Search

Background and purpose Recent research has highlighted non-operative management (NOM) as a viable alternative for frail older adults with hip fractures in the final phase of life. This study aims to guide Dutch physicians and hospitals nationwide in a standardised implementation of shared decision-making regarding surgery or NOM in selected frail older adults with a hip fracture.Methods and analysis The patient population for implementation includes frail older adults aged ≥70 years with an acute proximal femoral fracture, nursing home care or a similar level of care elsewhere and at least one additional criterion (ie, malnutrition, severe mobility impairment or ASA≥4). The 2-year implementation study will be conducted in four phases. In phases 1 and 2, barriers and facilitators for implementation will be identified and an implementation protocol, educational materials and patient information will be developed. Phase 3 will involve an implementation pilot in 14 hospitals across the Netherlands. The protocol and educational material will be improved based on healthcare provider and patient experiences gathered through interviews. Phase 4 will focus on upscaling to nationwide implementation and the effect of the implementation on NOM rate will be measured using data from the Dutch Hip Fracture Audit.Ethics and dissemination The study was exempted by the local Medical Research Ethics Committee (MEC-2023-0270, 10 May 2023) and Medical Ethics Committee United (W23.083, 26 April 2023). The study’s results will be submitted to an open access international peer-reviewed journal. Its protocols, tools and results will be presented at several national and international academic conferences of relevant orthogeriatric (scientific) associations.Trial registration number NCT06079905.

Abstract Background To evaluate the effects of a shared decision making (SDM) intervention for older adults with multiple chronic conditions (MCCs). Methods A pragmatic trial evaluated the effects of the SDMMCC intervention, existing of SDM training for nine geriatricians in two hospitals and a preparatory tool for patients. A prospective pre-intervention post-intervention multi-center clinical study was conducted in which an usual care group of older patients with MCC and their informal caregivers was included before the implementation of the intervention and a new cohort of patients and informal caregivers after the implementation of the intervention. SDM was observed using the OPTIONMCC during video-recorded consultations. Patient- and caregivers reported outcomes regarding their role in SDM, involvement, perceived SDM and decisional conflict were measured. The differences between groups regarding the level of observed SDM (OPTIONMCC) were analyzed with a mixed model analysis. Dichotomous patient-reported outcomes were analyzed with a logistic mixed model. Results From two outpatient geriatric clinics 216 patients with MCCs participated. The mean age was 77.3 years, and 56.3% of patients were female. No significant difference was found in the overall level of SDM as measured with the OPTIONMCC or in patient-reported outcomes. However, at item level the items discussing ‘goals’, ‘options’, and ‘decision making’ significantly improved after the intervention. The items discussing ‘partnership’ and ‘evaluating the decision-making process’ showed a significant decrease. Fifty-two percent of the patients completed the preparatory tool, but the results were only discussed in 12% of the consultations. Conclusion This study provides scope for improvement of SDM in geriatrics. Engaging older adults with MCCs and informal caregivers in the decision making process should be an essential part of SDM training for geriatricians, beyond the SDM steps of explaining options, benefits and harms. More attention should be paid to the integration of preparatory work in the consultation.

Abstract Many individuals with muscular dystrophies remain genetically undiagnosed despite clinical diagnostic testing, including exome sequencing. Some may harbor previously undetected structural variants (SVs) or cryptic splice sites. We enrolled 10 unrelated families: nine had muscular dystrophy but lacked complete genetic diagnoses and one had an asymptomatic DMD duplication. Nanopore genomic long‐read sequencing identified previously undetected pathogenic variants in four individuals: an SV in DMD, an SV in LAMA2, and two single nucleotide variants in DMD that alter splicing. The DMD duplication in the asymptomatic individual was in tandem. Nanopore sequencing may help streamline genetic diagnostic approaches for muscular dystrophy.

Herpesviruses are enveloped and have an amorphous protein layer surrounding the capsid, which is termed the tegument. Tegument proteins perform critical functions throughout the viral life cycle. This review provides a comprehensive and comparative analysis of the roles of specific tegument proteins in capsid transport and virion morphogenesis of selected, well-studied prototypes of each of the three subfamilies of Herpesviridae i.e., human herpesvirus-1/herpes simplex virus-1 (Alphaherpesvirinae), human herpesvirus-5/cytomegalovirus (Betaherpesvirinae) and human herpesvirus -8/Kaposi’s sarcomavirus (Gammaherpesvirinae). Most of the current knowledge is based on alpha herpesviruses, in particular HSV-1. While some tegument proteins are released into the cytoplasm after virus entry, several tegument proteins remain associated with the capsid and are responsible for transport to and docking at the nucleus. After replication and capsid formation, the capsid is enveloped at the nuclear membrane, which is referred to as primary envelopment, followed by de-envelopment and release into the cytoplasm. This requires involvement of at least three tegument proteins. Subsequently, multiple interactions between tegument proteins and capsid proteins, other tegument proteins and glycoproteins are required for assembly of the virus particles and envelopment at the Golgi, with certain tegument proteins acting as the central hub for these interactions. Some redundancy in these interactions ensures appropriate morphogenesis.

This paper compares different low-cost sensors that can measure (5G) RF-EMF exposure. The sensors are either commercially available (off-the-shelf Software Defined Radio (SDR) Adalm Pluto) or constructed by a research institution (i.e., imec-WAVES, Ghent University and Smart Sensor Systems research group (S³R), The Hague University of Applied Sciences). Both in-lab (GTEM cell) and in-situ measurements have been performed for this comparison. The in-lab measurements tested the linearity and sensitivity, which can then be used to calibrate the sensors. The in-situ testing confirmed that the low-cost hardware sensors and SDR can be used to assess the RF-EMF radiation. The variability between the sensors was 1.78 dB on average, with a maximum deviation of 5.26 dB. Values between 0.09 V/m and 2.44 V/m were obtained at a distance of about 50 m from the base station. These devices can be used to provide the general public and governments with temporal and spatial 5G electromagnetic field values.

Abstract Background The aim of this study was to describe barriers and facilitators for shared decision making (SDM) as experienced by older patients with multiple chronic conditions (MCCs), informal caregivers and health professionals. Methods A structured literature search was conducted with 5 databases. Two reviewers independently assessed studies for eligibility and performed a quality assessment. The results from the included studies were summarized using a predefined taxonomy. Results Our search yielded 3838 articles. Twenty-eight studies, listing 149 perceived barriers and 67 perceived facilitators for SDM, were included. Due to poor health and cognitive and/or physical impairments, older patients with MCCs participate less in SDM. Poor interpersonal skills of health professionals are perceived as hampering SDM, as do organizational barriers, such as pressure for time and high turnover of patients. However, among older patients with MCCs, SDM could be facilitated when patients share information about personal values, priorities and preferences, as well as information about quality of life and functional status. Informal caregivers may facilitate SDM by assisting patients with decision support, although informal caregivers can also complicate the SDM process, for example, when they have different views on treatment or the patient’s capability to be involved. Coordination of care when multiple health professionals are involved is perceived as important. Conclusions Although poor health is perceived as a barrier to participate in SDM, the personal experience of living with MCCs is considered valuable input in SDM. An explicit invitation to participate in SDM is important to older adults. Health professionals need a supporting organizational context and good communication skills to devise an individualized approach for patient care.

Background In order to provide the best care, the perspective of older COVID-19 patients must be involved in the development of treatment protocols. This study describes the experiences of older adults affected by COVID-19 who recovered in the hospital or at home. Methods Qualitative semi-structured interviews were conducted with 23 older adults affected by COVID-19. A content-based thematic analysis was conducted. Results Nine categories were identified as recurring topics, which were grouped into three major themes. The first theme describes experiences in the first phase of the disease when older adults fell ill. The second theme includes experiences during the illness, ranging from illness severity to participation in decision-making, communication barriers and isolation effects. The final theme covers the recovery course, residual symptoms and social aspects. Conclusion Older adults treated for COVID-19 experienced a feeling of being in a fast-paced whirlwind and lost total control over the situation. Extra attention should be paid to shared decision making, coordinated information provision and the instalment of a primary contract to the patient. The uncertainty of their situation, isolation measures and fears could result in psychological consequences and hinder rehabilitation in older adults.

Abstract Background Shared decision making (SDM) contributes to personalized decisions that fit the personal preferences of patients when choosing a treatment for a condition. However, older adults frequently face multiple chronic conditions (MCC). Therefore, implementing SDM requires special features. The aim of this paper is to describe the development of an intervention to improve SDM in older adults with MCC. Methods Following the Medical Research Council framework for developing complex interventions, the SDMMCC intervention was developed step-wise. Based on a literature review and empirical research in a co-creation process with end users, we developed training for geriatricians and a preparatory tool for older patients with MCC and informal caregivers. After assessing feasibility, the intervention was implemented in a pilot study (N = 108) in two outpatient geriatric clinics of an academic and a non-academic teaching hospital in Amsterdam, the Netherlands. Results Key elements of the training for geriatricians include developing skills to involve older adults with MCC and informal caregivers in SDM and following the six-step ‘Dynamic model for SDM with frail older patients’, as well as learning how to explore personal goals related to quality of life and how to form a partnership with the patient and the informal caregiver. Key elements of the preparatory tool for patients include an explicit invitation to participate in SDM, nomination that the patient’s own knowledge is valuable, invitation to form a partnership with the geriatrician, encouragement to share information about daily and social functioning and exploration of possible goals. Furthermore, the invitation of informal caregivers to share their concerns was also a key element. Conclusions Through a process of co-creation, both training for geriatricians and a preparatory tool for older adults and their informal caregivers were developed, tailored to the needs of the end users and based on the ‘Dynamic model of SDM with frail older patients’.

VP8, the most abundant tegument protein of bovine herpesvirus-1 (BoHV-1), plays an important role in viral replication. According to our previous studies, VP8 localizes to the Golgi apparatus of BoHV-1-infected cells where it can be packaged into the virus; however, Golgi localization of VP8 does not occur outside of the context of infection. The goal of this study was to identify the viral factor(s) involved in the tropism of VP8 towards the Golgi. VP8 was found to interact with glycoprotein M (gM), and the VP8 and gM domains that are essential for this interaction were identified. VP8 and gM colocalized to the Golgi apparatus in BoHV-1-infected cells. In cells co-transfected with VP8- and gM-encoding plasmids, VP8 was also found to be localized to the Golgi, suggesting gM to be sufficient. The localization of VP8 to the Golgi was lost in cells infected with a gM deletion mutant, and the amount of VP8 incorporated into mature virus was significantly reduced. However, with the restoration of gM in a revertant virus, the localization to the Golgi and the amount of VP8 incorporated in the virions were restored. These results indicate that gM plays a critical role in VP8 subcellular localization to the Golgi and packaging into mature virions.

Introduction: Adjuvants form an integral component in most of the inactivated and subunit vaccine formulations. Careful and proper selection of adjuvants helps in promoting appropriate immune responses against target pathogens at both innate and adaptive levels such that protective immunity can be elicited. Areas covered: Herein, we describe the recent progress in our understanding of the mode of action of adjuvants that are licensed for use in human vaccines or in clinical or pre-clinical stages at both innate and adaptive levels. Different pathogens have distinct characteristics, which require the host to mount an appropriate immune response against them. Adjuvants can be selected to elicit a tailor-made immune response to specific pathogens based on their unique properties. Identification of biomarkers of adjuvanticity for several candidate vaccines using omics-based technologies can unravel the mechanism of action of modern and experimental adjuvants. Expert opinion: Adjuvant technology has been revolutionized over the last two decades. In-depth understanding of the role of adjuvants in activating the innate immune system, combined with systems vaccinology approaches, have led to the development of next-generation, novel adjuvants that can be used in vaccines against challenging pathogens and in specific target populations.

Respiratory syncytial virus (RSV) is the most common cause of respiratory tract infections in both children and elderly people. In this study we evaluated the short- and long-term protective efficacy of a single intranasal (IN) immunization with a RSV vaccine formulation consisting of a codon-optimized fusion (F) protein formulated with poly(I:C), an innate defense regulator peptide and a polyphosphazene (ΔF/TriAdj). This vaccine induced strong systemic and local immune responses, including RSV F-specific IgG1 and IgG2a, SIgA and virus neutralizing antibodies in mice. Furthermore, ΔF/TriAdj promoted production of IFN-γ-secreting T cells and RSV F85–93-specific CD8+ effector T cells. After RSV challenge, no virus was recovered from the lungs of the vaccinated mice. To evaluate the duration of immunity induced by a single IN vaccination, mice were again immunized once with ΔF/TriAdj and challenged with RSV five months later. High levels of IgG1, IgG2a and virus neutralizing antibodies were detected in the ΔF/TriAdj-vaccinated animals. Moreover, this vaccine formulation induced robust local SIgA production and IgA-secreting memory B cell development, and conferred complete protection against subsequent RSV challenge. In conclusion, a single IN vaccination with RSV ΔF protein formulated with TriAdj induced robust, long-term protective immune responses against RSV infection.

Bovine herpesvirus-1 (BoHV-1) is a major cause of rhinotracheitis and vulvovaginitis in cattle. VP8, the major tegument protein of BoHV-1, is essential for viral replication in the host. VP8 is phosphorylated by the viral kinase US3, mediating its translocation to the cytoplasm. VP8 remains nuclear when not phosphorylated. Interestingly, VP8 has a significant presence in mature BoHV-1YmVP8, in which the VP8 phosphorylation sites are mutated. This suggests that VP8 might be packaged during primary envelopment of BoHV-1. This was investigated by mass spectrometry and Western blotting, which showed VP8, as well as VP22, to be constituents of the primary enveloped virions. VP8 and VP22 were shown to interact via co-immunoprecipitation experiments, in both BoHV-1-infected and VP8-transfected cells. VP8 and VP22 also co-localised with one another and with nuclear lamin-associated protein 2 in BoHV-1-infected cells, suggesting an interaction between VP8 and VP22 in the perinuclear region. In cells infected with VP22-deleted BoHV-1 (BoHV-1ΔUL49), VP8 was absent from the primary enveloped virions, implying that VP22 might be critical for the early packaging of VP8. In conclusion, a novel VP22-dependent mechanism for packaging of VP8 was identified, which may be responsible for a significant amount of VP8 in the viral particle.

In shared decision making, the exploration of preferred personal health outcomes is important. Patient-reported outcome measures (PROMs) provide input for discussions between patients and healthcare professionals. The Older Persons and Informal Caregivers Survey Minimum DataSet (TOPICS-MDS) PROM is a multidimensional questionnaire on the physical and mental health and wellbeing of older adults. This study investigates how the TOPICS-MDS could be used in individual healthcare conversations. We explored views of older adults regarding 1) whether the health domains they want to discuss are included in the TOPICS-MDS and 2) the comprehensibility of the TOPICS-MDS for healthcare conversations with older adults. A three-round Delphi study was conducted. A total of 57 older adults participated in the study, the mean (SD) age was 71.5 (8.5) years, and 78.9% of the participants were female. The participants were divided into four panels based on educational level and cultural background. We used online questionnaires and focus groups. Consensus was pre-defined to be the point when ≥75% of the participants agreed that a domain was important or very important (scored on a 5-point Likert scale). The inter-expert agreement was computed for Round 1 and 3 with Kendall's W. Round 2 was a focus-group. Qualitative data were analyzed by content analysis. Older adults considered 'functional limitations', 'emotional wellbeing', 'social functioning' and 'quality of life' to be important domains of the TOPICS-MDS to discuss in healthcare conversations. The participants added 'coping with stress', 'dealing with health conditions and the effects on life' as extra domains for healthcare conversations. Challenges regarding the comprehensibility of the TOPICS-MDS included difficult words and lengthy or sensitive questions. Questions that included multiple topics were difficult to understand. The TOPICS-MDS covers the domains of life that older adults value as important to discuss with healthcare professionals, and two additional domains were identified. For older adults with a low level of education or a culturally diverse background, the TOPICS-MDS needs to be adjusted for comprehensibility.

Background: Eye movement desensitization and reprocessing (EMDR) is an effective psychological treatment for posttraumatic stress disorder. Recalling a memory while simultaneously making eye movements (EM) decreases a memory’s vividness and/or emotionality. It has been argued that non-specific factors, such as treatment expectancy and experimental demand, may contribute to the EMDR’s effectiveness. Objective: The present study was designed to test whether expectations about the working mechanism of EMDR would alter the memory attenuating effects of EM. Two experiments were conducted. In Experiment 1, we examined the effects of pre-existing (non-manipulated) knowledge of EMDR in participants with and without prior knowledge. In Experiment 2, we experimentally manipulated prior knowledge by providing participants without prior knowledge with correct or incorrect information about EMDR’s working mechanism. Method: Participants in both experiments recalled two aversive, autobiographical memories during brief sets of EM (Recall+EM) or keeping eyes stationary (Recall Only). Before and after the intervention, participants scored their memories on vividness and emotionality. A Bayesian approach was used to compare two competing hypotheses on the effects of (existing/given) prior knowledge: (1) Prior (correct) knowledge increases the effects of Recall+EM vs. Recall Only, vs. (2) prior knowledge does not affect the effects of Recall+EM. Results: Recall+EM caused greater reductions in memory vividness and emotionality than Recall Only in all groups, including the incorrect information group. In Experiment 1, both hypotheses were supported by the data: prior knowledge boosted the effects of EM, but only modestly. In Experiment 2, the second hypothesis was clearly supported over the first: providing knowledge of the underlying mechanism of EMDR did not alter the effects of EM. Conclusions: Recall+EM appears to be quite robust against the effects of prior expectations. As Recall+EM is the core component of EMDR, expectancy effects probably contribute little to the effectiveness of EMDR treatment.

Adjuvants are crucial components of vaccines. They significantly improve vaccine efficacy by modulating, enhancing, or extending the immune response and at the same time reducing the amount of antigen needed. In contrast to previously licensed adjuvants, current successful adjuvant formulations often consist of several molecules, that when combined, act synergistically by activating a variety of immune mechanisms. These “combination adjuvants” are already registered with several vaccines, both in humans and animals, and novel combination adjuvants are in the pipeline. With improved knowledge of the type of immune responses needed to successfully induce disease protection by vaccination, combination adjuvants are particularly suited to not only enhance, but also direct the immune responses desired to be either Th1-, Th2- or Th17-biased. Indeed, in view of the variety of disease and population targets for vaccine development, a panel of adjuvants will be needed to address different disease targets and populations. Here, we will review well-known and new combination adjuvants already licensed or currently in development—including ISCOMs, liposomes, Adjuvant Systems Montanides, and triple adjuvant combinations—and summarize their performance in preclinical and clinical trials. Several of these combination adjuvants are promising having promoted improved and balanced immune responses.

Respiratory syncytial virus (RSV) is the leading cause of infant bronchiolitis. The closely related pneumonia virus of mice (PVM) causes a similar immune-mediated disease in mice, which allows an analysis of host factors that lead to severe illness. This project was designed to compare the immune responses to lethal and sublethal doses of PVM strain 15 in Balb/c and C57Bl/6 mice. Balb/c mice responded to PVM infection with an earlier and stronger innate response that failed to control viral replication. Production of inflammatory cyto- and chemokines, as well as infiltration of neutrophils and IFN-γ secreting natural killer cells into the lungs, was more predominant in Balb/c mice. In contrast, C57Bl/6 mice were capable of suppressing both viral replication and innate inflammatory responses. After a sublethal infection, PVM-induced IFN-γ production by splenocytes was stronger early during infection and weaker at late time points in C57Bl/6 mice when compared to Balb/c mice. Furthermore, although the IgG levels were similar and the mucosal IgA titres lower, the virus neutralizing antibody titres were higher in C57Bl/6 mice than in Balb/c mice. Overall, the difference in susceptibility of these two strains appeared to be related not to an inherent T helper bias, but to the capacity of the C57Bl/6 mice to control both viral replication and the immune response elicited by PVM.

In the last few years, the performance of the cryogenic gravity instruments has been further improved by the development of a new generation of superconducting gravimeter (SG): the so-called iOSG which is a superconducting gravimeter designed for observatory purpose with a heavier sphere than previous SGs. The first iOSG (iOSG-024) has been installed in July 2015 at the LSSB low background noise underground research laboratory in Rustrel (France), funded by the EQUIPEX MIGA (Matter wave-laser based Interferometer Gravitation Antenna) project and by the European FEDER 2006-2013 “PFM LSBB – Développement des qualités environnementales du LSBB”. This instrument is operational since September 2015. We present the first tidal analyses of the 7-month time-varying gravity records of this newly installed instrument as well as the calibration results performed by parallel FG5 absolute gravity measurements. We also show the performances of iOSG-024 in terms of noise levels in the seismic (in the millihertz frequency range) band using a standardized procedure based on the computation of the residual power spectral densities over a quiet time period. The obtained noise levels are compared with other SG sites and with seismological reference noise models. The combination of the instrumental performance of the iOSG with the LSBB site properties makes this gravimetric station one of the quietest in the world, comparable to the lower sensor of the OSG-56 at BFO, at seismic frequencies.

In bovenstaand commentaar “Indicatoren voor kwaliteit van zorg. Wie worden er wijzer van, de patiënten of de managers?” wordt als casus het Europese PROGRESS-project “Quality management by result-oriented indicators” ingebracht. 1 Vilans, landelijk kenniscentrum voor langdurende zorg, heeft namens Nederland aan dit project deelgenomen. De auteurs van het commentaar plaatsen op een aantal punten kanttekeningen bij het project. Op uitnodiging van de redactie geven wij hier graag een reactie op.

In bovenstaand commentaar “Indicatoren voor kwaliteit van zorg.Wie worden er wijzer van, de patiënten of de managers?” wordt als casus het Europese PROGRESS-project “Quality management by result-oriented indicators” ingebracht.1 Vilans, landelijk kenniscentrum voor langdurende zorg, heeft namens Nederland aan dit project deelgenomen. De auteurs van het commentaar plaatsen op een aantal punten kanttekeningen bij het project. Op uitnodiging van de redactie geven wij hier graag een reactie op.

INTRODUCTION: The role of inhibitory control in addictive behaviors is highlighted in several models of addictive behaviors. Although reduced inhibitory control has been observed in addictive behaviors, it is inconclusive whether this is evident in smokers. Furthermore, it has been proposed that drug abuse individuals with poor response inhibition may experience greater difficulties not consuming substances in the presence of drug cues. The major aim of the current study was to provide electrophysiological evidence for reduced inhibitory control in smokers and to investigate whether this is more pronounced during smoking cue exposure. METHODS: Participants (19 smokers and 20 non-smoking controls) performed a smoking Go/NoGo task. Behavioral accuracy and amplitudes of the N2 and P3 event-related potential (ERP), both reflecting aspects of response inhibition, were the main variables of interest. RESULTS: Reduced NoGo N2 amplitudes in smokers relative to controls were accompanied by decreased task performance, whereas no differences between groups were found in P3 amplitudes. This was found to represent a general lack of inhibition in smokers, and not dependent on the presence of smoking cues. CONCLUSIONS: The current results suggest that smokers have difficulties with response inhibition, which is an important finding that eventually can be implemented in smoking cessation programs. More research is needed to clarify the exact role of cue exposure on response inhibition.

Attentional bias is considered an important concept in addiction since it has been found to correlate with subjective craving and is strongly associated with relapse after periods of abstinence. Hence, investigating in ways to regulate attention for drug cues would be of major clinical relevance. The present study examined deliberate, cognitive modulation of motivated attention for smoking cues in smokers. The effects of three different reappraisal strategies on an electrophysiological measure of attentive processing were investigated. Early and late LPP components in response to passively viewed neutral and smoking pictures were compared with LPPs in response to smoking pictures that were reappraised with three different reappraisal strategies. Results show that when smokers actively imagine how pleasant it would be to smoke (pleasant condition), their early LPP in response to smoking cues increases, but when smokers actively focus on an alternative stimulus (distraction condition) or think of a rational, uninvolved interpretation of the situation (rational condition), smoking-related late LPP amplitude decreases to the processing level of neutral stimuli. Present results are the first to indicate that smoking cue-elicited LPP amplitudes can be modulated by cognitive strategies, suggesting that attentive processing of smoking cues can be intentionally regulated by smokers with various levels of dependence. Although cognitive strategies can lead to enhanced processing of smoking cues, it is not completely clear whether cognitive strategies are also successful in reducing smoking-related motivated attention. Although findings do point in this direction, present study is best considered preliminary and a starting point for other research on this topic. A focus on the distraction strategy is proposed, as there are indications that this strategy is more successful than the rational strategy in decreasing LPP amplitude.

Abstract Background Classical conditioning has been suggested to play an important role in the development, maintenance, and relapse of tobacco smoking. Several studies have shown that initially neutral stimuli that are directly paired with smoking are able to elicit conditioned responses. However, there have been few human studies that demonstrate the contribution of higher-order conditioning to smoking addiction, although it is assumed that higher-order conditioning predominates learning in the outside world. In the present study a higher-order conditioning task was designed in which brain responses of smokers and non-smokers were conditioned by pairing smoking-related and neutral stimuli (CS1smoke and CS1neutral) with two geometrical figures (CS2smoke and CS2neutral). ERPs were recorded to all CSs. Results Data showed that the geometrical figure that was paired with smoking stimuli elicited significantly larger P2 and P3 waves than the geometrical figure that was paired with neutral stimuli. During the first half of the experiment this effect was only present in smokers whereas non-smokers displayed no significant differences between both stimuli, indicating that neutral cues paired with motivationally relevant smoking-related stimuli gain more motivational significance even though they were never paired directly with smoking. These conclusions are underscored by self-reported evidence of enhanced second-order conditioning in smokers. Conclusions It can be concluded that smokers show associative learning for higher-order smoking-related stimuli. The present study directly shows the contribution of higher-order conditioning to smoking addiction and is the first to reveal its electrophysiological correlates. Although results are preliminary, they may help in understanding the etiology of smoking addiction and its persistence.