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Institute
- Medizin (541) (remove)
Background: Prostate cancer is a major health concern in aging men. Paralleling an aging society, prostate cancer prevalence increases emphasizing the need for efcient diagnostic algorithms.
Methods: Retrospectively, 106 prostate tissue samples from 48 patients (mean age,
66 ± 6.6 years) were included in the study. Patients sufered from prostate cancer (n = 38) or benign prostatic hyperplasia (n = 10) and were treated with radical prostatectomy or Holmium laser enucleation of the prostate, respectively. We constructed tissue microarrays (TMAs) comprising representative malignant (n = 38) and benign (n = 68) tissue cores. TMAs were processed to histological slides, stained, digitized and assessed for the applicability of machine learning strategies and open–source tools in diagnosis of prostate cancer. We applied the software QuPath to extract features for shape, stain intensity, and texture of TMA cores for three stainings, H&E, ERG, and PIN-4. Three machine learning algorithms, neural network (NN), support vector machines (SVM), and random forest (RF), were trained and cross-validated with 100 Monte Carlo random splits into 70% training set and 30% test set. We determined AUC values for single color channels, with and without optimization of hyperparameters by exhaustive grid search. We applied recursive feature elimination to feature sets of multiple color transforms.
Results: Mean AUC was above 0.80. PIN-4 stainings yielded higher AUC than H&E and
ERG. For PIN-4 with the color transform saturation, NN, RF, and SVM revealed AUC of 0.93 ± 0.04, 0.91 ± 0.06, and 0.92 ± 0.05, respectively. Optimization of hyperparameters improved the AUC only slightly by 0.01. For H&E, feature selection resulted in no increase of AUC but to an increase of 0.02–0.06 for ERG and PIN-4.
Conclusions: Automated pipelines may be able to discriminate with high accuracy between malignant and benign tissue. We found PIN-4 staining best suited for classifcation. Further bioinformatic analysis of larger data sets would be crucial to evaluate the reliability of automated classifcation methods for clinical practice and to evaluate potential discrimination of aggressiveness of cancer to pave the way to automatic precision medicine.
This prospective study sought to evaluate potential savings of radiation dose to medical staff using real-time dosimetry coupled with visual radiation dose feedback during angiographic interventions. For this purpose, we analyzed a total of 214 angiographic examinations that consisted of chemoembolizations and several other types of therapeutic interventions. The Unfors RaySafe i2 dosimeter was worn by the interventionalist at chest height over the lead protection. A total of 110 interventions were performed with real-time radiation dosimetry allowing the interventionalist to react upon higher x-ray exposure and 104 examinations served as the comparative group without real-time radiation monitoring. By using the real-time display during interventions, the overall mean operator radiation dose decreased from 3.67 (IQR, 0.95–23.01) to 2.36 μSv (IQR, 0.52–12.66) (−36%; p = 0.032) at simultaneously reduced operator exposure time by 4.5 min (p = 0.071). Dividing interventions into chemoembolizations and other types of therapeutic interventions, radiation dose decreased from 1.31 (IQR, 0.46-3.62) to 0.95 μSv (IQR, 0.53-3.11) and from 24.39 (IQR, 12.14-63.0) to 10.37 μSv (IQR, 0.85-36.84), respectively, using live-screen dosimetry (p ≤ 0.005). Radiation dose reductions were also observed for the participating assistants, indicating that they could also benefit from real-time visual feedback dosimetry during interventions (−30%; p = 0.039). Integration of real-time dosimetry into clinical processes might be useful in reducing occupational radiation exposure time during angiographic interventions. The real-time visual feedback raised the awareness of interventionalists and their assistants to the potential danger of prolonged radiation exposure leading to the adoption of radiation-sparing practices. Therefore, it might create a safer environment for the medical staff by keeping the applied radiation exposure as low as possible.
The combination of histological and biomolecular analyses provides deep understanding of different biological processes and is of high interest for basic and applied research. However, the available analytical methods are still limited, especially when considering bone samples. This study compared different fixation media to identify a sufficient analytical method for the combination of histological, immuno-histological and biomolecular analyses of the same fixed, processed and paraffin embedded bone sample. Bone core biopsies of rats’ femurs were fixed in different media (RNAlater + formaldehyde (R + FFPE), methacarn (MFPE) or formaldehyde (FFPE)) for 1 week prior to decalcification by EDTA and further histological processing and paraffin embedding. Snap freezing (unfixed frozen tissue, UFT) and incubation in RNAlater were used as additional controls. After gaining the paraffin sections for histological and immunohistological analysis, the samples were deparaffined and RNA was isolated by a modified TRIZOL protocol. Subsequently, gene expression was evaluated using RT-qPCR. Comparable histo-morphological and immuno-histological results were evident in all paraffin embedded samples of MFPE, FFPE and R + FFPE. The isolated RNA in the group of MFPE showed a high concentration and high purity, which was comparable to the UFT and RNAlater groups. However, in the groups of FFPE and R + FFPE, the RNA quality and quantity were statistically significantly lower when compared to MFPE, UFT and RNAlater. RT-qPCR results showed a comparable outcome in the group of MFPE and UFT, whereas the groups of FFPE and R + FFPE did not result in a correctly amplified gene product. Sample fixation by means of methacarn is of high interest for clinical samples to allow a combination of histological, immunohistological and biomolecular analysis. The implementation of such evaluation method in clinical research may allow a deeper understanding of the processes of bone formation and regeneration.
Background: Survival data regarding cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (mRCC) patients according to the type and extent of tumor-associated vascular thrombus are scarce.
Objective: To test for survival differences in mRCC patients treated with CN according to the type and extent of tumor-associated vascular thrombus.
Design, setting, and participants: Within Surveillance, Epidemiology, and End Results Research Plus (2004–2017), we identified CN mRCC patients with renal vein (pT3a-TT) versus infradiaphragmatic inferior vena cava (IVC; pT3b) versus supradiaphragmatic IVC tumor thrombus/IVC invasion (pT3c).
Outcome measurements and statistical analysis: Overall survival (OS) was addressed in Kaplan-Meier and Cox regression analyses, in addition to 3-mo landmark analyses.
Results and limitations: Of 2170 mRCC patients, 1880 (87%), 204 (9%), and 86 (4%) harbored pT3a-TT, pT3b, and pT3c, respectively. The respective median OS periods were 21, 23, and 12 mo (p < 0.001). In multivariable Cox regression models, pT3c stage, but not pT3b stage, was an independent predictor of higher overall mortality (hazard ratio [HR]: 1.37; 95% confidence interval [CI]: 1.09–1.73; p = 0.007), as well as in 6-mo landmark analyses (HR: 1.36; 95% CI: 1.02–1.80; p = 0.04). In the sensitivity analysis, relying on all pT3a patients, the predictor status of pT3c stage remained unchanged (HR: 1.37; 95% CI: 1.09–1.71; p = 0.007). Limitations have to be addressed regarding the sample size and the retrospective design of the current study.
Conclusions: Although overall mortality is significantly higher in pT3c mRCC patients than in their pT3b and pT3a-TT counterparts, these individuals may still expect 12-mo or better OS after CN versus virtually 2-yr OS in their pT3a and pT3b counterparts.
Patient summary: In this study, we looked at the survival outcomes of metastatic renal cell carcinoma patients who presented with tumor thrombus at cytoreductive nephrectomy. Even though these patients with most advanced tumor thrombus stage demonstrated lower survival rates, the median overall survival was still 1 yr.
Middle-aged persons with multimorbidity have to take their illnesses into account in their daily work, family and leisure activities. The MuMiA project aims to identify early preventive measures that make it easier for those between 30 and 60 years of age with multiple chronic diseases to manage their illnesses in their everyday lives. An interdisciplinary workshop and interviews with multimorbid middle-aged adults and their principal healthcare providers will be used to collect information on the management of care in the contexts of patients’ daily work, family and leisure activities. Data obtained in the interviews will be coded inductively and analysed using content analysis. Workshop outputs will be transcribed and evaluated by the authors. This study has received ethical approval from the Faculty of Medicine Ethics Committee of Goethe University (2021-47). The project will generate prevention recommendations that reflect the experiences of middle-aged persons living with multimorbidity and the views of their principal healthcare providers. The findings will be disseminated via conferences and peer-reviewed publications.
Development of a multidimensional pain questionnaire in professional dance (MPQDA): a pilot study
(2022)
Background: Pain is part of the everyday life of professional dancers. It can indicate health risks and impair the ability to work. Suitable screening tools can be used to identify pain and its risk potential. A comprehensive, multidimensional, differentiated assessment tool for pain in professional dance does not currently exist.
Methods: An initial questionnaire was developed in German and English and was assessed in a qualitative pretest. In a field study with a cross-sectional design including n = 72 dancers from Germany (n = 36 responses each in the English and German language versions), the questionnaire was optimized by item analysis, its psychometric properties (dimensionality, construct validity, reliability) were examined and the ability of the pain dimensions to classify the subjective ability to work in training was analyzed (ROC analysis).
Results: The developed Multidimensional Pain Questionnaire in Professional Dance (MPQDA) was reduced and optimized in its psychometric properties. Following questions were reduced in their items or answer categories: pain localizations (from 20 to 15 regions), accompanying symptoms (from 6 to 3 items), sensory and affective pain quality (from 20 to 10 items), pain frequency (from 4 to 3 answer categories), and the motives of working with pain (from 14 to 12 items). Regarding the subjective ability to work in training, the variables of the ability to work in rehearsals and in performances, as well as the accompanying symptoms of tension and mobility restrictions, showed a relatively good classification ability (Area under the Curve (AUC) ≥ 0.7 in the 95% confidence interval) and significant, moderate to strong correlations (Somers' D > 0.25, p < 0.05). The classification ability of the other pain dimensions was largely absent or poor.
Conclusion: The MPQDA differentiates various pain dimensions in professional dancers and is available in a compatible manner in German and English. The clinical relevance needs to be explored further in the future.
Up to the present, there has been a lack of studies on the skin health of professional and recreational dancers. Dancers are at risk of skin diseases due to contact with allergenic or irritating substances and working in humid environments. The aim of the present study was, therefore, to examine skin health in two different dance styles and training periods. Methods: Physical dermatological examination of professional dancers (PD; n = 35) and Latin American formation dancers (LD; n = 79) after a 4-week period of recovery (T0) and a period of high training or work load (T1). Results: PD are significantly more frequently affected by skin dermatoses than LD (T0, p = 0.004) (frontal traction alopecia, hair loss, facial seborrhoea, xerosis cutis of the trunk and extremities, and facial folliculitis). The following significant differences between the sexes were observed in the LD: more folliculitis of the trunk in male subjects (T0 and T1, p = 0.009), more frequent xerosis cutis of the extremities (p < 0.001) and perioral dermatitis in female subjects (T1, p = 0.043). Subjects with skin lesions trained more frequently, performed more times per year, and had longer dance experience. Discussion: Based on the findings, preventive measures for skin protection (especially informing dancers about skin health) are necessary. At the same time, further studies on this topic are important.
The deep fascia is intimately linked to skeletal muscle and may be involved in delayed onset muscle soreness (DOMS). The present study therefore explored the effect of eccentric exercise on fascia stiffness and its relation with DOMS. Healthy active male adults (n = 19, 27 ± 4 years) performed 6 x 10 maximal eccentric knee flexions using an isokinetic dynamometer. Before (baseline) as well as immediately (T0), 1 hour (T1), and each day up to 72 hours (T24 to T72) afterwards, shear wave elastography was used to measure the mechanical stiffness of the biceps femoris muscle and the overlying fascia. As a surrogate of DOMS, pain upon palpation was captured by means of a 100mm visual analogue scale. While muscle stiffness remained unchanged (p > 0.05), deep fascia stiffness increased from baseline to T24 (median: 18 kPa to 21.12 kPa, p = 0.017) and T72 (median: 18 kPa to 21.3 kPa, p = 0.001) post-exercise. Linear regression showed an association of stiffness changes at T24 and pressure pain at T72 (r2 = 0.22, p < 0.05). Maximal eccentric exercise leads to a stiffening of the fascia, which, in turn, is related to the magnitude of future DOMS. Upcoming research should therefore gauge the effectiveness of interventions modifying the mechanical properties of the connective tissue in order to accelerate recovery.
Background: Primary viral myocarditis associated with severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) infection is a rare diagnosis.
Case presentation: We report the case of an unvaccinated, healthy patient with cardiogenic shock in the context of a COVID-19-associated myocarditis and therapy with simultaneous veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and percutaneous left ventricular decompression therapy with an Impella. The aim of this review is to provide an overview of therapeutic options for patients with COVID-19-associated myocarditis.
Conclusions: The majority of patients required a combination of two assist devices to achieve sufficient cardiac output until recovery of left ventricular ejection fraction. Due to the rapid onset of this fulminant cardiogenic shock immediate invasive bridging therapy in a specialized center was lifesaving.
Introduction: Studies of vocational ballet students are sparce. In particular, there is a lack of gender comparisons. The aim of the present study, therefore, was to give a musculoskeletal and sociodemographic description of the typical vocational ballet student in gender comparison. Methods: In this study, n = 414 female and n = 192 male students of the John Cranko School (JCS), aged between 5 and 22 years (Mean ± SD: 13.9 ± 3.5), were examined by an experienced orthopedist and dance physician. Results: Males started ballet (5.8/8.2 years, p < 0.001) and training at later age than females (13.5/14.6 years, p < 0.05). There was a high prevalence of low body weight among both sexes; however, particularly among female participants (58.4/16.2%, p < 0.001). Both sexes showed a large external rotation of the hip (f/m: 59/62°, p < 0.001), a large turnout (f/m: 82/86°, p < 0.01), high values for plantarflexion of the ankle joint (f/m: 72/68°, p < 0.001) and dorsiflexion of the metatarsophalangeal joint of the big toe (f/m: 90/87°, p < 0.001). Discussion: Differences in ballet-specific characteristics between genders (f/m) are converging and are smaller than described in the past. The particularly high prevalence of low body weight among students in the vocational training sector, particularly among females, highlights the need for deeper diagnostic investigation.
Structural brain morphometry as classifier and predictor of ADHD and reward-related comorbidities
(2022)
Attention deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, and around two-thirds of affected children report persisting problems in adulthood. This negative trajectory is associated with high comorbidity with disorders like obesity, depression, or substance use disorder (SUD). Decreases in cortical volume and thickness have also been reported in depression, SUD, and obesity, but it is unclear whether structural brain alterations represent unique disorder-specific profiles. A transdiagnostic exploration of ADHD and typical comorbid disorders could help to understand whether specific morphometric brain changes are due to ADHD or, alternatively, to the comorbid disorders. In the current study, we studied the brain morphometry of 136 subjects with ADHD with and without comorbid depression, SUD, and obesity to test whether there are unique or common brain alterations. We employed a machine-learning-algorithm trained to classify subjects with ADHD in the large ENIGMA-ADHD dataset and used it to predict the diagnostic status of subjects with ADHD and/or comorbidities. The parcellation analysis demonstrated decreased cortical thickness in medial prefrontal areas that was associated with presence of any comorbidity. However, these results did not survive correction for multiple comparisons. Similarly, the machine learning analysis indicated that the predictive algorithm grouped most of our ADHD participants as belonging to the ADHD-group, but no systematic differences between comorbidity status came up. In sum, neither a classical comparison of segmented structural brain metrics nor an ML model based on the ADHD ENIGMA data differentiate between ADHD with and without comorbidities. As the ML model is based in part on adolescent brains, this might indicate that comorbid disorders and their brain changes are not captured by the ML model because it represents a different developmental brain trajectory.
Objectives: The range of motion (ROM) of the cervical spine and postural stability are important for an economical and motorically adequate adaptation of the body to any situation. Therefore, this study aims to analyze whether these two components of postural and movement control can be influenced by means of a splint in a centric position compared to habitual occlusion.
Methods: 38 recreational male athletes volunteered. Cervical spine ROM was recorded using an ultrasound system and the a pressure measuring plate for postural stability (length of center of pressure (CoP) movement, area of CoP). The two dental occlusion conditions employed were the habitual occlusion and wearing a splint in an idealized, condylar position close to the centric position. Level of significance was set at ρ ≤ 0.05.
Results: The cervical spine mobility increased significantly by wearing the splint regarding rotation to the left (+3.9%) and right (+2.7%) and lateral flexion to the left (+4.4%) and right (+6.7%). Wearing the splint reduced the area of sway deflections by about 31.5% in the bipedal stance and by about 2.4% (left) and 28.2% (right) in the unipedal stance. The CoP trace was reduced in the sagittal plane by approximately 8.2% in the right single-leg stance.
Conclusions: The major findings seem to demonstrate that wearing a splint that keeps the jaw close to the centric relation may increase the cervical ROM and may improve balance stability in male recreational athletes. Changing the jaw relation in athletes can possibly aid the release of performance potentials by improving coordination skills.
Background: In order to determine possible pathological deviations in body weight distribution and body sway, it is helpful to have reference values for comparison: gender and age are two main influencing factors. For this reason, it was the aim of the present study to present reference values for women between 51 and 60 years of age.
Methods: For this study, 101 subjectively healthy female Germans aged between 51 and 60 years (55.16 ± 2.89 years) volunteered and were required to stand in a habitual posture on a pressure measuring platform.
Results: The average BMI of this age group was 25.02 ± 4.55 kg/m². The left and right foot showed an almost evenly balanced load distribution with a median load of 52.33% on the left foot [tolerance interval (TR) 38.00%/68.03%; confidence interval (CI) 51.00%/53.33%] and 47.67% on the right foot [TR 31.97%/62.00%; CI 46.67%/49.00%]. The measured median load of the forefoot was 33.33% [TR 21.37%/54.60%; CI 30.67%/36.00%] and that of the rear foot was 66.67% [TR 45.50%/78.63%; CI 64.00%/69.33%]. The median body sway in the frontal plane was 11 mm [TR 5.70 mm/26.30 mm; CI 10.00 mm/11.67 mm] and that of the sagittal plane was 16 mm [TR 7.37 mm/34.32 mm; CI 14.67 mm/18.67 mm]. The median ellipse area was 1.17 cm² [TR 0.29 cm²/4.96 cm²; CI 0.98 cm²/1.35 cm²], the median ellipse width was 0.91 cm [TR 0.42 cm/1.9 cm; CI 0.84 cm/1.02 cm] and its height was 0.40 cm [TR 0.22 cm/0.89 cm; CI 0.38 cm/0.43 cm].
Conclusions: The left-to-right ratio is almost balanced. The load distribution of the forefoot to the rear foot is approximately 1:2. The median body sway values for the frontal and sagittal planes (11 and 16 mm, respectively) agree with other values. The values for the height, body weight and the BMI are comparable to the values of average German women at this age; therefore, the measured values show a presentable cross section of women in the 51–60 age group in Germany. The present data can be used as a basis for women aged 51–60 years and can support the detection of possible dysfunctions as well as injury prevention in the parameters of postural control.
Background: In the COVID-19 pandemic, numerous researchers postponed their patient and public involvement (PPI) activities. This was mainly due to assumptions on patients’ willingness and skills to participate digitally. In fact, digital PPI workshops differ from in-person meetings as some forms of non-verbal cues and body language may be missing and technical barriers may exist. Within our project HYPERION-TransCare we adapted our PPI workshop series for intervention development to a digital format and assessed whether these digital workshops were feasible for patients, health care professionals and researchers.
Methods: We used a digital meeting tool that included communication via audio, video and chat. Discussions were documented simultaneously on a digital white board. Technical support was provided via phone and chat during the workshops and with a technical introduction workshop in advance. The workshop evaluation encompassed observation protocols, participants’ feedback via chat after each workshop on their chance to speak and the usability of the digital tools, and telephone interviews on patients’ and health professionals’ experiences after the end of the workshop series.
Results: Observation protocols showed an active role of moderators in verbally encouraging every participant to get involved. Technical challenges occurred, but were in most cases immediately addressed and solved. Participants median rating of their chance to speak and the usability of the digital tool was “very good”. In the evaluation interviews participants reported a change of perspective and mutual understanding as a main benefit from the PPI workshops and described the atmosphere as inclusive and on equal footing. Benefits of the digital format such as overcoming geographical distance, saving time and combining workshop participation with professional or childcare obligations were reported. Technical support was stressed as a pre-condition for getting actively involved in digital PPI.
Conclusions: Digital formats using different didactic and documentation techniques, accompanied by technical support, can foster active patient and public involvement. The advantages of digital PPI formats such as geographical flexibility and saving time for participants as well as the opportunity to prepare and hold workshops in geographically stretched research teams persists beyond the pandemic and may in some cases outweigh the advantages of in-person communication.
Although exercise guidelines now recommend exercise for patients with MCI, the long-term effects of exercise in patients with MCI has not been reviewed systematically. The aim was to assess (1) the effectiveness of exercise and physical activity (EXPA) interventions in improving long-term patient-relevant cognitive and non-cognitive outcomes in people with mild cognitive impairment, (2) how well the included trials reported details of the intervention, and (3) the extent to which reported endpoints were in line with patient preferences that were assessed in patient workshops. Following PRISMA guidelines, we performed a systematic review and meta-analysis including randomized controlled trials. A total of ten studies were included after searching in six electronic sources from 1995 onwards. There is a trend that 6 + -month EXPA interventions improve global cognition 12 months after initiation. Evidence on long-term effects of EXPA interventions on non-cognitive health outcomes could not be meaningfully pooled and the individual studies reported mixed results. Workshop participants considered freedom from pain and stress, mood, motivation and self-efficacy to be important, but these outcomes were rarely addressed. Too little information is available on intervention details for EXPA programs to be replicated and confidently recommended for patients with MCI. PROSPERO registration in December, 2021 (CRD42021287166).
Association of mortality and early tracheostomy in patients with COVID-19: a retrospective analysis
(2022)
COVID-19 adds to the complexity of optimal timing for tracheostomy. Over the course of this pandemic, and expanded knowledge of the disease, many centers have changed their operating procedures and performed an early tracheostomy. We studied the data on early and delayed tracheostomy regarding patient outcome such as mortality. We performed a retrospective analysis of all tracheostomies at our institution in patients diagnosed with COVID-19 from March 2020 to June 2021. Time from intubation to tracheostomy and mortality of early (≤ 10 days) vs. late (> 10 days) tracheostomy were the primary objectives of this study. We used mixed cox-regression models to calculate the effect of distinct variables on events. We studied 117 tracheostomies. Intubation to tracheostomy shortened significantly (Spearman’s correlation coefficient; rho = − 0.44, p ≤ 0.001) during the course of this pandemic. Early tracheostomy was associated with a significant increase in mortality in uni- and multivariate analysis (Hazard ratio 1.83, 95% CI 1.07–3.17, p = 0.029). The timing of tracheostomy in COVID-19 patients has a potentially critical impact on mortality. The timing of tracheostomy has changed during this pandemic tending to be performed earlier. Future prospective research is necessary to substantiate these results.
Perceptual expectations influence perception, attention and the perceptual decision bias during visuospatial orienting, which is impaired in individuals with Autism Spectrum Disorder (ASD). In this study, we investigated whether during visuospatial orienting, perceptual expectations in ASD differentially influence perception, attention and the perceptual decision bias relative to neurotypical controls (NT). Twenty-three children and adolescents with ASD and 23 NT completed a visuospatial orienting task, which compared the effect of a valid relative to an invalid perceptual expectation on target detection (cue validity effect). Group differences were calculated regarding the cue validity effect on neural correlates of processing gain (N1a amplitude) and attention (N1pc amplitude), the perceptual decision bias and mean reaction time (RT). In ASD relative to NT, findings showed a reduced processing gain for validly relative to invalidly cued targets and increased attentional response following invalidly relative to validly cued targets. Increased attention correlated with faster performance across groups. Increased processing correlated with a higher perceptual decision bias and faster mean RT in NT, but not in ASD. Results suggest that during visuospatial orienting, perceptual expectations in ASD may drive changes in sensory processing and stimulus-driven attention, which may differentially guide behavioural responses.
Macrophages are plastic and heterogeneous immune cells that adapt pro- or anti-inflammatory phenotypes upon exposure to different stimuli. Even though there has been evidence supporting a crosstalk between coagulation and innate immunity, the way in which protein components of the hemostasis pathway influence macrophages remains unclear. We investigated the effect of thrombin on macrophage polarization. On the basis of gene expression and cytokine secretion, our results suggest that polarization with thrombin induces an anti-inflammatory, M2-like phenotype. In functional studies, thrombin polarization promoted oxLDL phagocytosis by macrophages, and conditioned medium from the same cells increased endothelial cell proliferation. There were, however, clear differences between the classical M2a polarization and the effects of thrombin on gene expression. Finally, the deletion and inactivation of secreted modular Ca2+-binding protein 1 (SMOC1) attenuated phagocytosis by thrombin-stimulated macrophages, a phenomenon revered by the addition of recombinant SMOC1. Manipulation of SMOC1 levels also had a pronounced impact on the expression of TGF-β-signaling-related genes. Taken together, our results show that thrombin induces an anti-inflammatory macrophage phenotype with similarities as well as differences to the classical alternatively activated M2 polarization states, highlighting the importance of tissue levels of SMOC1 in modifying thrombin-induced macrophage polarization.
Background: The categorization of individuals as normosmic, hyposmic, or anosmic from test results of odor threshold, discrimination, and identification may provide a limited view of the sense of smell. The purpose of this study was to expand the clinical diagnostic repertoire by including additional tests. Methods: A random cohort of n = 135 individuals (83 women and 52 men, aged 21 to 94 years) was tested for odor threshold, discrimination, and identification, plus a distance test, in which the odor of peanut butter is perceived, a sorting task of odor dilutions for phenylethyl alcohol and eugenol, a discrimination test for odorant enantiomers, a lateralization test with eucalyptol, a threshold assessment after 10 min of exposure to phenylethyl alcohol, and a questionnaire on the importance of olfaction. Unsupervised methods were used to detect structure in the olfaction-related data, followed by supervised feature selection methods from statistics and machine learning to identify relevant variables. Results: The structure in the olfaction-related data divided the cohort into two distinct clusters with n = 80 and 55 subjects. Odor threshold, discrimination, and identification did not play a relevant role for cluster assignment, which, on the other hand, depended on performance in the two odor dilution sorting tasks, from which cluster assignment was possible with a median 100-fold cross-validated balanced accuracy of 77–88%. Conclusions: The addition of an odor sorting task with the two proposed odor dilutions to the odor test battery expands the phenotype of olfaction and fits seamlessly into the sensory focus of standard test batteries.
Background: Acute bleeding requires fast and targeted therapy. Therefore, knowledge of the patient's potential to form a clot is crucial. Point-of-care testing (POCT) provides fast and reliable information on coagulation. Structural circumstances, such as person-bound sample transport, can prolong the reporting of the results. The aim of the present study was to investigate the diagnostic quality and accuracy between POCT INR diagnostics and standard laboratory analysis (SLA) as well as the time advantage between a pneumatic tube and a personal-based transport system. Methods: Two groups of haemorrhagic patients (EG: emergency department; OG: delivery room; each n = 12) were examined in the context of bleeding emergencies using POCT and SLA. Samples were transported via a pneumatic tube system or by a personal transport service. Results: INR results between POCT and SLA showed a high and significant correlation (EG: p < 0.001; OG: p < 0.001). POCT results were reported significantly more quickly (EG: 1.1 vs. 39.6 min; OG: 2.0 vs. 75.0 min; p < 0.001) and required less time for analysis (EG: 0.3 vs. 24.0 min; OG: 0.5 vs. 45.0 min; p < 0.001) compared to SLA. The time for transportation with the pneumatic tube was significantly shorter (8.0 vs. 18.5 min; p < 0.001) than with the personal-based transport system. Conclusion: The results of the present study suggest that POCT may be a suitable method for the emergency diagnosis and may be used as prognostic diagnostic elements in haemotherapy algorithms to initiate targeted haemotherapy at an early point in time.
Molecular surveillance of carbapenem-resistant gram-negative bacteria in liver transplant candidates
(2021)
Background: Carbapenem-resistant Gram-negative bacteria (CRGN) cause life-threatening infections due to limited antimicrobial treatment options. The occurrence of CRGN is often linked to hospitalization and antimicrobial treatment but remains incompletely understood. CRGN are common in patients with severe illness (e.g., liver transplantation patients). Using whole-genome sequencing (WGS), we aimed to elucidate the evolution of CRGN in this vulnerable cohort and to reconstruct potential transmission routes.
Methods: From 351 patients evaluated for liver transplantation, 18 CRGN isolates (from 17 patients) were analyzed. Using WGS and bioinformatic analysis, genotypes and phylogenetic relationships were explored. Potential epidemiological links were assessed by analysis of patient charts.
Results: Carbapenem-resistant (CR) Klebsiella pneumoniae (n=9) and CR Pseudomonas aeruginosa (n=7) were the predominating pathogens. In silico analysis revealed that 14/18 CRGN did not harbor carbapenemase-coding genes, whereas in 4/18 CRGN, carbapenemases (VIM-1, VIM-2, OXA-232, and OXA-72) were detected. Among all isolates, there was no evidence of plasmid transfer-mediated carbapenem resistance. A close phylogenetic relatedness was found for three K. pneumoniae isolates. Although no epidemiological context was comprehensible for the CRGN isolates, evidence was found that the isolates resulted of a transmission of a carbapenem-susceptible ancestor before individual radiation into CRGN.
Conclusion: The integrative epidemiological study reveals a high diversity of CRGN in liver cirrhosis patients. Mutation of carbapenem-susceptible ancestors appears to be the dominant way of CR acquisition rather than in-hospital transmission of CRGN or carbapenemase-encoding genetic elements. This study underlines the need to avoid transmission of carbapenem-susceptible ancestors in vulnerable patient cohorts.
Childbirth-related post-traumatic stress disorder (CB-PTSD) occurs in 3–7% of all pregnancies and about 35% of women after preterm birth (PTB) meet the criteria for acute stress reaction. Known risk factors are trait anxiety and pain intensity, whereas planned delivery mode, medical support, and positive childbirth experience are protective factors. It has not yet been investigated whether the effects of anxiety and delivery mode are mediated by other factors, and whether a PTB-risk alters these relationships. 284 women were investigated antepartum and six weeks postpartum (risk-group with preterm birth (RG-PB) N = 95, risk-group with term birth (RG-TB) N = 99, and control group (CG) N = 90). CB-PTSD symptoms and anxiety were measured using standardized psychological questionnaires. Pain intensity, medical support, and childbirth experience were assessed by single items. Delivery modes were subdivided into planned vs. unplanned delivery modes. Group differences were examined using MANOVA. To examine direct and indirect effects on CB-PTSD symptoms, a multi-sample path analysis was performed. Rates of PTS were highest in the RG-PB = 11.58% (RG-TB = 7.01%, CG = 1.1%). MANOVA revealed higher values of CB-PTSD symptoms and pain intensity in RG-PB compared to RG-TB and CG. Women with planned delivery mode reported a more positive birth experience. Path modeling revealed a good model fit. Explained variance was highest in RG-PB (R2 = 44.7%). Direct enhancing effects of trait anxiety and indirect reducing effects of planned delivery mode on CB-PTSD symptoms were observed in all groups. In both risk groups, CB-PTSD symptoms were indirectly reduced via support by medical staff and positive childbirth experience, while trait anxiety indirectly enhanced CB-PTSD symptoms via pain intensity in the CG. Especially in the RG-PB, a positive birth experience serves as protective factor against CB-PTSD symptoms. Therefore, our data highlights the importance of involving patients in the decision process even under stressful birth conditions and the need for psychological support antepartum, mainly in patients with PTB-risk and anxious traits.
Introduction: Cesarean section (CS) rates are increasing worldwide. One constant indication is the breech presentation at term. By offering external cephalic version (ECV) and vaginal breech delivery CS rates can be further reduced. Objective: This study aimed to analyze the ECV at 38 weeks of gestation with the associate uptake rate, predicting factors, success rate, and complications at a tertiary healthcare provider in Germany specializing in vaginal breech delivery. Methods: We conducted a prospective cohort study with retrospective data acquisition. All women with a singleton fetus in breech presentation presenting after 34 weeks of gestation for counseling between 2013 and 2017 were included. ECV impact factors were analyzed using logistic regression. Results: A total of 1,598 women presented for breech birth planning. ECV was performed on 353 patients. The overall success rate was 22.4%. A later week of gestation (odds ratio [OR] 1.69), an abundant amniotic fluid index (AFI score) (OR 5.74), fundal (OR 3.78) and anterior (OR 0.39) placental location, and an oblique lie (OR 9.08) were significantly associated with successful ECV in our population. No major complications were observed. The overall vaginal delivery rates could be increased to approximately 14% with ECV. Conclusion: The demand for alternative birth modes other than CS for breech birth is high in the area of Frankfurt, Germany. Our study offers evidence of the safety of ECV at 38 weeks. Centers with expertise in vaginal breech delivery and ECV can reduce CS-rates. To further establish vaginal breech delivery and ECV as alternate options, the required knowledge and skill should be implemented in the revised curricula.
Background: Pathogenesis of portal hypertension is multifactorial and includes pathologic intrahepatic angiogenesis, whereby TIPS insertion is an effective therapy of portal hypertension associated complications. While angiogenin is a potent contributor to angiogenesis in general, little is known about its impact on TIPS function over time. Methods: In a total of 118 samples from 47 patients, angiogenin concentrations were measured in portal and inferior caval vein plasma at TIPS insertion (each blood compartment n = 23) or angiographic intervention after TIPS (each blood compartment n = 36) and its relationship with patient outcome was investigated. Results: Angiogenin levels in the inferior caval vein were significantly higher compared to the portal vein (P = 0.048). Ten to 14 days after TIPS, inferior caval vein angiogenin level correlated inversely with the portal systemic pressure gradient (P<0.001), measured invasively during control angiography. Moreover, patients with TIPS revision during this angiography, showed significantly lower angiogenin level in the inferior caval vein compared to patients without TIPS dysfunction (P = 0.01). Conclusion: In cirrhosis patients with complications of severe portal hypertension, circulating levels of angiogenin are derived from the injured liver. Moreover, angiogenin levels in the inferior caval vein after TIPS may predict TIPS dysfunction.
Introduction: Clinically complex patients often require multiple medications. Polypharmacy is associated with inappropriate prescriptions, which may lead to negative outcomes. Few effective tools are available to help physicians optimise patient medication. This study assesses whether an electronic medication management support system (eMMa) reduces hospitalisation and mortality and improves prescription quality/safety in patients with polypharmacy. Methods and analysis: Planned design: pragmatic, parallel cluster-randomised controlled trial; general practices as randomisation unit; patients as analysis unit. As practice recruitment was poor, we included additional data to our primary endpoint analysis for practices and quarters from October 2017 to March 2021. Since randomisation was performed in waves, final study design corresponds to a stepped-wedge design with open cohort and step-length of one quarter. Scope: general practices, Westphalia-Lippe (Germany), caring for BARMER health fund-covered patients. Population: patients (≥18 years) with polypharmacy (≥5 prescriptions). Sample size: initially, 32 patients from each of 539 practices were required for each study arm (17 200 patients/arm), but only 688 practices were randomised after 2 years of recruitment. Design change ensures that 80% power is nonetheless achieved. Intervention: complex intervention eMMa. Follow-up: at least five quarters/cluster (practice). recruitment: practices recruited/randomised at different times; after follow-up, control group practices may access eMMa. Outcomes: primary endpoint is all-cause mortality and hospitalisation; secondary endpoints are number of potentially inappropriate medications, cause-specific hospitalisation preceded by high-risk prescribing and medication underuse. Statistical analysis: primary and secondary outcomes are measured quarterly at patient level. A generalised linear mixed-effect model and repeated patient measurements are used to consider patient clusters within practices. Time and intervention group are considered fixed factors; variation between practices and patients is fitted as random effects. Intention-to-treat principle is used to analyse primary and key secondary endpoints.
DNA methylation-based prediction of response to immune checkpoint inhibition in metastatic melanoma
(2021)
Background: Therapies based on targeting immune checkpoints have revolutionized the treatment of metastatic melanoma in recent years. Still, biomarkers predicting long-term therapy responses are lacking. Methods: A novel approach of reference-free deconvolution of large-scale DNA methylation data enabled us to develop a machine learning classifier based on CpG sites, specific for latent methylation components (LMC), that allowed for patient allocation to prognostic clusters. DNA methylation data were processed using reference-free analyses (MeDeCom) and reference-based computational tumor deconvolution (MethylCIBERSORT, LUMP). Results: We provide evidence that DNA methylation signatures of tumor tissue from cutaneous metastases are predictive for therapy response to immune checkpoint inhibition in patients with stage IV metastatic melanoma. Conclusions: These results demonstrate that LMC-based segregation of large-scale DNA methylation data is a promising tool for classifier development and treatment response estimation in cancer patients under targeted immunotherapy.
Cancer stem cells (CSCs) are nowadays one of the major focuses in tumor research since this subpopulation was revealed to be a great obstacle for successful treatment. The identification of CSCs in pediatric solid tumors harbors major challenges because of the immature character of these tumors. Here, we present CD34, CD90, OV-6 and cell-surface vimentin (csVimentin) as reliable markers to identify CSCs in hepatoblastoma cell lines. We were able to identify CSC characteristics for the subset of CD34+CD90+OV-6+csVimentin+-co-expressing cells, such as pluripotency, self-renewal, increased expression of EMT markers and migration. Treatment with Cisplatin as the standard chemotherapeutic drug in hepatoblastoma therapy further revealed the chemo-resistance of this subset, which is a main characteristic of CSCs. When we treated the cells with the Hsp90 inhibitor 17-AAG, we observed a significant reduction in the CSC subset. With our study, we identified CSCs of hepatoblastoma using CD34, CD90, OV-6 and csVimentin. This set of markers could be helpful to estimate the success of novel therapeutic approaches, as resistant CSCs are responsible for tumor relapses.
Rodent models of Parkinson’s disease are based on transgenic expression of mutant synuclein, deletion of PD genes, injections of MPTP or rotenone, or seeding of synuclein fibrils. The models show histopathologic features of PD such as Lewi bodies but mostly only subtle in vivo manifestations or systemic toxicity. The models only partly mimic a predominant loss of dopaminergic neurons in the substantia nigra. We therefore generated mice that express the transgenic diphtheria toxin receptor (DTR) specifically in DA neurons by crossing DAT-Cre mice with Rosa26 loxP-STOP-loxP DTR mice. After defining a well-tolerated DTx dose, DAT-DTR and DTR-flfl controls were subjected to non-toxic DTx treatment (5 × 100 pg/g) and subsequent histology and behavioral tests. DAT protein levels were reduced in the midbrain, and tyrosine hydroxylase-positive neurons were reduced in the substantia nigra, whereas the pan-neuronal marker NeuN was not affected. Despite the promising histologic results, there was no difference in motor function tests or open field behavior. These are tests in which double mutant Pink1−/−SNCAA53T Parkinson mice show behavioral abnormalities. Higher doses of DTx were toxic in both groups. The data suggest that DTx treatment in mice with Cre/loxP-driven DAT-DTR expression leads to partial ablation of DA-neurons but without PD-reminiscent behavioral correlates.
Gaining detailed knowledge about sex-related immunoregulation remains a crucial prerequisite for the development of adequate disease models and therapeutic strategies enabling personalized medicine. Here, the key parameter of the production of cytokines mediating disease resolution was investigated. Among these cytokines, STAT3-activating interleukin (IL)-22 is principally associated with recovery from tissue injury. By investigating paradigmatic acetaminophen-induced liver injury, we demonstrated that IL-22 expression is enhanced in female mice. Increased female IL-22 was confirmed at a cellular level using murine splenocytes stimulated by lipopolysaccharide or αCD3/CD28 to model innate or adaptive immunoactivation. Interestingly, testosterone or dihydrotestosterone reduced IL-22 production by female but not by male splenocytes. Mechanistic studies on PMA/PHA-stimulated T-cell-lymphoma EL-4 cells verified the capability of testosterone/dihydrotestosterone to reduce IL-22 production. Moreover, we demonstrated by chromatin immunoprecipitation that testosterone impairs binding of the aryl hydrocarbon receptor to xenobiotic responsive elements within the murine IL-22 promoter. Overall, female mice undergoing acute liver injury and cultured female splenocytes upon inflammatory activation display increased IL-22. This observation is likely related to the immunosuppressive effects of androgens in males. The data presented concur with more pronounced immunological alertness demonstrable in females, which may relate to the sex-specific course of some immunological disorders.
A high incidence of thromboembolic events associated with high mortality has been reported in severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infections with respiratory failure. The present study characterized post-transcriptional gene regulation by global microRNA (miRNA) expression in relation to activated coagulation and inflammation in 21 critically ill SARS-CoV-2 patients. The cohort consisted of patients with moderate respiratory failure (n = 11) and severe respiratory failure (n = 10) at an acute stage (day 0–3) and in the later course of the disease (>7 days). All patients needed supplemental oxygen and severe patients were defined by the requirement of positive pressure ventilation (intubation). Levels of D-dimers, activated partial thromboplastin time (aPTT), C-reactive protein (CRP), and interleukin (IL)-6 were significantly higher in patients with severe compared with moderate respiratory failure. Concurrently, next generation sequencing (NGS) analysis demonstrated increased dysregulation of miRNA expression with progression of disease severity connected to extreme downregulation of miR-320a, miR-320b and miR-320c. Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis revealed involvement in the Hippo signaling pathway, the transforming growth factor (TGF)-β signaling pathway and in the regulation of adherens junctions. The expression of all miR-320 family members was significantly correlated with CRP, IL-6, and D-dimer levels. In conclusion, our analysis underlines the importance of thromboembolic processes in patients with respiratory failure and emphasizes miRNA-320s as potential biomarkers for severe progressive SARS-CoV-2 infection.
Selfish genetic elements that act as post-segregation distorters cause lethality in non-carrier individuals after fertilization. Two post-segregation distorters have been previously identified in Caenorhabditis elegans, the peel-1/zeel-1 and the sup-35/pha-1 elements. These elements seem to act as modification-rescue systems, also called toxin/antidote pairs. Here we show that the maternal-effect toxin/zygotic antidote pair sup-35/pha-1 is required for proper expression of apical junction (AJ) components in epithelia and that sup-35 toxicity increases when pathways that establish and maintain basal epithelial characteristics, die-1, elt-1, lin-26, and vab-10, are compromised. We demonstrate that pha-1(e2123) embryos, which lack the antidote, are defective in epidermal morphogenesis and frequently fail to elongate. Moreover, seam cells are frequently misshaped and mispositioned and cell bond tension is reduced in pha-1(e2123) embryos, suggesting altered tissue material properties in the epidermis. Several aspects of this phenotype can also be induced in wild-type embryos by exerting mechanical stress through uniaxial loading. Seam cell shape, tissue mechanics, and elongation can be restored in pha-1(e2123) embryos if expression of the AJ molecule DLG-1/Discs large is reduced. Thus, our experiments suggest that maternal-effect toxicity disrupts proper development of the epidermis which involves distinct transcriptional regulators and AJ components.
Background: This study aims to test the effect of the 10 most common nonurological primary cancers (skin, rectal, colon, lymphoma, leukemia, pancreas, stomach, esophagus, liver, lung) on overall mortality (OM) after secondary prostate cancer (PCa). Material and Methods: Within the Surveillance, Epidemiology, and End Results (SEER) database, patients with 10 most common primary cancers and concomitant secondary PCa (diagnosed 2004–2016) were identified and were matched in 1:4 fashion (age, year at diagnosis, race/ethnicity, treatment type, TNM stage) with primary PCa controls. OM was compared between secondary and primary PCa patients and was stratified according to primary cancer type, as well as according to time interval between primary cancer vs. secondary PCa diagnoses. Results: We identified 24,848 secondary PCa patients (skin, n = 3,871; rectal, n = 798; colon, n = 3,665; lymphoma, n = 2,583; leukemia, n = 1,102; pancreatic, n = 118; stomach, n = 361; esophagus, n = 219; liver, n = 160; lung, n = 1,328) vs. 531,732 primary PCa patients. Secondary PCa characteristics were less favorable than those of primary PCa patients (PSA and grade), and smaller proportions of secondary PCa patients received active treatment. After 1:4 matching, all secondary PCa exhibited worse OM than primary PCa patients. Finally, subgroup analyses showed that the survival disadvantage of secondary PCa patients decreased with longer time interval since primary cancer diagnosis and subsequent secondary PCa. Conclusion: Patients with secondary PCa are diagnosed with less favorable PSA and grade. Even after matching for PCa characteristics, secondary PCa patients still exhibit worse survival. However, the survival disadvantage is attenuated, when secondary PCa diagnosis is made after longer time interval, since primary cancer diagnosis.
Preeclampsia (PE), a gestational hypertensive disease originating from the placenta, is characterized by an imbalance of various cellular processes. The cell cycle regulator p21Cip1/CDKN1A (p21) and its family members p27 and p57 regulate signaling pathways fundamental to placental development. The aim of the present study was to enlighten the individual roles of these cell cycle regulators in placental development and their molecular involvement in the pathogenesis of PE. The expression and localization of p21, phospho-p21 (Thr-145), p27, and p57 was immunohistochemically analyzed in placental tissues from patients with early-onset PE, early-onset PE complicated by the HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome as well as late-onset PE compared to their corresponding control tissues from well-matched women undergoing caesarean sections. The gene level was evaluated using real-time quantitative PCR. We demonstrate that the delivery mode strongly influenced placental gene expression, especially for CDKN1A (p21) and CDKN1B (p27), which were significantly upregulated in response to labor. Cell cycle regulators were highly expressed in first trimester placentas and impacted by hypoxic conditions. In support of these observations, p21 protein was abundant in trophoblast organoids and hypoxia reduced its gene expression. Microarray analysis of the trophoblastic BeWo cell line depleted of p21 revealed various interesting candidate genes and signaling pathways for the fusion process. The level of p21 was reduced in fusing cytotrophoblasts in early-onset PE placentas and depletion of p21 led to reduced expression of fusion-related genes such as syncytin-2 and human chorionic gonadotropin (β-hCG), which adversely affected the fusion capability of trophoblastic cells. These data highlight that cell cycle regulators are important for the development of the placenta. Interfering with p21 influences multiple pathways related to the pathogenesis of PE.
Although anti-cancer properties of the natural compound curcumin have been reported, low absorption and rapid metabolisation limit clinical use. The present study investigated whether irradiation with visible light may enhance the inhibitory effects of low-dosed curcumin on prostate cancer cell growth, proliferation, and metastasis in vitro. DU145 and PC3 cells were incubated with low-dosed curcumin (0.1–0.4 µg/mL) and subsequently irradiated with 1.65 J/cm2 visible light for 5 min. Controls remained untreated and/or non-irradiated. Cell growth, proliferation, apoptosis, adhesion, and chemotaxis were evaluated, as was cell cycle regulating protein expression (CDK, Cyclins), and integrins of the α- and β-family. Curcumin or light alone did not cause any significant effects on tumor growth, proliferation, or metastasis. However, curcumin combined with light irradiation significantly suppressed tumor growth, adhesion, and migration. Phosphorylation of CDK1 decreased and expression of the counter-receptors cyclin A and B was diminished. Integrin α and β subtypes were also reduced, compared to controls. Irradiation distinctly enhances the anti-tumor potential of curcumin in vitro and may hold promise in treating prostate cancer.
Background: Dentists (Ds) and dental assistants (DAs) have a high lifetime prevalence of musculoskeletal disorders (MSDs). In this context, it is assumed that they have an increased intake of substances such as pain medication. Currently, there exist no data on the use of medication among Ds and DAs with MSDs in Germany. Methods: The online questionnaire (i.e., the Nordic Questionnaire) analysed the medical therapies used by 389 Ds (240 f/149 m) and 406 DAs (401 f/5 m) to treat their MSDs. Results: Ds (28.3–11.5%) and DAs (29.4–10.3%) with MSDs took medication depending on the affected body region. A trend between the Ds and DAs in the intake of drug therapy and the frequency was found for the neck region (Ds: 21.1%, DAs: 28.7%). A single medication was taken most frequently (Ds: 60.0–33.3%, DAs: 71.4–27.3%). The frequency of use varied greatly for both occupational groups depending on the region affected. Conclusion: Ds and DAs perceived the need for medical therapies because of their MSDs. Painkillers such as ibuprofen and systemic diclofenac were the medications most frequently taken by both occupational groups. The intake of pain killers, most notably for the neck, should prevent sick leave.
The capacity of convalescent and vaccine-elicited sera and monoclonal antibodies (mAb) to neutralize SARS-CoV-2 variants is currently of high relevance to assess the protection against infections. We performed a cell culture-based neutralization assay focusing on authentic SARS-CoV-2 variants B.1.617.1 (Kappa), B.1.617.2 (Delta), B.1.427/B.1.429 (Epsilon), all harboring the spike substitution L452R. We found that authentic SARS-CoV-2 variants harboring L452R had reduced susceptibility to convalescent and vaccine-elicited sera and mAbs. Compared to B.1, Kappa and Delta showed a reduced neutralization by convalescent sera by a factor of 8.00 and 5.33, respectively, which constitutes a 2-fold greater reduction when compared to Epsilon. BNT2b2 and mRNA1273 vaccine-elicited sera were less effective against Kappa, Delta, and Epsilon compared to B.1. No difference was observed between Kappa and Delta towards vaccine-elicited sera, whereas convalescent sera were 1.51-fold less effective against Delta, respectively. Both B.1.617 variants Kappa (+E484Q) and Delta (+T478K) were less susceptible to either casirivimab or imdevimab. In conclusion, in contrast to the parallel circulating Kappa variant, the neutralization efficiency of convalescent and vaccine-elicited sera against Delta was moderately reduced. Delta was resistant to imdevimab, which, however, might be circumvented by combination therapy with casirivimab together.
Background: Inflammation is essential for the pathogenesis of multiple sclerosis (MS). While the immune system contribution to the development of neurological symptoms has been intensively studied, inflammatory biomarkers for mental symptoms such as depression are poorly understood in the context of MS. Here, we test if depression correlates with peripheral and central inflammation markers in MS patients as soon as the diagnosis is established. Methods: Forty-four patients were newly diagnosed with relapsing-remitting MS, primary progressive MS or clinically isolated syndrome. Age, gender, EDSS, C-reactive protein (CRP), albumin, white blood cells count in cerebrospinal fluid (CSF WBC), presence of gadolinium enhanced lesions (GE) on T1-weighted images and total number of typical MS lesion locations were included in linear regression models to predict Beck Depression Inventory (BDI) score and the depression dimension of the Symptoms Checklist 90-Revised (SCL90RD). Results: CRP elevation and GE predicted significantly BDI (CRP: p = 0.007; GE: p = 0.019) and SCL90RD (CRP: p = 0.004; GE: p = 0.049). The combination of both factors resulted in more pronounced depressive symptoms (p = 0.04). CSF WBC and EDSS as well as the other variables were not correlated with depressive symptoms. Conclusions: CRP elevation and GE are associated with depressive symptoms in newly diagnosed MS patients. These markers can be used to identify MS patients exhibiting a high risk for the development of depressive symptoms in early phases of the disease.
Genes encoding endocannabinoid and sphingolipid metabolism pathways were suggested to contribute to the genetic risk towards attention deficit hyperactivity disorder (ADHD). The present pilot study assessed plasma concentrations of candidate endocannabinoids, sphingolipids and ceramides in individuals with adult ADHD in comparison with healthy controls and patients with affective disorders. Targeted lipid analyses of 23 different lipid species were performed in 71 mental disorder patients and 98 healthy controls (HC). The patients were diagnosed with adult ADHD (n = 12), affective disorder (major depression, MD n = 16 or bipolar disorder, BD n = 6) or adult ADHD with comorbid affective disorders (n = 37). Canonical discriminant analysis and CHAID analyses were used to identify major components that predicted the diagnostic group. ADHD patients had increased plasma concentrations of sphingosine-1-phosphate (S1P d18:1) and sphinganine-1-phosphate (S1P d18:0). In addition, the endocannabinoids, anandamide (AEA) and arachidonoylglycerol were increased. MD/BD patients had increased long chain ceramides, most prominently Cer22:0, but low endocannabinoids in contrast to ADHD patients. Patients with ADHD and comorbid affective disorders displayed increased S1P d18:1 and increased Cer22:0, but the individual lipid levels were lower than in the non-comorbid disorders. Sphingolipid profiles differ between patients suffering from ADHD and affective disorders, with overlapping patterns in comorbid patients. The S1P d18:1 to Cer22:0 ratio may constitute a diagnostic or prognostic tool.
Study design: Systematic review. Background and objectives: Preoperative neuromuscular function is predictive for knee function and return to sports (RTS) after reconstruction of the anterior cruciate ligament (ACL). The aim of this review was to examine the potential benefits of prehabilitation on pre-/postoperative objective, self-reported and RTS-specific outcomes. Methods: A systematic search was conducted within three databases. From the 1.071 studies screened, two randomized control trials (RCTs), two control trials (CTs) and two cohort studies (CS) met the inclusion criteria. Methodological quality rating adopted the PEDro- (RCT, CT) or Newcastle-Ottawa-Scale (CS). Results and conclusions: Methodological quality of the included studies was moderate (PEDro score: 6.5 ± 1.7; range 4 to 9). Two studies reported higher increases of the maximal quadriceps torque from baseline to pre-reconstruction: one study in the limb symmetry index (LSI), and one in both legs of the prehabilitation group compared to the controls. At 12-weeks post-reconstruction, one study (from two) indicated that the prehabilitation group had a lesser post-operative decline in the single-leg-hop for distance LSI (clinically meaningful). Similar findings were found in terms of quadriceps strength LSI (one study). At both pre-reconstruction (three studies) and two-year post-surgery (two studies), the prehabilitation groups reached significantly higher self-reported knee function (clinically meaningful) than the controls. RTS tended to be faster (one study). At two years post-surgery, RTS rates (one study) were higher in the prehabilitation groups. The results provide evidence for the relevance of prehabilitation prior to ACL-reconstruction to improve neuromuscular and self-reported knee function as well as RTS. More high quality confirmatory RCTs are warranted.
Class I and II histone deacetylases (HDAC) are considered important regulators of immunity and inflammation. Modulation of HDAC expression and activity is associated with altered inflammatory responses but reports are controversial and the specific impact of single HDACs is not clear. We examined class I and II HDACs in TLR-4 signaling pathways in murine macrophages with a focus on IκB kinase epsilon (IKKε) which has not been investigated in this context before. Therefore, we applied the pan-HDAC inhibitors (HDACi) trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA) as well as HDAC-specific siRNA. Administration of HDACi reduced HDAC activity and decreased expression of IKKε although its acetylation was increased. Other pro-inflammatory genes (IL-1β, iNOS, TNFα) also decreased while COX-2 expression increased. HDAC 2, 3 and 4, respectively, might be involved in IKKε and iNOS downregulation with potential participation of NF-κB transcription factor inhibition. Suppression of HDAC 1–3, activation of NF-κB and RNA stabilization mechanisms might contribute to increased COX-2 expression. In conclusion, our results indicate that TSA and SAHA exert a number of histone- and HDAC-independent functions. Furthermore, the data show that different HDAC enzymes fulfill different functions in macrophages and might lead to both pro- and anti-inflammatory effects which have to be considered in therapeutic approaches.
Objectives: The ongoing coronavirus pandemic is challenging, especially in severely affected patients who require intubation and sedation. Although the potential benefits of sedation with volatile anesthetics in coronavirus disease 2019 patients are currently being discussed, the use of isoflurane in patients with coronavirus disease 2019–induced acute respiratory distress syndrome has not yet been reported. Design: We performed a retrospective analysis of critically ill patients with hypoxemic respiratory failure requiring mechanical ventilation. Setting: The study was conducted with patients admitted between April 4 and May 15, 2020 to our ICU. Patients: We included five patients who were previously diagnosed with severe acute respiratory syndrome coronavirus 2 infection. Intervention: Even with high doses of several IV sedatives, the targeted level of sedation could not be achieved. Therefore, the sedation regimen was switched to inhalational isoflurane. Clinical data were recorded using a patient data management system. We recorded demographical data, laboratory results, ventilation variables, sedative dosages, sedation level, prone positioning, duration of volatile sedation and outcomes. Measurements & Main Results: Mean age (four men, one women) was 53.0 (± 12.7) years. The mean duration of isoflurane sedation was 103.2 (± 66.2) hours. Our data demonstrate a substantial improvement in the oxygenation ratio when using isoflurane sedation. Deep sedation as assessed by the Richmond Agitation and Sedation Scale was rapidly and closely controlled in all patients, and the subsequent discontinuation of IV sedation was possible within the first 30 minutes. No adverse events were detected. Conclusions: Our findings demonstrate the feasibility of isoflurane sedation in five patients suffering from severe coronavirus disease 2019 infection. Volatile isoflurane was able to achieve the required deep sedation and reduced the need for IV sedation.
Introduction Disseminated infection due to non-tuberculous mycobacteria has been a major factor of mortality and comorbidity in HIV patients. Until 2018, U.S. American guidelines have recommended antimycobacterial prophylaxis in patients with low CD4 cell counts, a practice that has not been adopted in Europe. This study aimed at examining the impact of disseminated NTM disease on clinical outcome in German HIV patients with a severe immunodeficiency. Materials and methods In this retrospective case control study, HIV patients with disseminated NTM disease were identified by retrospective chart review and matched by their CD4 cell counts to HIV patients without NTM infection in a 1:1 alocation. Primary endpoints were mortality and time to first rehospitalisation. In addition, other opportunistic diseases, as well as antimycobacterial and antiretroviral treatments were examined. Results Between 2006 and 2016, we identified 37 HIV patients with disseminated NTM disease. Most of them were suffering from infections due to M. avium complex (n = 31, 77.5%). Time to event analysis showed a non-significant trend to higher mortality in patients with disseminated NTM disease (p = 0.24). Rehospitalisation took place significantly earlier in patients with disseminated NTM infections (median 40.5 days vs. 109 days, p<0.0001). Conclusion In this retrospective case control study, we could demonstrate that mortality is not significantly higher in HIV patients with disseminated NTM disease in the ART era, but that they require specialised medical attention in the first months following discharge.
Quantitative MRI allows to probe tissue properties by measuring relaxation times and may thus detect subtle changes in tissue composition. In this work we analyzed different relaxation times (T1, T2, T2* and T2′) and histological features in 321 samples that were acquired from 25 patients with newly diagnosed IDH wild-type glioma. Quantitative relaxation times before intravenous application of gadolinium-based contrast agent (GBCA), T1 relaxation time after GBCA as well as the relative difference between T1 relaxation times pre-to-post GBCA (T1rel) were compared with histopathologic features such as the presence of tumor cells, cell and vessel density, endogenous markers for hypoxia and cell proliferation. Image-guided stereotactic biopsy allowed for the attribution of each tissue specimen to its corresponding position in the respective relaxation time map. Compared to normal tissue, T1 and T2 relaxation times and T1rel were prolonged in samples containing tumor cells. The presence of vascular proliferates was associated with higher T1rel values. Immunopositivity for lactate dehydrogenase A (LDHA) involved slightly longer T1 relaxation times. However, low T2′ values, suggesting high amounts of deoxyhemoglobin, were found in samples with elevated vessel densities, but not in samples with increased immunopositivity for LDHA. Taken together, some of our observations were consistent with previous findings but the correlation of quantitative MRI and histologic parameters did not confirm all our pathophysiology-based assumptions.
Olfactory self-assessments have been analyzed with often negative but also positive conclusions about their usefulness as a surrogate for sensory olfactory testing. Patients with nasal polyposis have been highlighted as a well-predisposed group for reliable self-assessment. In a prospective cohort of n = 156 nasal polyposis patients, olfactory threshold, odor discrimination, and odor identification were tested using the “Sniffin’ Sticks” test battery, along with self-assessments of olfactory acuity on a numerical rating scale with seven named items or on a 10-point scale with only the extremes named. Apparent highly significant correlations in the complete cohort proved to reflect the group differences in olfactory diagnoses of anosmia (n = 65), hyposmia (n = 74), and normosmia (n = 17), more than the true correlations of self-ratings with olfactory test results, which were mostly very weak. The olfactory self-ratings correlated with a quality of life score, however, only weakly. By contrast, olfactory self-ratings proved as informative in assigning the categorical olfactory diagnosis. Using an olfactory diagnostic instrument, which consists of a mapping rule of two numerical rating scales of one’s olfactory function to the olfactory functional diagnosis based on the “Sniffin’ Sticks” clinical test battery, the diagnoses of anosmia, hyposmia, or normosmia could be derived from the self-ratings at a satisfactorily balanced accuracy of about 80%. It remains to be seen whether this approach of translating self-assessments into olfactory diagnoses of anosmia, hyposmia, and normosmia can be generalized to other clinical cohorts in which olfaction plays a role.
Throughout life, macrophages are located in every tissue of the body, where their main roles are to phagocytose cellular debris and recycle aging red blood cells. In the tissue niche, they promote homeostasis through trophic, regulatory, and repair functions by responding to internal and external stimuli. This in turn polarizes macrophages into a broad spectrum of functional activation states, also reflected in their iron-regulated gene profile. The fast adaptation to the environment in which they are located helps to maintain tissue homeostasis under physiological conditions.
In humans, alterations of circadian rhythms and autophagy are linked to metabolic, cardiovascular and neurological dysfunction. Autophagy constitutes a specific form of cell recycling in many eukaryotic cells. Aging is the principal risk factor for the development of neurodegenerative diseases. Thus, we assume that both the circadian clock and autophagy are indispensable to counteract aging. We have previously shown that the hippocampus of Per1−/−-mice exhibits a reduced autophagy and higher neuronal susceptibility to ischemic insults compared to wild type (WT). Therefore, we chose to study the link between aging and loss of clock gene Per1−/−-mice. Young and aged C3H- and Per1−/−-mice were used as models to analyze the hippocampal distribution of Aβ42, lipofuscin, presenilin, microglia, synaptophysin and doublecortin. We detected several changes in the hippocampus of aged Per1−/−-mice compared to their wild type littermates. Our results show significant alterations of microglia morphology, an increase in Aβ42 deposition, overexpression of presenilin, decrease in synaptophysin levels and massive accumulation of lipofuscin in the hippocampus of 24-month-old Per1−/−-mice, without alteration of adult neurogenesis. We suggest that the marked lipofuscin accumulation, Aβ42 deposition, and overexpression of presenilin-2 observed in our experiments may be some of the consequences of the slowed autophagy in the hippocampus of aged Per1−/−-mice. This may lead during aging to excessive accumulation of misfolded proteins which may, consequently, result in higher neuronal vulnerability.
The group of proton-sensing G-protein coupled receptors (GPCRs) consists of the four receptors GPR4, TDAG8 (GPR65), OGR1 (GPR68), and G2A (GPR132). These receptors are cellular sensors of acidification, a property that has been attributed to the presence of crucial histidine residues. However, the pH detection varies considerably among the group of proton-sensing GPCRs and ranges from pH of 5.5 to 7.8. While the proton-sensing GPCRs were initially considered to detect acidic cellular environments in the context of inflammation, recent observations have expanded our knowledge about their physiological and pathophysiological functions and many additional individual and unique features have been discovered that suggest a more differentiated role of these receptors in health and disease. It is known that all four receptors contribute to different aspects of tumor biology, cardiovascular physiology, and asthma. However, apart from their overlapping functions, they seem to have individual properties, and recent publications identify potential roles of individual GPCRs in mechanosensation, intestinal inflammation, oncoimmunological interactions, hematopoiesis, as well as inflammatory and neuropathic pain. Here, we put together the knowledge about the biological functions and structural features of the four proton-sensing GPCRs and discuss the biological role of each of the four receptors individually. We explore all currently known pharmacological modulators of the four receptors and highlight potential use. Finally, we point out knowledge gaps in the biological and pharmacological context of proton-sensing GPCRs that should be addressed by future studies.
Exogenous adenosine and its metabolite inosine exert anti-inflammatory effects in synoviocytes of osteoarthritis (OA) and rheumatoid arthritis (RA) patients. We analyzed whether these cells are able to synthesize adenosine/inosine and which adenosine receptors (ARs) contribute to anti-inflammatory effects. The functionality of synthesizing enzymes and ARs was tested using agonists/antagonists. Both OA and RA cells expressed CD39 (converts ATP to AMP), CD73 (converts AMP to adenosine), ADA (converts adenosine to inosine), ENT1/2 (adenosine transporters), all AR subtypes (A1, A2A, A2B and A3) and synthesized predominantly adenosine. The CD73 inhibitor AMPCP significantly increased IL-6 and decreased IL-10 in both cell types, while TNF only increased in RA cells. The ADA inhibitor DAA significantly reduced IL-6 and induced IL-10 in both OA and RA cells. The A2AAR agonist CGS 21680 significantly inhibited IL-6 and induced TNF and IL-10 only in RA, while the A2BAR agonist BAY 60-6583 had the same effect in both OA and RA. Taken together, OA and RA synoviocytes express the complete enzymatic machinery to synthesize adenosine/inosine; however, mainly adenosine is responsible for the anti- (IL-6 and IL-10) or pro-inflammatory (TNF) effects mediated by A2A- and A2BAR. Stimulating CD39/CD73 with simultaneous ADA blockage in addition to TNF inhibition might represent a promising therapeutic strategy.