[Prospective monitoring of a university rheumatology outpatient clinic throughout the first wave of the COVID-19 pandemic : What lessons can be learned?] / Prospektive Verlaufsbeobachtung einer universitären Rheumaambulanzkohorte während der ersten Welle der COVID-19-Pandemie : Welche Lehren kann man ziehen?

BACKGROUND: In March 2020 the SARS-CoV­2 pandemic disseminated initially especially in Bavaria. At that time data on patients with rheumatic diseases and immunomodulatory treatment was lacking. OBJECTIVE: The aim was to analyze the influence of the SARS-CoV­2 pandemic on the clinical treatment strategy. MATERIAL AND METHODS: Between 16 March and 31 July 2020 all patients who consecutively presented at the rheumatology outpatient clinic of the Klinikum rechts der Isar of the Technical University of Munich were included in the study. Individual treatment adjustments were based on clinical judgment and the recommendations for action of the German Society for Rheumatology (DGRh). RESULTS: A total of 322 patients were included. The most frequent diagnosis was rheumatoid arthritis with 17%, ANCA-associated vasculitis (AAV) with 14% and SLE with 12%. Of the patients 262 were on DMARD treatment and 77 received oral glucocorticoids. There were 5 cases of suspected SARS-CoV­2 infection; however, no patient verifiably became ill due to COVID-19. In 40 patients, treatment adjustments were done due to the pandemic, whereby 3 patients developed a flare of the underlying disease. In retrospect, treatment de-escalation occurred most frequently in AAV, IgG4-related disease, immunosuppressive treatment with rituximab and the simultaneous presence of malignant diseases. CONCLUSION: The total lack of confirmed SARS-CoV­2 infections in an otherwise strongly affected region could indicate that the infection risk for SARS-CoV­2 is not substantially increased for patients with inflammatory rheumatic diseases. A continuation of most immunosuppressive medications therefore seems reasonable during the ongoing pandemic.

Rapid point-of-care detection of SARS-CoV-2 infection in exhaled breath using ion mobility spectrometry: a pilot study.

BACKGROUND: An effective testing strategy is essential for pandemic control of the novel Coronavirus disease 2019 (COVID-19) caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Breath gas analysis can expand the available toolbox for diagnostic tests by using a rapid, cost-beneficial, high-throughput point-of-care test. We conducted a bi-center clinical pilot study in Germany to evaluate breath gas analysis using multi-capillary column ion mobility spectrometry (MCC-IMS) to detect SARS-CoV-2 infection. METHODS: Between September 23, 2020, and June 11, 2021, breath gas measurements were performed on 380 patients (SARS-CoV-2 real-time polymerase chain reaction (PCR) positive: 186; PCR negative: 194) presenting to the emergency department (ED) with respiratory symptoms. RESULTS: Breath gas analysis using MCC-IMS identified 110 peaks; 54 showed statistically significant differences in peak intensity between the SARS-CoV-2 PCR-negative and PCR-positive groups. A decision tree analysis classification resulted in a sensitivity of 83% and specificity of 86%, but limited robustness to dataset changes. Modest values for the sensitivity (74%) and specificity (52%) were obtained using linear discriminant analysis. A systematic search for peaks led to a sensitivity of 77% and specificity of 67%; however, validation by transferability to other data is questionable. CONCLUSIONS: Despite identifying several peaks by MCC-IMS with significant differences in peak intensity between PCR-negative and PCR-positive samples, finding a classification system that allows reliable differentiation between the two groups proved to be difficult. However, with some modifications to the setup, breath gas analysis using MCC-IMS may be a useful diagnostic toolbox for SARS-CoV-2 infection. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov on September 21, 2020 (NCT04556318; Study-ID: HC-N-H-2004).

Clinical evaluation of a new tracheal impedance cardiography method.

Non-invasive cardiac output measurement by means of impedance cardiography has been evaluated before, and agreement with other methods has been variable. We decided to study a newly developed tracheal impedance device, that is claimed to be more accurate and reliable. This incorporates new software and mathematical formulae, that are designed to reduce signal noise from diathermy, leading to improved accuracy. In 25 cardiothoracic surgery patients, simultaneous measurements were performed using both pulmonary artery thermodilution and the tracheal impedance device, at five peri-operative time points: before skin incision; after weaning from cardiopulmonary bypass; after sternal closure; and 30 min and 2 h after arrival in the intensive care unit. Mean cardiac output, bias and 95% limits of agreement were 5.3, 0.03 and -2.8 to 2.8 l.min(-1) , respectively. Tracheal impedance showed good correlation with measurement trends using thermodilution in 88% of measurements, with a mean (95% limit of agreement) angular bias of -9.0° (-83.3 to 65.3°). However, the wide limits of agreement and high percentage error of 53% that were apparent in this study mean that, in its present guise, tracheal impedance is not an acceptable alternative to thermodilution in cardiac surgical patients.

Extent of spontaneous motor recovery after traumatic cervical sensorimotor complete spinal cord injury.

STUDY DESIGN: Retrospective, longitudinal analysis of motor recovery data from individuals with cervical (C4-C7) sensorimotor complete spinal cord injury (SCI) according to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI). OBJECTIVES: To analyze the extent and patterns of spontaneous motor recovery over the first year after traumatic cervical sensorimotor complete SCI. METHODS: Datasets from the European multicenter study about SCI (EMSCI) and the Sygen randomized clinical trial were examined for conversion of American Spinal Injury Association (ASIA) Impairment Scale (AIS) grade, change in upper extremity motor score (UEMS) or motor level, as well as relationships between these measures. RESULTS: There were no overall differences between the EMSCI and Sygen datasets in motor recovery patterns. After 1 year, up to 70% of subjects spontaneously recovered at least one motor level, but only 30% recovered two or more motor levels, with lesser values at intermediate time points. AIS grade conversion did not significantly influence motor level changes. At 1 year, the average spontaneous improvement in bilateral UEMS was 10-11 motor points. There was only moderate relationship between a change in UEMS and a change in cervical motor level (r(2)=0.30, P<0.05). Regardless of initial cervical motor level, most individuals recover a similar number of motor points or motor levels. CONCLUSION: Careful tracking of cervical motor recovery outcomes may provide the necessary sensitivity and accuracy to reliably detect a subtle, but meaningful treatment effect after sensorimotor complete cervical SCI. The distribution of the UEMS change may be more important functionally than the total UEMS recovered.

Dose profiles and x-ray energy optimization for microbeam radiation therapy by high-dose, high resolution dosimetry using Sm-doped fluoroaluminate glass plates and Monte Carlo transport simulation.

Microbeam radiation therapy (MRT) utilizes highly collimated synchrotron generated x-rays to create narrow planes of high dose radiation for the treatment of tumors. Individual microbeams have a typical width of 30-50 µm and are separated by a distance of 200-500 µm. The dose delivered at the center of the beam is lethal to cells in the microbeam path, on the order of hundreds of Grays (Gy). The tissue between each microbeam is spared and helps aid in the repair of adjacent damaged tissue. Radiation interactions within the peak of the microbeam, such as the photoelectric effect and incoherent (atomic Compton) scattering, cause some dose to be delivered to the valley areas adjacent to the microbeams. As the incident x-ray energy is modified, radiation interactions within a material change and affect the probability of interactions, as well as the directionality and energy of ionizing particles (electrons) that deposit energy in the valley regions surrounding the microbeam peaks. It is crucial that the valley dose between microbeams be minimal to maintain the effectiveness of MRT. Using a monochromatic x-ray source with x-ray energies ranging from 30 to 150 keV, a detailed investigation into the effect of incident x-ray energy on the dose profiles of microbeams was performed using samarium doped fluoroaluminate (FA) glass as the medium. All dosimetric measurements were carried out using a purpose-built fluorescence confocal microscope dosimetric technique that used Sm-doped FA glass plates as the irradiated medium. Dose profiles are measured over a very a wide range of x-ray energies at micrometer resolution and dose distribution in the microbeam are mapped. The measured microbeam profiles at different energies are compared with the MCNP6 radiation transport code, a general transport code which can calculate the energy deposition of electrons as they pass through a given material. The experimentally measured distributions can be used to validate the results for electron energy deposition in fluoroaluminate glass. Code validation is necessary for using transport codes in future treatment planning for MRT and other radiation therapies. It is shown that simulated and measured micro beam-profiles are in good agreement, and micrometer level changes can be observed using this high-resolution dosimetry technique. Full width at 10% of the maximum peak (FW@10%) was used to quantify the microbeam width. Experimental measurements on FA glasses and simulations on the dependence of the FW@10% at various energies are in good agreement. Simulations on energy deposited in water indicate that FW@10% reaches a local minimum around energies 140 keV. In addition, variable slit width experiments were carried out at an incident x-ray energy of 100 keV in order to determine the effect of the narrowing slit width on the delivered peak dose. The microbeam width affects the peak dose, which decreases with the width of the microbeam. Experiments suggest that a typical microbeam width for MRT is likely to be between 20-50 µm based on this work.

Acetogenin-Based Formulated Bioinsecticides on Anastrepha fraterculus: Toxicity and Potential Use in Insecticidal Toxic Baits.

The present study evaluated the lethal toxicity and oviposition deterrence of ethanolic extracts of Annona mucosa Jacq., Annona muricata L., and Annona sylvatica A. St.-Hil on Anastrepha fraterculus (Wiedemann) (Diptera: Tephritidae) compared with those of a limonoid-based bioinsecticide (Azamax™ 1.2 EC-azadiractin +3-tigloyl-azadiractol) and a synthetic spinosyn-based insecticide (Delegate™ 250 WG-spinetoram). In addition, the efficacy of the selected toxic bait formulations was evaluated by mixing them with food attractants (Anamed™, 3% Biofruit and 7% sugarcane molasses). In the topical application and ingestion bioassays (2000 mg L-1), the aqueous emulsion of the A. mucosa extract caused greater than 80% mortality of A. fraterculus adults in a similar manner to the spinosyn-based synthetic insecticide. Concentration-response curves were performed for the most promising treatments and showed an activity level dependent on the mode of contamination, exposure time, and applied concentration. In bioassays with and without choice, the A. mucosa (77%), A. muricata (51%), A. sylvatica (60%), Azamax™ (74%), and Delegate™ 250 WG (100%) significantly reduced the number of punctures and galleries in grape berries. In combination with the food attractants Anamed™, 3% Biofruit, and 7% sugarcane molasses, the emulsion of the A. mucosa extract had a residual effect similar to that of the spinetoram insecticide, with a mortality rate of over 80% of A. fraterculus adults up to 14 days after application (DAA) in the absence of rain. Thus, acetogenin-rich formulations, especially from A. mucosa seeds, are useful alternatives for the integrated management of A. fraterculus in agricultural orchards.

Deuterium micromapping of biological samples by using the D(T,n)4He reaction and plastic track detectors.

A technique has been developed to micromap deuterium by using the D(T,n)(4)He reaction and plastic track detectors. Labeling of cells with subpicogram quantities of deuterium was demonstrated. The technique was used to localize human lymphocytes transformed in vitro.

4G versus 3G-enabled telemedicine in prehospital acute stroke care.

BACKGROUND: Time to reperfusion treatment is closely related to outcome in ischemic stroke. Prehospital stroke work-up in CT-equipped mobile stroke units is effective in reducing time to thrombolytic treatment. Current evidence predominantly comes from mobile stroke units staffed with neurologists but telemedicine-guided management may be acceptable for providing neurological expertise in ambulances. With unsatisfactory experiences in third-generation (3G)-based approaches, fourth-generation (4G) networks may provide adequate audio-visual quality but systematic comparisons of technological parameters and decision-making are lacking. METHODS: Trained actors presented stroke symptoms and paramedics assisted the remotely guided extended National Institutes of Health Stroke Scale (eNIHSS) assessment on the mobile stroke unit in Berlin, Germany. We compared technical parameters of 4G and 3G connections, assessed audio-visual quality of examination, and analyzed reliability of neurological assessment and treatment decisions made by the remote neurologist versus the mobile stroke unit neurologist. RESULTS: 4G and 3G connections were evaluated in 40 scenarios each. Connectivity was not available in 17% of 4G- and 15% of 3G-attempts with 6% simultaneous unavailability of both networks. The remote examiners graded audio and video quality in 4G better than in 3G with slightly shorter assessment duration in 4G (mean: 9 (SD:5) vs. mean 11 (SD:3) min, p = 0.10). Reliability of the eNIHSS sum scores was high with intraclass correlation coefficients of 0.99 (95% CI: 0.987-1.00) for 4G and 0.98 (95% CI: 0.96-0.99) for 3G. None of the remote treatment decisions differed from onsite decisions. CONCLUSIONS: 4G mobile communications provided higher quality of video-examination and allowed reliable remote assessment of stroke symptoms but coverage was still incomplete in both networks.

[Suicide attempt with sotalol: a proarrhythmic intoxication]. / Tentamen suicidii met sotalol: een proaritmische intoxicatie.

A 62-year-old man was brought into the intensive care unit because of a cardiac arrest. After extensive resuscitation, including defibrillation, sinus bradycardia occurred with marked QT prolongation, followed by recurrent episodes of torsade de pointes. Hetero-anamnestic data revealed a suicide attempt with sotalol. Treatment consisted largely of temporary pacing using an external transvenous overdrive pacemaker and administration of glucagon, milrinon and norepinephrine. Eventually, the patient was discharged in good condition. A suicide attempt with sotalol is a rare intoxication with considerable morbidity and mortality. Treatment is primarily based upon counteracting the proarrhythmic effects of sotalol. However, even when therapeutic levels of this drug are used, proarrhythmic effects can occur.

Kras(G12D) induces EGFR-MYC cross signaling in murine primary pancreatic ductal epithelial cells.

Epidermal growth factor receptor (EGFR) signaling has a critical role in oncogenic Kras-driven pancreatic carcinogenesis. However, the downstream targets of this signaling network are largely unknown. We developed a novel model system utilizing murine primary pancreatic ductal epithelial cells (PDECs), genetically engineered to allow time-specific expression of oncogenic Kras(G12D) from the endogenous promoter. We show that primary PDECs are susceptible to Kras(G12D)-driven transformation and form pancreatic ductal adenocarcinomas in vivo after Cdkn2a inactivation. In addition, we demonstrate that activation of Kras(G12D) induces an EGFR signaling loop to drive proliferation. Interestingly, pharmacological inhibition of EGFR fails to decrease Kras(G12D)-activated ERK or PI3K signaling. Instead our data provide novel evidence that EGFR signaling is needed to activate the oncogenic and pro-proliferative transcription factor c-MYC. EGFR and c-MYC have been shown to be essential for pancreatic carcinogenesis. Importantly, our data link both pathways and thereby explain the crucial role of EGFR for Kras(G12D)-driven carcinogenesis in the pancreas.

Depression in patients with acute traumatic brain injury.

OBJECTIVE: This study was undertaken to examine patients with closed head injuries for the presence of depressive disorders. METHOD: A consecutive series of 66 patients with closed head injuries but no significant spinal cord or other organ system injury were examined by means of a semistructured psychiatric interview. The Hamilton Rating Scale for Depression as well as scales measuring impairment in activities of daily living, intellectual functioning, and social functioning were administered. The patients' CT scans were also examined. RESULTS: Seventeen patients had major depression and two had minor depression. The presence of left dorsolateral frontal lesions and/or left basal ganglia lesions and, to a lesser extent, parietal-occipital and right hemisphere lesions was associated with an increased probability of developing major depression. Compared to the nondepressed group, the group with major depression had a higher frequency of previous psychiatric disorder and showed evidence of poorer social functioning. CONCLUSIONS: Major depression occurs in about one-quarter of patients after traumatic brain injury. This is the same frequency as in other major disorders such as stroke. Major depression appears to be provoked by one or more factors that include poor premorbid social functioning and previous psychiatric disorder or injury to certain critical brain locations.

Secondary mania following traumatic brain injury.

OBJECTIVE: In this study patients were examined during the first year after traumatic brain injury to determine the presence of secondary mania. METHOD: A consecutive series of 66 patients with closed-head injury were evaluated in the hospital and at 3-, 6-, and 12-month follow-ups. The patients were examined with a semistructured psychiatric interview and scales for measurement of impairment in activities of daily living, intellectual function, and social functioning. Patients fulfilling the DSM-III-R criteria for mania were compared to patients with major depression and to patients without affective disturbances in regard to their background characteristics, impairment variables, and lesion locations. RESULTS: Six patients (9%) met the criteria for mania at some point during follow-up. The presence of temporal basal polar lesions was significantly associated with secondary mania even when the effect of other lesion locations was taken into account. Secondary mania was not found to be associated with the severity of brain injury, degree of physical or cognitive impairment, level of social functioning, or previous family or personal history of psychiatric disorder. The duration of mania, however, appeared to be brief, lasting approximately 2 months. CONCLUSIONS: The 9% frequency of secondary mania in these patients with traumatic brain injury is significantly greater than that seen in other brain-injured populations (e.g., patients with stroke). The major correlate was the presence of a temporal basal polar lesion.

GM-1 ganglioside in human spinal cord injury.

Spinal cord injury is typically a devastating injury with no or only limited neurologic recovery. Recent papers have reported enhancement of neurologic recovery following spinal cord injury with both methylprednisolone and GM-1 ganglioside. This paper provides additional details of the GM-1 study and a further analysis of recovery of motor function for each of the ten neurologic levels assessed in the study. This additional analysis provides further evidence that the largest enhanced recovery of motor function in the GM-1 treatment group occurred in the muscles of the lower extremities and is consistent with the enhanced recovery occurring in the white matter tracts passing through the level of injury.

GM-1 ganglioside in human spinal cord injury.

Spinal cord injury is typically a devastating injury with no or only limited neurologic recovery. Recent papers have reported enhancement of neurologic recovery following spinal cord injury with both methylprednisolone and GM-1 ganglioside. This paper provides additional details of the GM-1 study and a further analysis of recovery of motor function for each of the ten neurologic levels assessed in the study. This additional analysis provides further evidence that the largest enhanced recovery of motor function in the GM-1 treatment group occurred in the muscles of the lower extremities and is consistent with the enhanced recovery occurring in the white matter tracts passing through the level of injury.

Clinical trials of pharmacotherapy for spinal cord injury.

Spinal cord injury remains with limited natural recovery and only a few general ineffective treatment options. Recent publications have reported enhanced neurologic recovery with the use of methylprednisolone and GM-1 ganglioside. The results of the Maryland GM-1 Ganglioside Study reported a significant drug effect with respect to the fraction of patients that had a change of two or more Frankel grades from entrance into the study to 1-year follow-up. This study formed the basis for the currently ongoing larger placebo-controlled multicentered study using Sygen GM-1 following acute spinal cord injury. This study has entered 797 patients and is expected to present results in early 1998.

Comprehensive predictions of outcome in closed head-injured patients. The development of prognostic equations.

A comprehensive diagnostic evaluation was administered to 162 closed head-injured patients within 1 to 21 days (mean, 7.5 days) after injury. Each evaluation consisted of (1) power spectral analyses of electroencephalogram (EEG) recorded from 19 scalp locations referenced to age-matched norms, (2) brainstem auditory evoked potentials, (3) computed tomography (CT)-scan, and (4) Glasgow Coma Score (GCS) at time of admission (GCS-A) and at time of EEG test (GCS-T). Functional outcome at one year following injury was assessed using the Rappaport Disability Rating Scale (DRS), which measures the level of disability in the six diagnostic categories of (1) eye opening, (2) best verbal response, (3) best motor response, (4) self-care ability for feeding, grooming, and toileting, (5) level of cognitive functioning, and (6) employability. The ability of the different diagnostic measures to predict outcome at one year following injury was assessed using stepwise discriminant analyses to identify patients in the extreme outcome categories of complete recovery versus death and multivariate regression analyses to predict patients with intermediate outcome scores. The best combination of predictor variables was EEG and GCS-T, which accounted for 74.6% of the variance in the multivariate regression analysis of intermediate outcome scores and 95.8% discriminant accuracy between good outcome and death. The best single predictors of outcome in both the discriminant analyses and the regression analyses were EEG coherence and phase. A gradient of prognostic strength of diagnostic measures was EEG phase greater than EEG coherence greater than GCS-T greater than CT-scan greater than EEG relative power. The value of EEG coherence and phase in the assessment of diffuse axonal injury was discussed.

Endomorphin-1 and -2, endogenous ligands for the mu-opioid receptor, inhibit striated and smooth muscle contraction in the rat oesophagus.

Recently, morphological evidence for an interaction of autonomic nerve fibres and extrinsic motor innervation of the rat oesophagus has emerged. The aim of the present study was to investigate the possible influence of endogenous and exogenous opioids on rat oesophageal smooth and striated muscle function in vitro. The entire oesophagus (excluding the lower oesophageal sphincter) with both Nervi (Nn) vagi, including the Nn recurrentes, was dissected and placed in an organ bath (100 mL, 37 degrees) with oxygenated Krebs-Ringer buffer. Contractile activity was measured in a longitudinal direction with a force transducer. Both Nn vagi were placed on a bipolar platinum electrode 2 cm distant from the oesophagus. Vagal stimulation (VS), applied for 1 s (40 V, 0.5 ms, 20 Hz) resulted in a biphasic contractile response that was completely blocked by 10(-6) M tetrodotoxin. The first part consisted of a tetanic striated muscle contraction, as it was abolished by tubocurarine (10(-5) M, n=5) but unaffected by atropine (10(-6) M, n=3) or hexamethonium (10(-4) M, n=4). In contrast, the second part was completely inhibited by hexamethonium (10(-4) M) and atropine (10(-6)M), whereas tubocurarine (10(-5) M) showed no influence, indicating a stimulation of preganglionic nerve fibres supplying oesophageal smooth muscle (muscularis mucosae) via relays in myenteric ganglia. In order to characterize opioid influence on the oesophageal striated and smooth muscle contractility, the following experiments were carried out. 10(-6) M endomorphin-1 and -2, endogenous mu-opioid-receptor agonists, reduced the contractile response of the striated (EM-2, -25.1+/-5.3%; n=16), and the smooth muscle (EM-2, -81.9+/-3.3%; n=11). Both effects were reversible by the opioid receptor antagonist naloxone (10(-6) M) and therefore, mediated via opioid receptors. Neither SNC-80, an agonist on the delta-opioid-receptor, U-69593, an agonist on the kappa-opioid-receptor, nor nociceptin, an agonist at the ORL1 (opioid receptor-like) receptor, had a significant effect on the striated muscle contraction. In contrast to SNC-80, U-69593 and nociceptin inhibited smooth muscle contraction but this relaxation could not be antagonized by naloxone. None of the opioid receptor antagonists used had an effect on basal tonus or muscle contraction following VS. Our data provide evidence for an autonomic modulation of vagal motor innervation of the striated and smooth oesophageal muscle. Endomorphin-1 and -2, both selective mu-opioid receptor agonists, cause an inhibition of striated and smooth muscle response which is reversible by naloxone, an opioid receptor antagonist. The location of the mu-opioid receptor still has to be established.

Intraoperative sonography of cervical spinal cord injury: results in 30 patients.

Intraoperative spinal sonography (IOSS) with a 7.5-MHz sector transducer was performed in 30 patients with cervical spine injury associated with neurologic deficits. A laminectomy (25 patients) or anterior corpectomy (five patients) during spinal surgery provided the IOSS imaging window. The surgery was performed for either spinal decompression or fixation as part of the initial care of these patients and occurred 1 to 39 days (mean, 12.4 days) after injury. Parenchymal spinal cord lesions at the level of cervical fracture or stenosis that were compatible with the initial neurologic deficits were detected by IOSS in 28 (96.5%) of 29 patients with technically adequate studies. Lesions appeared as foci of increased echogenicity and were sorted into five injury grades (0 through IV). The IOSS injury grade in each patient was determined by the maximal diameter of regions of increased echogenicity and/or cyst formation in either the sagittal or transverse image plane. The extent of initial neurologic injury and its recovery was assessed by using the ASIA motor score (0 to 100 unit scale) at admission and during follow-up. The IOSS injury grade was correlated with the initial ASIA motor score (p less than 0.009, Spearman's Rank Order Test), indicating that the IOSS echogenicity is related to the extent of initial clinical motor deficit. Regression analysis disclosed that both the IOSS injury grade and the initial ASIA score were correlated with the follow-up ASIA score (p less than 0.05 and p less than 0.001, respectively). However, the addition of the IOSS injury grade to the initial ASIA motor score did not improve the predictive ability of the follow-up ASIA motor score.(ABSTRACT TRUNCATED AT 250 WORDS)