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Metabolic Changes After Bronchoscopic Lung Volume Reduction With Endobronchial Valves in COPD Patients
No full textOBJECTIVES: Little is known about the effect of bronchoscopic lung volume reduction using endobronchial valves (BLVR-EBV) on extrapulmonary manifestations like body composition, muscle function or metabolism. Pulmonary rehabilitation (PR) clearly addresses extrapulmonary manifestations of COPD, including physical inactivity and low muscle mass. However, the added impact of BLVR-EBV+PR remains unknown. Therefore, this study aimed to assess the effect of BLVR-EBV on body composition, muscle function and metabolic markers and whether PR has an additional impact on these outcomes. METHODS: Subjects with severe COPD eligible for both PR and BLVR-EBV were randomized into three groups: PR+BLVR-EBV, BLVR-EBV+PR, or only BLVR-EBV (n=97). Assessments included Dual Energy X-ray Absorptiometry, thigh muscle Computed Tomography, muscle strength measurements, accelerometry, and plasma (leptin, adiponectin, insulin, and triglycerides) at baseline and six months after the last intervention. RESULTS: A total of 74 participants completed the study. At follow-up, there were significant increases in the groups combined and both groups separated in total weight, lean mass, fat mass, muscle strength, daily physical activity, and triglyceride levels while leptin/fat mass ratio levels were significantly reduced. No differences were found between groups who underwent BLVR-EVR alone or BLVR-EBV with PR. CONCLUSIONS: BLVR-EBV results in significant increases in body weight, lean and fat mass, muscle strength and daily physical activity level, and impacts on adipokine profile, irrespective of PR. This underscores the systemic benefits of addressing lung hyperinflation in patients with severe COPD
Citrullination of tissue factor pathway inhibitor alpha by peptidylarginine deiminase 4 impairs its natural anticoagulant activity toward factors Xa and VIIa/tissue factor and reduces binding to its cofactor protein S
No full textBACKGROUND: Neutrophils are known to externalize their DNA and intracellular contents to neutralize invading pathogens. This process may enhance blood coagulation during inflammation. TFPI binds to extracellular DNA and may be citrullinated by peptidylarginine deiminase 4 (PAD4). Citrullination of TFPI reduces its anticoagulant activity towards factor Xa, but appeared to retain its inhibition of tissue factor (TF)-triggered thrombin generation, indicating a differential regulation of TFPI functions by PAD4. AIM: This work aims to study effects of citrullination of TFPI alpha on the inhibition of FXa, FVIIa/TF, and the cofactor activity of protein S. METHODS: The effect of TFPI citrullination on inhibition of FXa and FVIIa/TF was measured by chromogenic assays using purified components and by calibrated automated thrombography. Interaction with protein S was assessed by SPR and solid-phase binding assays using immobilized protein S, recombinant TFPI, and synthetic TFPI domains. RESULTS: Citrullination of TFPI abolished its ability to inhibit FXa- and FXIa-triggered thrombin generation. However, its impaired inhibition of TF-triggered thrombin generation was still enhanced by protein S. Chromogenic assays revealed that citrullinated TFPI was essentially inactive as an inhibitor of the FVIIa-TF complex in the absence of protein S, but partially restored by protein S. Interaction studies revealed that binding of citrullinated TFPI to protein S was reduced approximately fourfold. CONCLUSION: Citrullinated TFPI shows impaired natural anticoagulant activity. While anti-FXa activity is essentially absent, its anti-TF/FVIIa activity can still be enhanced by protein S. This enhancement is incomplete however, as protein S binding to citrullinated TFPI is impaired
Heterogeneity and Penumbra of White Matter Hyperintensities in Small Vessel Diseases Determined by Quantitative MRI
Get PDFBACKGROUND: White matter hyperintensities (WMHs) are established structural imaging markers of cerebral small vessel disease. The pathophysiologic condition of brain tissue varies over the core, the vicinity, and the subtypes of WMH and cannot be interpreted from conventional magnetic resonance imaging. We aim to improve our pathophysiologic understanding of WMHs and the adjacently injured normal-appearing white matter in terms of microstructural and microvascular alterations using quantitative magnetic resonance imaging in patients with sporadic and genetic cerebral small vessel disease. METHODS: Structural T2-weighted imaging, multishell diffusion imaging, and dynamic contrast-enhanced magnetic resonance imaging were performed at 3T in 44 participants with sporadic cerebral small vessel disease and 32 participants with monogenic cerebral small vessel disease (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; 59±12 years, 41 males) between June 2017 and May 2020 as part of the prospective, multicenter (Edinburgh, the United Kingdom; Maastricht, the Netherlands; and Munich, Germany), observational INVESTIGATE-SVDs study (Imaging Neurovascular, Endothelial and Structural Integrity in Preparation to Treat Small Vessel Diseases). The mean diffusivity, free water content, and perfusion (all derived from multishell diffusion imaging), as well as the blood-brain barrier leakage and plasma volume fraction (derived from dynamic contrast-enhanced magnetic resonance imaging), were compared between deep and periventricular WMH types using paired t tests. Additional spatial analyses were performed inside and outside the WMH types to determine the internal heterogeneity and the extent of the penumbras, that is, adjacent white matter at risk for conversion to WMH. RESULTS: Periventricular WMH had higher mean diffusivity, higher free water content, and more plasma volume compared with deep WMH (P<0.001, P=0.01, and P<0.001, respectively). No differences were observed in perfusion (P=0.94) and blood-brain barrier leakage (P=0.65) between periventricular and deep WMHs. The spatial analyses inside WMH and the adjacent white matter revealed a gradual gradient in white matter microstructure, free water content, perfusion, and plasma volume but not in blood-brain barrier leakage. CONCLUSIONS: We showed different pathophysiological heterogeneity of the 2 WMH types. Periventricular WMHs display more severe damage and fluid accumulation compared with deep WMH, whereas deep WMHs reflect stronger hypoperfusion in the lesion's core. REGISTRATION: URL: https://www.isrctn.com; Unique identifier: ISRCTN10514229.</p
Investigating the impact of the effective point of measurement for plane-parallel ionization chambers in clinical proton beams
No full textObjective.To investigate the impact of the positioning of plane-parallel ionization chambers in proton beams on the calculation of the chamber-specific factorfQand, hence, the beam quality correction factorkQ,Q0.Approach.Monte Carlo simulations were performed to calculate the chamber-specific factorfQin monoenergetic proton beams for six different plane-parallel ionization chambers while positioning the chambers with a) their reference point and b) their effective point of measurement accounting for the water equivalent thickness of the entrance window.Main results.For all ionization chamber models investigated in this study, the difference infQbetween both positioning approaches was larger for steeper dose gradients and bigger differences between the geometrical thickness and water-equivalent thickness of the entrance window. The largest effect was 1.2% for the IBA PPC-05 ionization chamber at an energy of 60 MeV.Significance.The positioning of plane-parallel ionization chambers in proton beams has a systematic impact on thefQfactor. This is especially of relevance for thekQ,Q0factors presented in the recently updated TRS-398 code of practice (CoP) from IAEA. The background is that a positioning with the effective point of measurement is prescribed in TRS-398 CoP, however, all Monte Carlo derived data that have been employed for the update are based on a positioning of the ionization chambers with their reference point. Hence, the updatedkQ,Q0factors for plane-parallel ionization chambers in proton beams are subject to systematic errors that can be as large as 0.5%.</p
Memory, post-fascism and the far-right
Get PDFAfter 78 years of democracy, Italy continues to grapple with its recent past in the political, social, and cultural spheres. Its experience of fascism under Mussolini, its dual participation in the Second World War, and the continuous and still existent connections between the ideological factions of the 1930s-1940s and now render the country a rich case for the study of public history and memory. The specificity of these characteristics has often made Italian history and memory look like an outlier, shaped by circumstances difficult to compare with those of other countries'. This paper argues that contemporary Italian memory politics are in reality a valuable source of information about the kind of mnemonic discourses that may arise in other (Western) European countries, given the increasingly polarised and populist European landscape. Our study of discourses put forwarded by the post-fascist party Fratelli d'Italia reveals a set of mnemonic tools with which they successfully banalise fascism and chip at Italian public discourse slowly but surely. The comparison between this discourse and that of VOX and AfD in Spain and Germany, respectively, shows that these tools, ranging from nativism to policy (de)legitimation linked to fascist imagery, has started to transfer to other countries' political strategies
Incentivizing Responses in International Organization Elite Surveys:Evidence from the World Bank
No full textScholars of International Organizations ( IOs) increasingly use elite surveys to study the preferences and decisions of policymakers. When designing these surveys, one central concern is low statistical power, because respondents are typically recruited from a small and inaccessible population. However, much of what we know about how to incentivize elites to participate in surveys is based on anecdotal reflections, rather than systematic evidence on which incentives work best. In this article, we study the efficacy of three incentives in a preregistered experiment with World Bank staff. These incentives were the chance to win an Amazon voucher, a donation made to a relevant charity, and a promise to provide a detailed report on the findings. We find that no incentive outperformed the control group, and the monetary incentive decreased the number of respondents on average by one-third compared to the control group (from around 8% to around 5%)
Underlying Working Mechanisms of Virtual Reality Exposure:Exploring the Role of Fearful Expectancies and Habituation
No full textWhile research has primarily focused on establishing the efficacy of virtual reality (VR) exposure, relatively scant attention has been paid to the underlying working mechanisms that drive the effects. The present study examined the role of fearful expectancies and fear reduction (habituation) in VR exposure. Fearful expectancies were measured before, during (retrospectively), and after a VR exposure session in 121 participants with elevated fear of spiders. In addition, skin-conductance and heart rate were measured throughout the exposure session to examine fear reduction within the exercises and across the session. Fearful expectancies decreased after VR exposure. Larger decreases were associated with better outcomes 1 week (in the verbal and behavioral measures) and 3 months (in one of the verbal measures) after exposure. Levels of expectancies during exposure were not associated with the outcome. We did not find evidence that expectancies about own reactions were better testable in VR exposure than expectancies about the spider. Fear reduction within the exercises or across the session did generally not predict VR exposure outcome. It is recommended to focus on various operationalizations and experimental manipulations of the mechanisms, as well as to compare these mechanisms between VR and in vivo exposure in future research
Attention and Nocebo Hyperalgesia:Testing a Novel Virtual Reality Attention Bias Modification Paradigm
No full textNocebo effects in pain (nocebo hyperalgesia) have received significant attention recently, with negative expectancies and anxiety proposed to be explanatory factors. While both expectancy and anxiety can bias attention, attention has been rarely explored as a potential mechanism involved in nocebo hyperalgesia. The present study aimed to explore whether attention bias modification (ABM) using an immersive, ecologically valid VR paradigm successfully induced attention biases (AB) and subsequently influenced nocebo hyperalgesia. One-hundred and two healthy participants were randomised in a 2 (AB training: towards vs. away from pain) x 2 (nocebo condition: nocebo vs. control) design. Pain-related AB was successfully changed by the VR paradigm as measured by reaction time and gaze, with moderate to large effects. Participants then completed either a nocebo instruction and conditioning procedure (nocebo paradigm) or a matched control procedure. The primary outcome was self-reported pain intensity. Secondary outcomes were attention bias and self-reports of expectancy, anticipatory anxiety, and state anxiety. The nocebo paradigm induced significantly greater pain expectancy, anticipatory anxiety and pain intensity during the test phase for the nocebo group compared to control. Pain expectancy also fully mediated the effect of the nocebo group on nocebo hyperalgesia and anticipatory anxiety in separate models. ABM did not, however, affect nocebo hyperalgesia or pain expectancy, casting doubt on the potential for ABM to inoculate against nocebo hyperalgesia. Unexpected effects of ABM were observed for state anxiety and anticipatory anxiety, whereby training away from pain exacerbated each, which necessitates further exploration. PERSPECTIVE: This article tests the efficacy of a novel attention bias modification paradigm, designed in virtual reality, for inducing pain-related biases, and whether these biases exacerbate or inoculate against nocebo hyperalgesia. While pain-related biases were successfully induced, there was no relationship with the strength of induced nocebo hyperalgesia
Expanding phenotypic insights of palmoplantar keratodermas based on novel FAM83G variants
No full textWe report two unrelated patients with new pathogenic variants in the FAM83G gene, supporting the causal link to previously identified families with recessive hereditary palmoplantar keratoderma. Although structural changes of the hairs are a key feature of FAM83G-associated disease, a complete loss of the gene, seen in one of the patients, shows normal hair and does not support this part of the clinical phenotype
