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Objective: Specific phobia is a common anxiety disorder, but the literature on associated brain structure alterations exhibits substantial gaps. The ENIGMA Anxiety Working Group examined brain structure differences between individuals with specific phobias and healthy control subjects as well as between the animal and blood-injection-injury (BII) subtypes of specific phobia. Additionally, the authors investigated associations of brain structure with symptom severity and age (youths vs. adults)., Methods: Data sets from 31 original studies were combined to create a final sample with 1,452 participants with phobia and 2,991 healthy participants (62.7% female; ages 5-90). Imaging processing and quality control were performed using established ENIGMA protocols. Subcortical volumes as well as cortical surface area and thickness were examined in a preregistered analysis., Results: Compared with the healthy control group, the phobia group showed mostly smaller subcortical volumes, mixed surface differences, and larger cortical thickness across a substantial number of regions. The phobia subgroups also showed differences, including, as hypothesized, larger medial orbitofrontal cortex thickness in BII phobia (N=182) compared with animal phobia (N=739). All findings were driven by adult participants; no significant results were observed in children and adolescents., Conclusions: Brain alterations associated with specific phobia exceeded those of other anxiety disorders in comparable analyses in extent and effect size and were not limited to reductions in brain structure. Moreover, phenomenological differences between phobia subgroups were reflected in diverging neural underpinnings, including brain areas related to fear processing and higher cognitive processes. The findings implicate brain structure alterations in specific phobia, although subcortical alterations in particular may also relate to broader internalizing psychopathology.

Advancements in digitalisation with cardiac implantable electronic devices (CIEDs) allow patients opportunities for improved autonomy, quality of life, and a potential increase in life expectancy. However, with the digital and functional practicalities of CIEDs, there exists also cyber safety issues with transferring wireless information. If a digital network were to be hacked, a CIED patient could experience both the loss of sensitive data and the loss of functional control of the CIED due to an unwelcome party. Moreover, if a CIED patient were to become victim of a cyber attack, which resulted in a serious or lethal event, and if this information were to become public, the trust in healthcare would be impacted and legal consequences could result. A cyber attack therefore poses not only a direct threat to the patient's health but also the confidentiality, integrity, and availability of the CIED, and these cyber threats could be considered "patient-targeted threats." Informed consent is a key component of ethical care, legally concordant practice, and promoting patient-as-partner therapeutic relationships [1]. To date, there are no standardised guidelines for listing cybersecurity risks within the informed consent or for discussing them during the consent process. Providers are responsible for adhering to the ethical principles of autonomy, beneficence, non-maleficence, and justice, both in medical practice generally and the informed consent process specifically. At present, the decision to include cybersecurity risks is mainly left to the provider's discretion, who may also have limited cyber risk information. Without effective and in-depth communication about all possible cybersecurity risks during the consent process, CIED patients can be left unaware of the privacy and physical risks they possess by carrying such a device. Therefore, cyber risk factors should be covered within the patients' informed consent and reviewed on an ongoing basis as new risk information becomes available. By including cyber risk information in the informed consent process, patients are given the autonomy to make the best-informed decision., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Torgersen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Recently, recommendations were given for a new scoring of the Oral Health Impact Profile (OHIP). The original seven domain structure should be replaced by a four-dimensional scale., Objectives: To investigate the effect of dental prosthetic treatment on the seven domains and the four-dimensional scale of the OHIP-G49/53 questionnaire., Methods: Seventy four patients were grouped according their pre- and post-treatment situation and the type of treatment they received. Patients completed the OHIP-G49/53 questionnaire before prosthetic treatment (T0), and at 1 week (T1), 3 months (T2) and 6 months (T3) after treatment. Treatment effects on the seven domains and the four dimensions of the OHIP scale were analysed, and the oral health-related quality of life (OHRQoL) was measured. Patients' expectations of their prosthetic treatment were also evaluated. Data were analysed using two-way Mixed ANOVA, regression analysis, and Cronbach's alpha test with a level of significance of α ≤ .017., Results: OHRQoL significantly improved following prosthetic treatment compared with baseline. The largest improvement was found between T0 and T1 evaluations (all p ≤ .001). Unlike the seven-domain scale, the four OHIP dimensions demonstrated further significant improvements across the T1/T2/T3 evaluations (all p ≤ .017). Different pre-treatment findings had different treatment effects on the four OHIP dimensions and seven OHIP domains. Patients' expectations were mainly fulfilled., Conclusion: Compared with the seven-domain scale, the four dimensions showed significant follow-up changes, suggesting the four dimensions are suitable for evaluating treatment effects up to 6 months. Clinically meaningful effects of dental prosthetic treatment can be sensitively measured using the four-dimensional OHIP scale., (© 2023 The Authors. Journal of Oral Rehabilitation published by John Wiley & Sons Ltd.)

To define frailty in older cancer patients, the aim of this study was to assess the geriatric status and quality of life (QoL) aspects in patients suffering from recurrent/metastatic head and neck squamous cell carcinoma (r/m HNSCC) under palliative treatment. A comprehensive geriatric assessment (CGA) was performed on 21 r/m HNSCC patients at two defined assessments, and the QoL aspects and the impact of descriptive data were evaluated. The Kolmogorov-Smirnov test, Spearman's rho correlation, and two-way mixed ANOVA were used for statistical analysis. All patients were found to be "frail". Pain, fatigue, and the burden of illness were the highest-rated symptoms. Oral function and orofacial appearance were highly impaired. A significant impact of descriptive data on the CGA and QoL results was found (all p ≤ 0.05). Thus, the CGA results revealed high frailty, severe comorbidities, and high impairments in QoL aspects. The CGA and QoL results were negatively affected by the primary HNSCC treatment approach, the need for prosthetic treatment, and worse oral functional capacity. Therefore, frailty in r/m HNSCC patients seems to be multidimensional. The evaluation of the CGA and QoL aspects in r/m HNSCC patients can be recommended to detect special needs, organize aftercare, and improve the support for frail and vulnerable cancer patients to create a multidisciplinary treatment approach.

Objective: Despite the transdiagnostic importance of emotional dysregulation in psychopathology, the exact nature of emotional dysregulation in somatic symptom disorders (SSDs) is still unclear. The present study compared measures of emotional reactivity, emotion regulation (ER), and regulatory choice between n = 62 individuals with SSD ( Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ) and n = 61 healthy participants., Methods: Participants underwent two ER tasks, assessing a) efficacy of reappraisal and suppression, and 2) regulatory choice, while electrodermal activity and heart rate variability were recorded. In addition, self-reports (Emotion Reactivity Scale, Emotion Regulation Questionnaire, Difficulties in Emotion Regulation Scale) regarding habitual emotional reactions and regulation strategies were assessed., Results: Individuals with SSD reported significantly higher trait emotional reactivity (Emotion Reactivity Scale; p < .001, d = 1.61), significantly more trait ER difficulties (Difficulties in Emotion Regulation Scale; p < .001, d = 1.62), and significantly lower reappraisal use in daily life (Emotion Regulation Questionnaire; p < .001, d = -0.75). On a behavioral and physiological levels, no significant group differences were found regarding emotional reactivity (subjective ratings of emotional stimuli in task 1, p values = .653-.667; electrodermal activity: p values = .224-.837), ER (task 1: p values = .077-.731; heart rate variability: p values = .522-.832), or regulatory choice (task 2: p = .380). Although individuals with SSD were equally effective in state ER (task 1), they perceived ER during the task as significantly more effortful ( p = .038, d = -0.38)., Conclusions: Results suggest that dysregulated emotions might not result from lacking abilities in implementing ER effectively, but rather could arise from less frequent ER initiation because ER is perceived as more effortful., (Copyright © 2022 by the American Psychosomatic Society.)

Medication-related osteonecrosis of the jaw (MRONJ) represents an adverse side effect of antiresorptive and antiangiogenic medications. It is associated with impaired quality of life, oral health, and oral function and can be classified into various stages. The purpose of this prospective clinical study is to evaluate the impact of stages I and II MRONJ on oral-health-related quality of life (OHRQoL) and related parameters. Patients' OHRQoL, satisfaction with life, oral discomfort, and oral health were assessed using the German version of the Oral Health Impact Profile (OHIP-G49), visual analog scales (VAS), and Satisfaction with Life Scale (SWLS) at baseline (T0), 10 days (T1), and 3 months after treatment (T2) in 36 patients. Data were analyzed using Kolmogorov-Smirnov test, two-way mixed ANOVAs, and follow-up Mann-Whitney U tests. The impact of treatment effects on the original seven OHIP domain structures and the recently introduced four-dimensional OHIP structure were evaluated using linear regression analysis. Thirty-six patients received surgical MRONJ treatment. Before treatment, patients' perceived OHRQoL, oral discomfort, oral health, and satisfaction with life were negatively affected by MRONJ. Surgical treatment significantly improved OHRQoL and related parameters (all p ≤ 0.012). This improvement was greater in patients with higher impairment at T0. OHRQoL and oral restrictions were still impaired after treatment in patients who needed prosthetic treatment. The four-dimensional structure revealed valuable information beyond the standard seven OHIP domains. Increased awareness of MRONJ risks and an interdisciplinary treatment approach for MRONJ patients are needed.

Religion and social support along with trait emotional intelligence (EI) help individuals to reduce stress caused by difficult situations. Their implications may vary across cultures in reference to predicting health-related quality of life (HRQoL). A convenience sample of N = 200 chronic heart failure (CHF) patients was recruited at cardiology centers in Germany (n = 100) and Pakistan (n = 100). Results indicated that trait-EI predicted better mental component of HRQoL in Pakistani and German CHF patients. Friends as social support appeared relevant for German patients only. Qualitative data indicate an internal locus of control in German as compared to Pakistani patients. Strengthening the beneficial role of social support in Pakistani patients is one example of how the current findings may inspire culture-specific treatment to empower patients dealing with the detrimental effects of CHF., (© 2021. The Author(s).)

The aim of this study was to translate the Liverpool Oral Rehabilitation Questionnaire version 3 (LORQv3) into German and validate this version in order to assess oral-health-related quality of life (OHRQoL) among head and neck cancer patients. This study was conducted at a German university clinic among patients who had completed therapy for squamous cell carcinoma of the head and neck (HNSCC). The original English-language LORQv3 was translated into German according to the forward-backward approach. Validity and reliability were evaluated using further questionnaires related to OHRQoL and psychological impairments. Subgroups were built with reference to oral rehabilitation status and type of cancer therapy. Furthermore, OHRQoL was evaluated. Test-retest reliability was assessed by weighted kappa with a 10-14 day interval. Data were analysed by using Spearman's correlation and the following tests: Shapiro-Wilk, Kruskal-Wallis, Mann-Whitney U and Cronbach's alpha. The level of significance was set at α = 0.05. Analysis of the LORQv3 evaluations revealed excellent Cronbach's alpha and high test-retest reliability. Construct validity were supported by the data. LORQv3 summary score and domains were significantly affected by status of oral rehabilitation (p = 0.003, p = 0.008, p = 0.024) and treatment approach (p < 0.001, p = 0.025, p = 0.035). The German version of the LORQv3 showed high reliability and validity and an impaired OHRQoL of HNSCC patients. It can therefore be recommended for the assessment of OHRQoL., Competing Interests: Declaration of competing interest None., (Copyright © 2021 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Background: The study aimed to assess the mental well-being of healthcare professionals at a German department of anesthesiology and critical care with a specialized ICU for treatment of COVID-19 patients during the first two peaks of the 2020 pandemic, and identifying risk and protective factors. Methods: A single-center longitudinal, online-based survey was conducted in healthcare workers from a department of anesthesiology and critical care in Bavaria, the most affected federal state in Germany at the time of assessment. Validated scores for depression, anxiety, somatic disorders, burnout, resilience, and self-management were used and complemented by questions about perceived COVID-19-related stressors. In parallel, patient characteristics in the ICU were collected. Results: 24 and 23 critically ill COVID-19 patients were treated during both observation periods in April/May and November/December 2020, respectively. 87.5% and 78.2% of patients had moderate to severe acute respiratory distress syndrome. From March 6, 2020 onwards, the hospital had switched to a command and control-based hospital incident command system (HICS) and increased work forces. Point prevalence of depression-like symptoms (13.6% and 12.8%) and burnout (21.6% and 17.4%) in the department's healthcare professionals was high. Exposure to SARS-CoV-2 did not increase psychological burden. Consequences of the lockdown were rated as highly distressing by a majority of all ICU personnel. High self-reported trait resilience was protective against signs of depression, generalized anxiety, and burnout. Conclusions: During the pandemic, healthcare professionals have been suffering from increased psychological distress compared to reference data for both the general population and ICU personnel. General effects of the lockdown appear more relevant than actual COVID-19 patient contact. High trait resilience has a protective effect, yet vulnerable individuals may require specific support. Prevention against potential after effects of the lockdown, and in particular measures allowing to avoid another lockdown, appear warranted., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2021 Schmid et al.)

Sulfur mustard (SM) is a lipid soluble alkylating agent that causes genotoxic injury. The eye is highly sensitive to SM toxicity and exposures exceeding 400 mg min/m 3 can elicit irreversible corneal pathophysiologies. Development of medical countermeasures for ocular SM exposure has been hindered by a limited understanding of dose-dependent effects of SM on corneal injury. Here, clinical, histological and ultrastructural analyses were used to characterize the effects of SM dose on corneal injury progression. Corneas were evaluated for up to 20 wk following exposure to saturated SM vapor for 30-150 s, which corresponds to 300-1,500 mg min/m 3 . In acute studies, a ceiling effect on corneal edema developed at doses associated with full-thickness corneal lesions, implicating endothelial toxicity in corneal swelling. Recurrent edematous lesions (RELs) transiently emerged after 2 wk in a dose-dependent fashion, followed by the development of secondary corneal pathophysiologies such as neovascularization, stromal scarring and endothelial abnormalities. RELs appeared in 96 % of corneas exposed for ≥ 90 s, 52 % of corneas exposed for 60 s and 0 % of corneas exposed for 30 s. While REL latency was variable in corneas exposed for 60 s, REL emergence was synchronized at exposures ≥ 90 s. Corneas did not exhibit more than one REL, suggesting RELs are part of a programmed pathophysiological response to severe alkylating lesions. In post-mortem studies at 12 wk, corneal edema was positively correlated to severity of endothelial pathologies, consistent with previous findings that endothelial toxicity influences long-term outcomes. These results provide novel insight into long-term corneal pathophysiological responses to acute toxicity and identify exposure conditions suitable for therapeutic testing., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Vaginal colonization with Ureaplasma ( U. ) spp. has been shown to be associated with adverse pregnancy outcome; however, data on neonatal outcome are scarce. The aim of the study was to investigate whether maternal vaginal colonization with U. spp. in early pregnancy represents a risk factor for adverse short- or long-term outcome of preterm infants. Previously, 4330 pregnant women were enrolled in an observational multicenter study, analyzing the association between vaginal U. spp. colonization and spontaneous preterm birth. U. spp. colonization was diagnosed via PCR analysis from vaginal swabs. For this study, data on short-term outcome were collected from medical records and long-term outcome was examined via Bayley Scales of Infant Development at 24 months adjusted age. Two-hundred-and-thirty-eight children were born <33 weeks gestational age. After exclusion due to asphyxia, malformations, and lost-to-follow-up, data on short-term and long-term outcome were available from 222 and 92 infants, respectively. Results show a significant association between vaginal U. spp. colonization and severe intraventricular hemorrhage (10.4% vs. 2.6%, p = 0.03), retinopathy of prematurity (21.7% vs. 10.3%, p = 0.03), and adverse psychomotor outcome (24.3% vs. 1.8%, OR 13.154, 95%CI 1.6,110.2, p = 0.005). The data suggest an association between vaginal U. spp. colonization in early pregnancy and adverse short- and long-term outcome of very preterm infants.

Maternal hypothalamic-pituitary-adrenal axis activity may prenatally program sex-specific stress-response pathways. We investigated associations between maternal cortisol during pregnancy and infant parasympathetic responsivity to stress among 204 mother-infant pairs. Cortisol indices included 3rd trimester hair cortisol, as well as diurnal slope and area under the curve, derived from saliva samples collected during pregnancy. Mother-infant dyads participated in the Repeated Still-Face Paradigm (SFP-R) at age 6 months. We calculated respiration-adjusted respiratory sinus arrhythmia (RSA c ), an indicator of parasympathetic activation, from infant respiration and cardiac activity measured during the SFP-R. We used multivariable linear mixed models to examine each cortisol index in relation to infant RSA c and investigated sex differences using cross-product terms. Diurnal cortisol indices were not associated with RSA c . There was no association between hair cortisol and baseline RSA c . However, hair cortisol was associated with sex-specific changes in RSA c over the SFP-R such that, among girls, parasympathetic withdrawal was reduced with increasing prenatal exposure to cortisol. Consistently higher levels of prenatal cortisol exposure may lead to dampened parasympathetic responsivity to stress during infancy, particularly among girls. Maternal hair cortisol may be particularly valuable for studying the effects of prenatal cortisol exposure on infant autonomic reactivity., (© 2020 Wiley Periodicals LLC.)

Infant autonomic reactivity to stress is a potential predictor of later life health complications, but research has not sufficiently examined sympathetic activity, controlled for effects of physical activity and respiration, or studied associations among autonomic adjustments, cardiac activity, and affect in infants. We studied 278 infants during the repeated Still-Face Paradigm, a standardized stressor, while monitoring cardiac activity (ECG) and respiratory pattern (respiratory inductance plethysmography). Video ratings of physical activity and affect were also performed. Respiratory sinus arrhythmia (RSA) and T-wave amplitude (TWA) served as noninvasive indicators of cardiac parasympathetic and sympathetic activity, respectively. Responses were compared between infants who completed two still-face exposures and those who terminated after one exposure due to visible distress. Findings, controlled for physical activity, showed robust reductions in respiration-adjusted RSA and TWA, with more tonic attenuation of TWA. Infants completing only one still-face trial showed more pronounced autonomic changes and less recovery from stress. They also showed elevated minute ventilation, suggesting hyperventilation. Both reductions in adjusted RSA and TWA contributed equally to heart rate changes and were associated with higher negative and lower positive affect. These associations were more robust in the group of distressed infants unable to complete both still-face trials. Thus, cardiac sympathetic activation and parasympathetic withdrawal are part of the infant stress response, beyond associated physical activity and respiration changes. Their association with cardiac chronotropy and affect increases as infants' distress level increases. This excess reactivity to social stress should be examined as a predictor of future cardiovascular disease., (© 2020 Society for Psychophysiological Research.)

The exact causes of Idiopathic Environmental Intolerance Attributed to Electromagnetic Fields (IEI-EMF, i.e., experience of somatic symptoms attributed to low-level electromagnetic fields) are still unknown. Psychological causation such as nocebo effects seem plausible. This study aimed to experimentally induce a nocebo effect for somatic symptom perception and examined whether it was reproducible after one week. We also examined whether these effects were associated with increased sympathetic activity and whether interoceptive accuracy (IAcc) moderated these relationships. Participants were recruited from the general population and instructed that electromagnetic exposure can enhance somatosensory perception. They participated twice in a cued exposure experiment with tactile stimulation and sham WiFi exposure in 50% of trials. The two sessions were scheduled one week apart (session 1: N = 65, session 2: N = 63). Before session 1, participants watched either a 6-min film on adverse health effects of EMF or a neutral film on trade of mobile phones. IAcc was assessed with the heartbeat detection paradigm. Electrodermal activity served as a measure of sympathetic activation. Evidence for a nocebo effect (i.e., increased self-reported intensity and aversiveness and electrodermal activity) during sham WiFi exposure was observed in both sessions. IAcc moderated the nocebo effect, depending on stimulus intensity. Contrary to previous findings, no difference emerged between the health-related EMF and the neutral films. Based on negative instructions, somatic perception and physiological responding can be altered. This is consistent with the assumption that IEI-EMF could be due to nocebo effects, suggesting an important role for psychological interventions., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aims: Anxiety, depression, and reduced quality of life (QoL) are common in patients with implantable cardioverter-defibrillators (ICDs). Treatment options are limited and insufficiently defined. We evaluated the efficacy of a web-based intervention (WBI) vs. usual care (UC) for improving psychosocial well-being in ICD patients with elevated psychosocial distress., Methods and Results: This multicentre, randomized controlled trial (RCT) enrolled 118 ICD patients with increased anxiety or depression [≥6 points on either subscale of the Hospital Anxiety and Depression Scale (HADS)] or reduced QoL [≤16 points on the Satisfaction with Life Scale (SWLS)] from seven German sites (mean age 58.8 ± 11.3 years, 22% women). The primary outcome was a composite assessing change in heart-focused fear, depression, and mental QoL 6 weeks after randomization to WBI or UC, stratified for age, gender, and indication for ICD placement. Web-based intervention consisted of 6 weeks' access to a structured interactive web-based programme (group format) including self-help interventions based on cognitive behaviour therapy, a virtual self-help group, and on-demand support from a trained psychologist. Linear mixed-effects models analyses showed that the primary outcome was similar between groups (ηp2 = 0.001). Web-based intervention was superior to UC in change from pre-intervention to 6 weeks (overprotective support; P = 0.004, ηp2 = 0.036), pre-intervention to 1 year (depression, P = 0.004, ηp2 = 0.032; self-management, P = 0.03, ηp2 = 0.015; overprotective support; P = 0.02, ηp2 = 0.031), and 6 weeks to 1 year (depression, P = 0.02, ηp2 = 0.026; anxiety, P = 0.03, ηp2 = 0.022; mobilization of social support, P = 0.047, ηp2 = 0.018)., Conclusion: Although the primary outcome was neutral, this is the first RCT showing that WBI can improve psychosocial well-being in ICD patients., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objectives: Low emotional intelligence (EI) may predispose individuals to applying maladaptive coping strategies. This may maintain anxious worrying, which is highly prevalent in patients with chronic heart failure (CHF) and may affect mental (MCS) and physical component summaries (PCS) of health-related quality of life (HRQoL)., Design: The current study is a cross-sectional and cross-cultural survey., Methods: N = 200 outpatients with CHF were recruited at cardiology institutes in Germany and Pakistan and assessed with self-report questionnaires., Results: Path analysis (χ 2 (4) = 7.59, p = .11, GFI = .99) revealed that the expected associations between low EI and lower SF-36 MCS and PCS of HRQoL were fully mediated by negative metacognition and maladaptive coping in the Pakistani sample (p's ≤ .05). The German sample applied different maladaptive coping strategies, which also led to lower MCS and PCS scores, but did not mediate a direct positive effect of EI on HRQoL., Conclusion: The current findings support culture-independent validity of the metacognitive model but also reveal major cultural differences regarding the application and effect of specific maladaptive coping strategies. This has important implications for caregivers in a cross-cultural context and highlights the need for culture-specific tailoring of psychosocial interventions. Statement of contribution What is already known on this subject? Worry, an integral component of generalized anxiety disorder (GAD) and highly comorbid in chronic heart failure (CHF) patients, contributes to anxiety and resulting stress as evident from metacognitive model of GAD. In addition, previous literature has also established the protective role of emotional intelligence (EI) against stress, thus maintaining quality of life. What does this study add? Cross-cultural (Pakistan vs. Germany) validation of the metacognitive model of GAD. Supportive evidence for the metacognitive model in patients with CHF. Mediation of maladaptive metacognitions and negative coping in the relationship of low trait EI and low health-related quality of life., (© 2019 The British Psychological Society.)

Effective use of brain-computer interfaces (BCIs) typically requires training. Improved understanding of the neural mechanisms underlying BCI training will facilitate optimisation of BCIs. The current study examined the neural mechanisms related to training for electroencephalography (EEG)-based communication with an auditory event-related potential (ERP) BCI. Neural mechanisms of training in 10 healthy volunteers were assessed with functional magnetic resonance imaging (fMRI) during an auditory ERP-based BCI task before (t1) and after (t5) three ERP-BCI training sessions outside the fMRI scanner (t2, t3, and t4). Attended stimuli were contrasted with ignored stimuli in the first-level fMRI data analysis (t1 and t5); the training effect was verified using the EEG data (t2-t4); and brain activation was contrasted before and after training in the second-level fMRI data analysis (t1 vs. t5). Training increased the communication speed from 2.9 bits/min (t2) to 4 bits/min (t4). Strong activation was found in the putamen, supplementary motor area (SMA), and superior temporal gyrus (STG) associated with attention to the stimuli. Training led to decreased activation in the superior frontal gyrus and stronger haemodynamic rebound in the STG and supramarginal gyrus. The neural mechanisms of ERP-BCI training indicate improved stimulus perception and reduced mental workload. The ERP task used in the current study showed overlapping activations with a motor imagery based BCI task from a previous study on the neural mechanisms of BCI training in the SMA and putamen. This suggests commonalities between the neural mechanisms of training for both BCI paradigms., (© 2019 Wiley Periodicals, Inc.)

Background: Ureaplasma species (spp) are the bacteria most often isolated from the amniotic cavity of women with preterm labor or preterm premature rupture of membranes; thus, the link between intrauterine Ureaplasma spp infection and adverse pregnancy outcome clearly is established. However, because vaginal Ureaplasma spp colonization is very common in pregnant women, the reason that these microorganisms cause ascending infections in some cases but remain asymptomatic in most pregnancies is not clear. Previous studies suggested an association between vaginal colonization with Ureaplasma parvum as opposed to U urealyticum and preterm delivery. However, because of the high frequency of vaginal Ureaplasma spp colonization during pregnancy, additional risk factors are needed to select a group of women who might benefit from treatment., Objective: To further identify pregnant women who are at increased risk for preterm delivery, the aim of the present study was to investigate U parvum serovar-specific pathogenicity in a large clinical cohort., Study Design: We serotyped 1316 samples that were positive for U parvum using a high-resolution melt polymerase chain reaction assay, and results were correlated with pregnancy outcome., Results: Within U parvum positive samples, serovar 3 was the most common isolate (43.3%), followed by serovar 6 (31.4%) and serovar 1 (25.2%). There was a significantly increased risk for spontaneous preterm birth at very low (<32 weeks gestation; P<.005) and extremely low (<28 weeks gestation; P<.005) gestational age in the group with vaginal U parvum serovar 3 colonization compared with the control group of pregnant women who tested negative for vaginal Ureaplasma spp colonization. This association was found for neither serovar 1 nor serovar 6. The combination of vaginal U parvum serovar 3 colonization and diagnosis of bacterial vaginosis in early pregnancy or a history of preterm birth further increased the risk for adverse pregnancy outcome., Conclusion: Colonization with U parvum serovar 3, but not serovar 1 or serovar 6, in early pregnancy is associated with preterm delivery at very and extremely low gestational age. The combination of U parvum serovar 3 colonization and a history of preterm birth or bacterial vaginosis further increases the risk for spontaneous preterm birth at low gestational age and may define a target group for therapeutic intervention studies., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: While there is a proven association of upper genital tract Ureaplasma infection during pregnancy with adverse pregnancy outcome, the effect of vaginal Ureaplasma colonization on preterm delivery has been controversially debated., Objectives: We hypothesized that women with isolation of vaginal U. parvum but not U. urealyticum are at increased risk for spontaneous preterm birth (SPB) compared to women with negative results., Methods: A vaginal swab taken between 12 and 14 weeks of gestation was analyzed for the presence of Ureaplasma biovars by PCR in 4,330 pregnant women., Results: Of the study cohort, 37% were positive for U. parvum, 5.9% for U. urealyticum, and 3.1% for both. The rates of SPB were 10.4% (OR 1.7, 95% CI 1.3, 2.2, p < 0.001) and 8.9% (OR 1.4, 95% CI 0.9, 2.3, p = 0.193) in the groups with isolation of U. parvum and U. urealyticum, respectively, compared to 6.4% in the group with negative PCR results. Multiple logistic regression and interaction analyses showed that vaginal colonization with U. parvum but not U. urealyticum was a statistically significant risk factor for SPB (adjusted OR 1.6, 95% CI 1.2, 2.1, p < 0.001), independent of other risk factors such as bacterial vaginosis and history of SPB., Conclusion: Our study demonstrates a statistically significant and independent association between first-trimester vaginal colonization with U. parvum and subsequent SPB., (© 2017 S. Karger AG, Basel.)

Negative emotions such as anxiety enhance pain perception. However, certain threat characteristics are discussed to have different or even divergent effects on pain (hypoalgesia vs hyperalgesia). In order to investigate the neurobiological basis of different threats, we compared the impact of conditioned threat (CT) vs instructed threat (IT) on pain using fMRI. In two groups, participants underwent either Pavlovian threat conditioning or an instructed threat procedure. Afterwards, in an identical test phase participants watched the same visual cues from the previous phase indicating potential threat or safety, and received painful thermal stimulation. In the test phase, pain ratings were increased in both groups under threat. Group comparisons show elevated responses in amygdala and hippocampus for pain under threat in the CT group, and higher activation of the mid-cingulate gyrus (MCC) in the IT group. Psychophysiological interaction analyses in CT demonstrated elevated connectivity of the amygdala and the insula for the comparison of pain under threat vs safety. In IT, the same comparison revealed elevated functional connectivity of the MCC and the insula. The results suggest a similar pain augmenting effect of CT and IT, which, however, seems to rely on different networks mediating the impact of threat on pain., (© The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.)

Objective: Self-determination theory suggests that autonomy-enhancing social support helps individuals to perceive stressors as challenging rather than stressing. Overprotective support may reduce stress in the short-run but undermines autonomy, thus hampering stress-coping in the long run, particularly when social support is terminated., Method: Heartrate, blood-pressure and ratings were examined in N=44 undergraduate students receiving autonomy support (calculation steps) or overprotection (solutions) from a close friend or no support for solving arithmetic tasks as well as during a subsequent stress-challenge (solving arithmetic tasks alone)., Results: Overprotection resulted in increased heartrate, diastolic blood-pressure, stress ratings, and decreased subjective control during stress-challenge. Autonomy support did not lead to unfavorable stress responding., Conclusion: The current findings are in line with assumptions derived from self-determination theory and indicate that autonomy support can help to prevent stress. Overprotection does not buffer stress and is associated with increased stress when discontinued., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Interoception is the ability to perceive one's internal body state including visceral sensations. Heart-focused interoception has received particular attention, in part due to a readily available task for behavioural assessment, but also due to accumulating evidence for a significant role in emotional experience, decision-making and clinical disorders such as anxiety and depression. Improved understanding of the underlying neural correlates is important to promote development of anatomical-functional models and suitable intervention strategies. In the present meta-analysis, nine studies reporting neural activity associated with interoceptive attentiveness (i.e. focused attention to a particular interoceptive signal for a given time interval) to one's heartbeat were submitted to a multilevel kernel density analysis. The findings corroborated an extended network associated with heart-focused interoceptive attentiveness including the posterior right and left insula, right claustrum, precentral gyrus and medial frontal gyrus. Right-hemispheric dominance emphasizes non-verbal information processing with the posterior insula presumably serving as the major gateway for cardioception. Prefrontal neural activity may reflect both top-down attention deployment and processing of feed-forward cardioceptive information, possibly orchestrated via the claustrum.This article is part of the themed issue 'Interoception beyond homeostasis: affect, cognition and mental health'., (© 2016 The Author(s).)

Emotional processing is probably the most crucial tool for orienting oneself in our everyday social life and has been considered to be highly automatic for a long time. Dual task (DT) research shows that information competing for working memory resources impairs the identification of emotional facial expressions. Effects of cognitive load in DT paradigms have been confirmed in numerous neuroimaging studies. However, interference occurring during a DT comprised of decoding emotional facial expressions and a visuo-spatial working memory task has yet to be visualized. To investigate the DT interference effect on brain areas associated not only with working memory, but also emotional and visuo-spatial processing, we recorded brain activation within the prefrontal cortex and parietal-occipital sensory areas using functional near-infrared spectroscopy (fNIRS) and electroencephalography (EEG) simultaneously. Our study consisted of N = 36 participants (27 female) performing the following tasks: a) Corsi blocks, b) identification of emotional facial expressions or c) DT comprising of tasks a) and b). We predicted higher activation of the prefrontal cortex during DT and corresponding reduced P100 and P300 amplitudes. As expected, fNIRS measurements revealed significantly higher neuronal activation within the prefrontal cortex in the DT condition. When comparing DT to the single tasks, the P100 amplitude was reduced, but the P300 amplitude did not show the expected reduction. Our findings underline that at least some aspects of emotional processing are not entirely automatic, but depend on prefrontal control and are therefore affected by cognitive load, in particular visuo-spatial working memory resources., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Facilitated processing of interoceptive and exteroceptive information in the salience network is suggested to promote the development of anxiety and anxiety disorders. Here, it was investigated whether the adenosine 2 A receptor gene (ADORA2A) 1976T/C (rs5751876) variant - previously associated with anxiety disorders and anxiety-related phenotypes as well as general attentional efficiency -was involved in the regulation of this network. In detail, fMRI recordings of 65 healthy participants (female=35) were analyzed regarding ADORA2A genotype effects on brain connectivity related to (1) interoceptive processing in terms of functional connectivity resting-state fMRI, and (2) exteroceptive processing using dynamic causal modeling in task-based fMRI. In a subsample, cardiac interoceptive accuracy was furthermore measured via the Mental Tracking Task. ADORA2A genotype was found to modulate a fronto-insular network at rest (interoceptive processing) and while performing an executive control task (exteroceptive processing). Across both modalities, the ADORA2A TT risk genotype was associated with increased connectivity between the insula and the prefrontal cortex. The strength in connectivity correlated with interoceptive accuracy. It is concluded that alterations in fronto-insular connectivity are modulated by both the adenosinergic system and interoceptive accuracy. Thus, fronto-insular connectivity in synopsis with ADORA2A genotypic information could serve as combined biomarkers for personalized treatment approaches in anxiety disorders targeting exteroceptive and interoceptive dysfunction., (Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.)

Anxiety disorder patients were repeatedly found to overestimate the association between disorder-relevant stimuli and aversive outcomes despite random contingencies. Such an illusory correlation (IC) might play an important role in the return of fear after extinction learning; yet, little is known about how this cognitive bias emerges in the brain. In a functional magnetic resonance imaging study, 18 female patients with spider phobia and 18 healthy controls were exposed to pictures of spiders, mushrooms and puppies followed randomly by either a painful electrical shock or nothing. In advance, both patients and healthy controls expected more shocks after spider pictures. Importantly, only patients with spider phobia continued to overestimate this association after the experiment. The strength of this IC was predicted by increased outcome aversiveness ratings and primary sensory motor cortex activity in response to the shock after spider pictures. Moreover, increased activation of the left dorsolateral prefrontal cortex (dlPFC) to spider pictures predicted the IC. These results support the theory that phobia-relevant stimuli amplify unpleasantness and sensory motor representations of aversive stimuli, which in turn may promote their overestimation. Hyper-activity in dlPFC possibly reflects a pre-occupation of executive resources with phobia-relevant stimuli, thus complicating the accurate monitoring of objective contingencies and the unlearning of fear., (© The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.)

Contextual fear conditioning takes place if the occurrence of threat cannot be predicted by specific cues. As a consequence the context becomes the best predictor of the threat and later induces anxiety (sustained fear response). Previous studies suggest that both the amygdala and the hippocampus are crucial for contextual fear conditioning. First, we wanted to further elucidate the neuronal correlates of long-lasting contextual threat within a highly ecologically setting created in virtual reality (VR). Second, we wanted to distinguish between initial and sustained components of the anxiety response to a threatening situation. Twenty-four participants were guided through two virtual offices for 30s each. They received unpredictable electric stimuli (unconditioned stimulus, US) in one office (anxiety context, CXT+), but never in the second office (safety context, CXT-). Successful contextual fear conditioning was indexed by higher anxiety and enhanced US-expectancy ratings for CXT+ versus CXT-. Initial neural activity was assessed by modeling the onsets of both contexts, and sustained neural activity by considering the entire context duration (contrasts: CXT+ > CXT-). Amygdala and hippocampus revealed sustained activity. Initial and sustained activities were found in the middle temporal gyrus, and primary motor cortex (M1). Additional initial activity was obvious in orbitofrontal (OFC), dorsomedial (dmPFC), and dorsolateral prefrontal cortex (dlPFC). These results suggest that entering a threatening context initially induces conditioned fear reactions (M1), recall of contingency awareness (dlPFC), and explicit threat appraisal (dmPFC, OFC). While remaining in the threatening context might involve anxiety-like conditioned responses (amygdala, M1) and the generation of a spatial map to predict where and when a threatening event may occur (hippocampus). We conclude that in humans initial versus sustained anxiety responses triggered by a threat associated context are associated with distinguishable brain activation patterns involving a fear network and a "contingency-cognitive" network, respectively., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: Somatic marker theory predicts that somatic cues serve intuitive decision making; however, cardiovascular symptoms are threat cues for patients with panic disorder (PD). Therefore, enhanced cardiac perception may aid intuitive decision making only in healthy individuals, but impair intuitive decision making in PD patients., Methods: PD patients and age-and sex-matched volunteers without a psychiatric diagnosis (n = 17, respectively) completed the Iowa Gambling Task (IGT) as a measure of intuitive decision making. Interindividual differences in cardiac perception were assessed with a common mental-tracking task., Results: In line with our hypothesis, we found a pattern of opposing associations (Fisher's Z = 1.78, P = 0.04) of high cardiac perception with improved IGT-performance in matched control-participants (r = 0.36, n = 14) but impaired IGT-performance in PD patients (r = -0.38, n = 13)., Conclusion: Interoceptive skills, typically assumed to aid intuitive decision making, can have the opposite effect in PD patients who experience interoceptive cues as threatening, and tend to avoid them. This may explain why PD patients frequently have problems with decision making in everyday life. Screening of cardiac perception may help identifying patients who benefit from specifically tailored interventions.

Objective: A sudden gain is defined as a large and stable individual improvement occurring between two consecutive treatment sessions. Sudden gains have been shown to predict better long-term improvement in several treatment studies, including cognitive behavioural therapy for depression and anxiety disorders, but have not been studied in the treatment of health anxiety or any form of internet-based cognitive behavioural therapy. The aim of this study was to investigate the role of sudden gains in internet-based cognitive behavioural therapy for severe health anxiety., Method: We examined the occurrence and significance of sudden gains in measures of health anxiety in 81 participants receiving internet-based cognitive behavioural therapy. We compared patients with sudden gains, patients without sudden gains, and patients with gradual gains., Results: Thirteen participants (16%) experienced one sudden gain in health anxiety with individual sudden gains distributed across the treatment. As expected, patients with a sudden gain showed larger improvements than patients without a sudden gain at post-treatment (d = 1.04) and at one-year follow-up (d = 0.91) on measures of health anxiety., Conclusions: Consistent with previous studies, sudden gains in internet-based cognitive behavioural therapy are associated with significantly larger and stable treatment effects up to one-year follow-up., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Automatic facial reactions to near-threshold presented facial displays of emotion can be due to motor-mimicry or evaluation. To examine the mechanisms underlying such automatic facial responses we presented facial displays of joy, anger, and disgust for 16.67ms with a backwards masking technique and assessed electromyographic activity over the zygomaticus major, the levator labii, and the corrugator supercilii. As expected, we found that participants responded to displays of joy with contractions of the zygomaticus major and to expressions of anger with contractions of the corrugator supercilii. Critically, facial displays of disgust automatically activated the corrugator supercilii rather than the levator labii. This supports the notion that evaluative processes mediate facial responses to near-threshold presented facial displays of emotion rather than direct mimicry of emotional facial features., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Diagnosis of bacterial sepsis in preterm neonates can be difficult when using serum markers that rely on physiological changes because these changes may not necessarily be the result of bacterial infections alone. This retrospective investigation explores the potential use of the DNA methylation pattern of CpG sites in the promoter region of the calcitonin-related polypeptide α (CALCA) gene as an epigenetic biomarker for bacterial sepsis in preterm newborns. Four novel changes in the DNA methylation of eight CpG sites were detected in this gene and are present only in neonates with bacterial sepsis: (1) partial methylation at -769 CpG in gram-negative or gram-positive early onset sepsis (EOS) and late onset sepsis (LOS) episodes; (2) demethylation of 8 CpGs in gram-negative EOS followed by LOS (ELS) and in gram-negative EOS; (3) demethylation of 7 CpGs in gram-positive ELS and gram-positive EOS; (4) -771 C:G>T:A; 5' de novo -778 CpG mutation on both alleles in EOS. These changes were not detected in birth weight and gestational age matched controls or in newborns with isolated infections. Our results indicate that the DNA methylation pattern of the promoter region of the CALCA gene varies in different types of bacterial preterm sepsis, thus suggesting a potential use as an epigenetic biomarker. A prospective confirmation of these results is essential.

Previous studies suggest in line with dual process models that interoceptive skills affect controlled decisions via automatic or implicit processing. The "framing effect" is considered to capture implicit effects of task-irrelevant emotional stimuli on decision-making. We hypothesized that cardiac awareness, as a measure of interoceptive skills, is positively associated with susceptibility to the framing effect. Forty volunteers performed a risky-choice framing task in which the effect of loss versus gain frames on decisions based on identical information was assessed. The results show a positive association between cardiac awareness and the framing effect, accounting for 24% of the variance in the framing effect. These findings demonstrate that good interoceptive skills are linked to poorer performance in risky choices based on ambivalent information when implicit bias is induced by task-irrelevant emotional information. These findings support a dual process perspective on decision-making and suggest that interoceptive skills mediate effects of implicit bias on decisions., (Copyright © 2013 Cognitive Science Society, Inc.)

Objectives: Recently, we proposed a new stimulation paradigm for brain computer interfaces (BCI) based on event-related potentials (ERP), i.e. flashing characters with superimposed pictures of well-known faces. This new face flashing (FF) paradigm significantly outperformed the commonly used character flashing (CF) approach, i.e. simply highlighting characters., Methods: In the current study we assessed the impact of face stimuli on BCI inefficiency in patients with neurodegenerative disease, i.e. on their inability to communicate by means of a BCI. Healthy participants (N = 16) and those with neurodegenerative disease (N = 9) performed spelling tasks using CF and FF paradigms., Results: Online performance with FF was significantly increased as compared to CF in both, healthy and impaired users. Importantly, two patients who were classified "highly inefficient" with the classic CF stimulation were able to spell with high accuracy using FF. Our results particularly emphasize great benefit of the FF paradigm for those users displaying low signal-to-noise ratio of the recorded ERPs in the classic stimulation approach., Conclusion: In conclusion, we confirm previously reported results now systematically validated in an online setting and display specifically beneficial effects of FF for motor-impaired users., Significance: The FF paradigm thus constitutes a big step forward against the BCI inefficiency phenomenon., (Copyright © 2012 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Objectives: To examine the temporal contingency of anxiety and implantable cardioverter defibrillator (ICD) therapy (anti-tachycardia-pacing and shocks to prevent ventricular tachycardia and/or fibrillation)., Background: It is under debate whether anxiety is a precursor and/or consequence of ICD-therapy., Methods: In a prospective longitudinal study, fifty-four patients undergoing first-time ICD-implantation were assessed for anxiety, frequency of ICD-shocks and anti-tachycardia-pacing up to two days before ICD-implantation (T0) and twelve months later (T1)., Results: Anxiety at T0 did not predict frequency of ICD-shocks at T1, but ICD-shocks significantly predicted increased anxiety at T1. In contrast, anxiety at T0 and T1 was unrelated to frequency of anti-tachycardia-pacing. Effects remained stable when we controlled for potentially confounding variables (e.g. age, sex, cardiac health and depression at T0)., Conclusion: Our findings indicate that repeated ICD-shocks are a cause of anxiety in ICD-patients rather than a consequence, thus shock frequency should be minimized., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Soman (GD) and VX are chemical warfare agents that can be absorbed through the skin. We determined the median lethal dose (MLD) for the cutaneous application of GD and VX in anesthetized haired guinea pigs and then tested the ability of a currently fielded decontamination kit, the M291 Skin Decontamination Kit (SDK), and decontaminating foam made by SANDIA Labs to decontaminate areas that have been exposed to cutaneous applications of GD and VX. The fur of guinea pigs was clipped on the left flank 24h prior to exposure. Animals were anesthetized and 5 min later neat GD or neat VX was applied. The MLD for percutaneous exposure to GD was 11.6 mg/kg, and to VX it was 0.10mg/kg. To test the ability of the M291 SDK, either GD or VX was applied and removed 1 min later with the pads of the M291 SDK clasped in a pair of forceps and wiped across the flank of the animal. The MLDs for GD and VX removed with the M291 SDK pads were 76.9 mg/kg and 0.87 mg/kg, respectively. When neat GD or neat VX was applied and removed 1 min later in the same manner with gauze soaked in SANDIA foam (MDF-100), the MLDs were 412 mg/kg and 10.4 mg/kg respectively. These data demonstrate that GD and VX are significantly less potent when applied cutaneously than previously reported for subcutaneous injections and indicate that improvement is needed on the limited protective ratio provided by the M291 SDK., (Published by Elsevier Ireland Ltd.)

Respiratory sinus arrhythmia (RSA) is related to cardiac vagal outflow and the respiratory pattern. Prior infant studies have not systematically examined respiration rate and tidal volume influences on infant RSA or the extent to which infants' breathing is too fast to extract a valid RSA. We therefore monitored cardiac activity, respiration, and physical activity in 23 six-month old infants during a standardized laboratory stressor protocol. On average, 12.6% (range 0-58.2%) of analyzed breaths were too short for RSA extraction. Higher respiration rate was associated with lower RSA amplitude in most infants, and lower tidal volume was associated with lower RSA amplitude in some infants. RSA amplitude corrected for respiration rate and tidal volume influences showed theoretically expected strong reductions during stress, whereas performance of uncorrected RSA was less consistent. We conclude that stress-induced changes of peak-valley RSA and effects of variations in breathing patterns on RSA can be determined for a representative percentage of infant breaths. As expected, breathing substantially affects infant RSA and needs to be considered in studies of infant psychophysiology.

The importance of appropriate handling of artifacts in interbeat interval (IBI) data must not be underestimated. Even a single artifact may cause unreliable heart rate variability (HRV) results. Thus, a robust artifact detection algorithm and the option for manual intervention by the researcher form key components for confident HRV analysis. Here, we present ARTiiFACT, a software tool for processing electrocardiogram and IBI data. Both automated and manual artifact detection and correction are available in a graphical user interface. In addition, ARTiiFACT includes time- and frequency-based HRV analyses and descriptive statistics, thus offering the basic tools for HRV analysis. Notably, all program steps can be executed separately and allow for data export, thus offering high flexibility and interoperability with a whole range of applications.

Currently, the event-related potential (ERP)-based spelling device, often referred to as P300-Speller, is the most commonly used brain-computer interface (BCI) for enhancing communication of patients with impaired speech or motor function. Among numerous improvements, a most central feature has received little attention, namely optimizing the stimulus used for eliciting ERPs. Therefore we compared P300-Speller performance with the standard stimulus (flashing characters) against performance with stimuli known for eliciting particularly strong ERPs due to their psychological salience, i.e. flashing familiar faces transparently superimposed on characters. Our results not only indicate remarkably increased ERPs in response to familiar faces but also improved P300-Speller performance due to a significant reduction of stimulus sequences needed for correct character classification. These findings demonstrate a promising new approach for improving the speed and thus fluency of BCI-enhanced communication with the widely used P300-Speller.

Implantable cardioverter-defibrillators (ICD) are increasingly used for the prevention of potentially lethal cardiac arrhythmias due to their confirmed superior medical efficiency. Nevertheless, ICD-patients often suffer from psychosocial problems, e.g., anxiety and depression. These issues are rarely addressed in routine medical follow-up care. Due to the limited mobility of many ICD-patients, Internet-based care may be ideal for delivering psychosocial care to patients in their homes. Our pilot study and case studies illustrate prospects and challenges of this approach. We developed icd-forum.de, a 6-week internet-based prevention program that provides a platform for information, a virtual self-help group, and a professionally moderated chat room in order to help decrease anxiety and to improve quality of life. A critical evaluation in the context of other published studies on the subject allows recommendations for the implementation of future internet-based psychosocial programs for ICD-patients to be deduced. It is the authors' opinion that such programs offer advantages specifically for heart failure patients and they recommend their broader use. Prior to this, conclusive evaluation studies are needed.

Allergens are diverse proteins from mammals, birds, arthropods, plants, and fungi. Allergens associated with asthma (asthmagens) share a common protease activity that may directly impact respiratory epithelial biology and lead to symptoms of asthma. Alternaria alternata is a strong asthmagen in semiarid regions. We examined the impact of proteases from A. alternata on lung inflammation in vivo and on cleaving protease-activated receptor-2 (PAR(2)) in vitro. A. alternata filtrate applied to the airway in nonsensitized Balb/c mice induced a protease-dependent lung inflammation. Moreover, A. alternata filtrate applied to human bronchial epithelial cells (16HBE14o-) induced changes in intracellular Ca(2+) concentration ([Ca(2+)](i)), consistent with PAR(2) activation. These effects were blocked by heat inactivation or by serine protease inhibition of A. alternata filtrates, and mimicked by PAR(2) specific ligands SLIGRL-NH(2) or 2-furoyl-LIGRLO-NH(2), but not the PAR(1)-specific ligand TFLLR-NH(2). Desensitization of PAR(2) in 16HBE14o- cells with 2-furoyl-LIGRLO-NH(2) or trypsin prevented A. alternata-induced [Ca(2+)](i) changes while desensitization of PAR(1), PAR(3), and PAR(4) with thrombin had no effect on A. alternata-induced Ca(2+) responses. Furthermore, the Ca(2+) response to A. alternata filtrates was dependent on PAR(2) expression in stably transfected HeLa cell models. These data demonstrate that A. alternata proteases act through PAR(2) to induce rapid increases in human airway epithelial [Ca(2+)](i) in vitro and cell recruitment in vivo. These responses are likely critical early steps in the development of allergic asthma.

Transcriptional regulators play an important role for the survival of Neisseria meningitidis within its human host. We have recently shown that FarR acts as transcriptional repressor of the adhesin nadA in N. meningitidis. Here, we examined the FarR regulon by microarray analyses, qRT-PCR, and electrophoretic mobility shift assays, revealing that FarR is a highly specific repressor of nadA. We demonstrate by reporter gene fusion assays that alterations of the FarR binding site within the nadA promoter are sufficient to induce transcription of nadA. Furthermore, farR expression is growth phase-dependent. The highest transcription rate was observed in the late-exponential growth phase of meningococci. Upon contact with active components of the complement system in normal human serum, expression of farR is slightly downregulated. Concluding, we present FarR as an exquisitely specialized, growth phase-dependent, possibly complement-responsive transcriptional regulator in N. meningitidis., (Copyright © 2011 Elsevier GmbH. All rights reserved.)

Novel peptidomimetic pharmacophores to PAR(2) were designed based on the known activating peptide SLIGRL-NH(2). A set of 15 analogues was evaluated with a model cell line (16HBE14o-) that highly expresses PAR(2). Cells exposed to the PAR(2) activating peptide with N-terminal 2-furoyl modification (2-furoyl-LIGRLO-NH(2)) initiated increases in intracellular calcium concentration ([Ca(2+)](i) EC(50) = 0.84 μM) and in vitro physiological responses as measured by the xCELLigence real time cell analyzer (RTCA EC(50) = 138 nM). We discovered two selective PAR(2) agonists with comparable potency: compound 1 (2-aminothiazol-4-yl; Ca(2+) EC(50) = 1.77 μM, RTCA EC(50) = 142 nM) and compound 2 (6-aminonicotinyl; Ca(2+) EC(50) = 2.60 μM, RTCA EC(50) = 311 nM). Unlike the previously described agonist, these novel agonists are devoid of the metabolically unstable 2-furoyl modification and thus provide potential advantages for PAR(2) peptide design for in vitro and in vivo studies. The novel compounds described herein also serve as a starting point for structure-activity relationship (SAR) design and are, for the first time, evaluated via a unique high throughput in vitro physiological assay. Together these will lead to discovery of more potent agonists and antagonists of PAR(2).

It remains uncertain whether generalized anxiety disorder (GAD) and major depressive disorder (MDD) represent two separate diagnostic entities. The goal of this study was to examine whether comorbid MDD distinguishes individuals with GAD on a psychophysiological level during an experimentally-induced worrying procedure. Participants included 39 individuals with GAD, 14 of whom met the criteria for MDD. During the experimental procedure, participants were asked to worry or relax after an initial baseline phase while measuring their heart rate, high frequency heart rate variability (HF-HRV), skin conductance level, and subjective level of anxiety. The two groups did not differ in their subjective anxiety, heart rate response, and skin conductance levels. However, participants with comorbid MDD had greater HF-HRV values throughout the experiment than did those without MDD. At baseline, HF-HRV was significantly correlated with a self-report measure of depression. These results suggest that individuals with comorbid GAD and MDD can be distinguished based on HF-HRV from individuals with GAD but without MDD. These results support the distinction between GAD and MDD., (2010 Elsevier B.V. All rights reserved.)

The administration of purified human plasma-derived butyrylcholinesterase (HuBuChE) as a pretreatment has been demonstrated to enhance survival and protect against decreased cognitive function after exposure to organophosphorus poisons (OPs). Based on efficacy data obtained with guinea pigs and non-human primates and the lack of behavioral side effects, plasma-derived HuBuChE has been granted investigational new drug status by the US Food and Drug Administration. The recent availability of a recombinant form of HuBuChE (rHuBuChE) from the milk of transgenic goats has now allowed us to determine the pharmacokinetics of that material in guinea pigs and use it as a therapy following exposure to the VX. The rHuBuChE was expressed as a dimer and following intramuscular (i.m.) administration had more a rapid adsorption and clearance profile in guinea pigs than the plasma-derived material. Based on those data, we administered rHuBuChE i.m. 1h after a percutaneous exposure of guinea pigs to either 2xLD(50) or 5xLD(50) of VX. Post-exposure therapy with rHuBuChE provided improved survival at both challenge levels, 90% and 33% respectively versus 20% or 0% respectively for animals that did not receive therapy. These studies showed that BuChE can be efficacious as a therapy against percutaneous exposure to VX., (Published by Elsevier Ireland Ltd.)

Novel therapeutics to overcome the toxic effects of organophosphorus (OP) chemical agents are needed due to the documented use of OPs in warfare (e.g. 1980-1988 Iran/Iraq war) and terrorism (e.g. 1995 Tokyo subway attacks). Standard OP exposure therapy in the United States consists of atropine sulfate (to block muscarinic receptors), the acetylcholinesterase (AChE) reactivator (oxime) pralidoxime chloride (2-PAM), and a benzodiazepine anticonvulsant to ameliorate seizures. A major disadvantage is that quaternary nitrogen charged oximes, including 2-PAM, do not cross the blood brain barrier (BBB) to treat brain AChE. Therefore, we have synthesized and evaluated pro-2-PAM (a lipid permeable 2-PAM derivative) that can enter the brain and reactivate CNS AChE, preventing seizures in guinea pigs after exposure to OPs. The protective effects of the pro-2-PAM after OP exposure were shown using (a) surgically implanted radiotelemetry probes for electroencephalogram (EEG), (b) neurohistopathology of brain, (c) cholinesterase activities in the PNS and CNS, and (d) survivability. The PNS oxime 2-PAM was ineffective at reducing seizures/status epilepticus (SE) in diisopropylfluorophosphate (DFP)-exposed animals. In contrast, pro-2-PAM significantly suppressed and then eliminated seizure activity. In OP-exposed guinea pigs, there was a significant reduction in neurological damage with pro-2-PAM but not 2-PAM. Distinct regional areas of the brains showed significantly higher AChE activity 1.5h after OP exposure in pro-2-PAM treated animals compared to the 2-PAM treated ones. However, blood and diaphragm showed similar AChE activities in animals treated with either oxime, as both 2-PAM and pro-2-PAM are PNS active oximes. In conclusion, pro-2-PAM can cross the BBB, is rapidly metabolized inside the brain to 2-PAM, and protects against OP-induced SE through restoration of brain AChE activity. Pro-2-PAM represents the first non-invasive means of administering a CNS therapeutic for the deleterious effects of OP poisoning by reactivating CNS AChE., (Published by Elsevier Ireland Ltd.)

Respiratory sinus arrhythmia (RSA) is a common estimator of vagal outflow to the heart, dependent on parasympathetic activity. During variable breathing, both respiration rate and tidal volume contribute substantially to within-individual RSA variance. A respiratory control method allows for within-individual correction of the time-domain index of RSA. rsaToolbox is a set of MATLAB programs for scoring respiration-corrected RSA using measurements of cardiac interbeat intervals, respiratory-cycle times, and tidal volumes, recorded at different paced-breathing frequencies. The within-individual regression of RSA divided by tidal volume upon total respiratory cycle time is then used to estimate the baseline vagal tone for each breath of a given total respiratory-cycle time. During a subsequent analysis, the difference between the observed RSA (divided by the tidal volume at each breath) and the RSA divided by the tidal volume that was predicted by the baseline equation serves as an estimate of changes in vagal tone. rsaToolbox includes a graphical user interface for intuitive handling. Modular implementation of the algorithm also allows for flexible integration within other analytic strategies or for batch processing.

IL-12 is essential for protective T cell-mediated immunity against Salmonella infection. To characterize the role of the related cytokine IL-23, wild-type (WT) C57BL/6 and p19(-/-) mice were infected systemically with an attenuated strain of Salmonella enterica serovar Enteritidis (S. Enteritidis). IL-23-deficient mice controlled infection with S. Enteritidis similarly as WT mice. Similar IFN-gamma production as compared with WT mice, but defective IL-17A and IL-22 production was found in the absence of IL-23. Nevertheless, although IL-23 is required for T cell-dependent cytokine responses, IL-23 is dispensable for protection against S. Enteritidis when IL-12 is present. To analyze the role of IL-23 in the absence of IL-12, low doses of S. Enteritidis were administered to p35(-/-) mice (lacking IL-12), p35/19(-/-) mice (lacking IL-12 and IL-23), p35/40(-/-) mice (lacking IL-12, IL-23, and homodimeric IL-12p40), or p35/IL-17A(-/-) mice (lacking IL-12 and IL-17A). We found survival of p35(-/-) and p35/IL-17A(-/-) mice, whereas p35/19(-/-) and p35/40(-/-) mice died within 3-6 wk and developed liver necrosis. This indicates that IL-23, but not homodimeric IL-12p40, is required for protection, which, surprisingly, is independent of IL-17A. Moreover, protection was associated with IL-22, but not IL-17F or IL-21 expression or with neutrophil recruitment. Finally, anti-IL-22 treatment of S. Enteritidis-infected p35(-/-) mice resulted in liver necrosis, indicating a central role of IL-22 in hepatocyte protection during salmonellosis. In conclusion, IL-23-dependent IL-22, but not IL-17 production is associated with protection against systemic infection with S. Enteritidis in the absence of IL-12.

T(h)17 cells represent a new pro-inflammatory T(h) cell lineage distinct from T(h)1 and T(h)2 cells. T(h)17 cells have been shown to be involved in extracellular bacterial infection but their role in intracellular infection remains unclear. We found antigen-specific IL-17A production during a systemic infection of mice with the facultative intracellular bacterium Salmonella enterica serovar Enteritidis (S. Enteritidis) and examined the function and cellular source of IL-17A during the adaptive immune response to S. Enteritidis. Infected IL-17A-/- mice survived completely after inoculation with the highest infection dose found to be sub-lethal for wild-type (WT) C57BL/6 mice. However, at 20 and 80 days post-infection (d.p.i.), we repeatedly found mildly elevated bacterial burden in spleen and liver of IL-17A-/- mice as compared with WT mice. Overall, IL-17A-/- mice showed reduced clearance of S. Enteritidis. S. Enteritidis-specific IL-17A production was induced in splenocytes and lymph node cells of infected WT mice at both time points, 20 and 80 d.p.i. Classical CD4+ T(h)17 cells developed upon infection with Salmonella. CD4- gammadelta TCR+ and CD4- gammadelta TCR- cells were found to be additional IL-17A-producing cell populations. In infected IL-17A-/- mice, a normal T(h)1 cytokine profile was observed consistent with the overall subtle phenotype. Nevertheless, in the absence of IL-17A, recruitment of neutrophils and delayed-type hypersensitivity (DTH) reactivity was significantly compromised. Our data indicate that IL-17A responses are induced by Salmonella and mildly contribute to protective immunity during S. Enteritidis infection. Thus, IL-17A complements the IL-12/IFN-gamma axis which is essential for protective immunity against salmonellosis in mice and men.