Changes of immunosuppressive medication because of COVID-19 by patients with chronic inflammatory rheumatic diseases: anxiety was not a major driver.

OBJECTIVES: To study treatment decisions of patients with chronic inflammatory rheumatic diseases (CIRD) at the beginning of the SARS- CoV-2 pandemic in relation to disease characteristics with focus on anxiety. METHODS: A total of 970 CIRD patients diagnosed with rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), psoriasis arthritis (PsA) and connective tissue diseases (CTD), selected from our records who had presented to our hospital at least twice during last year, were contacted by telephone to be asked about medication changes, health status and therapy satisfaction. Standardised tools were used to assess disease activity, anxiety and depression, the latter by Hospital Anxiety and Depression Score (HADS) with a score ≥8 denoting definite anxiety and/or depression. The cut-off for RADAI was set at ≥3.2 and for BASDAI ≥4. Compliance with prevention rules and vaccination status were assessed. RESULTS: Complete interviews of 557 patients (57.4%) made between April and July 2020 were available for analysis. The median age was 55 (47-63), disease duration 9.0 (4.5-17.0) years, 61.9% females. A recent change in medication was reported by 197 patients (35.4%), 51.2% of which admitted that this decision was mainly made due to the pandemic with more changes occurring with bDMARDs (21.8%) than cDMARDs (6.6%) and corticosteroids (5.4%). There was no major difference between patients who changed because of the pandemic or self-reported inactive disease versus patients who did not change therapy regarding disease activity, depression and anxiety (41%, 17.2%, 31.3% vs. 47.5%, 22.5%, 35.0% vs. 48.9%, 27.7%, 34.1%). More than 90% of patients reported that they rigorously followed Corona prevention rules. The majority of patients were vaccinated against influenza (55.3%) and pneumococci (61.3%), respectively. CONCLUSIONS: Anxiety, depression and disease activity did not play an important role in decisions favouring change of therapy, even though many patients changed medication due to the pandemic. Patients probably protected themselves by strictly adhering to hygiene recommendations. Vaccination rates against influenza and pneumococci were better than previously reported, but still too low.

Cortisol during adolescence organises personality traits and behavioural syndromes.

Despite the growing evidence for the importance of developmental experiences shaping consistent individual differences in behaviour and physiology, the role of endocrine factors underlying the development and maintenance of such differences across multiple traits, remains poorly understood. Here, we investigated how an experimental manipulation of circulating glucocorticoids during early adolescence affects behavioural and physiological variation and covariation later in life in the precocial cavy (Cavia aperea). Plasma cortisol concentrations were experimentally elevated by administering cortisol via food for 3 weeks. Struggle docility, escape latency, boldness, exploration and social behaviour were then tested three times after individuals attained sexual maturity. In addition, blood samples were taken repeatedly to monitor circulating cortisol concentrations. Exogenous cortisol affected mean trait expression of plasma cortisol levels, struggle docility and escape latency. Repeatability of cortisol and escape latency was increased and repeatability of struggle docility tended to be higher (approaching significance) in treated individuals. Increased repeatability was mainly caused by an increase of among-individual variance. Correlations among docility, escape latency and cortisol were stronger in treated animals compared to control animals. These results suggest that exposure to elevated levels of cortisol during adolescence can alter animal personality traits as well as behavioural syndromes. Social and risk-taking traits showed no correlation with cortisol levels and were unaffected by the experimental manipulation, indicating behavioural modularity. Taken together, our data highlight that cortisol can have organising effects during adolescence on the development of personality traits and behavioural syndromes, adding to the increasing evidence that not only early life but also adolescence is an important sensitive period for behavioural development.

Ropeginterferon alfa-2b, a novel IFNα-2b, induces high response rates with low toxicity in patients with polycythemia vera.

In this prospective, open-label, multicenter phase 1/2 dose escalation study, we used a next-generation, mono-pegylated interferon (IFN) α-2b isoform, ropeginterferon alfa-2b. The unique feature of ropeginterferon alfa-2b is a longer elimination half-life, which allows administration every 2 weeks. We present data from 51 polycythemia vera patients. The main goal was to define the maximum tolerated dose and to assess safety and efficacy. A dose range of 50 to 540 µg was tested without the appearance of dose-limiting toxicities. All drug-related adverse events were known toxicities associated with IFN-α. The cumulative overall response rate was 90%, comprising complete response in 47% and partial response in 43% of patients; the best individual molecular response level was a complete response in 21% of patients and partial response in 47%. Notably, we did not observe any correlation between the dose level and the response rate or response duration, suggesting that already low levels of ropeginterferon alfa-2b are sufficient to induce significant hematologic and molecular responses. These data suggest promising efficacy and safety of ropeginterferon alfa-2b and support the development of the drug in a randomized phase 3 clinical trial. The study was disclosed at www.clinicaltrials.gov as #NCT01193699 before including the first patient.

Dysautonomia in prodromal α-synucleinopathy: peripheral versus central autonomic degeneration.

BACKGROUND AND PURPOSE: There is an urgent need for early predictive markers for the course of disease in prodromal α-synucleinopathies such as idiopathic rapid eye movement (REM) sleep behaviour disorder. Autonomic cardiac/vascular dysfunction is a prominent feature in advanced α-synucleinopathies, but its diagnostic value as an early neurodegenerative marker remains unclear. The latter may be complicated since synuclein-mediated neurodegeneration may involve central and peripheral components of the autonomic nervous system. METHODS: The diagnostic value of autonomic symptoms and central and peripheral autonomic markers of blood pressure and heart rate regulation were prospectively evaluated in 20 subjects with idiopathic REM sleep behaviour disorder and 20 age-matched healthy controls. RESULTS: Although subjects with REM sleep behaviour disorder showed no clinical autonomic symptoms, blood pressure (P ≤ 0.035) and heart rate response (P ≤ 0.065) were slightly diminished during orthostatic challenge. Autonomic dysregulation was distinctively reflected in lower resting heart rate (all components, P ≤ 0.05) and blood pressure variability (low frequency component, P ≤ 0.024) indicating peripheral cardiac/vascular denervation. In contrast, baroreflex sensitivity and central cardiac autonomic outflow (sympathovagal balance) were well preserved indicating intact central autonomic regulation. Heart rate variability [very low frequency component, receiver operating characteristic (ROC) area under the curve (AUC) 0.80, P ≤ 0.001] and blood pressure variability (low frequency component ROC AUC 0.73, P ≤ 0.01) but not baroreflex sensitivity and sympathovagal balance showed an excellent diagnostic accuracy in identifying subjects with REM sleep behaviour disorder and healthy controls. CONCLUSIONS: Cardiac/vascular dysfunction in prodromal α-synucleinopathy arises from peripheral rather than from central autonomic degeneration. Autonomic indices encoded in heart rate and blood pressure variability are precise functional markers of early synuclein-mediated neurodegeneration.

Perceived cognitive impairments after critical illness: a longitudinal study in survivors and family member controls.

BACKGROUND: Many former intensive care unit (ICU) patients report difficulties in cognitive functions especially in their daily life. We aimed to measure perceived cognitive impairments in daily life in survivors of critical illness and their family member controls (FMC). METHODS: Perceived cognitive impairments were assessed two times after ICU discharge using an adapted German version of the "Functional Assessment of Cancer Therapy - Cognitive Function" questionnaire. After 3 months, 127 former patients and 52 FMC participated and 103/127 patients and 36/52 FMC were followed up after 6 months. Baseline information was obtained retrospectively. RESULTS: We found no significant differences between the patient sample and FMC, 3 and 6 months after ICU discharge. Based on questionnaire ratings, cluster analysis divided patients and FMC into a cognitively 'impaired' and a 'non-impaired' cluster. Questionnaire scales differed significantly prior to ICU admission as well as 3 and 6 months after ICU discharge between both clusters. While differences between patients and FMC were less pronounced in the 'non-impaired' cluster, patients were significantly more impaired than FMC at 3 and 6 months after ICU discharge in the 'impaired' cluster. DISCUSSION: A substantial part of former patients were affected by post-ICU cognitive impairment in daily life. Pre-existing cognitive impairments were a risk factor. These patients would probably profit from tailored neurorehabilitative therapy. Therefore, an efficient tool to identify potential patients for neurorehabilitation is needed. The questionnaire revealed good psychometric properties. We recommend a comprehensive validation of the questionnaire in this patient population.

Pressurized intraperitoneal aerosol chemotherapy in women with recurrent ovarian cancer: A phase 2 study.

OBJECTIVE: Recurrent ovarian, fallopian or peritoneal cancer with peritoneal carcinomatosis (ROCPC) is resistant to systemic chemotherapy. We assessed the safety and activity of laparoscopic pressurized intraperitoneal aerosol chemotherapy (PIPAC) in women with this cancer. METHODS: In this open-label, single-arm phase 2 study, patients underwent 3 courses q 28-42 days of PIPAC with doxorubicin 1·5 mg/m(2) followed by cisplatin 7·5 mg/m(2). A pressure of 12 mm Hg and a temperature of 37 °C were applied for 30 min/course. The primary endpoint was the proportion of patients who had an objective tumor response (OTR) according to RECIST version 1.1 criteria. Analysis was by intention to treat. Secondary endpoints were tumor regression on histology, PC Index improvement on repeated video-laparoscopy, and quality of life measured with the EORTC QLQ-30 questionnaire. RESULTS: Sixty-four patients were enrolled. Laparoscopic non-access rate was 11/64 (17%). 53 patients were eligible for analyses. 33/53 (62%) patients had an OTR - three had a partial response and 30 patients had stable disease. Tumor regression on histology and PC Index improvement were observed in 26/34 (76%) and in 26/34 (76%) patients who underwent all 3 PIPACs. There were no treatment-related deaths. No grade 4 toxicity was observed. Grade 3 toxicities were trocar hernia (n=2), bowel obstruction (n=2), abdominal pain (n=2), hematoma (n=1), intraoperative bleeding (n=1), and cystitis with urosepsis (n=1). EORTC QLQ-30 global physical health scores, nausea/vomiting, appetite loss, diarrhea, and constipation improved during therapy. CONCLUSION: PIPAC is well tolerated and active in women with ROCPC and warrants further investigation in these patients.

Molecular responses and chromosomal aberrations in patients with polycythemia vera treated with peg-proline-interferon alpha-2b.

Fifty-one polycythemia vera (PV) patients were enrolled in the phase I/II clinical study PEGINVERA to receive a new formulation of pegylated interferon alpha (peg-proline-IFNα-2b, AOP2014/P1101). Peg-proline-IFNα-2b treatment led to high response rates on both hematologic and molecular levels. Hematologic and molecular responses were achieved for 46 and 18 patients (90 and 35% of the whole cohort), respectively. Although interferon alpha (IFNα) is known to be an effective antineoplastic therapy for a long time, it is currently not well understood which genetic alterations influence therapeutic outcomes. Apart from somatic changes in specific genes, large chromosomal aberrations could impact responses to IFNα. Therefore, we evaluated the interplay of cytogenetic changes and IFNα responses in the PEGINVERA cohort. We performed high-resolution SNP microarrays to analyze chromosomal aberrations prior and during peg-proline-IFNα-2b therapy. Similar numbers and types of chromosomal aberrations in responding and non-responding patients were observed, suggesting that peg-proline-IFNα-2b responses are achieved independently of chromosomal aberrations. Furthermore, complete cytogenetic remissions were accomplished in three patients, of which two showed more than one chromosomal aberration. These results imply that peg-proline-IFNα-2b therapy is an effective drug for PV patients, possibly including patients with complex cytogenetic changes.

Unrecognized volatile and semi-volatile organic compounds from brake wear.

Motor vehicles are among the major sources of pollutants and greenhouse gases in urban areas and a transition to "zero emission vehicles" is underway worldwide. However, emissions associated with brake and tire wear will remain. We show here that previously unrecognized volatile and semi-volatile organic compounds, which have a similarity to biomass burning emissions are emitted during braking. These include greenhouse gases or, these classified as Hazardous Air Pollutants, as well as nitrogen-containing organics, nitrogen oxides and ammonia. The distribution and reactivity of these gaseous emissions are such that they can react in air to form ozone and other secondary pollutants with adverse health and climate consequences. Some of the compounds may prove to be unique markers of brake emissions. At higher temperatures, nucleation and growth of nanoparticles is also observed. Regions with high traffic, which are often disadvantaged communities, as well as commuters can be impacted by these emissions even after combustion-powered vehicles are phased out.

Persisting myelin oligodendrocyte glycoprotein antibodies in aquaporin-4 antibody negative pediatric neuromyelitis optica.

BACKGROUND: Recently we showed that antibodies to myelin oligodendrocyte glycoprotein (MOG) can be found in aquaporin-4 (AQP4)-immunoglobulin (IgG) seronegative pediatric and adult patients with definite and high-risk neuromyelitis optica (NMO). OBJECTIVE: The purpose of this study was to describe the clinical characteristics and temporal dynamics of MOG-IgG in AQP4-IgG seronegative pediatric patients presenting with definite NMO. METHODS: Children with definite NMO who were referred for further testing of serum antibodies for AQP4 and MOG with a cell-based assay were included in this study. Clinical disease course, cerebrospinal fluid and magnetic resonance imaging (MRI) studies of these patients were reviewed. RESULTS: Between 2008 and 2012 eight children who fulfilled the diagnostic criteria of definite NMO were recruited. Two children with definite NMO tested positive for AQP4-IgG but were negative for MOG-IgG antibodies. Three children had an absence of AQP4-IgG and MOG-IgG antibodies. Three children with definite NMO had high titers of serum MOG-IgG antibodies (≥1: 160), but no AQP4-directed humoral immune response. Longitudinal analysis of serum samples of the latter three children showed persisting high MOG-IgG titers over time. CONCLUSION: Pediatric patients presenting with clinical symptoms and MRI findings highly suggestive of NMO but with high and persisting MOG-IgG antibody titers are most likely to represent a distinct subgroup of acute demyelinating diseases with important clinical and therapeutic implications.

Electrostatic conveyer for excitons.

We report on the study of indirect excitons in moving lattices-conveyers created by a set of ac voltages applied to the electrodes on the sample surface. The wavelength of this moving lattice is set by the electrode periodicity, the amplitude is controlled by the applied voltage, and the velocity is controlled by the ac frequency. We found the dynamical localization-delocalization transition for excitons in the conveyers and determined its dependence on exciton density and conveyer amplitude and velocity.

Differences in efficacy of monepantel, derquantel and abamectin against multi-resistant nematodes of sheep.

Drug resistance has become a global phenomenon in gastrointestinal nematodes of sheep, particularly resistance to macrocyclic lactones. New anthelmintics are urgently needed for both the control of infections with multi-resistant nematodes in areas where classical anthelmintics are no longer effective, and the prevention of the spread of resistance in areas where the problem is not as severe. Recently, two new active ingredients became commercially available for the treatment of nematode infections in sheep, monepantel (Zolvix®) and derquantel, the latter used only in a formulated combination with the macrocyclic lactone, abamectin (Startect®). In order to assess the potential of the new actives for the control and prevention of spread of anthelmintic resistance, two characterized multi-resistant field isolates from Australia were used in a GLP (good laboratory practice) conducted efficacy study in sheep. Eight infected sheep in each group were treated orally according to the product labels with 2.5 mg/kg body weight monepantel, 0.2 mg/kg abamectin, or with the combination of 2.0 mg/kg derquantel and 0.2 mg/kg abamectin. The results demonstrate that monepantel was fully effective against multi-resistant species, Trichostrongylus colubriformis and Haemonchus contortus (99.9%). In contrast, the combination of derquantel and abamectin was effective against T. colubriformis (99.9%), but was not effective against larval stages of the barber's pole worm H. contortus (18.3%).

Cropland trees need to be included for accurate model simulations of land-atmosphere heat fluxes, temperature, boundary layer height, and ozone.

Trees significantly impact land-atmosphere feedbacks through evapotranspiration, photosynthesis and isoprene emissions. These processes influence the local microclimate, air quality and can mitigate temperature extremes and sequester carbon dioxide. Despite such importance, currently only 5 out of 15 atmospheric chemistry climate models even partially account for the presence of cropland trees. We first show that the tree cover over intensely farmed regions in Asia, Australia and South America is significantly underestimated (e.g. only 1-3% tree cover over north-India) in the Model of Emissions of Gases and Aerosol from Nature (MEGAN) and absent in Noah land-surface module of the Weather Research and Forecasting (WRF-Chem) Model. By including the actual tree cover (~10%) over the north-west Indo Gangetic Plain in the Noah land-surface module of the WRF-Chem and the MEGAN module, during the rice growing monsoon season in August, we find that the latent heat flux alone increases by 100%-300% while sensible heat flux reduces by 50%-100%, leading to a reduction in daytime boundary layer height by 200-400 m. This greatly improves agreement between the modelled and measured temperature, boundary layer height and surface ozone, which were earlier overestimated and isoprene and its oxidation products which were earlier underestimated. Mitigating peak daytime temperatures and ozone improves rice production by 10 to 20%. Our findings from north west Indo-Gangetic Plain establish that such plantations mitigate heat stress, and have beneficial effects on crop yields while also sequestering carbon. Expanding agroforestry practices to 50% of the cropland area could result in up to 40% yield gain regionally. Implementing such strategies globally could increase crop production and sequester 0.3-30 GtC per year, and therefore future climate mitigation and food security efforts should consider stakeholder participation for increased cropland agroforestry in view of its beneficial effects.

Kinetics of nanoparticle reassembly mediated by UV-photolysis of surfactant.

Real-time reassembly of an ordered nanoparticle monolayer due to UV-photolysis of the surfactant shell of nanoparticles was observed. The technique of grazing-incidence small-angle X-ray scattering provided the possibility to track in situ the nanoparticle pair correlation function of the sample processed in a UV-ozone reactor. The analysis revealed a total shift of approximately 1 nm of the nanoparticle nearest-neighbor distance. The temporal evolution of the interparticle distance proved to be the first-order process governed by the UV-photolysis and described by a single-exponential decay function. The nanoparticles tend to agglomerate into a labyrinth-like structure with a typical length scale of some 30 nm.

Association Between Systemic Inflammation, Carotid Arteriosclerosis, and Autonomic Dysfunction.

Systemic inflammation is associated with arteriosclerotic disease progression and worse stroke outcome in patients with carotid arteriosclerotic disease. We hypothesize that systemic inflammation is mediated by impaired carotid baroreceptor and chemoreceptor function induced by carotid arteriosclerosis rather than by the generalized inflammatory arteriosclerotic process.Heart rate variability (HRV), serum levels of inflammatory markers, demographic and life style factors, and concomitant diseases with potential impact on systemic inflammation were determined in 105 patients with asymptomatic carotid stenosis of varying degree. Multivariate linear regression analyses were performed to ascertain independent determinants of carotid stenosis severity, autonomic function, and inflammation.Systemic inflammation (C-reactive protein, beta = .255; P = .014), age (beta = .232; P < .008), and arterial hypertension (beta = .206; P = .032) were associated with carotid stenosis severity. Only carotid stenosis severity and not generalized arteriosclerotic disease, concomitant diseases (arterial hypertension, diabetes mellitus, dyslipidemia, hypothyroidism), life style factors (smoking, obesity), or age was associated with a reduction in vagal tone (HRV HF band power beta = - .193; P < 0.049). Systemic inflammation was related to a reduction in vagal tone (HRV HF band power, beta = - .214; P = .031), and not to generalized arteriosclerotic disease, concomitant diseases (arterial hypertension, diabetes mellitus, dyslipidemia), life style factors (smoking, obesity), and age.In conclusion, systemic inflammation is associated with carotid rather than with generalized arteriosclerotic disease. The association between systemic inflammation and carotid arteriosclerosis is mediated by a reduction in vagal tone which indicates a major role of carotid arteriosclerosis-mediated autonomic dysfunction in the pathogenesis of systemic inflammation in arteriosclerotic disease.

Carbon isotope analysis of acetaldehyde emitted from leaves following mechanical stress and anoxia.

Although the emission of acetaldehyde from plants into the atmosphere following biotic and abiotic stresses may significantly impact air quality and climate, its metabolic origin(s) remains uncertain. We investigated the pathway(s) responsible for the production of acetaldehyde in plants by studying variations in the stable carbon isotope composition of acetaldehyde emitted during leaf anoxia or following mechanical stress. Under an anoxic environment, C3 leaves produced acetaldehyde during ethanolic fermentation with a similar carbon isotopic composition to C3 bulk biomass. In contrast, the initial emission burst following mechanical wounding was 5-12 per thousand more depleted in (13)C than emissions under anoxia. Due to a large kinetic isotope effect during pyruvate decarboxylation catalysed by pyruvate dehydrogenase, acetyl-CoA and its biosynthetic products such as fatty acids are also depleted in (13)C relative to bulk biomass. It is well known that leaf wounding stimulates the release of large quantities of fatty acids from membranes, as well as the accumulation of reactive oxygen species (ROS). We suggest that, following leaf wounding, acetaldehyde depleted in (13)C is produced from fatty acid peroxidation reactions initiated by the accumulation of ROS. However, a variety of other pathways could also explain our results, including the conversion of acetyl-CoA to acetaldehyde by the esterase activity of aldehyde dehydrogenase.

Characterization of the molecular interaction between caveolin-1 and the P2X receptors 4 and 7 in E10 mouse lung alveolar epithelial cells.

P2X(4) and P2X(7) receptors are abundantly expressed in alveolar epithelial cells, and are thought to play a role in regulating fluid haemostasis. Here, we analyzed the expression and localization of the P2X(4)R, and characterized the interaction between Cav-1 and both P2X(4)R and P2X(7)R in the mouse alveolar epithelial cell line E10. Using the biotinylation assay, we found that only glycosylated P2X(4)R is exposed at the cell surface. Triton X-100 solubility experiments and sucrose gradient centrifugation revealed that P2X(4)R was partially localized in Cav-1 rich membrane fractions. Cholesterol depletion with Mbeta-CD displaced Cav-1 and P2X(4)R from the low-density to the high-density fractions. Suppression of Cav-1 protein expression using short hairpin RNAs resulted in a large reduction in P2X(4)R levels. Double immunofluorescence showed that P2X(4)R and Cav-1 partially colocalize in vitro. Using the GST pull-down assay, we showed that Cav-1 interacts in vitro with both P2X(4)R and P2X(7)R. Co-immunoprecipitation experiments confirmed the interaction between P2X(7)R and Cav-1. ATP stimulation increased the level of P2X(4)R in the lipid raft/caveolae fraction, whereas Cav-1 content remained constant. Our results support recent evidence that P2X receptors are present in both raft and non-raft compartments of the plasma membrane and thus exhibit variable ATP sensitivity.

Terpene Composition Complexity Controls Secondary Organic Aerosol Yields from Scots Pine Volatile Emissions.

Secondary organic aerosol (SOA) impact climate by scattering and absorbing radiation and contributing to cloud formation. SOA models are based on studies of simplified chemical systems that do not account for the chemical complexity in the atmosphere. This study investigated SOA formation from a mixture of real Scots pine (Pinus sylvestris) emissions including a variety of monoterpenes and sesquiterpenes. SOA generation was characterized from different combinations of volatile compounds as the plant emissions were altered with an herbivore stress treatment. During active herbivore feeding, monoterpene and sesquiterpene emissions increased, but SOA mass yields decreased after accounting for absorption effects. SOA mass yields were controlled by sesquiterpene emissions in healthy plants. In contrast, SOA mass yields from stressed plant emissions were controlled by the specific blend of monoterpene emissions. Conservative estimates using a box model approach showed a 1.5- to 2.3-fold aerosol enhancement when the terpene complexity was taken into account. This enhancement was relative to the commonly used model monoterpene, "α-pinene". These results suggest that simplifying terpene complexity in SOA models could lead to underpredictions in aerosol mass loading.

Caveolin-1 influences P2X7 receptor expression and localization in mouse lung alveolar epithelial cells.

The P2X7 receptor has recently been described as a marker for lung alveolar epithelial type I cells. Here, we demonstrate both the expression of P2X7 protein and its partition into lipid rafts in the mouse lung alveolar epithelial cell line E10. A significant degree of colocalization was observed between P2X7 and the raft marker protein Caveolin-1; also, P2X7 protein was associated with caveolae. A marked reduction in P2X7 immunoreactivity was observed in lung sections prepared from Caveolin-1-knockout mice, indicating that Caveolin-1 expression was required for full expression of P2X7 protein. Indeed, suppression of Caveolin-1 protein expression in E10 cells using short hairpin RNAs resulted in a large reduction in P2X7 protein expression. Our data demonstrate a potential interaction between P2X7 protein and Caveolin-1 in lipid rafts, and provide a basis for further functional and biochemical studies to probe the physiologic significance of this interaction.