Publications by authors named "Stefan Schneider"

307 Publications

Ein interessanter Fall: Rezidivierendes Ulcus zentrofazial.

J Dtsch Dermatol Ges 2021 Jul;19 Suppl 1:5-7

Universitätsklinikum Hamburg-Eppendorf.

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http://dx.doi.org/10.1111/ddg.14471DOI Listing
July 2021

Hyperprogression fortgeschrittener Melanomerkrankung unter Pembrolizumab adjuvant.

J Dtsch Dermatol Ges 2021 Jul;19 Suppl 1:37-39

Klinik und Poliklinik für Dermatologie und Venerologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

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http://dx.doi.org/10.1111/ddg.14480DOI Listing
July 2021

START (Supporting Treatment Adherence Readiness through Training) Improves Both HIV Antiretroviral Adherence and Viral Reduction, and is Cost Effective: Results of a Multi-site Randomized Controlled Trial.

AIDS Behav 2021 Apr 2. Epub 2021 Apr 2.

RAND Corporation, 1776 Main St, Santa Monica, CA, 90407, USA.

The START (Supporting Treatment Adherence Readiness through Training) intervention was examined for its effects on ART adherence and virologic suppression relative to usual care. A sample of 176 clients about to start or restart ART were randomized (83 to START, 93 to usual care) at HIV clinics in the Los Angeles area. Primary outcomes included electronically monitored dose-taking adherence and HIV viral load; primary end points were months 6 and 24, with group differences examined using nonresponse-weighted means or proportions, effect sizes, and significance testing. Item nonresponse was addressed using multiple imputation. 166 (94.3%) participants started ART, of whom 124 (74.7%) were still in care at month 6, and 90 (54.2%) at month 24. In comparison to the usual care control group, the START group had higher dose-taking adherence at month 6 (86.2% vs. 71.6%, d = 0.56, p = 0.01), which was sustained through month 24 (86.0% vs. 61.1%, d =1.01, p < 0.0001). While rates of undetectable viral load did not differ between groups at month 6 or 24, the mean reduction in viral load (log copies/mm) at month 24 was significantly greater in the intervention arm (3.0 vs. 2.7; d = 0.40, p = 0.047). An estimated cost of $132 per person was needed to obtain a 10% increase in dose-taking adherence over 24 months from the intervention. These findings suggest that START is cost effective in producing a medium to large effect on dose-taking adherence that is durable over 24 months, and a modest long-term effect on viral reduction.Trial registration Clinicaltrials.gov NCT02329782 (registered December 22, 2014).
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http://dx.doi.org/10.1007/s10461-021-03188-xDOI Listing
April 2021

Single Femtosecond Laser-Pulse-Induced Superficial Amorphization and Re-Crystallization of Silicon.

Materials (Basel) 2021 Mar 27;14(7). Epub 2021 Mar 27.

Bundesanstalt für Materialforschung und -prüfung (BAM), Unter den Eichen 87, D-12205 Berlin, Germany.

Superficial amorphization and re-crystallization of silicon in <111> and <100> orientation after irradiation by femtosecond laser pulses (790 nm, 30 fs) are studied using optical imaging and transmission electron microscopy. Spectroscopic imaging ellipsometry (SIE) allows fast data acquisition at multiple wavelengths and provides experimental data for calculating nanometric amorphous layer thickness profiles with micrometric lateral resolution based on a thin-film layer model. For a radially Gaussian laser beam and at moderate peak fluences above the melting and below the ablation thresholds, laterally parabolic amorphous layer profiles with maximum thicknesses of several tens of nanometers were quantitatively attained. The accuracy of the calculations is verified experimentally by high-resolution transmission electron microscopy (HRTEM) and energy dispersive X-ray spectroscopy (STEM-EDX). Along with topographic information obtained by atomic force microscopy (AFM), a comprehensive picture of the superficial re-solidification of silicon after local melting by femtosecond laser pulses is drawn.
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http://dx.doi.org/10.3390/ma14071651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037179PMC
March 2021

[Early onset of methotrexate-associated lymphoproliferative disorder mimicking Hodgkin's lymphoma].

Hautarzt 2021 Apr 1. Epub 2021 Apr 1.

Klinik und Poliklinik für Dermatologie und Venerologie, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Deutschland.

Long-term methotrexate (MTX) treatment is known to cause MTX-associated lymphoproliferative disorder (MTX-LPD). A 58-year-old woman with psoriasis vulgaris and pityriasis rubra pilaris was treated with a combination of MTX and ustekinumab for 4 months when she developed generalized lymphadenopathy. The initial histopathological analysis indicated Hodgkin's lymphoma; however, assessing the patient's clinical history revealed the diagnosis of MTX-LPD. To our knowledge, this is the first case of a MTX-LPD after only 4 months of treatment.
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http://dx.doi.org/10.1007/s00105-021-04804-6DOI Listing
April 2021

Arthroscopic Minced Cartilage Implantation (MCI): A Technical Note.

Arthrosc Tech 2021 Jan 19;10(1):e97-e101. Epub 2020 Dec 19.

Gelenkzentrum Rhein-Main, Wiesbaden, Germany.

Articular cartilage lesions are identified with increasing frequency. Several cartilage repair techniques are available to treat symptomatic cartilage defects. The ultimate goal of any cartilage repair procedure is the prevention of premature osteoarthritis. Autologous chondrocyte implantation provides the best tissue quality. However, 2 operations and a resource-intense culturing process with high regulatory demands are disadvantages of this cartilage repair procedure. Furthermore, cellular dedifferentiation and senescence display further cell culture-associated drawbacks that hamper the procedure. Minced cartilage implantation is a relatively simple and cost-effective one-step procedure with promising biologic potential and satisfying clinical results. We present an arthroscopic surgical technique where the surgeon can apply autologous chondrocytes in a one-step procedure to treat articular cartilage defects at the knee joint.
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http://dx.doi.org/10.1016/j.eats.2020.09.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823081PMC
January 2021

NeuroExercise: The Effect of a 12-Month Exercise Intervention on Cognition in Mild Cognitive Impairment-A Multicenter Randomized Controlled Trial.

Front Aging Neurosci 2020 14;12:621947. Epub 2021 Jan 14.

Institute of Movement and Neurosciences, German Sport University, Cologne, Germany.

Exercise intervention studies in mild cognitive impairment (MCI), a prodromal stage of Alzheimer's disease (AD), have demonstrated inconsistent yet promising results. Addressing the limitations of previous studies, this trial investigated the effects of a 12-month structured exercise program on the progression of MCI. The NeuroExercise study is a multicenter randomized controlled trial across three European countries (Ireland, Netherlands, Germany). Hundred and eighty-three individuals with amnestic MCI were included and were randomized to a 12-month exercise intervention (3 units of 45 min) of either aerobic exercise (AE; = 60), stretching and toning exercise (ST; = 65) or to a non-exercise control group (CG; = 58). The primary outcome, cognitive performance, was determined by an extensive neuropsychological test battery. For the primary complete case (CC) analyses, between-group differences were analyzed with analysis of covariance under two conditions: (1) the exercise group (EG = combined AE and ST groups) compared to the CG and (2) AE compared to ST. Primary analysis of the full cohort ( = 166, 71.5 years; 51.8% females) revealed no between-group differences in composite cognitive score [mean difference (95% CI)], 0.12 [(-0.03, 0.27), = 0.13] or in any cognitive domain or quality of life. VO peak was significantly higher in the EG compared to the CG after 12 months [-1.76 (-3.39, -0.10), = 0.04]. Comparing the two intervention groups revealed a higher VOpeak level in the aerobic exercise compared to the stretching and toning group, but no differences for the other outcomes. A 12-month exercise intervention did not change cognitive performance in individuals with amnestic MCI in comparison to a non-exercise CG. An intervention effect on physical fitness was found, which may be an important moderator for long term disease progression and warrants long-term follow-up investigations. https://clinicaltrials.gov/ct2/show/NCT02913053, identifier: NCT02913053.
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http://dx.doi.org/10.3389/fnagi.2020.621947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840533PMC
January 2021

Immunoglobulin M pemphigoid.

J Am Acad Dermatol 2021 Jan 13. Epub 2021 Jan 13.

Department of Dermatology, University of Lübeck, Lübeck, Germany; Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany. Electronic address:

Background: Pemphigoid diseases are a heterogeneous group of autoimmune blistering disorders characterized by predominant deposition of immunoglobulin G or immunoglobulin A autoantibodies against structural proteins of the dermoepidermal junction (DEJ). Sole linear immunoglobulin M (IgM) deposits at the DEJ in pemphigoid diseases have been observed; however, IgM-specific target antigens have not been identified.

Objective: Characterization of patients with IgM pemphigoid.

Methods: Skin biopsy specimens and sera from IgM-positive patients were assessed using histopathology, direct and indirect immunofluorescence microscopy, enzyme-linked immunosorbent assays, immunoblotting, cryosection assay, complement fixation test, and internalization assays.

Results: Tissue-bound linear IgM deposits along the DEJ and circulating IgM autoantibodies against type XVII collagen (Col17) were detected. These circulating IgM autoantibodies showed no complement activating or blister inducing capacity, but the ability of Col17 internalization ex vivo.

Limitations: Limited number of patients.

Conclusion: This study provides further evidence for the role of IgM autoantibodies in pemphigoid disease and highlights Col17 as a target antigen in IgM pemphigoid.
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http://dx.doi.org/10.1016/j.jaad.2021.01.017DOI Listing
January 2021

Platelet endothelial cell adhesion molecule-1 is a gatekeeper of neutrophil transendothelial migration in ischemic stroke.

Brain Behav Immun 2021 Mar 31;93:277-287. Epub 2020 Dec 31.

Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

Rationale: Adhesion molecules are key elements in stroke-induced brain injury by regulating the migration of effector immune cells from the circulation to the lesion site. Platelet endothelial cell adhesion molecule-1 (PECAM-1) is an adhesion molecule highly expressed on endothelial cells and leukocytes, which controls the final steps of trans-endothelial migration. A functional role for PECAM-1 in post-ischemic brain injury has not yet been demonstrated.

Objective: Using genetic Pecam-1 depletion and PECAM-1 blockade using a neutralizing anti-PECAM-1 antibody, we evaluated the role of PECAM-1 mediated trans-endothelial immune cell migration for ischemic injury, delayed brain atrophy, and brain immune cell infiltrates. Trans-endothelial immune cell migration was furthermore evaluated in cultured human cerebral microvascular endothelial cells.

Methods And Results: Transient middle cerebral artery occlusion (tMCAO) was induced in 10-12-week-old male Pecam-1 and Pecam-1 wildtype mice. PECAM-1 levels increased in the ischemic brain tissue due to the infiltration of PECAM-1 leukocytes. Using magnetic resonance imaging, we observed smaller infarct volume, less edema formation, and less brain atrophy in Pecam-1 compared with Pecam-1 wildtype mice. The transmigration of leukocytes, specifical neutrophils, was selectively reduced by Pecam-1, as shown by immune fluorescence and flow cytometry in vivo and transmigration assays in vitro. Importantly, inhibition with an anti-PECAM-1 antibody in wildtype mice decreased neutrophil brain influx and infarct.

Conclusion: PECAM-1 controls the trans-endothelial migration of neutrophils in a mouse model of ischemic stroke. Antibody blockade of PECAM-1 after stroke onset ameliorates stroke severity in mice, making PECAM-1 an interesting target to dampen post-stroke neuroinflammation, reduce ischemic brain injury, and enhance post-ischemic brain remodeling.
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http://dx.doi.org/10.1016/j.bbi.2020.12.026DOI Listing
March 2021

Gain-of-function variant p.Pro2555Arg of von Willebrand factor increases aggregate size through altering stem dynamics.

Thromb Haemost 2020 Dec 31. Epub 2020 Dec 31.

University Medical Centre Hamburg-Eppendorf, Department of Dermatology and Venerology, Hamburg, Germany.

The multimeric plasma glycoprotein von Willebrand factor (VWF) is best known for recruiting platelets to sites of injury during primary hemostasis. Generally, mutations in the VWF gene lead to loss of hemostatic activity and thus the bleeding disorder von Willebrand Disease. By employing cone and platelet aggregometry and microfluidic assays, we uncovered a platelet glycoprotein (GP)IIb/IIIa-dependent prothrombotic gain-of-function (GOF) for variant p.Pro2555Arg, located in the C4-domain, leading to an increase in platelet aggregate size. We performed complementary biophysical and structural investigations using circular dichroism spectra, small angle X-ray scattering, NMR spectroscopy, molecular dynamics simulations on the single C4-domain and dimeric wildtype and p.Pro2555Arg constructs. C4-p.Pro2555Arg retained the overall structural conformation with minor populations of alternative conformations exhibiting increased hinge flexibility and slow conformational exchange. The dimeric protein becomes disordered and more flexible. Our data suggest that the GOF is not affecting the binding affinity of the C4-domain for GPIIb/IIIa. Instead, the increased VWF dimer flexibility enhances temporal accessibility of platelet binding sites. Using an interdisciplinary approach, we revealed that p.Pro2555Arg is the first VWF variant, which increases platelet aggregate size and show a shear-dependent function of the VWF stem region, which can become hyperactive through mutations. Prothrombotic GOF variants of VWF are a novel concept of a VWF-associated pathomechanism of thromboembolic events, which is of general interest to vascular health but which is not yet considered in diagnostics. Thus, awareness should be raised for the risk they pose. Furthermore, our data implicate the C4-domain as a novel anti-thrombotic drug target.
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http://dx.doi.org/10.1055/a-1344-4405DOI Listing
December 2020

Differences of the tumour cell glycocalyx affect binding of capsaicin-loaded chitosan nanocapsules.

Sci Rep 2020 12 31;10(1):22443. Epub 2020 Dec 31.

Experimental Dermatology, Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, Research Campus, Martinistraße 52, 20246, Hamburg, Germany.

The glycocalyx regulates the interaction of mammalian cells with extracellular molecules, such as cytokines. However, it is unknown to which extend the glycocalyx of distinct cancer cells control the binding and uptake of nanoparticles. In the present study, exome sequencing data of cancer patients and analysis of distinct melanoma and bladder cancer cell lines suggested differences in cancer cell-exposed glycocalyx components such as heparan sulphate. Our data indicate that glycocalyx differences affected the binding of cationic chitosan nanocapsules (Chi-NCs). The pronounced glycocalyx of bladder cancer cells enhanced the internalisation of nanoencapsulated capsaicin. Consequently, capsaicin induced apoptosis in the cancer cells, but not in the less glycosylated benign urothelial cells. Moreover, we measured counterion condensation on highly negatively charged heparan sulphate chains. Counterion condensation triggered a cooperative binding of Chi-NCs, characterised by a weak binding rate at low Chi-NC doses and a strongly increased binding rate at high Chi-NC concentrations. Our results indicate that the glycocalyx of tumour cells controls the binding and biological activity of nanoparticles. This has to be considered for the design of tumour cell directed nanocarriers to improve the delivery of cytotoxic drugs. Differential nanoparticle binding may also be useful to discriminate tumour cells from healthy cells.
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http://dx.doi.org/10.1038/s41598-020-79882-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775450PMC
December 2020

Local blood coagulation drives cancer cell arrest and brain metastasis in a mouse model.

Blood 2021 Mar;137(9):1219-1232

Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.

Clinically relevant brain metastases (BMs) frequently form in cancer patients, with limited options for effective treatment. Circulating cancer cells must first permanently arrest in brain microvessels to colonize the brain, but the critical factors in this process are not well understood. Here, in vivo multiphoton laser-scanning microscopy of the entire brain metastatic cascade allowed unprecedented insights into how blood clot formation and von Willebrand factor (VWF) deposition determine the arrest of circulating cancer cells and subsequent brain colonization in mice. Clot formation in brain microvessels occurred frequently (>95%) and specifically at intravascularly arrested cancer cells, allowing their long-term arrest. An extensive clot embedded ∼20% of brain-arrested cancer cells, and those were more likely to successfully extravasate and form a macrometastasis. Mechanistically, the generation of tissue factor-mediated thrombin by cancer cells accounted for local activation of plasmatic coagulation in the brain. Thrombin inhibition by treatment with low molecular weight heparin or dabigatran and an anti-VWF antibody prevented clot formation, cancer cell arrest, extravasation, and the formation of brain macrometastases. In contrast, tumor cells were not able to directly activate platelets, and antiplatelet treatments did reduce platelet dispositions at intravascular cancer cells but did not reduce overall formation of BMs. In conclusion, our data show that plasmatic coagulation is activated early by intravascular tumor cells in the brain with subsequent clot formation, which led us to discover a novel and specific mechanism that is crucial for brain colonization. Direct or indirect thrombin and VWF inhibitors emerge as promising drug candidates for trials on prevention of BMs.
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http://dx.doi.org/10.1182/blood.2020005710DOI Listing
March 2021

Age patterns in subjective well-being are partially accounted for by psychological and social factors associated with aging.

PLoS One 2020 2;15(12):e0242664. Epub 2020 Dec 2.

Dornsife Center for Self-Report Science, University of Southern California, Los Angeles, California, United States of America.

Subjective well-being has captured the interest of scientists and policy-makers as a way of knowing how individuals and groups evaluate and experience their lives: that is, their sense of meaning, their satisfaction with life, and their everyday moods. One of the more striking findings in this literature is a strong association between age and subjective well-being: in Western countries it has a U-shaped association over the lifespan. Despite many efforts, the reason for the curve is largely unexplained, for example, by traditional demographic variables. In this study we examined twelve social and psychological variables that could account for the U-shaped curve. In an Internet sample of 3,294 adults ranging in age from 40 to 69 we observed the expected steep increase in a measure of subjective well-being, the Cantril Ladder. Regression analyses demonstrated that the social-psychological variables explained about two-thirds of the curve and accounting for them significantly flattened the U-shape. Perceived stress, distress-depression, an open perspective about the future, wisdom, satisfaction with social relationships, and family strain were measures that had pronounced impacts on reducing the curve. These findings advance our understanding of why subjective well-being is associated with age and point the way to future studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242664PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710094PMC
January 2021

II. Indices of Pain Intensity Derived From Ecological Momentary Assessments and Their Relationships With Patient Functioning: An Individual Patient Data Meta-analysis.

J Pain 2021 Apr 24;22(4):371-385. Epub 2020 Oct 24.

Dornsife Center for Self-Report Science, University of Southern California, California; Deparment of Psychology, University of Southern California, California.

Pain intensity is a complex and dynamic experience. A focus on assessing patients' average pain levels may miss important aspects of pain that impact functioning in daily life. In this second of 3 articles investigating alternative indices of pain intensity derived from Ecological Momentary Assessments (EMA), we examine the indices' associations with physical and psychosocial functioning. EMA data from 10 studies (2,660 patients) were reanalyzed to construct indices of Average Pain, Maximum Pain, Minimum Pain, Pain Variability, Time in High Pain, Time in Low Pain, Pain after Wake-up. Three sets of individual patient data meta-analyses examined 1) the test-retest reliability of the pain indices, 2) their convergent validity in relation to physical functioning, fatigue, depression, mental health, and social functioning, and 3) the incremental validity of alternative indices above Average Pain. Reliabilities approaching or exceeding a level of .7 were observed for all indices, and most correlated significantly with all functioning domains, with small to medium effect sizes. Controlling for Average Pain, Maximum Pain and Pain Variability uniquely predicted all functioning measures, and Time in High Pain predicted physical and social functioning. We suggest that alternative pain indices can provide new perspectives for understanding functioning in chronic pain. PERSPECTIVE: Alternative summary measures of pain intensity derived from EMA have the potential to help better understand patients' pain experience. Utilizing EMA for the assessment of Maximum Pain, Pain Variability, and Time in High Pain may provide an enhanced window into the relationships between pain and patients' physical and psychosocial functioning.
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http://dx.doi.org/10.1016/j.jpain.2020.10.002DOI Listing
April 2021

[Screening for mental comorbidities in dermatology : Successful implementation of a screening for mental comorbidities in the field of inpatient dermatological treatment].

Hautarzt 2021 Mar;72(3):244-248

Klinik und Poliklinik für Dermatologie und Venerologie, Universitätsklinikum Hamburg Eppendorf, Martinistr. 52, 20246, Hamburg, Deutschland.

Background: Anxiety and depression are common in the field of inpatient somatic treatment. Especially in dermatology in which the treatment of chronic diseases is very common and the risk of stigmatization by society is particularly high, mental disorders appear in every third patient. Dermatological diseases and mental disorders often negatively interact with each other leading to increased morbidity. Dermatological guidelines recommend early detection, but this is often not adequately done in practice.

Materials And Methods: We present the implementation of an easy screening for mental comorbidities in the field of inpatient dermatological treatment by using a short questionnaire. This so-called Patient Health Questionnaire‑4 (PHQ-4) consists of four questions regarding anxiety disorders and depression. Upon reaching a certain number of points, a psychosomatic consult is automatically requested. As a result the patient's stress is relieved and the necessary holistic treatment becomes possible.

Results: In 2019, 83% of inpatients in our clinic were screened using the PHQ‑4; 98 psychosomatic consults were performed.

Conclusion: Our findings so far have shown the benefit of the screening with a minimal investment of time. We recommend its comprehensive use in the field of inpatient dermatological treatment.
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http://dx.doi.org/10.1007/s00105-020-04723-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935736PMC
March 2021

III. Detecting Treatment Effects in Clinical Trials With Different Indices of Pain Intensity Derived From Ecological Momentary Assessment.

J Pain 2021 Apr 24;22(4):386-399. Epub 2020 Oct 24.

Dornsife Center for Self-Report Science, University of Southern California, California; Deparment of Psychology, University of Southern California, California.

Pain intensity represents the primary outcome in most pain clinical trials. Identifying methods to measure aspects of pain that are most sensitive to treatment may facilitate discovery of effective interventions. In this third of 3 articles examining alternative indices of pain intensity derived from ecological momentary assessments (EMA), we compare treatment effects based on Average Pain, Maximum Pain, Minimum Pain, Pain Variability, Time in High Pain, Time in Low Pain, and Pain After Wake-Up. We also examine which indices contribute to Patient Global Impressions of Change (PGIC). Data came from 2 randomized, double-blind, placebo-controlled trials examining the efficacy of milnacipran for fibromyalgia treatment; 2,084 patients provided >1 million EMA pain intensity ratings over 24 (Study 1) or 26 (Study 2) treatment weeks. Pain Variability and Time in High Pain produced significantly smaller treatment effects than Average Pain; other pain indices showed effects that were numerically smaller, but not significantly different from Average Pain. Changes in all pain indices were significantly associated with PGIC, with improvements in Maximum Pain and in Pain Variability offering small incremental contributions to understanding PGIC over Average Pain. Results suggest that different pain indices could be used to detect treatment effects in pain clinical trials. PERSPECTIVE: Alternative summary measures of pain intensity derived from EMA may broaden the scope of outcomes useful in pain clinical trials. In this analysis of a pharmacological treatment for fibromyalgia, most pain summary measures indicated similar effects; improvements in Maximum Pain and Pain Variability contributed to understanding PGIC over Average Pain.
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http://dx.doi.org/10.1016/j.jpain.2020.10.003DOI Listing
April 2021

Organ-on-a-disc: A platform technology for the centrifugal generation and culture of microphysiological 3D cell constructs amenable for automation and parallelization.

APL Bioeng 2020 Dec 1;4(4):046101. Epub 2020 Oct 1.

Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB, Nobelstrasse 12, 70569 Stuttgart, Germany.

Organ-on-a-chip (OoC) systems have evolved to a promising alternative to animal testing and traditional cell assays in drug development and enable personalization for precision medicine. So far, most OoCs do not fully exploit the potential of microfluidic systems regarding parallelization and automation. To date, many OoCs still consist of individual units, integrating only one single tissue per chip, and rely on manual, error-prone handling. However, with limited parallelization and automation, OoCs remain a low-throughput technology, preventing their widespread application in industry. To advance the concept of microphysiological systems and to overcome the limitations of current OoCs, we developed the Organ-on-a-disc (Organ-Disc) technology. Driven only by rotation, Organ-Discs enable the parallelized generation and culture of multiple 3D cell constructs per disc. We fabricated polydimethylsiloxane-free Organ-Discs using thermoplastic materials and scalable fabrication techniques. Utilizing precisely controllable centrifugal forces, cells were loaded simultaneously into 20 tissue chambers, where they formed uniform cell pellets. Subsequently, the cells compacted into dense 3D cell constructs and were cultured under vasculature-like perfusion through pump- and tubing-free, centrifugal pumping, solely requiring a low-speed rotation (<1 g) of the Organ-Disc. Here, we provide a proof-of-concept of the Organ-Disc technology, showing the parallelized generation of tissue-like cell constructs and demonstrating the controlled centrifugal perfusion. Furthermore, Organ-Discs enable versatile tissue engineering, generating cell constructs with a customizable shape and a layered multi-cell type structure. Overall, the Organ-Disc provides a user-friendly platform technology for the parallelization and automation of microphysiological systems, bringing this technology one-step closer to high-throughput applications in industry.
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http://dx.doi.org/10.1063/5.0019766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532019PMC
December 2020

Schmerzhafte Rötung am Skrotum.

J Dtsch Dermatol Ges 2020 Sep;18(9):1059-1061

Klinik und Poliklinik für Dermatologie und Venerologie, Universitätsklinikum Hamburg Eppendorf, Hamburg.

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http://dx.doi.org/10.1111/ddg.14133_gDOI Listing
September 2020

Comparability of Emotion Dynamics Derived From Ecological Momentary Assessments, Daily Diaries, and the Day Reconstruction Method: Observational Study.

J Med Internet Res 2020 09 24;22(9):e19201. Epub 2020 Sep 24.

University of Southern California, Los Angeles, CA, United States.

Background: Interest in the measurement of the temporal dynamics of people's emotional lives has risen substantially in psychological and medical research. Emotions fluctuate and change over time, and measuring the ebb and flow of people's affective experiences promises enhanced insights into people's health and functioning. Researchers have used a variety of intensive longitudinal assessment (ILA) methods to create measures of emotion dynamics, including ecological momentary assessments (EMAs), end-of-day (EOD) diaries, and the day reconstruction method (DRM). To date, it is unclear whether they can be used interchangeably or whether ostensibly similar emotion dynamics captured by the methods differ in meaningful ways.

Objective: This study aims to examine the extent to which different ILA methods yield comparable measures of intraindividual emotion dynamics.

Methods: Data from 90 participants aged 50 years or older were collected in a probability-based internet panel, the Understanding America Study, and analyzed. Participants provided positive and negative affect ratings using 3 ILA methods: (1) smartphone-based EMA, administered 6 times per day over 1 week, (2) web-based EOD diaries, administered daily over the same week, and (3) web-based DRM, administered once during that week. We calculated 11 measures of emotion dynamics (addressing mean levels, variability, instability, and inertia separately for positive and negative affect, as well as emotion network density, mixed emotions, and emotional dialecticism) from each ILA method. The analyses examined mean differences and correlations of scores addressing the same emotion dynamic across the ILA methods. We also compared the patterns of intercorrelations among the emotion dynamics and their relationships with health outcomes (general health, pain, and fatigue) across ILA methods.

Results: Emotion dynamics derived from EMAs and EOD diaries demonstrated moderate-to-high correspondence for measures of mean emotion levels (ρ≥0.95), variability (ρ≥0.68), instability (ρ≥0.51), mixed emotions (ρ=0.92), and emotional dialecticism (ρ=0.57), and low correspondence for measures of inertia (ρ≥0.17) and emotion network density (ρ=0.36). DRM-derived measures showed correlations with EMAs and EOD diaries that were high for mean emotion levels and mixed emotions (ρ≥0.74), moderate for variability (ρ=0.38-.054), and low to moderate for other measures (ρ=0.03-0.41). Intercorrelations among the emotion dynamics showed high convergence across EMAs and EOD diaries, and moderate convergence between the DRM and EMAs as well as EOD diaries. Emotion dynamics from all 3 ILA methods produced very similar patterns of relationships with health outcomes.

Conclusions: EMAs and EOD diaries provide corresponding information about individual differences in various emotion dynamics, whereas the DRM provides corresponding information about emotion levels and (to a lesser extent) variability, but not about more complex emotion dynamics. Our results caution researchers against viewing these ILA methods as universally interchangeable.
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http://dx.doi.org/10.2196/19201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545330PMC
September 2020

I. Indices of Pain Intensity Derived From Ecological Momentary Assessments: Rationale and Stakeholder Preferences.

J Pain 2021 Apr 15;22(4):359-370. Epub 2020 Sep 15.

Dornsife Center for Self-Report Science, University of Southern California, Los Angeles, California. Electronic address:

Pain assessment that fully represents patients' pain experiences is essential for chronic pain research and management. The traditional primary outcome measure has been a patient's average pain intensity over a time period. In this series of 3 articles, we examine whether pain assessment can be enhanced by considering additional outcome measures capturing temporal aspects of pain, such as pain maxima, duration, and variability. Ecological momentary assessment makes the assessment of such indices readily available. In this first article, we discuss the rationale for considering additional pain indices derived from ecological momentary assessment and examine which are most important to stakeholders. Patients (n = 32), clinicians (n = 20), and clinical trialists (n = 20) were interviewed about their preference rankings for Average, Worst, and Least Pain, Time in High Pain, Time in No/Low Pain, Pain Variability, and Pain Unpredictability. Each stakeholder group displayed a distinct preference hierarchy for different indices, and there were few commonalities between groups. Patients favored Worst Pain and Time in High Pain, followed by Pain Variability and Unpredictability. Trialists favored Average Pain, whereas clinicians favored Worst Pain. Results suggest that multiple temporal aspects of pain are relevant for stakeholders and should be considered when evaluating the efficacy of pain management. PERSPECTIVE: Examining which aspects of pain are most important to measure from the perspective of different stakeholders can facilitate efforts to include all relevant treatment outcomes. Our study suggests that multiple temporal aspects of pain intensity are important to stakeholders. This should be considered when evaluating the efficacy of pain management.
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http://dx.doi.org/10.1016/j.jpain.2020.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956922PMC
April 2021

Individual differences in momentary pain-affect coupling and their associations with mental health in patients with chronic pain.

J Psychosom Res 2020 11 28;138:110227. Epub 2020 Aug 28.

Dornsife Center for Self-Report Science, University of Southern California, Los Angeles, CA, USA. Electronic address:

Objective: Pain and affect are generally associated. However, individuals may differ in the magnitude of the coupling between pain and affect, which may have important implications for their mental health. The present study uses ecological momentary assessments (EMA) to examine individual differences in momentary pain-affect coupling and their associations with depressive and anxiety symptoms.

Methods: This study is a secondary data analysis of three primary EMA studies. Participants were a total of 290 patients with chronic pain. Results were synthesized across studies using meta-analytic techniques.

Results: Individuals whose pain was more strongly concurrently coupled with affect (positively associated with negative affect or negatively associated with positive affect) reported higher levels of depressive and anxiety symptoms. Results from lagged analyses suggest that individual differences in affect reactivity to pain were not significantly associated with depressive or anxiety symptoms.

Conclusion: These findings suggest that individuals with greater concurrent coupling between pain and affect experience more mental health problems. Potential avenues for future research include intervention strategies that target the decoupling of pain and affect experiences in patients with chronic pain.
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http://dx.doi.org/10.1016/j.jpsychores.2020.110227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606064PMC
November 2020

Platelet adhesion and aggregate formation controlled by immobilised and soluble VWF.

BMC Mol Cell Biol 2020 Sep 11;21(1):64. Epub 2020 Sep 11.

University Medical Centre Hamburg-Eppendorf, Centre for Internal Medicine, Martinistr. 52, 20246, Hamburg, Germany.

Background: It has been demonstrated that von Willebrand factor (VWF) mediated platelet-endothelium and platelet-platelet interactions are shear dependent. The VWF's mobility under dynamic conditions (e.g. flow) is pivotal to platelet adhesion and VWF-mediated aggregate formation in the cascade of VWF-platelet interactions in haemostasis.

Results: Combining microfluidic tools with fluorescence and reflection interference contrast microscopy (RICM), here we show, that specific deletions in the A-domains of the biopolymer VWF affect both, adhesion and aggregation properties independently. Intuitively, the deletion of the A1-domain led to a significant decrease in both adhesion and aggregate formation of platelets. Nevertheless, the deletion of the A2-domain revealed a completely different picture, with a significant increase in formation of rolling aggregates (gain of function). We predict that the A2-domain effectively 'masks' the potential between the platelet glycoprotein (GP) Ib and the VWF A1-domain. Furthermore, the deletion of the A3-domain led to no significant variation in either of the two functional characteristics.

Conclusions: These data demonstrate that the macroscopic functional properties i.e. adhesion and aggregate formation cannot simply be assigned to the properties of one particular domain, but have to be explained by cooperative phenomena. The absence or presence of molecular entities likewise affects the properties (thermodynamic phenomenology) of its neighbours, therefore altering the macromolecular function.
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http://dx.doi.org/10.1186/s12860-020-00309-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488753PMC
September 2020

High-resolution, field approaches for assessing pain: Ecological Momentary Assessment.

Pain 2021 Jan;162(1):4-9

Dornsife Center for Self-Report Science, University of Southern California, Los Angeles, CA, United States.

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http://dx.doi.org/10.1097/j.pain.0000000000002049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737856PMC
January 2021

A combination of pain indices based on momentary assessments can predict placebo response in patients with fibromyalgia syndrome.

Pain 2021 Feb;162(2):543-551

Dornsife Center for Self-Report Science, Center for Economic & Social Research, University of Southern California, Los Angeles, CA, United States.

Abstract: Many factors are known to affect assay sensitivity; however, limited attention has been devoted to understanding whether characteristics of patients' baseline pain impact assay sensitivity. In this study, we tested whether a combination of 3 baseline pain indices based on ecological momentary assessments (EMA) could detect patients with enhanced responses to placebo. The analysis was conducted with secondary data from 2 clinical trials in fibromyalgia patients (N = 2084). For each patient, pain intensity, pain variability (individual SD), and pain consistency (first-order autocorrelation) were computed from baseline EMA. A latent profile analysis identified 3 subgroups of patients based on these indices. Group 1 (n = 857, 41.3%) showed the lowest pain intensity levels, coupled with the highest consistency and greatest variability of pain. Group 3 (n = 110, 5.3%) showed the opposite pattern, and group 2 (n = 1109, 53.4%) showed intermediate levels on all pain indices. It was then tested whether the subgroups moderated treatment effects (changes in pain for active treatment vs placebo) using repeated-measures analysis of variance. Treatment effects varied significantly between subgroups. Patients in group 3 demonstrated greater reduction in pain in response to placebo then those in groups 1 and 2. Further analysis showed that the removal of patients in class 3 would significantly enhance the observed treatment effect by 8% to 15%. In conclusion, profiles of pain characteristics derived from baseline EMA may be useful for detecting patient subgroups with enhanced placebo responses that can diminish assay sensitivity in pain clinical trials.
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http://dx.doi.org/10.1097/j.pain.0000000000002025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854765PMC
February 2021

Sensorimotor performance and haptic support in simulated weightlessness.

Exp Brain Res 2020 Oct 7;238(10):2373-2384. Epub 2020 Aug 7.

Institute of Movement and Neurosciences, German Sport University, Cologne, Germany.

The success of many space missions critically depends on human capabilities and performance. Yet, it is known that sensorimotor performance is degraded under conditions of weightlessness. Therefore, astronauts prepare for their missions in simulated weightlessness under water. In the present study, we investigated sensorimotor performance in simulated weightlessness (induced by shallow water immersion) and whether performance can be improved by choosing appropriate haptic settings of the human-machine interface (e.g., motion damping). Twenty-two participants performed basic aiming and tracking tasks with a force feedback joystick under water and on land and with different haptic settings of the joystick (no haptics, three spring stiffnesses, and two motion dampings). While higher resistive forces should be avoided for rapid aiming tasks in simulated weightlessness, tracking performance is best with higher motions damping in both land and water setups, although the performance losses due to water immersion cannot be compensated. The overall result pattern also provides insights into the causal mechanism behind the slowing effect during aiming motions and decreased accuracy of tracking motions in simulated weightlessness. Findings provide evidence that distorted proprioception due to altered muscle spindle activity seemingly is the main trigger of impaired sensorimotor performance in simulated weightlessness.
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http://dx.doi.org/10.1007/s00221-020-05898-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496033PMC
October 2020

Skin Barriers in Dermal Drug Delivery: Which Barriers Have to Be Overcome and How Can We Measure Them?

Pharmaceutics 2020 Jul 20;12(7). Epub 2020 Jul 20.

Department of Dermatology and Venerology, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.

Although, drugs are required in the various skin compartments such as viable epidermis, dermis, or hair follicles, to efficiently treat skin diseases, drug delivery into and across the skin is still challenging. An improved understanding of skin barrier physiology is mandatory to optimize drug penetration and permeation. The various barriers of the skin have to be known in detail, which means methods are needed to measure their functionality and outside-in or inside-out passage of molecules through the various barriers. In this review, we summarize our current knowledge about mechanical barriers, i.e., stratum corneum and tight junctions, in interfollicular epidermis, hair follicles and glands. Furthermore, we discuss the barrier properties of the basement membrane and dermal blood vessels. Barrier alterations found in skin of patients with atopic dermatitis are described. Finally, we critically compare the up-to-date applicability of several physical, biochemical and microscopic methods such as transepidermal water loss, impedance spectroscopy, Raman spectroscopy, immunohistochemical stainings, optical coherence microscopy and multiphoton microscopy to distinctly address the different barriers and to measure permeation through these barriers in vitro and in vivo.
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http://dx.doi.org/10.3390/pharmaceutics12070684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407329PMC
July 2020

Heightened Stress in Employed Individuals Is Linked to Altered Variability and Inertia in Emotions.

Front Psychol 2020 16;11:1152. Epub 2020 Jun 16.

Center for Self-Report Science, University of Southern California, Los Angeles, CA, United States.

Stress has been widely recognized as a key factor contributing to health outcomes and psychological well-being. While some growing evidence points to stress as having an effect on emotion dynamics characteristics, there has yet to be a test of how global perceptions of stress are associated with not only average levels of emotions but also the variability in the intensity of the emotions, as well as how emotions linger (inertia), and whether these characteristics differ by age. In an effort to better understand how stress influences the emotional experiences of individuals, we examined associations between perceived stress levels and emotion dynamics indices in a sample of 859 working individuals over 24 h. Participants ranged in age from 21 to 81 years. Each participant was prompted at approximately 28 min intervals throughout a 24 h period to report intensity of emotional states. Overall, individuals who were more stressed experienced lower mean levels of positive emotions (with the exception of higher levels of excitement) and higher mean levels of negative emotions. They also experienced more pronounced variability in both positive and negative emotions, and greater inertia in negative emotions. We also found some evidence for age-related differences in mean levels and variability in certain emotions. The relationship of emotion dynamics indices to stress levels was not moderated by age. Many of the stress-emotion dynamics associations did not remain statistically significant upon controlling for the mean level of momentary emotions, indicating that the mean is a large component in the association.
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http://dx.doi.org/10.3389/fpsyg.2020.01152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309515PMC
June 2020

COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis.

Nat Biotechnol 2020 08 26;38(8):970-979. Epub 2020 Jun 26.

Center for Digital Health, Berlin Institute of Health (BIH) and Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.

To investigate the immune response and mechanisms associated with severe coronavirus disease 2019 (COVID-19), we performed single-cell RNA sequencing on nasopharyngeal and bronchial samples from 19 clinically well-characterized patients with moderate or critical disease and from five healthy controls. We identified airway epithelial cell types and states vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In patients with COVID-19, epithelial cells showed an average three-fold increase in expression of the SARS-CoV-2 entry receptor ACE2, which correlated with interferon signals by immune cells. Compared to moderate cases, critical cases exhibited stronger interactions between epithelial and immune cells, as indicated by ligand-receptor expression profiles, and activated immune cells, including inflammatory macrophages expressing CCL2, CCL3, CCL20, CXCL1, CXCL3, CXCL10, IL8, IL1B and TNF. The transcriptional differences in critical cases compared to moderate cases likely contribute to clinical observations of heightened inflammatory tissue damage, lung injury and respiratory failure. Our data suggest that pharmacologic inhibition of the CCR1 and/or CCR5 pathways might suppress immune hyperactivation in critical COVID-19.
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http://dx.doi.org/10.1038/s41587-020-0602-4DOI Listing
August 2020

Examining Correlates of Pre-ART and Early ART Adherence to Identify Key Factors Influencing Adherence Readiness.

AIDS Behav 2021 Jan;25(1):113-123

Long Beach Education and Research Consultants, Long Beach, CA, USA.

Although current standard of care for HIV typically involves immediate initiation of antiretroviral therapy (ART), most patients can benefit from first assessing adherence readiness and addressing any barriers to optimal adherence. A sample of 176 HIV patients planning to start ART enrolled in a controlled trial of an adherence intervention that was based on the Information Motivation and Behavioral skills (IMB) model of health behavior. We examined correlates of multiple adherence readiness measures, as well as electronically measured early ART adherence, to identify variables most important for readiness to adhere well at the start of treatment. Education level, recency of HIV diagnosis and knowledge and commitment to adherence were found to be associated with both ART readiness and early ART adherence. These findings suggest that resources to support adherence readiness should target more experienced HIV patients, and strive to bolster knowledge and attitudes that reinforce commitment to adherence.
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http://dx.doi.org/10.1007/s10461-020-02947-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752814PMC
January 2021