estimates of the likelihood of bacterial infection (p for trend <0.02). PCT influenced the post-test probability of antibiotic initiation with a greater effect in patients with non-pneumonia LRTI (e.g., for bronchitis: -23 % if PCT ≤ 0.25 μg/L and +31 % if PCT > 0.25 μg/L), in European centers (e.g., in France -22 % if PCT ≤ 0.25 μg/L and +13 % if PCT > 0.25 μg/L) and in centers, which had previous experience with the PCT-algorithm (-16 % if PCT ≤ 0.25 μg/L and +19 % if PCT > 0.25 μg/L). Algorithm non-compliance, i.e. antibiotic prescribing despite low PCT-levels, was independently predicted by the likelihood of a bacterial infection as judged by the treating physician. Compliance was significantly associated with identification of a bacterial etiology (p = 0.01). Compliance with PCT-guided antibiotic stewardship was affected by geographically and culturally-influenced subjective clinical judgment. Initiation of antibiotic therapy was altered by PCT levels. Differential compliance with antibiotic stewardship efforts contributes to geographical differences in antibiotic prescribing habits and potentially influences antibiotic resistance rates.

Background: Acute decompensated heart failure (ADHF) causes a substantial burden for health care systems. Data to rationally define the need for hospitalization or the appropriate length of stay (LOS) is limited. Our aim was to personalize length of stay in patients admitted to hospital for acute decompensated heart failure., Methods: Consecutive patients with ADHF presenting to our emergency department were prospectively followed. We daily conducted a multidisciplinary risk assessment and compared proposed with actually observed triage decisions., Results: At presentation, all patients required hospitalization. Median LOS was 11 days including 1 day after reaching medical stability. In 42.7% of patients, hospitalization was prolonged after medical stability mainly for nursing and organizational reasons. Within 30 days of enrollment, 7 (9.3%) patients were rehospitalized, 3 of them for persisting or relapsing heart failure., Conclusions: There appears to be potential to shorten inhospital stay in patients with ADHF mainly by providing post discharge ambulatory nursing care in order to improve resource utilization and to diminish "hospitalization-associated disability".

Background: In controlled studies, procalcitonin (PCT) has safely and effectively reduced antibiotic drug use for lower respiratory tract infections (LRTIs). However, controlled trial data may not reflect real life., Methods: We performed an observational quality surveillance in 14 centers in Switzerland, France, and the United States. Consecutive adults with LRTI presenting to emergency departments or outpatient offices were enrolled and registered on a website, which provided a previously published PCT algorithm for antibiotic guidance. The primary end point was duration of antibiotic therapy within 30 days., Results: Of 1759 patients, 86.4% had a final diagnosis of LRTI (community-acquired pneumonia, 53.7%; acute exacerbation of chronic obstructive pulmonary disease, 17.1%; and bronchitis, 14.4%). Algorithm compliance overall was 68.2%, with differences between diagnoses (bronchitis, 81.0%; AECOPD, 70.1%; and community-acquired pneumonia, 63.7%; P < .001), outpatients (86.1%) and inpatients (65.9%) (P < .001), algorithm-experienced (82.5%) and algorithm-naive (60.1%) centers (P < .001), and countries (Switzerland, 75.8%; France, 73.5%; and the United States, 33.5%; P < .001). After multivariate adjustment, antibiotic therapy duration was significantly shorter if the PCT algorithm was followed compared with when it was overruled (5.9 vs 7.4 days; difference, -1.51 days; 95% CI, -2.04 to -0.98; P < .001). No increase was noted in the risk of the combined adverse outcome end point within 30 days of follow-up when the PCT algorithm was followed regarding withholding antibiotics on hospital admission (adjusted odds ratio, 0.83; 95% CI, 0.44 to 1.55; P = .56) and regarding early cessation of antibiotics (adjusted odds ratio, 0.61; 95% CI, 0.36 to 1.04; P = .07)., Conclusions: This study validates previous results from controlled trials in real-life conditions and demonstrates that following a PCT algorithm effectively reduces antibiotic use without increasing the risk of complications. Preexisting differences in antibiotic prescribing affect compliance with antibiotic stewardship efforts., Trial Registration: isrctn.org Identifier: ISRCTN40854211.

It has been demonstrated that written and spoken language processing are tightly linked. Here we focus on the development of this relationship at the time children start reading and writing. We hypothesize that the newly acquired knowledge about graphemes shapes lexical access in neural spoken word recognition. A group of preliterate children (six years old) and two groups of beginning readers (six and eight years old) were tested in a spoken word identification task. Using word onset priming we compared behavioural and neural facilitation for target words in identical prime-target pairs (e.g., mon-monster) and in prime target pairs that varied in the first speech sound (e.g., non-monster, Variation condition). In both groups of beginning readers priming was less effective in the Variation condition than in the Identity condition. This was indexed by less behavioural facilitation and enhanced P350 amplitudes in the event related potentials (ERPs). In the group of preliterate children, by contrast, both conditions did not differ. Together these results reveal that lexical access in beginning readers is based on more acoustic detail than lexical access in preliterate children. The results are discussed in the light of bidirectional speech and print interactions in readers., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: Despite recommendations for outpatient management, low risk patients with lower respiratory tract infections (LRTIs) are often hospitalized. This survey analyzed perceptions of physicians, nurses, patients and relatives about feasibility of outpatient management and required duration of hospital stay., Methods: We performed a prospective, observational questionnaire survey in hospitalized patients with LRTI as part of a multicenter trial. Treating physicians and nurses, patients and their relatives were asked on admission and before discharge about feasibility of outpatient treatment over 5 dimensions (medical, nursing, organizational factors, and patients' and relatives' preferences) using continuous scales., Results: On admission, 12.6% of physicians, 15.1% of nurses, 18.0% of patients and 5.2% of relatives believed that outpatient treatment would be possible. Before hospital discharge, 31.1% of physicians, 32.2% of nurses, 11.6% of patients and 4.1% of relatives thought that earlier discharge would have been feasible. Medical factors were the most frequently perceived motives for inpatient management. These perceptions were similar in all LRTI subgroups and independent of disease severity and associated expected mortality risks as assessed by the Pneumonia Severity Index (PSI)., Conclusion: Independent of type and severity of respiratory tract infection, the misperceived high severity and expected mortality and morbidity were the predominant reasons why treating physicians, nurses, patients and their relatives unanimously believed that inpatient management was necessary. Better assessment and communication about true expected medical risks might contribute to a pathway to shorten in-hospital days and to introduce a more risk-targeted and individually tailored allocation of health-care resources., Trial Registration: NCT00350987.

Introduction: Measurement of prohormones representing different pathophysiological pathways could enhance risk stratification in patients with community-acquired pneumonia (CAP) and other lower respiratory tract infections (LRTI)., Methods: We assessed clinical parameters and five biomarkers, the precursor levels of adrenomedullin (ADM), endothelin-1 (ET1), atrial-natriuretic peptide (ANP), anti-diuretic hormone (copeptin), and procalcitonin in patients with LRTI and CAP enrolled in the multicenter ProHOSP study. We compared the prognostic accuracy of these biomarkers with the pneumonia severity index (PSI) and CURB65 (Confusion, Urea, Respiratory rate, Blood pressure, Age 65) score to predict serious complications defined as death, ICU admission and disease-specific complications using receiver operating curves (ROC) and reclassification methods., Results: During the 30 days of follow-up, 134 serious complications occurred in 925 (14.5%) patients with CAP. Both PSI and CURB65 overestimated the observed mortality (X2 goodness of fit test: P = 0.003 and 0.01). ProADM or proET1 alone had stronger discriminatory powers than the PSI or CURB65 score or any of either score components to predict serious complications. Adding proADM alone (or all five biomarkers jointly) to the PSI and CURB65 scores, significantly increased the area under the curve (AUC) for PSI from 0.69 to 0.75, and for CURB65 from 0.66 to 0.73 (P < 0.001, for both scores). Reclassification methods also established highly significant improvement (P < 0.001) for models with biomarkers if clinical covariates were more flexibly adjusted for. The developed prediction models with biomarkers extrapolated well if evaluated in 434 patients with non-CAP LRTIs., Conclusions: Five biomarkers from distinct biologic pathways were strong and specific predictors for short-term adverse outcome and improved clinical risk scores in CAP and non-pneumonic LRTI. Intervention studies are warranted to show whether an improved risk prognostication with biomarkers translates into a better clinical management and superior allocation of health care resources., Trial Registration: NCT00350987.

Context: In previous smaller trials, a procalcitonin (PCT) algorithm reduced antibiotic use in patients with lower respiratory tract infections (LRTIs)., Objective: To examine whether a PCT algorithm can reduce antibiotic exposure without increasing the risk for serious adverse outcomes., Design, Setting, and Patients: A multicenter, noninferiority, randomized controlled trial in emergency departments of 6 tertiary care hospitals in Switzerland with an open intervention of 1359 patients with mostly severe LRTIs randomized between October 2006 and March 2008., Intervention: Patients were randomized to administration of antibiotics based on a PCT algorithm with predefined cutoff ranges for initiating or stopping antibiotics (PCT group) or according to standard guidelines (control group). Serum PCT was measured locally in each hospital and instructions were Web-based., Main Outcome Measures: Noninferiority of the composite adverse outcomes of death, intensive care unit admission, disease-specific complications, or recurrent infection requiring antibiotic treatment within 30 days, with a predefined noninferiority boundary of 7.5%; and antibiotic exposure and adverse effects from antibiotics., Results: The rate of overall adverse outcomes was similar in the PCT and control groups (15.4% [n = 103] vs 18.9% [n = 130]; difference, -3.5%; 95% CI, -7.6% to 0.4%). The mean duration of antibiotics exposure in the PCT vs control groups was lower in all patients (5.7 vs 8.7 days; relative change, -34.8%; 95% CI, -40.3% to -28.7%) and in the subgroups of patients with community-acquired pneumonia (n = 925, 7.2 vs 10.7 days; -32.4%; 95% CI, -37.6% to -26.9%), exacerbation of chronic obstructive pulmonary disease (n = 228, 2.5 vs 5.1 days; -50.4%; 95% CI, -64.0% to -34.0%), and acute bronchitis (n = 151, 1.0 vs 2.8 days; -65.0%; 95% CI, -84.7% to -37.5%). Antibiotic-associated adverse effects were less frequent in the PCT group (19.8% [n = 133] vs 28.1% [n = 193]; difference, -8.2%; 95% CI, -12.7% to -3.7%)., Conclusion: In patients with LRTIs, a strategy of PCT guidance compared with standard guidelines resulted in similar rates of adverse outcomes, as well as lower rates of antibiotic exposure and antibiotic-associated adverse effects., Trial Registration: isrctn.org Identifier: ISRCTN95122877.

Spoken word onset syllables (prime fragments) have been used to track neurophysiological processing of following written words (targets). Between 300 and 400 ms event-related potentials (ERPs) over the left hemisphere were more positive for targets that did not match their preceding prime fragments (e.g., hun-dragon) compared to matching targets (e.g., dra-dragon). This P350 effect has been related to the activation of modality independent neural word form representations. In the present experiment we set out to characterize neural word processing specific to the auditory domain. Spoken word onset syllables (prime fragments) were followed by spoken words (targets). Reduced amplitudes for matching targets were found for the N100 and the T-complex (100-300 ms), for the P350 (300-400 ms) and for a central negativity starting at 300 ms. The early potentials possibly index the priming of speech sound processing. The P350 replicates previous work with written words. This constitutes further evidence for shared neural word form representations in auditory and visual word recognition. The central negativity might be related to the rapid phonological matching of prime and target; or to the immediate testing of phonological expectations in speech recognition.

Background: Acute respiratory tract infections are the most common reason for antibiotic therapy in primary care despite their mainly viral etiology. A laboratory test measuring procalcitonin levels in blood specimens was suggested as a tool to reduce unnecessary prescribing of antibiotics. We consider whether antibiotic therapy guided by procalcitonin reduces the use of antibiotics without increasing the restrictions experienced by patients by more than 1 day., Methods: Fifty-three primary care physicians recruited 458 patients, each patient with an acute respiratory tract infection and, in the physician's opinion, in need of antibiotics. Patients were centrally randomized to either a procalcitonin-guided approach to antibiotic therapy or to a standard approach. For patients randomized to procalcitonin-guided therapy, the use of antibiotics was more or less strongly discouraged (procalcitonin level, < or =0.1 or < or =0.25 microg/L, respectively) or recommended (procalcitonin level, >0.25 microg/L). Follow-up data were collected at 7 days by treating physicians and at 14 and 28 days by blinded interviewers., Results: Adjusted for baseline characteristics, the mean increase at 14 days in days in which activities were restricted was 0.14 with procalcitonin-guided therapy (95% confidence interval [CI], -0.53 to 0.81 days), which met our criterion of an increase in days in which activities were restricted by no more than 1 day. With procalcitonin-guided therapy, the antibiotic prescription rate was 72% lower (95% CI, 66%-78%) than with standard therapy. Both approaches led to a similar proportion of patients reporting symptoms of ongoing or relapsing infection at 28 days (adjusted odds ratio, 1.0 [95% CI, 0.7-1.5])., Conclusions: As an adjunct to guidelines, procalcitonin-guided therapy markedly reduces antibiotic use for acute respiratory tract infections in primary care without compromising patient outcome. In practice, this could be achieved with 1 to 2 procalcitonin measurements in patients for whom the physician intends to prescribe antibiotics.

Background: As supra-physiological intake of corticosteroids is a well known risk factor for the development of adrenal insufficiency, we investigated the function of the hypothalamic-pituitary-adrenal (HPA) axis during a 14-day course of systemic corticosteroids in patients with acute exacerbation of chronic obstructive pulmonary disease using clinical and laboratory measures., Methods: A systematic clinical and laboratory assessment including measurement of basal cortisol levels and the response to low dose (1 mug) ACTH stimulation was performed in nine patients before, on the first and the last day of treatment, as well as 2, 7 and 21 days after corticosteroid withdrawal., Results: At baseline, all nine patients had normal responses to 1 mug ACTH. On the first day of steroid treatment, 78% had a blunted peak cortisol response. This percentage increased to 89% after 14 days of steroid treatment. 78%, 33% and 33% of the patients had a blunted cortisol response to ACTH 2, 7, and 21 days after corticosteroid withdrawal, respectively. ROC curve analysis revealed that only basal cortisol concentrations (AUC 0.89), but not ACTH concentrations (AUC 0.49) or clinical signs (AUC 0.47) were predictive of an impaired function of the HPA axis. Basal cortisol levels of > 400 and < 150 nmol/l were 96% and 100% sensitive for a normal or pathological response to the ACTH stimulation test, respectively., Conclusion: Immediate and prolonged suppression of the HPA axis is a common finding in otherwise asymptomatic patients undergoing systemic steroid treatment for acute exacerbation of chronic obstructive pulmonary disease and can reliably be assessed with the low-dose ACTH test.

Background: Lower respiratory tract infections like acute bronchitis, exacerbated chronic obstructive pulmonary disease and community-acquired pneumonia are often unnecessarily treated with antibiotics, mainly because of physicians' difficulties to distinguish viral from bacterial cause and to estimate disease-severity. The goal of this trial is to compare medical outcomes, use of antibiotics and hospital resources in a strategy based on enforced evidence-based guidelines versus procalcitonin guided antibiotic therapy in patients with lower respiratory tract infections., Methods and Design: We describe a prospective randomized controlled non-inferiority trial with an open intervention. We aim to randomize over a fixed recruitment period of 18 months a minimal number of 1002 patients from 6 hospitals in Switzerland. Patients must be >18 years of age with a lower respiratory tract infections <28 days of duration. Patients with no informed consent, not fluent in German, a previous hospital stay within 14 days, severe immunosuppression or chronic infection, intravenous drug use or a terminal condition are excluded. Randomization to either guidelines-enforced management or procalcitonin-guided antibiotic therapy is stratified by centre and type of lower respiratory tract infections. During hospitalization, all patients are reassessed at days 3, 5, 7 and at the day of discharge. After 30 and 180 days, structured phone interviews by blinded medical students are conducted. Depending on the randomization allocation, initiation and discontinuation of antibiotics is encouraged or discouraged based on evidence-based guidelines or procalcitonin cut off ranges, respectively. The primary endpoint is the risk of combined disease-specific failure after 30 days. Secondary outcomes are antibiotic exposure, side effects from antibiotics, rate and duration of hospitalization, time to clinical stability, disease activity scores and cost effectiveness. The study hypothesis is that procalcitonin-guidance is non-inferior (i.e., at worst a 7.5% higher combined failure rate) to the management with enforced guidelines, but is associated with a reduced total antibiotic use and length of hospital stay., Discussion: Use of and prolonged exposure to antibiotics in lower respiratory tract infections is high. The proposed trial investigates whether procalcitonin-guidance may safely reduce antibiotic consumption along with reductions in hospitalization costs and antibiotic resistance. It will additionally generate insights for improved prognostic assessment of patients with lower respiratory tract infections., Trial Registration: ISRCTN95122877.

The aim of the present study was to assess the in vivo error of the method as well as the effect of thresholding when obtaining and evaluating standardized periapical radiographs for computer-assisted densitometric image analysis (CADIA). Twenty healthy volunteers participated in an experimental gingivitis study in which neither mechanical nor chemical plaque control was performed for 21 days. Two pairs of standardized periapical radiographs were taken at days 0 (baseline) and 21 (follow-up), one from a maxillary area (15 volunteers) and one from a mandibular molar/premolar area (17 volunteers). Each baseline radiograph was digitized and its image displayed on a monitor. The follow-up radiograph was then superimposed and digitized as well. After gray level correction, subtraction radiographic images were produced. The difference in gray level between the baseline and the follow-up image was calculated within each region of interest (ROI) at each picture point (pixel). In bone ROI, changes in density reflected the amount of change due to methodological errors plus the basic bone remodeling over 3 weeks. For gingival ROI, changes in density reflected the methodological error plus a possible change in soft tissue density during the experimental gingivitis. Within all of the ROI, some pixels indicated a change in gray level. A change in gray level was then thresholded; i.e., only changes >5 and then >10 gray levels were registered and used for calculation of the CADIA values. With a threshold of 5, 44/45 maxillary bone ROI and 60/66 mandibular bone ROI showed a change in density, while 41/45 maxillary gingiva ROI and 26/66 mandibular gingiva ROI indicated a change in density. With a threshold of 10, 16/45 maxillary bone ROI and 12/66 mandibular bone ROI indicated a change in density, while 13/45 maxillary gingiva ROI and 1/66 mandibular gingiva ROI indicated a change. The amounts of changes in density calculated in the various ROI were low even when applying no threshold, ranging from -0.279 to 0.621. Applying a threshold of 5, the CADIA values ranged from -0.234 to 0.727. With a threshold of 10, the changes in density ranged from -0.318 to 0.133. In vivo, CADIA of standardized radiographs indicated change in density due to methodological errors. Application of thresholds may avoid false-positive diagnoses. When applying CADIA in clinical research, the range of change to be expected due to methodological limitations as well as the threshold for true change should be evaluated. These thresholds may differ in various areas of the mouth, i.e., bone or gingival, maxillary/mandibular, anterior/posterior ROI.

The aim of the present study was to evaluate the effects of a 1-month period of chlorhexidine (CHX) rinses on the periodontal conditions of teeth adjacent to extraction sockets. 40 patients signed consent forms for this double blind trial and were randomly assigned to either the test group rinsing 2 x daily with 15 ml of a 0.12% CHX solution (Peridex) starting 2 days after tooth extraction or the control group rinsing with a placebo solution for 30 days. Clinical periodontal parameters were obtained from test sites located adjacent to as well as matched controls distant to the extraction sites. The measurements were performed at baseline before the extraction and 1, 2, 3 and 6 months thereafter. During the observation period, the patients were exposed to initial periodontal therapy. The test sites of the group rinsing with CHX demonstrated significantly reduced (p < 0.05) plaque indices, gingival indices and lower %s of sites bleeding on probing one month following the extraction. The test sites of the control group rinsing with the placebo demonstrated a tendency for loss of clinical attachment between 1 and 2 months after the tooth extraction. The mean pocket probing depth (PPD) at test sites of the CHX rinsing group was smaller than in the placebo rinsing group at the one month examination. Also, the mean PPD of the test sites in the CHX group was significantly smaller than at the control sites at 1 month. This difference was not observed in the control group rinsing with placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Receptors for the Fc portion of immunoglobulin E (IgE; CD23) can be detected on the surface of alveolar macrophages (AM) in extrinsic allergic alveolitis (EAA), using monoclonal antibodies in immunocytology. More than 50% of AM were positive in 16 of the 20 patients reported here, while the remaining 4 had 11-47% positive cells. Staining with anti-IgE antibody can, in addition, demonstrate endogenous IgE bound to the AM. This suggests that IgE might be involved in the process. Since IgE-mediated asthma is associated with bronchoconstriction, we asked whether EAA patients do in fact exhibit an obstructive component. In 3 out of 10 patients we did indeed find clearly increased airway resistance (greater than 30 kPa x s x l-1). These findings are consistent with the observation of immediate bronchoconstriction observed in some patients upon allergen challenge. Since only 1 of the 20 patients studied was a smoker, and since in the literature the majority of reported cases of EAA are in nonsmokers, we speculate that smoking may interfere with immunological processes leading to EAA.