Personalized therapy in rheumatoid arthritis (PETRA): a protocol for a randomized controlled trial to test the effect of a psychological intervention in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that primarily affects cartilage and bone. Psychological stress can both trigger disease exacerbation and result from disease activity. As standard pharmacological interventions alone have limited success in treating RA, a more comprehensive biopsychosocial approach to treatment has been recommended. In this prospective randomized controlled trial (RCT), a psychotherapeutically guided, group-based intervention program will be conducted with RA patients over a period of 9 months. This program combines a dynamic-interactional model with disorder-specific coping-oriented perspectives to improve patients' social, emotional, and problem-solving competencies as well as stress system functional status. The enrolment of 440 patients, randomly allocated to either an intervention (n = 220) or control group (n = 220), is planned. To evaluate the intervention effect, various indicators of RA disease activity, stress system activity, and psychological condition will be assessed through sets of standardized questionnaires and biochemical analyses of blood and saliva samples. Moreover, healthcare-related costs for each patient will be obtained using routine health insurance data. Outcome variables will be measured in all patients at regular intervals prior to intervention (baseline), during the 9-month intervention (five time points), and during a 9-month follow-up phase (three time points), allowing the comprehensive analysis of within- and between-subject effects, i.e. trajectories of the target variables in the intervention and control groups. In addition, to investigate the intervention effects on real-life stress system functioning in RA, 10 integrative single-case studies (n = 5 from the intervention group, n = 5 from the control group) will be conducted. In each study, once before and after the 9-month intervention, urine samples will be collected, and patients will fill out questionnaires for approximately 1 month at 12-h intervals. Moreover, weekly in-depth interviews will be conducted with patients to determine their previous week's emotionally positive and negative incidents. Using time series analysis, it is then possible to investigate whether and how stress system function in these RA patients has improved from the applied intervention. By using both an investigational macro- and microperspective, this project aims to evaluate a psychological intervention in the routine care of individuals with RA.Trial registration German Clinical Trials Register DRKS00028144. Registered on 1 March 2022.

Emotional states predict cellular immune system activity under conditions of life as it is lived: A multivariate time-series analysis approach.

The relationship between emotional states and immune system activity is characterized by bidirectional influences; however, limited information is available regarding the temporal dynamics of these effects. The goal of this investigation was to examine how these psychoimmunological interdependencies unfold over time under conditions of "life as it is lived". For this purpose, three healthy women collected their entire urine over a period of approximately two months at 12-h intervals (8 am-8 pm, 8 pm-8 am), resulting in a total of 112 to 126 consecutive measurements per subject. In addition, among other regular psychological assessments, the subjects completed the EWL-60-S, an emotional state questionnaire, each morning and evening. To assess the extent of T-helper type 1 immune activation, the neopterin per creatinine concentration was measured in the urine samples using high-pressure liquid chromatography. The dynamic relationships between the time series of the six emotional states (performance-related activity, general inactivity, extraversion/introversion, general feeling of comfort, emotional irritation, anxiety/depressiveness) and urinary neopterin levels were estimated in vector-autoregressive models and evaluated using Granger-causality tests, impulse-response functions and forecast error variance decompositions. The findings showed that emotional states explained up to 20% of the variance of urinary neopterin per creatinine levels, whereby most of the effects occurred within a period of approximately three days. Across all subjects, increases in anxiety/depressiveness and extraversion led to increases in neopterin levels, while a general feeling of comfort led to decreases in neopterin. These results emphasize the importance of the interdependencies between emotional states and immune system activity and showcase the potential that intensive longitudinal study designs offer for psychoneuroimmunology.

The deep space quantum link: prospective fundamental physics experiments using long-baseline quantum optics.

The National Aeronautics and Space Administration's Deep Space Quantum Link mission concept enables a unique set of science experiments by establishing robust quantum optical links across extremely long baselines. Potential mission configurations include establishing a quantum link between the Lunar Gateway moon-orbiting space station and nodes on or near the Earth. This publication summarizes the principal experimental goals of the Deep Space Quantum Link. These goals, identified through a multi-year design study conducted by the authors, include long-range teleportation, tests of gravitational coupling to quantum states, and advanced tests of quantum nonlocality.

On the Role of Psychoneuroimmunology in Oral Medicine.

Psychoneuroimmunology (PNI) is an area of interdisciplinary research exploring the complex interactions within the immuno-neuro-endocrine system in response to psychosocial influences. Such influences can trigger neurological changes, leading to immunological effects related to the emergence and course of various diseases. This concise clinical review explores the role of PNI in oral medicine in three exemplary models of oral disease: periodontitis, herpes labialis, and oral lichen planus. Previous literature has shown that psychosocial stress is related to exacerbations in these three oral diseases and to poorer overall oral health. The presumed biological mechanisms affect the activity of stress axes, i.e. the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS), and subsequent immune system dysregulation. Although these PNI mechanisms remain poorly understood, several stress reduction interventions in clinical oral medicine have already yielded promising results. In future work, the elucidation of pathways within PNI networks will require carefully designed studies with sensitive methodology, e.g. the integrative single-case design. A biopsychosocial approach has the potential to move disease models in oral medicine from simple connections rooted in empirical dualism and reductionism to the establishment of network-based models. Further research on these complex connections should lead to novel clinical approaches and preventive strategies in oral medicine.

About-Weekly Pattern in the Dynamic Complexity of a Healthy Subject's Cellular Immune Activity: A Biopsychosocial Analysis.

In a previous integrative single-case study, we collected biological, psychological and social time-series data on a 25-year-old healthy woman over the course of 126 12-h intervals (63 days) and used urinary neopterin as an indicator of cellular immune activity [Schubert et al. 2012 (1)]. The present re-evaluation introduced Dynamic Complexity (DC) as an additional non-linear and non-stationary measure to further investigate the subject's biopsychosocial dynamics during the study. The new time series dealing with urinary neopterin complexity revealed a cyclic, circaseptan (about-weekly) repeating pattern (6.59 days). The only weekly reoccurring events over the course of the study that were associated with this immunological pattern were the in-depth interviews with the subject (mean distance between interviews: 6.5 days). Superposed epoch analysis (SEA) revealed a U-shaped relation between neopterin complexity and interviews, with a decrease in neopterin complexity before and during interviews and an increase after interviews. Furthermore, the complexity scores for irritation, anxiousness/depressiveness and mental activity were positively correlated with neopterin complexity. The results suggest that the interviews, which had been found to be related to the subject's need for educational and/or social accomplishment, were marked by stress (decrease in psycho-immunological flexibility and adaptability), which was then relieved after the interviews (increase in psycho-immunological flexibility and adaptability). It appears that the subject's cellular immune activity, as indicated by neopterin complexity, functionally mirrored the emotional meaning she ascribed to the in-depth interviews. This re-evaluation is in line with the view that biopsychosocial research requires multimodal analysis of single cases based on qualitative (e.g., in-depth interviews) and quantitative (e.g., time series analysis) data under conditions of "life as it is lived".

The influence of storage conditions on the chemistry and flavor of hoppy ales.

Understanding the factors which lead to the (in)stability of the chemistry and sensory of hoppy beer styles such as India Pale Ales (IPAs) has become a major concern for many brewers. Therefore, the evolution of several volatiles under different storage conditions (room temperature, cold storage, forced aging) was investigated in eleven hoppy ales and one lager which were commercially produced in Germany. Compared to the lager, the fresh ales contained higher initial aldehyde levels. Furthermore, the distribution of lipid oxidation and Maillard reaction products differed from those typically found in lager beer. Upon storage, significant increases of some staling aldehydes were observed. Interestingly, the concentrations of some hop aroma volatiles like terpenoids (i.e. linalool and geraniol) were relatively stable throughout storage and counteracted "oxidized" impressions in ales high in these compounds. In comparison, hop aroma in some ales was driven by less stable volatiles such as esters.

How deviations in the elemental profile of Humulus lupulus grown throughout the U.S. and Germany influence hop and beer quality.

Recently studies based on limited sample sizes procured from minor hop growing regions have speculated that the elemental profile of hops can possibly be used to authenticate the origin of a hop because changes in hop elemental profiles were realted to growing region and that these changes might also be related to beer quality. To explore this further, 205 hop samples (i.e. 203 whole cone hops and 2 pelletized samples) compromised of 19 varieties were procured from the major hop growing regions (i.e. the U.S. and Germany). These hops were digested with microwave digestion and analyzed for 25 elements using ICP-MS. Hops from most of the U.S. regions (mainly WA) had vastly different elemental profiles than hops from Germany. German hops had significantly lower concentrations for most of the elements except for Cu and K. Interestingly, high alpha varieties had significantly different elemental profiles than varieties bred for aroma purposes. Dry-hopping trials were then performed in an ale and a lager with the hops that had significantly different elemental profiles. Although heavy metals were extracted from hops into beer, at the 5 g/L dry-hopping load used in this study, beer concentrations of these elements remained below regulated water quality standards set by Germany, the U.S., and Canada. Based on electron paramagnetic resonance, dry-hopping had an antioxidant impact on beer regardless of the original elemental profile of the hops which was correlated to hop polyphenol and α/ ß - acid concentrations. Overall these results highlight that many factors including location have the potential to influence the elemental profile of hops and that changes in the elemental profiles of hops can be related to beer quality.

Multi-loop atomic Sagnac interferometry.

The sensitivity of light and matter-wave interferometers to rotations is based on the Sagnac effect and increases with the area enclosed by the interferometer. In the case of light, the latter can be enlarged by forming multiple fibre loops, whereas the equivalent for matter-wave interferometers remains an experimental challenge. We present a concept for a multi-loop atom interferometer with a scalable area formed by light pulses. Our method will offer sensitivities as high as [Formula: see text] rad/s at 1 s in combination with the respective long-term stability as required for Earth rotation monitoring.

Case Report: Dynamic Interdependencies Between Complementary and Alternative Medicine (CAM) Practice, Urinary Interleukin-6 Levels, and Fatigue in a Breast Cancer Survivor.

Background: This study investigated the influence of complementary and alternative medicine (CAM) techniques (i.e., Jin Shin Jyutsu, music, physiotherapy, Tai Chi, and energy healing) on urinary interleukin-6 (IL-6) levels and fatigue in a 49-year-old breast cancer survivor suffering from cancer-related fatigue and depression. Data were sampled under conditions of "life as it is lived." Methods: For 28 days, a female breast cancer survivor collected her full urine output in 12-h intervals from about 8 a.m. to 8 p.m. and from about 8 p.m. to 8 a.m. These urine samples were used to determine urinary IL-6 levels through ELISA and creatinine concentrations via HPLC. In 12-h intervals (every morning and evening), the patient completed the DIARI, which included fatigue measurement and notes on incidents and activities such as CAM practice. In addition, the patient was interviewed weekly to identify meaningful everyday incidents. In this context, CAM practice was also discussed. Time series analysis consisted of ARIMA modeling and cross-correlational analyses (p < 0.05). Results: When each CAM technique was considered separately in time series analysis, CAM was consistently associated with increases in urinary IL-6 release and decreases in fatigue. Furthermore, when all CAM techniques experienced as positive were included in one time series, a biphasic urinary IL-6 response pattern was found in which CAM practice was first preceded by decreases in IL-6 by 12-0 h and then followed by increases in IL-6 after 108-120 h. Finally, cross-correlations between IL-6 and fatigue showed that increases in IL-6 were followed by decreases in fatigue intensity after 48-60 h and, conversely, that decreases in fatigue intensity were followed by decreases in IL-6 after 24-36 h and 48-60 h. Conclusion: IL-6 increases and fatigue decreases highlight potential health-promoting effects of CAM practice. Moreover, a cyclic IL-6 pattern in response to all CAM activities experienced as positive underscores that CAM was meaningful to the patient. Additionally, a negative feedback circuit between IL-6 and fatigue intensity was detected. Taken together, this study confirms the necessity of integrating subjective meaning and dynamic complexity into biopsychosocial research in order to understand human functioning under real-life conditions.

Twin-lattice atom interferometry.

Inertial sensors based on cold atoms have great potential for navigation, geodesy, or fundamental physics. Similar to the Sagnac effect, their sensitivity increases with the space-time area enclosed by the interferometer. Here, we introduce twin-lattice atom interferometry exploiting Bose-Einstein condensates of rubidium-87. Our method provides symmetric momentum transfer and large areas offering a perspective for future palm-sized sensor heads with sensitivities on par with present meter-scale Sagnac devices. Our theoretical model of the impact of beam splitters on the spatial coherence is highly instrumental for designing future sensors.

Evaluation of Variety, Maturity, and Farm on the Concentrations of Monoterpene Diglycosides and Hop Volatile/Nonvolatile Composition in Five Humulus lupulus Cultivars.

Pentose-hexose monoterpene alcohol glycosides were isolated and semiquantitatively measured in dried Humulus lupulus cones using UHPLC-qTOF-MS/MS and HPLC fractionation followed by GC-MS. The samples evaluated included hop cones from five important dual-purpose cultivars (varieties) in the United States, from two locations (farms) per variety and from three distinct harvest time points (maturities) per location, as dictated by dry-matter (% w/w) at the time of harvest. Hop variety accounted for the biggest variation among the concentrations of pentose-hexose monoterpene alcohol glycosides as well as other volatile and nonvolatile chemical factors measured in the samples. This indicates that genetics plays a major role in hop flavor production. Interestingly, "maturity", or ripeness at the time of harvest, was the next most significant factor impacting the concentrations of pentose-hexose monoterpene alcohol glycosides along with most of the other volatile and nonvolatile factors (such as total oil concentration and composition). However, maturity notably had a bigger impact on some cultivars such as Sabro, Mosaic, Simcoe, and Citra. Surprisingly, farm (i.e., location, farming practices, etc.) accounted for the least amount of variation among the concentrations of the different analytical factors. These results highlight the importance of breeding/genetics as well as considering hop maturity/ripeness at the time of harvest on the production and subsequent development of analytical chemical factors associated with driving hoppy beer flavor. It is essential for future studies assessing the impact of different farming practices and locations (i.e., regionality, terroir, etc.) on the constituents in hops important for hoppy beer flavor to consider and account for the impact of hop maturity as well as genetics.

Dynamic Effects of CAM Techniques on Inflammation and Emotional States: An Integrative Single-Case Study on a Breast Cancer Survivor.

BACKGROUND: This study on a breast cancer survivor investigated how episodic practice of various complementary and alternative medicine (CAM) techniques affected the dynamics of emotional states and urinary neopterin-an inflammation marker. METHODS: The 49-year-old female patient (diagnosis: ductal breast carcinoma 5 years before study start, suffering from chronic fatigue and depression) collected her entire urine in 12-hour intervals (from about 8 a.m. to 8 p.m. and from about 8 p.m. to 8 a.m.) for 28 days. The resulting 55 consecutive urine samples were analyzed for neopterin and creatinine levels using HPLC. Also in 12-hour intervals, the patient filled out questionnaires on emotional states and everyday routine, including CAM practice. Weekly, she was interviewed to identify emotionally meaningful everyday incidents, including use of CAM techniques. Time series analysis consisted of ARIMA modeling and cross-correlational analyses. RESULTS: Qualitative evaluation revealed that, with the exception of Tai Chi, all CAM techniques, that is, Jin Shin Jyutsu, music, physiotherapy and energy healing, were experienced as positive. Cross-correlational analyses showed that practice of such CAM techniques was followed first by significant (P < .05) increases in positive mood and mental activity on the same day (lag 0) and then by decreases in positive mood after a total of 72 to 84 hours (+lag 6) and in mental activity after a total of 84 to 96 hours (+lag 7). Negative mood, by contrast, first decreased on the day of CAM practice (lag 0) and then increased after a total of 84 to 96 hours (+lag 7) following CAM. Moreover, urinary neopterin levels first increased on the day of CAM practice (lag 0) and then decreased after a total of 36 to 48 hours (+lag 3). Similar biphasic effects were also detected for irritation in response to CAM, although only partly significant. CONCLUSION: Cyclic psychophysiological response patterns following CAM practice were attributable to biopsychosocial feedback mechanisms involving personally meaningful experiences. As lower neopterin levels following CAM point to a health-promoting effect, the patient of this study may have actively contributed to her healing process through episodic CAM practice.

Real-Life Cause-Effect Relations Between Urinary IL-6 Levels and Specific and Nonspecific Symptoms in a Patient With Mild SLE Disease Activity.

Background: Little is known about the real-time cause-effect relations between IL-6 concentrations and SLE symptoms. Methods: A 52-year-old woman with mild SLE activity collected her entire urine for the determination of IL-6/creatinine and protein/creatinine levels (ELISA, HPLC) for a period of 56 days in 12 h intervals (total: 112 measurements). Additionally, she answered questionnaires (VAS) on oral ulceration, facial rash, joint pain, fatigue and tiredness and measured her temperature orally twice a day. Time-series analyses consisted of ARIMA modeling and cross-correlational analyses (one lag = 12 h, significance level = p < 0.05). Results: Statistical analyses showed that increased urinary IL-6 concentrations preceded increased urinary protein levels by 36-48 h (lag3: r=+.225; p=.017) and that, in the opposite direction of effect, increased urinary protein preceded urinary IL-6 decreases by 12-24 h (lag1: r=-.322; p<.001). Moreover, urinary IL-6 increases co-occurred with increased oral ulceration (lag0: r=+.186; p=.049); after 48-60 h, however, IL-6 increases showed a strong tendency to precede oral ulceration decreases (lag4: r=-.170; p=.072). Increases in facial rash preceded decreases in urinary IL-6 after 84-96 h (lag7: r=-.215; p=.023). As to fatigue, increases in urinary IL-6 co-occurred with decreased fatigue (lag0: r=-.193; p=.042); after 84-96 h, however, IL-6 increases preceded fatigue increases (+lag7: r=+.189; p=.046). Finally, joint pain, tiredness and body temperature did not significantly correlate with urinary IL-6 concentrations in either direction of effect. Conclusions: The results of this evaluation point to real-life feedback mechanisms between immune activity and SLE symptoms. Comparison with a previous evaluation of this patient suggests a counterregulatory mechanism between Th1 activity and IL-6. These findings are preliminary and require replication to draw firm conclusions about the real-time relation between IL-6 and SLE disease activity.

Evaluating the Chemical Components and Flavor Characteristics Responsible for Triggering the Perception of "Beer Flavor" in Non-Alcoholic Beer.

Forty-two commercial non-alcoholic beer (NAB) brands were analyzed using sensory and chemical techniques to understand which analytes and/or flavors were most responsible for invoking the perception of "beer flavor" (for Northern Californian consumers). The aroma and taste profiles of the commercial NABs, a commercial soda, and a carbonated seltzer water (n = 44) were characterized using replicated descriptive and CATA analyses performed by a trained sensory panel (i.e., 11 panelists). A number of non-volatile and volatile techniques were then used to chemically deconstruct the products. Consumer analysis (i.e., 129 Northern Californian consumers) was also used to evaluate a selection of these NABs (i.e., 12) and how similar they thought the aroma, taste and mouthfeels of these products were to beer, soda, and water. The results show that certain constituents drive the aroma and taste profiles which are responsible for invoking beer perception for these North American consumers. Further, beer likeness might not be a driver of preference in this diverse beverage class for Northern Californian consumers. These are important insights for brewers planning to create products for similar markets and/or more broadly for companies interested in designing other functional/alternative food and beverage products.

Characterizing Volatile and Nonvolatile Factors Influencing Flavor and American Consumer Preference toward Nonalcoholic Beer.

In this study, the chemical and sensory profiles of 42 different nonalcoholic beer (NAB) brands/styles already on the global market and produced through several different brewing techniques were evaluated. A trained panel (i.e., 11 panelists) performed standard-driven descriptive and check-all-that-apply analyses in triplicate to sensorially characterize the aroma and taste/mouthfeel profiles of 42 commercial NABs, a commercial soda, and a commercial seltzer water (n = 44). These beers were also chemically deconstructed using several different analytical techniques targeting volatile and nonvolatile compounds. Consumer analysis (n = 129) was then performed to evaluate the Northern Californian consumer hedonic liking of a selection (n = 12) of these NAB brands. These results provide direction to brewers and/or beverage producers on which techniques they should explore to develop desirable NAB offerings and suggest chemical targets that are indicators of specific flavor qualities and/or preference for American consumers.

The Lipopeptide MALP-2 Promotes Collateral Growth.

Beyond their role in pathogen recognition and the initiation of immune defense, Toll-like receptors (TLRs) are known to be involved in various vascular processes in health and disease. We investigated the potential of the lipopeptide and TLR2/6 ligand macrophage activating protein of 2-kDA (MALP-2) to promote blood flow recovery in mice. Hypercholesterolemic apolipoprotein E (Apoe)-deficient mice were subjected to microsurgical ligation of the femoral artery. MALP-2 significantly improved blood flow recovery at early time points (three and seven days), as assessed by repeated laser speckle imaging, and increased the growth of pre-existing collateral arteries in the upper hind limb, along with intimal endothelial cell proliferation in the collateral wall and pericollateral macrophage accumulation. In addition, MALP-2 increased capillary density in the lower hind limb. MALP-2 enhanced endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) release from endothelial cells and improved the experimental vasorelaxation of mesenteric arteries ex vivo. In vitro, MALP-2 led to the up-regulated expression of major endothelial adhesion molecules as well as their leukocyte integrin receptors and consequently enhanced the endothelial adhesion of leukocytes. Using the experimental approach of femoral artery ligation (FAL), we achieved promising results with MALP-2 to promote peripheral blood flow recovery by collateral artery growth.