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Objectives The pathogenesis of fibromyalgia syndrome (FMS) is unclear. Transcranial ultrasonography revealed anechoic alteration of midbrain raphe in depression and anxiety disorders, suggesting affection of the central serotonergic system. Here, we assessed midbrain raphe echogenicity in FMS. Methods Sixty-six patients underwent transcranial sonography, of whom 53 were patients with FMS (27 women, 26 men), 13 patients with major depression and physical pain (all women), and 14 healthy controls (11 women, 3 men). Raphe echogenicity was graded visually as normal or hypoechogenic, and quantified by digitized image analysis, each by investigators blinded to the clinical diagnosis. Results Quantitative midbrain raphe echogenicity was lower in patients with FMS compared to healthy controls (p Conclusion We found reduced echogenicity of the midbrain raphe area in patients with FMS and in patients with depression and physical pain, independent of the presence or severity of pain, FMS, and depressive symptoms. Further exploration of this sonographic finding is necessary before this objective technique may enter diagnostic algorithms in FMS and depression.

Whole animal perfusion is a well-established method that has been used for the past decades in multiple research fields. Particularly, it has been very important for the study of the brain. The rapid and uniform fixation of tissue is essential for the preservation of its integrity and the study of complex structures. For small tissue pieces submerging in formaldehyde solution oftentimes is sufficient to get a good fixation, larger tissues or organs with a more complicated structure present a greater difficulty. Here, we report the precise parameters to successfully perform trans-cardiac perfusion of neonatal mouse pups that allows a uniform fixation of the whole body for subsequent structural analysis and immunohistochemistry. In comparison to standard perfusion procedures of adult mice, changes in the pump velocity, the buffer volume and in the needle size lead to high quality fixation of neonatal mice pups. Further, we present a whole-body section staining, which results in a highly specific immunofluorescence signal suited for detailed analysis of multiple tissues or systems at the same time. Thus, our protocol provides a reproducible and reliable method for neonatal perfusion and staining that can rapidly be applied in any laboratory. It allows a high quality analysis of cellular structures and expression profiles at early developmental stages.

The paper presents a comparative study of the pulsatile attenuation amplitude (PAA) within the optic nerve head (ONH) at four different areas calculated from retinal video sequences and its relevance to the retinal nerve fiber layer thickness (RNFL) changes in normal subjects and patients with different stages of glaucoma. The proposed methodology utilizes processing of retinal video sequences acquired by a novel video ophthalmoscope. The PAA parameter measures the amplitude of heartbeat-modulated light attenuation in retinal tissue. Correlation analysis between PAA and RNFL is performed in vessel-free locations of the peripapillary region with the proposed evaluating patterns: 360° circular area, temporal semi-circle, nasal semi-circle. For comparison, the full ONH area is also included. Various positions and sizes of evaluating patterns in peripapillary region were tested which resulted in different outputs of correlation analysis. The results show significant correlation between PAA and RNFL thickness calculated in proposed areas. The highest correlation coefficient Rtemp = 0.557 (pRnasal = 0.332, p

Scientific publications about the application of machine learning models in healthcare often focus on improving performance metrics. However, beyond often short-lived improvements, many additional aspects need to be taken into consideration to make sustainable progress. What does it take to implement a clinical decision support system, what makes it usable for the domain experts, and what brings it eventually into practical usage? So far, there has been little research to answer these questions. This work presents a multidisciplinary view of machine learning in medical decision support systems and covers information technology, medical, as well as ethical aspects. The target audience is computer scientists, who plan to do research in a clinical context. The paper starts from a relatively straightforward risk prediction system in the subspecialty nephrology that was evaluated on historic patient data both intrinsically and based on a reader study with medical doctors. Although the results were quite promising, the focus of this article is not on the model itself or potential performance improvements. Instead, we want to let other researchers participate in the lessons we have learned and the insights we have gained when implementing and evaluating our system in a clinical setting within a highly interdisciplinary pilot project in the cooperation of computer scientists, medical doctors, ethicists, and legal experts.

PLOS ONE 18(4), e0284532 (2023). doi:10.1371/journal.pone.0284532, Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral polyneuropathy in humans, and its subtypes are linked to mutations in dozens of different genes, including the gene coding for ganglioside-induced differentiation-associated protein 1 (GDAP1). The main GDAP1-linked CMT subtypes are the demyelinating CMT4A and the axonal CMT2K. Over a hundred different missense CMT mutations in the GDAP1 gene have been reported. However, despite implications for mitochondrial fission and fusion, cytoskeletal interactions, and response to reactive oxygen species, the etiology of GDAP1-linked CMT is poorly understood at the protein level. Based on earlier structural data, CMT-linked mutations could affect intramolecular interaction networks within the GDAP1 protein. We carried out structural and biophysical analyses on several CMT-linked GDAP1 protein variants and describe new crystal structures of the autosomal recessive R120Q and the autosomal dominant A247V and R282H GDAP1 variants. These mutations reside in the structurally central helices ⍺3, ⍺7, and ⍺8. In addition, solution properties of the CMT mutants R161H, H256R, R310Q, and R310W were analysed. All disease variant proteins retain close to normal structure and solution behaviour. All mutations, apart from those affecting Arg310 outside the folded GDAP1 core domain, decreased thermal stability. In addition, a bioinformatics analysis was carried out to shed light on the conservation and evolution of GDAP1, which is an outlier member of the GST superfamily. GDAP1-like proteins branched early from the larger group of GSTs. Phylogenetic calculations could not resolve the exact early chronology, but the evolution of GDAP1 is roughly as old as the splits of archaea from other kingdoms. Many known CMT mutation sites involve conserved residues or interact with them. A central role for the ⍺6-⍺7 loop, within a conserved interaction network, is identified for GDAP1 protein stability. To conclude, we have expanded the structural analysis on GDAP1, strengthening the hypothesis that alterations in conserved intramolecular interactions may alter GDAP1 stability and function, eventually leading to mitochondrial dysfunction, impaired protein-protein interactions, and neuronal degeneration., Published by PLOS, San Francisco, California, US

Temporal aspects of ligand specificity have been shown to play a significant role in the case of pulsatile hormone secretion, as exemplified by parathyroid hormone (PTH) binding to its receptor (PTH1R), a G-protein-coupled receptor expressed on surfaces of osteoblasts and osteocytes. The latter binding reaction regulates intracellular signalling and subsequently modulates skeletal homeostasis via bone remodelling. PTH glandular secretion patterns dictate bone cellular activity. In healthy humans, 70% of PTH is secreted in a tonic fashion, whereas 30% is secreted in low-amplitude and high-frequency bursts occurring every 10–20 min, superimposed on the tonic secretion. Changes in the PTH secretion patterns have been associated with various bone diseases. In this paper, we analyse PTH glandular secretion patterns for healthy and pathological states and their link to bone cellular responsiveness (αR). We utilise a two-state receptor ligand binding model of PTH to PTH1R together with a cellular activity function which is able to distinguish various aspects of the stimulation signal including peak dose, time of ligand exposure, and exposure period. Formulating and solving several constrained optimisation problems, we investigate the potential of pharmacological manipulation of the diseased glandular secretion and via clinical approved external PTH injections to restore healthy bone cellular responsiveness. Based on the mean experimentally reported data, our simulation results indicate cellular responsiveness in healthy subjects is sensitive to the tonic baseline stimulus and it is 28% of the computed maximum responsiveness. Simulation results for pathological cases of glucocorticoid-induced osteoporosis, hyperparathyroidism, initial and steady state hypocalcemia clamp tests indicate αR values significantly larger than the healthy baseline (1.7, 2.2, 4.9 and 1.9-times, respectively). Manipulation of the pulsatile glandular secretion pattern, while keeping the mean PTH concentration constant, allowed restoration of healthy baseline values from these catabolic bone diseases. Conversely, PTH glandular diseases that led to maximum bone cellular responsiveness below the healthy baseline value can’t be restored to baseline via glandular manipulation. However, external PTH injections allowed restoration of these latter cases.

Water soaking is a common disorder of field-grown strawberries (Fragaria × ananassa Duch.). It develops when ripe fruit is exposed to rain. Here we investigate the effects of Ca on water soaking. Fruit was incubated in solutions of various Ca salts and the extent of water soaking quantified using a simple rating scheme. Exposure to CaCl2 (10 mM) decreased water soaking and anthocyanin leakage but had no effect on water uptake. The decrease in water soaking due to CaCl2 was not limited to a single cultivar but occurred in all cultivars examined. Incubating fruit in a chelating agent (EGTA) increased water soaking compared to the water control. Calcium salts of different acids varied in their effects on water soaking. Only CaCl2 reduced water soaking significantly. The chlorides of different cations, also varied in their effects on water soaking. Those of the monovalent cations had no effects on water soaking, while those of the divalent cations (CaCl2, BaCl2 and SrCl2) and of the trivalent cations (FeCl3 and AlCl3) were all effective in decreasing water soaking. Overall, CaCl2 decreased microcracking of the strawberry cuticle as compared to deionized water. Furthermore, CaCl2 also reduced the leakage of anthocyanins from flesh discs, irrespective of the osmotic potential of the incubation solution. Our results indicate that CaCl2 reduced water soaking by decreasing cuticular microcracking, by decreasing leakage of plasma membranes and, possibly, by increasing the crosslinking of cell wall constituents.

IntroductionGroup musical activities using wind instruments have been restricted during the CoVID19 pandemic due to suspected higher risk of virus transmission. It was presumed that the aerosols exhaled through the tubes while playing would be ejected over larger distances and spread into the room due to jet stream effects. In particular, the soprano recorder is widely used as instrument in school classes and for beginners of all age groups in their musical education, as well as in contexts of leisure activities and in professional concert performances.Understanding the aerosol impulse dispersion characteristics of playing the soprano recorder could assist with the establishment of concepts for safe music-making.MethodsFive adult professionally trained soprano recorder players (4 female, 1 male) played four bars of the main theme of L. van Beethoven’s “Ode to Joy” in low and in high octaves, as well as with 3 different potential protection devices in the high octave. For comparison they spoke the corresponding text by F. Schiller. Before each task, they inhaled .5 L of vapor from an e-cigarette filled with base liquid. The vapor cloud escaping during speaking or playing was recorded by cameras and its spread was measured as a function of time in the three spatial dimensions. The potential safety devices were rated in practicability with a questionnaire, and their influence on the sound was compared, generating a long-term average spectrum from the audio data.ResultsWhen playing in the high octave, at the end of the task the clouds showed a median distance of 1.06 m to the front and .57 m diameter laterally (maxima: x: 1.35 m and y: .97 m). It was found that the clouds’ expansion values in playing the recorder with and without safety measures are mostly lower when compared to the ordinary, raised speaking voice of the same subjects.The safety devices which covered the instrument did not show clear advantages and were rated as unpractical by the subjects. The most effective reduction of the cloud was reached when playing into a suction funnel.ConclusionThe aerosol dispersion characteristics of soprano recorders seem comparable to clarinets. The tested safety devices which covered holes of the instrument did not show clear benefits.

Deep Learning has a large impact on medical image analysis and lately has been adopted for clinical use at the point of care. However, there is only a small number of reports of long-term studies that show the performance of deep neural networks (DNNs) in such a clinical environment. In this study, we measured the long-term performance of a clinically optimized DNN for laryngeal glottis segmentation. We have collected the video footage for two years from an AI-powered laryngeal high-speed videoendoscopy imaging system and found that the footage image quality is stable across time. Next, we determined the DNN segmentation performance on lossy and lossless compressed data revealing that only 9% of recordings contain segmentation artefacts. We found that lossy and lossless compression are on par for glottis segmentation, however, lossless compression provides significantly superior image quality. Lastly, we employed continual learning strategies to continuously incorporate new data to the DNN to remove aforementioned segmentation artefacts. With modest manual intervention, we were able to largely alleviate these segmentation artefacts by up to 81%. We believe that our suggested deep learning-enhanced laryngeal imaging platform consistently provides clinically sound results, and together with our proposed continual learning scheme will have a long-lasting impact in the future of laryngeal imaging.

Recent research in economics emphasizes the role of in utero conditions for the health endowment at birth and in early childhood and for social as well as economic outcomes in later life. This paper analyzes the relation between maternal mental health during pregnancy and birth outcomes of the child. In particular, we analyze the relationship between maternal mental health during pregnancy and the probability of giving birth preterm (PT), having a newborn at low birth weight (LBW) or being small for gestational age (SGA). Based on large population-representative data from the German Socio-Economic Panel (SOEP) and cohort data from the National Educational Panel Study (NEPS), we present extensive descriptive evidence on the relationship between maternal mental health and preterm birth by carrying out OLS estimates controlling for a wide range of socioeconomic characteristics. In addition, we apply matching estimators and mother fixed effects models, which bring us closer toward a causal interpretation of estimates. In summary, the results uniformly provide evidence that poor maternal mental health is a risk factor for preterm birth and low birth weight in offspring. In contrast, we find no evidence for an relationship between maternal mental health and small for gestational age at birth.

Background Chronic low-grade inflammation has been suggested as a key factor in the association between stress exposure and long-term health. Care work is recognized as a profession with a high degree of job stress and health risks. However, for care professionals, the study base on inflammatory activity due to adverse working conditions is limited. Objective The aim of this study was to explore associations between self-reported psychosocial working conditions and care professionals’ biomarkers of systemic low-grade inflammation. Methods N = 140 geriatric care professionals (79.3% females, mean age = 44.1 years) of six care facilities were enrolled in a cross-sectional study consisting of standardized medical examinations and employee surveys. Standardized questionnaires were used for evaluation of psychosocial work characteristics (work overload, job autonomy, social support) based on Karasek’s job strain model. Blood samples were drawn for two biomarkers of inflammatory activity: C-reactive protein (CRP) and leukocyte count. Analyses comprised uni- and multivariate logistic and linear regression analyses. Results We determined a proportion of 5.4% of care professionals with increased low-grade inflammation. We further observed a relationship between job autonomy and CRP, such that reports of high job autonomy were associated with increased levels of CRP (adjusted OR = 4.10, 95% CI [1.10, 15.26], p = .035), which was robust in additional analyses on further potential confounders. No significant associations with participants’ leukocyte numbers were found. Conclusions This exploratory study contributes to the research base on links between workplace stress and ensuing illness in care professionals. Our findings may help to identify risk and protective factors of the work environment for chronic low-grade inflammation. The results require further scrutiny, and future prospective studies on associations of psychosocial working conditions, low-grade inflammation and long-term health outcomes in care professionals are needed.

Background and objective Prompt pathogen identification of blood stream infections is essential to provide appropriate antibiotic treatment. Therefore, the objective of this prospective single centre study was to establish an inexpensive, fast and accurate protocol for bacterial species identification with SDS protein-extraction directly from BacT/Alert® blood culture (BC) bottles by VitekMS®. Results Correct species identification was obtained for 198/266 (74.4%, 95%-CI = [68.8%, 79.6%]) of pathogens. The protocol was more successful in identifying 87/96 (91.4%, 95%-CI = [83.8%, 93.2%]) gram-negative bacteria than 110/167 (65.9%, 95%-CI = [58.1%, 73.0%]) gram-positive bacteria. The hands-on time for sample preparation and measurement was about 15 min for up to five samples. This is shorter than for most other protocols using a similar lysis-centrifugation approach for the combination of BacT/Alert® BC bottles and the Vitek® MS mass spectrometer. The estimated costs per sample were approx. 1.80€ which is much cheaper than for commercial kits. Conclusion This optimized protocol allows for accurate identification of bacteria directly from blood culture bottles for laboratories equipped with BacT/Alert® blood culture bottles and VitekMS® mass spectrometer.

PLOS ONE 17(1), 1-7 (2022). doi:10.1371/journal.pone.0261691, Published by PLOS, San Francisco, California, US

Parkinson’s disease (PD) is characterized by a long prodromal phase with a multitude of markers indicating an increased PD risk prior to clinical diagnosis based on motor symptoms. Current PD prediction models do not consider interdependencies of single predictors, lack differentiation by subtypes of prodromal PD, and may be limited and potentially biased by confounding factors, unspecific assessment methods and restricted access to comprehensive marker data of prospective cohorts. We used prospective data of 18 established risk and prodromal markers of PD in 1178 healthy, PD-free individuals and 24 incident PD cases collected longitudinally in the Tübingen evaluation of Risk factors for Early detection of NeuroDegeneration (TREND) study at 4 visits over up to 10 years. We employed artificial intelligence (AI) to learn and quantify PD marker interdependencies via a Bayesian network (BN) with probabilistic confidence estimation using bootstrapping. The BN was employed to generate a synthetic cohort and individual marker profiles. Robust interdependencies were observed for BN edges from age to subthreshold parkinsonism and urinary dysfunction, sex to substantia nigra hyperechogenicity, depression, non-smoking and to constipation; depression to symptomatic hypotension and excessive daytime somnolence; solvent exposure to cognitive deficits and to physical inactivity; and non-smoking to physical inactivity. Conversion to PD was interdependent with prior subthreshold parkinsonism, sex and substantia nigra hyperechogenicity. Several additional interdependencies with lower probabilistic confidence were identified. Synthetic subjects generated via the BN based representation of the TREND study were realistic as assessed through multiple comparison approaches of real and synthetic data. Altogether our work demonstrates the potential of modern AI approaches (specifically BNs) both for modelling and understanding interdependencies between PD risk and prodromal markers, which are so far not accounted for in PD prediction models, as well as for generating realistic synthetic data.

Background and objective Patients suffering from Parkinson’s disease (PD) present a reduction in facial movements called hypomimia. In this work, we propose to use machine learning facial expression analysis from face images based on action unit domains to improve PD detection. We propose different domain adaptation techniques to exploit the latest advances in automatic face analysis and face action unit detection. Methods Three different approaches are explored to model facial expressions of PD patients: (i) face analysis using single frame images and also using sequences of images, (ii) transfer learning from face analysis to action units recognition, and (iii) triplet-loss functions to improve the automatic classification between patients and healthy subjects. Results Real face images from PD patients show that it is possible to properly model elicited facial expressions using image sequences (neutral, onset-transition, apex, offset-transition, and neutral) with accuracy improvements of up to 5.5% (from 72.9% to 78.4%) with respect to single-image PD detection. We also show that our proposed action unit domain adaptation provides improvements of up to 8.9% (from 78.4% to 87.3%) with respect to face analysis. Finally, we also show that triplet-loss functions provide improvements of up to 3.6% (from 78.8% to 82.4%) with respect to action unit domain adaptation applied upon models created from scratch. The code of the experiments is available at https://github.com/luisf-gomez/Explorer-FE-AU-in-PD. Conclusions Domain adaptation via transfer learning methods seem to be a promising strategy to model hypomimia in PD patients. Considering the good results and also the fact that only up to five images per participant are considered in each sequence, we believe that this work is a step forward in the development of inexpensive computational systems suitable to model and quantify problems of PD patients in their facial expressions.

Background Patients with COVID-19 and severe acute respiratory failure may require veno-venous extracorporeal membrane oxygenation (VV ECMO). Yet, this procedure is resource-intensive and high mortality rates have been reported. Thus, predictors for identifying patients who will benefit from VV ECMO would be helpful. Methods This retrospective study included 129 patients with COVID-19 and severe acute respiratory failure, who had received VV ECMO at the University Medical Center Regensburg, Germany, between 1 March 2020 and 31 December 2021. Patient-specific factors and relevant intensive-care parameters at the time of the decision to start VV ECMO were investigated regarding their value as predictors of patient survival. In addition, the intensive-care course of the first 10 days of VV ECMO was compared between survivors and patients who had died in the intensive care unit. Results The most important parameters for predicting outcome were patient age and platelet count, which differed significantly between survivors and non-survivors (age: 52.6±8.1 vs. 57.4±10.1 years, p

Objectives In this in-vitro study, teeth were imaged using photoacoustic tomography (PAT), cone-beam computed tomography (CBCT), and micro-computed tomography (μ-CT). The study had aim: to identify the best wavelength for PAT images to determine the accuracy of the three imaging methods, and to determine whether PAT images of teeth can achieve acceptable reconstruction quality. Methods Nineteen human mandibular single-rooted incisors were extracted from patients with trauma or periodontitis. To determine the best wavelength for acquiring photoacoustic images, all 19 teeth were scanned in vitro with PAT, using different laser wavelengths between 680 and 960 nm. The images were analyzed using image analysis software. To assess the accuracy of PAT and compare it with the accuracy of CBCT, each tooth was also scanned in vitro using CBCT and the reference standard technique of μ-CT. Subsequently, three different three-dimensional models, one for each imaging technique, were created for each tooth. Finally, the three different three-dimensional models acquired for the same tooth were matched and analyzed regarding volume and surface. Results The highest quality tooth images were achieved using the 680 nm wavelength, which showed the best contrast ratio. The full geometry of the dental root (μ-CT compared with PAT) could be visualized with relative standard deviations of 0.12 mm for the surface and −7.33 mm3 for the volume (n = 19). The full geometry of the dental root (μ-CT compared with CBCT) could be visualized with relative standard deviations of 0.06 mm for the surface and −14.56 mm3 for the volume (n = 19). The difference between the PAT–μ-CT group and CBCT–μ-CT group regarding the total average of the root surface area was not significant (p>0.06). Conclusion Images, which were acquired using PAT at 680nm showed the best contrast ration, enabling the identification of dentin, cementum and the dental pulp. No significant differences were found between the PAT–μ-CT group and CBCT–μ-CT group regarding the total average of the RSA and the total volume. Thus, three-dimensional reconstructions based on in-vitro PAT are already of acceptable reconstruction quality.

Objectives Unintentional injuries such as falls, are particularly frequent in early childhood. To date, epidemiological studies in this field have been carried out using routine data sources or registries and many studies were observational studies with a cross-sectional design. The aims of the study are to describe unintentional injuries in the first two years of life in the Piccolipiù birth cohort, and to investigate the association between mother and children characteristics and the First Event of Raised surface Fall (FERF). Methods This longitudinal observational study included 3038 children from an Italian birth cohort. Data on socio-demographic factors, socio-economic indicators, maternal health and lifestyle characteristics and child’s sleeping behavior, obtained from questionnaires completed at birth, 12 and 24 months of age, were considered in the analyses as potential risk factors of FERF. Time of occurrence of FERF was analyzed using the Kaplan-Meier method. The multivariable analysis for time to event was carried out using a Cox proportional hazards model. Results Falls from raised surfaces are the leading cause of unintentional injuries in the cohort with 610 (21.1%) and 577 (20.0%) cases among children during the first and second year of life, respectively. An increased risk of FERF was associated with several risk factors: maternal psychological distress (HR 1.41, 95%CI 1.10–1.81), maternal alcohol intake (HR 1.26, 95%CI 1.10–1.45), and child’s sleeping problems (HR 1.28, 95%CI 1.09–1.51). Children with older aged mothers (HR 0.98, 95%CI 0.96–0.99) and living in northern Italy (HR 0.64, 95%CI 0.55–0.75) had a lower risk of FERF. Conclusion The results of the study suggest that a higher risk of FERF is associated with socio-demographic factors, maternal characteristics and child sleeping behavior that could hinder parent empowerment.

Background Patient decisions to take preventative treatments for osteoporosis depend on their perceptions of fracture risk, medication effect sizes (ES) of benefits and harms. However, physicians and lay persons may have differing perceptions of risks and medication efficacy. Both tend to overestimate medication benefits. This study surveyed at what risk physicians would prescribe and lay persons would be willing to take bisphosphonates, the minimum ES both groups do demand and the physicians estimates of the actual benefit of bisphosphonates. Design Cross-sectional online questionnaire survey. Methods Respondents were confronted with a case vignette with an osteoporotic patient (10-year femoral fracture risk: 32%). They were asked at what threshold of 10-year-risk of femoral neck fracture they would prescribe or take a drug. They were asked for the minimum ES (absolute risk reduction, ARR) they demand from bisphosphonates to prescribe or take them. Physicians were asked to provide their estimate of the actual ARR of bisphosphonates. Results 114 physicians and 140 lay persons answered (convenience sample/snowball distribution). The 10-year-risk threshold of lay persons (Mdnlay = 60%) willing to take medication was twice as high as the physicians’ threshold (Mdnphy = 30%) to prescribe it (p < .001). The median minimum ARR physicians demanded for bisphosphonates prescription was 17%, whereas lay persons demanded 22% (p < .001). Physicians estimated the actual ARR of bisphosphonates to be 12%. This estimated effect size was below their own minimum threshold for prescription. Conclusions Lay persons tolerate a higher fracture risk and demand a larger benefit of antiosteoporotic medication for fracture prevention than physicians. Physicians demand higher minimum benefits than their own estimates which in turn are above the benefit evidence suggests. Physicians should be more familiar with ES of antiosteoporotic drugs concerning patient outcomes and actively advise lay persons before preventive treatment decisions are taken.

PLOS ONE 17(7), e0269642 (2022). doi:10.1371/journal.pone.0269642, Published by PLOS, San Francisco, California, US

Adhesions formation after surgery for congenital heart defects can complicate follow-up procedures due to bleeding from detached adhesion bands, injury to cardiac structures or large vessels, all of which do prolong operation times. The problem is enhanced by the fact that detached adhesions are predilection sites for new adhesions setting off a downward spiral. 4DryField® PH gel barrier has demonstrated high efficacy in reducing postoperative adhesions in general surgical and gynecological studies. This retrospective controlled study of 22 patients evaluates whether these positive results can be confirmed in pediatric cardiac surgery. Adhesions were scored from photographs of follow-up interventions by an independent cardiac surgeon blinded to group assignment. The publication provides not only score numbers but also original photographs of all sites for better traceability and transparency. In addition, timesaving due to reduced adhesions was evaluated. Results show a significantly reduced adhesion score for the 4DryField® group. Importantly, this resulted in a significantly shorter period between skin incision and start of cardiopulmonary bypass. In addition, timesaving due reduced adhesion formation was evaluated. The use of 4DryField® was safe, although higher doses per kg were used than in adults.

PLOS ONE 16(11), e0246709 (2021). doi:10.1371/journal.pone.0246709, Published by PLOS, San Francisco, California, US

Resiniferatoxin (RTX), an extract from the spurge plant Euphorbia resinifera, is a potent agonist of the transient receptor potential cation channel subfamily V member 1 (TRPV1), mainly expressed on peripheral nociceptors—a prerequisite for nociceptive heat perception. Systemic overdosing of RTX can be used to desensitize specifically TRPV1-expressing neurons, and was therefore utilized here to selectively characterize the influence of TRPV1-signaling on central nervous system (CNS) temperature processing. Resting state and CNS temperature processing of male rats were assessed via functional magnetic resonance imaging before and after RTX injection. General linear model-based and graph-theoretical network analyses disentangled the underlying distinct CNS circuitries. At baseline, rats displayed an increase of nociception-related response amplitude and activated brain volume that correlated highly with increasing stimulation temperatures. In contrast, RTX-treated rats showed a clear disruption of thermal nociception, reflected in a missing increase of CNS responses to temperatures above 48°C. Graph-theoretical analyses revealed two distinct brain subnetworks affected by RTX: one subcortical (brainstem, lateral and medial thalamus, hippocampus, basal ganglia and amygdala), and one cortical (primary sensory, motor and association cortices). Resting state analysis revealed first, that peripheral desensitization of TRPV1-expressing neurons did not disrupt the basic resting-state-network of the brain. Second, only at baseline, but not after RTX, noxious stimulation modulated the RS-network in regions associated with memory formation (e.g. hippocampus). Altogether, the combination of whole-brain functional magnetic resonance imaging and RTX-mediated desensitization of TRPV1-signaling provided further detailed insight into cerebral processing of noxious temperatures.

Background Data of critically ill COVID-19 patients are being evaluated worldwide, not only to understand the various aspects of the disease and to refine treatment strategies but also to improve clinical decision-making. For clinical decision-making in particular, prognostic factors of a lethal course of the disease would be highly relevant. Methods In this retrospective cohort study, we analyzed the first 59 adult critically ill Covid-19 patients treated in one of the intensive care units of the University Medical Center Regensburg, Germany. Using uni- and multivariable regression models, we extracted a set of parameters that allowed for prognosing in-hospital mortality. Results Within the cohort, 19 patients died (mortality 32.2%). Blood pH value, mean arterial pressure, base excess, troponin, and procalcitonin were identified as highly significant prognostic factors of in-hospital mortality. However, no significant differences were found for other parameters expected to be relevant prognostic factors, like low arterial partial pressure of oxygen or high lactate levels. In the multivariable logistic regression analysis, the pH value and the mean arterial pressure turned out to be the most influential prognostic factors for a lethal course.

Background Minimally-invasive repair of pectus excavatum (MIRPE) has been shown to be associated with high release of trace metals into patient’s body. The aim of our study was to analyze the kinetics of metal contamination after MIRPE and after bar removal. Methods We prospectively assessed nickel and chromium changes in blood, urine, and local tissue in patients undergoing MIRPE with stainless-steel bar(s). Baseline samples were taken prior to surgery, further samples were taken at six defined time points until 30 months after bar removal. Clinical symptoms were evaluated at the time of every sample collection. Results 28 patients were included (mean age 16.4 years). At four weeks after MIRPE and persisting up to bar removal, we found significantly elevated trace metal levels in blood and urine. Tissue nickel and chromium levels were significantly elevated at the time of bar removal. After bar removal, the concentration of trace metal in urine and the concentration of chromium in plasma decreased gradually. In contrast, nickel levels in blood further increased. Five patients showed irritative symptoms after MIRPE, all symptomatic patients had elevated metal levels. Conclusions Following MIRPE, we found a rapid systemic increase of nickel and chromium. Our data indicate that trace metal release could cause irritative symptoms. The prolonged elevated systemic nickel levels beyond bar removal necessitate further investigations of the long-term side effects of MIRPE.

PLOS ONE 17(9), e0274114 (2022). doi:10.1371/journal.pone.0274114, Analysis of language geography on scales varying from countries down toneighborhoods is increasingly being used for studying spatial patterns of socialdynamics. This trend is fueled by social media platforms such as Twitter which provideaccess to large amounts of natural language data combined with geolocation and usermetadata enabling reconstruction of detailed spatial patterns of language use. Moststudies are performed on large spatial scales associated with countries and regions,where language dynamics are often dominated by the effects of geographic andadministrative borders. Extending to smaller, urban scales, however, offers thepossibility of visualizing spatial patterns of language use determined by socialdynamics within the city, providing valuable information for a range of social topics fromdemographic studies to urban planning. So far, few studies have been made in thisdomain, due, in part, to the challenges in developing algorithms that accurately classifylinguistic features. These studies include analysis of topics and foreign languageswhich are now identifiable using machine learning techniques but which provide limitedinformation about many socially relevant issues. Here we investigate the possibility ofextending urban-scale geographical studies of language use beyond lexical elementsto include other sociolinguistic markers that identify language style, dialect and socialgroups. Some features, which have not been explored with social-media data on theurban scale, can be used to target a range of social phenomena. Our study focuses onTwitter use in Buenos Aires, and our approach classifies tweets based on the presenceof specific tokens manually selected to target precise linguistic features. In order toincrease sensitivity to small variations and eliminate the dominant effect of populationdistributions, our approach is based on comparison of contrasting sets of tokens.Finally, we attempt to make direct connections between the observed patterns oflanguage use and spatial patterns associated with specific social contexts and socialgroups within the city. Identifying these connections is a key aspect of the socialdynamicsanalysis which has so far received insufficient attention., Published by PLOS, San Francisco, California, US

Introduction Excess mortality is a suitable indicator of health consequences of COVID-19 because death from any cause is clearly defined contrary to death from Covid-19. We compared the overall mortality in 2020 with the overall mortality in 2016 to 2019 in Germany, Sweden and Spain. Contrary to other studies, we also took the demographic development between 2016 and 2020 and increasing life expectancy into account. Methods Using death and population figures from the EUROSTAT database, we estimated weekly and cumulative Standardized Mortality Ratios (SMR) with 95% confidence intervals (CI) for the year 2020. We applied two approaches to calculate weekly numbers of death expected in 2020: First, we used mean weekly mortality rates from 2016 to 2019 as expected mortality rates for 2020, and, second, to consider increasing life expectancy, we calculated expected mortality rates for 2020 by extrapolation from mortality rates from 2016 to 2019. Results In the first approach, the cumulative SMRs show that in Germany and Sweden there was no or little excess mortality in 2020 (SMR = 0.976 (95% CI: 0.974-0.978), and 1.030 (1.023-1.036), respectively), while in Spain the excess mortality was 14.8% (1.148 (1.144-1.151)). In the second approach, the corresponding SMRs for Germany and Sweden increased to 1.009 (1.007-1.011) and 1.083 (1.076-1.090), respectively, whereas results for Spain were virtually unchanged. Conclusion In 2020, there was barely any excess mortality in Germany for both approaches. In Sweden, excess mortality was 3% without, and 8% with consideration of increasing life expectancy. Copyright: OA Förderung 2021

PLOS ONE 17(5), e0268439 (2022). doi:10.1371/journal.pone.0268439, Published by PLOS, San Francisco, California, US

Boosting techniques from the field of statistical learning have grown to be a popular tool for estimating and selecting predictor effects in various regression models and can roughly be separated in two general approaches, namely gradient boosting and likelihood-based boosting. An extensive framework has been proposed in order to fit generalised mixed models based on boosting, however for the case of cluster-constant covariates likelihood-based boosting approaches tend to mischoose variables in the selection step leading to wrong estimates. We propose an improved boosting algorithm for linear mixed models where the random effects are properly weighted, disentangled from the fixed effects updating scheme and corrected for correlations with cluster-constant covariates in order to improve quality of estimates and in addition reduce the computational effort. The method outperforms current state-of-the-art approaches from boosting and maximum likelihood inference which is shown via simulations and various data examples., 16 pages, 4 figures

Online data collection offers a wide range of benefits including access to larger and more diverse populations, together with a reduction in the experiment cycle. Here we compare performance in a spatial memory task, in which participants had to estimate object locations following viewpoint shifts, using data from a controlled lab-based setting and from an unsupervised online sample. We found that the data collected in a conventional laboratory setting and those collected online produced very similar results, although the online data was more variable with standard errors being about 10% larger than those of the data collected in the lab. Overall, our findings suggest that spatial memory studies using static images can be successfully carried out online with unsupervised samples. However, given the higher variability of the online data, it is recommended that the online sample size is increased to achieve similar standard errors to those obtained in the lab. For the current study and data processing procedures, this would require an online sample 25% larger than the lab sample., PLoS ONE, 16 (11), ISSN:1932-6203

Objectives Multiple studies show orthopedic health problems for medical staff due to wearing radiation protection aprons. The aim of this study was to evaluate the weight pressure on the shoulder as a marker of physical strain caused by different radiation-protection devices. Methods For the weight pressure measurement, a pressure sensor (OMD-30-SE-100N, OptoForce, Budapest, Hungary) placed on the left and right shoulder was used. Wearing different radiation protection systems the force measurement system was used to quantify the weight pressure. Measurements were acquired in still standing position and during various movements. Results A mean significant decreasing weight pressure on the shoulder between 74% and 84% (p Conclusions The free-hanging radiation protection system showed a significant lower weight pressure in comparison to the other radiation protection devices. Apart from this, use of a two-piece radiation protection apron or addition of a belt to a radiation protection coat proved to be further effective options to reduce weight pressure.

In this study, topology optimized, patient specific osteosynthesis plates (TOPOS-implants) are evaluated for the mandibular reconstruction using fibula segments. These shape optimized implants are compared to a standard treatment with miniplates (thickness: 1.0 mm, titanium grade 4) in biomechanical testing using human cadaveric specimen. Mandible and fibula of 21 body donors were used. Geometrical models were created based on automated segmentation of CT-scans of all specimens. All reconstructions, including cutting guides for osteotomy as well as TOPOS-implants, were planned using a custom-made software tool. The TOPOS-implants were produced by electron beam melting (thickness: 1.0 mm, titanium grade 5). The fibula-reconstructed mandibles were tested in static and dynamic testing in a multi-axial test system, which can adapt to the donor anatomy and apply side-specific loads. Static testing was used to confirm mechanical similarity between the reconstruction groups. Force-controlled dynamic testing was performed with a sinusoidal loading between 60 and 240 N (reconstructed side: 30% reduction to consider resected muscles) at 5 Hz for up to 5 · 105 cycles. There was a significant difference between the groups for dynamic testing: All TOPOS-implants stayed intact during all cycles, while miniplate failure occurred after 26.4% of the planned loading (1.32 · 105 ± 1.46 · 105 cycles). Bone fracture occurred in both groups (miniplates: n = 3, TOPOS-implants: n = 2). A correlation between bone failure and cortical bone thickness in mandible angle as well as the number of bicortical screws used was demonstrated. For both groups no screw failure was detected. In conclusion, the topology optimized, patient specific implants showed superior fatigue properties compared to miniplates in mandibular reconstruction. Additionally, the patient specific shape comes with intrinsic guiding properties to support the reconstruction process during surgery. This demonstrates that the combination of additive manufacturing and topology optimization can be beneficial for future maxillofacial surgery.

Objectives Unfractionated heparin (UFH) is the commonly used anticoagulant to prevent clotting of the ECMO circuit and thrombosis of the cannulated vessels. A side effect of UFH is heparin-induced thrombocytopenia (HIT). Little is known about HIT during ECMO and the impact of changing anticoagulation in ECMO patients with newly diagnosed HIT. The aim of the study was to determine the prevalence, complications, impact of switching anticoagulation to argatroban and outcomes of patients developing heparin-induced thrombocytopenia (HIT) during either veno-venous (VV) or veno-arterial (VA) ECMO. Methods Retrospective observational single centre study of prospectively collected data of consecutive patients receiving VV ECMO therapy for severe respiratory failure and VA ECMO for circulatory failure from January 2006 to December 2016 of the Medical intensive care unit (ICU) of the University Hospital of Regensburg. Treatment of HIT on ECMO was done with argatroban. Results 507 patients requiring ECMO were included. Further HIT-diagnostic was conducted if HIT-4T-score was ≥4. The HIT-confirmed group had positive HIT-enzyme-linked-immunosorbent-assay (ELISA) and positive heparin-induced-platelet-activation (HIPA) test, the HIT-suspicion group a positive HIT-ELISA and missing HIPA but remained on alternative anticoagulation until discharge and the HIT-excluded group a negative or positive HIT-ELISA, however negative HIPA. These were compared to group ECMO-control without any HIT suspicion. The prevalence of HIT-confirmed was 3.2%, of HIT-suspicion 2.0% and HIT-excluded 10.8%. Confirmed HIT was trendwise more frequent in VV than in VA (3.9 vs. 1.7% p = 0.173). Compared to the ECMO control group, patients with confirmed HIT were longer on ECMO (median 13 vs. 8 days, p = 0.002). Different types of complications were higher in the HIT-confirmed than in the ECMO-control group, but in-hospital mortality was not different (31% vs. 41%, p = 0.804). Conclusion HIT is rare on ECMO, should be suspected, if platelets are decreasing, but seems not to increase mortality if treated promptly.

Purpose The COVID-19 pandemic has imposed severe challenges on medical education at German university hospitals. In this first German nationwide expert survey, we addressed the responsible university teaching coordinators in obstetrics and gynecology departments and investigated their experiences during the pandemic as well as their opinions on future developments, especially with regard to the broader implementation of e-learning in the standard curriculum. Methods The questionnaire included 42 items and was disseminated among teaching coordinators at all 41 departments of obstetrics and gynecology at German university hospitals via an email that included a weblink to the online survey provider. Responses were collected between 19 April and 7 June 2021. Results In total, 30 responses were collected from 41 departments across Germany and their respective teaching coordinators in obstetrics and gynecology. The general opinion of the medical teaching provided during the pandemic was positive, whereas the teaching quality in practical skills was considered inferior and not equivalent to the standard face-to-face curriculum. Lectures and seminars had to be substituted by remote-learning alternatives, while clinical clerkships were reduced in length and provided less patient contact. Students in their final year experienced only a few differences in the clinical and teaching routine. Teaching coordinators in obstetrics and gynecology stated that they intend to incorporate more e-learning into the curriculum in the future. Conclusion The medical educators’ views presented here may help to complement the already-thoroughly investigated experiences of students under the restrictions of the COVID-19 pandemic. Medical educators in obstetrics and gynecology at German university hospitals have successfully established online and hybrid teaching alternatives to their standard face-to-face courses. Building on recent experiences, digitalization could help to improve future medical education.

Background COVID-19 is a severe disease with a high need for intensive care treatment and a high mortality rate in hospitalized patients. The objective of this study was to describe and compare the clinical characteristics and the management of patients dying with SARS-CoV-2 infection in the acute medical and intensive care setting. Methods Descriptive analysis of dying patients enrolled in the Lean European Open Survey on SARS-CoV-2 Infected Patients (LEOSS), a non-interventional cohort study, between March 18 and November 18, 2020. Symptoms, comorbidities and management of patients, including palliative care involvement, were compared between general ward and intensive care unit (ICU) by univariate analysis. Results 580/4310 (13%) SARS-CoV-2 infected patients died. Among 580 patients 67% were treated on ICU and 33% on a general ward. The spectrum of comorbidities and symptoms was broad with more comorbidities (≥ four comorbidities: 52% versus 25%) and a higher age distribution (>65 years: 98% versus 70%) in patients on the general ward. 69% of patients were in an at least complicated phase at diagnosis of the SARS-CoV-2 infection with a higher proportion of patients in a critical phase or dying the day of diagnosis treated on ICU (36% versus 11%). While most patients admitted to ICU came from home (71%), patients treated on the general ward came likewise from home and nursing home (44% respectively) and were more frequently on palliative care before admission (29% versus 7%). A palliative care team was involved in dying patients in 15%. Personal contacts were limited but more often documented in patients treated on ICU (68% versus 47%). Conclusion Patients dying with SARS-CoV-2 infection suffer from high symptom burden and often deteriorate early with a demand for ICU treatment. Therefor a demand for palliative care expertise with early involvement seems to exist.

Purpose To evaluate a multivariable model predicting the individual probability of successful intravitreal ocriplasmin (IVO) treatment in eyes with vitreomacular traction (VMT). Methods Data from three prospective, multicenter IVO studies (OASIS, ORBIT, and INJECT) were pooled. Patients were included if they were treated for a symptomatic VMT without a full-thickness macular hole. A prediction model for VMT resolution using the factors ‘age’ and ‘horizontal VMT diameter’ was validated by receiver operating characteristic analysis and according to grouped prediction after calibration. Multivariable regression analysis was performed to check robustness and explore further improvements. Results Data from 591 eyes was included. In the univariate analysis all key factors (age, gender, VMT diameter, lens status, ERM) significantly correlated to treatment success. The prediction model was robust and clinically applicable to estimate the success rate of IVO treatment (AUC of ROC: 0.70). A refinement of the model was achieved through a calibration process. Conclusion The developed multivariable model using ‘horizontal VMT diameter’ and ‘age’ is a valid tool for prediction of VMT resolution upon IVO treatment.

Background The association between life event stress and depressive symptoms has not been analyzed in the general population before. Methods In the population-based Heinz Nixdorf Recall study, we assessed the association of 1.) the presence of important life events and 2.) life event stress, with the amount of depressive symptoms in univariable linear regressions and in multivariable regressions adjusted for age and sex (model 1) and age, sex and optimism as important determinants of coping with life events (model 2). Presence of life events and life event stress were assessed with the Social Readjustment Rating Scale (SRRS), optimism with the Life Orientation Test-Revised (LOT-R), and depressive symptoms with the 15-item Center for Epidemiological Studies Depression Scale (CES-D). Results Of the total cohort of 4,814 participants, 1,120 had experienced important life events during the previous 6 months. Presence of important life events was significantly associated with higher CES-D scores (B = 2.6, 95%CI = 2.2 to 3.0, p < .001; model 2) compared to absence of life events. Associations were stronger for women than for men and for pessimists than for optimists. Among the participants with important life events, median (Q1; Q3) stress-score was 45.0 (39.0; 63.0). Stress-scores >Q3 were significantly associated with higher CES-D scores (2.2, 1.1 to 3.3, < .001) with a stronger association in pessimists than in optimists. Conclusions Experiencing life-changing events is associated with depression. Women and individuals with pessimistic personality are especially vulnerable which should be considered in prevention strategies.

Background Liver steatosis is often observed in chronic HCV infection and associated to genotype or comorbidities. NAFLD is an important risk factor for end-stage liver disease. We aimed to analyse the course of NAFLD as a concomitant disease in a cohort of HCV patients. Methods The German Hepatitis C-Registry is a national multicenter real-world cohort. In the current analysis, 8789 HCV patients were included and separated based on the presence of steatosis on ultrasound and/or histology. Fibrosis progression was assessed by transient elastography (TE), ultrasound or non-invasive surrogate scores. Results At the time of study inclusion 12.3% (n = 962) of HCV patients presented with steatosis (+S) (higher rate in GT-3). Diabetes mellitus was more frequent in GT-1 patients. HCV patients without steatosis (-S) had a slightly higher rate of fibrosis progression (FP) over time (30.3%) in contrast to HCV patients +S (26%). This effect was mainly observed in GT-3 patients (34.4% vs. 20.6%). A larger decrease of ALT, AST and GGT from baseline to FU-1 (4–24 weeks after EOT) was found in HCV patients (without FP) +S compared to -S. HCV patients -S and with FP presented more often metabolic comorbidities with a significantly higher BMI (+0.58kg/m2) compared to patients -S without FP. This was particularly pronounced in patients with abnormal ALT. Conclusion Clinically diagnosed steatosis in HCV patients does not seem to contribute to significant FP in this unique cohort. The low prevalence of steatosis could reflect a lower awareness of fatty liver in HCV patients, as patients -S and with FP presented more metabolic risk factors.

Background Much is known about the association between physical activity and the occurrence of stroke. However, the evidence about the correlation between pre-stroke physical activity and post-stroke quality of life remains inconsistent. Thus, there is a high public health relevance to the topic. Aim The aim of this study was to investigate the association between pre-stroke physical activity and physical quality of life after three months. Methods Data arises from 858 patients with stroke included a prospective single-centre observational cohort study in Augsburg, Germany, between September 2018 and November 2019. The participants were recruited at the Department of Neurology and Clinical Neurophysiology, University Hospital of Augsburg after their stroke event. The level of physical activity was determined following the short form of the International Physical Activity Questionnaire at baseline. Physical quality of life was assessed three months after hospital discharge using the German version of the Stroke Impact Scale (SIS). A multiple linear regression model and a quantile regression were carried out. Results A total of 497 patients were included in the analysis (mean age 69.6, 58.8% male), 26.2% had a high, 18.9% a moderate and 54.9% a low level of pre-stroke physical activity. Patients with high pre-stroke physical activity had a significantly better physical quality of life three months after stroke in the SIS physical domain (beta = 4.1) and in the SIS subdomains hand function (beta = 5.6), mobility (beta = 4.1) and activities of daily living (beta = 3.7). In the physical domain and the subdomain mobility, the effect was especially strong for persons with low physical quality of life after three months. Conclusion Pre-stroke physical activity seems to have an important and positive association with physical quality of life after three months in patients with mild disability. Further studies are needed to confirm these results.

Water movements through the fruit skin play critical roles in many disorders of strawberry (Fragaria × ananassa Duch.) such as water soaking, cracking and shriveling. The objective was to identify the mechanisms of fruit water loss (dry skin, transpiration) and water uptake (wet skin, osmosis). Fruits were held above dried silica gel or incubated in deionized water. Water movements were quantified gravimetrically. Transpiration and osmotic uptake increased linearly with time. Abrading the thin cuticle (0.62 g m-2) increased rates of transpiration 2.6–fold, the rates of osmotic uptake 7.9-fold. The osmotic potential of the expressed juice was nearly the same for green and for white fruit but decreased in red fruit stages. Fruit turgor was low throughout development, except for green fruit. There was no relationship between the rates of water movement and fruit osmotic potential. The skin permeance for transpiration and for osmotic uptake were both high (relative to other fruit species) but were two orders of magnitude greater for osmotic uptake than for transpiration. Incubating fruit in isotonic solutions of osmolytes of different sizes resulted in increases in fruit mass that depended on the osmolyte. The rate of osmotic uptake decreased asymptotically as molecular size of the osmolyte increased. When transpiration and osmotic uptake experiments were conducted sequentially on the same fruit, the rates of transpiration were higher for fruit previously incubated in water. Fluorescence microscopy revealed considerable microcracking in a fruit previously incubated in water. Our findings indicate that the high permeance for osmotic uptake is accounted for by an extremely thin cuticle and by viscous water flow through microcracks and along polar pathways.

IntroductionCurrent analysis approaches of accelerometry data use sum score measures which do not provide insight in activity patterns over 24 hours, and thus do not adequately depict circadian activity patterns. Here, we used a functional approach to analyze accelerometer data that models activity pattern and circadian rhythm. As a test case, we demonstrated its application in patients with mild cognitive impairment (MCI) and age-matched healthy older volunteers (HOV). Moreover, we assessed the impact of chronotype on distribution of activity data.MethodsData of two studies were pooled for this analysis. Following baseline cognitive assessment participants were provided with accelerometers for seven consecutive days. A function on scalar regression (FoSR) approach was used to analyze 24 hours accelerometer data. In a second step, analyses were controlled for chronotype using the German version of the morningness-eveningness questionnaire (d-MEQ).ResultsInformation on 47 HOV (mean age 66 SD 6 years) and 13 patients with MCI (mean age 69, SD 8 years) were available for this analysis. MCI patients displayed slightly higher activity in the morning hours as compared to HOV (maximum relative activity at 7:35 am: 75.6%, 95% CI 2.6 to 200.4%, p = 0.031). After controlling for d-MEQ, disturbed activity patterns were found in MCI of intermediate or evening chronotype, compared to HOV, i.e., MCI presented with higher activities in the morning hours (peak at 8:40 am: 357.6%, 95% CI 92.9 to 985.1, p < 0.001) and early afternoon hours (peak at 1:40 pm: 401.8%, 95% CI 63.9 to 1436.4, p < 0.001).DiscussionUsing a novel approach of FoSR, we found timeframes with higher activity levels in MCI patients compared to HOV which were not evident if sum scores of amount of activity were used. In addition, we found that previously described activity patterns as a function of chronotype swere altered in MCI patients, possibly indicating that changes in circadian rhythmicity in neurodegenerative disease are detectable using easy-to-administer accelerometry.Clinical TrialsEffects of Brain Stimulation During Nocturnal Sleep on Memory Consolidation in Patients With Mild Cognitive Impairments, https://clinicaltrials.gov/ct2/show/NCT01782391?term=NCT01782391&rank=1,ClinicalTrial.gov identifier: NCT01782391Effects of Brain Stimulation During a Daytime Nap on Memory Consolidation in Patients With Mild Cognitive Impairment,https://clinicaltrials.gov/ct2/show/NCT01782365?term=NCT01782365&rank=1,ClinicalTrial.gov identifier: NCT01782365

Background: The smoking-paradox of a better outcome in ischemic stroke patients who smoke may be due to increased efficacy of thrombolysis. We investigated the effect of smoking on outcome following endovascular therapy (EVT) with mechanical thrombectomy alone versus in combination with intra-arterial (IA-) thrombolysis. Methods: The primary endpoint was defined by three-month modified Rankin Scale (mRS). We performed a generalized linear model and reported relative risks (RR) for smoking (adjustment for age, sex, hypertension, atrial fibrillation, stroke severity, time to EVT) in patient data stemming from the Virtual International Stroke Trials Archive-Endovascular database. Results: Among 1,497 patients, 740(49.4%) were randomized to EVT; among EVT patients, 524(35.0%) received mechanical thrombectomy alone and 216(14.4%) received it in combination with IA-thrombolysis. Smokers (N = 396) had lower mRS scores (mean 2.9 vs. 3.2; p = 0.02) and mortality rates (10% vs. 17.3%; p1 (95%CI 0.77-3.55). Treatment with IA-thrombolysis itself led to reduced RR for favorable outcome (adjusted RR 0.30); interaction analysis of IA-thrombolysis and smoking revealed that non-smokers with IA-thrombolysis had mRS ≤ 2 in 47 cases (30%, adjusted RR 0.53 [0.41-0.69]) while smokers with IA-thrombolysis had mRS ≤ 2 in 23 cases (38%, adjusted RR 0.61 [0.42-0.87]). Conclusions: Smokers had no clear clinical benefit from EVT that incorporates IA-thrombolysis.

Background COVID-19 is only partly understood, and the level of evidence available in terms of pathophysiology, epidemiology, therapy, and long-term outcome remains limited. During the early phase of the pandemic, it was necessary to effectively investigate all aspects of this new disease. Autopsy can be a valuable procedure to investigate the internal organs with special techniques to obtain information on the disease, especially the distribution and type of organ involvement. Methods During the first wave of COVID-19 in Germany, autopsies of 19 deceased patients were performed. Besides gross examination, the organs were analyzed with standard histology and polymerase-chain-reaction for SARS-CoV-2. Polymerase chain reaction positive localizations were further analyzed with immunohistochemistry and RNA-in situ hybridization for SARS-CoV-2. Results Eighteen of 19 patients were found to have died due to COVID-19. Clinically relevant histological changes were only observed in the lungs. Diffuse alveolar damage in considerably different degrees was noted in 18 cases. Other organs, including the central nervous system, did not show specific micromorphological alterations. In terms of SARS-CoV-2 detection, the focus remains on the upper airways and lungs. This is true for both the number of positive samples and the viral load. A highly significant inverse correlation between the stage of diffuse alveolar damage and viral load was found on a case and a sample basis. Mediastinal lymph nodes and fat were also affected by the virus at high frequencies. By contrast, other organs rarely exhibited a viral infection. Moderate to strong correlations between the methods for detecting SARS-CoV-2 were observed for the lungs and for other organs. Conclusions The lung is the most affected organ in gross examination, histology and polymerase chain reaction. SARS-CoV-2 detection in other organs did not reveal relevant or specific histological changes. Moreover, we did not find CNS involvement.

Background Circulating levels of the endogenous inhibitor of nitric oxide synthase, asymmetric dimethylarginine (ADMA), are positively associated with the prevalence of metabolic syndrome (MetS) in cross-sectional investigations. It is unclear if circulating ADMA and other methylarginines are associated with incident MetS prospectively. Methods We related circulating ADMA, symmetric dimethylarginine (SDMA), L-arginine (ARG) concentrations (measured with a validated tandem mass spectrometry assay) and the ARG/ADMA ratio to MetS and its components in 2914 (cross-sectional analysis, logistic regression; mean age 58 years, 55% women) and 1656 (prospective analysis, Cox regression; mean age 56 years, 59% women) individuals from the Framingham Offspring Study who attended a routine examination. Results Adjusting for age, sex, smoking, and eGFR, we observed significant associations of ADMA (direct) and ARG/ADMA (inverse) with odds of MetS (N = 1461 prevalent cases; Odds Ratio [OR] per SD increment 1.13, 95%CI 1.04–1.22; and 0.89, 95%CI 0.82–0.97 for ADMA and ARG/ADMA, respectively). Upon further adjustment for waist circumference, systolic and diastolic blood pressure, glucose, high-density lipoprotein cholesterol, and triglycerides, we observed a positive relation between SDMA and MetS (OR per SD increment 1.15, 95% CI 1.01–1.30) but the other associations were rendered statistically non-significant. We did not observe statistically significant associations between any of the methylarginines and the risk of new-onset MetS (752 incident events) over a median follow-up of 11 years. Conclusion It is unclear whether dimethylarginines play an important role in the incidence of cardiometabolic risk in the community, notwithstanding cross-sectional associations. Further studies of larger samples are needed to replicate our findings.

Musical activities especially singing and playing wind instruments have been singled out as potentially high-risk activities for transmission of SARS CoV-2, because of a higher rate of aerosol production and emission. Playing wind instruments can produce condensation water, droplets of saliva, and aerosol particles, which hover and convectional spread in the environmental air and can be potentially infectious.The aim of this study is to investigate the primary impulse dispersion of aerosols during playing different wind instruments in comparison to breathing and speaking. Nine professional musicians (3 trumpeters, 3 cross flutists and 3 clarinetists) of the Bavarian Symphony Orchestra performed the main theme of Ludwig van Beethoven‘s 9th symphony, 4th movement in different pitches and loudness. Thereby, the inhaled air volume was marked with small aerosol particles produced with a commercial e-cigarette. The expelled aerosol cloud was recorded by cameras from different perspectives. Afterwards, the dimensions and dynamics of the aerosol cloud was measured by segmenting the video footage at every time point.Overall, the cross flutes produced the largest dispersion at the end of task of up to maximum distances of 1.88 m in front direction. Thereby it was observed an expulsion of aerosol in different directions: upwards and downwards at the mouthpiece, at the end of the instrument and along the cross flute at the key plane. In comparison, the maximum impulse dispersion generated by the trumpets and clarinets were lower in frontal and lateral direction (1.2 m and 1.0 m in front-direction). The expulsion to the sides was also lower. Consequently, a distance of 3 m to the front and to the sides of 2 m for the cross flutes in an orchestral formation is proposed, for trumpets and clarinets a safety distance of 2 m to the front and 1.5 m between instrumentalists are recommendable.

In recent years, Germany and Austria have been among the leading European receiving countries for asylum seekers and refugees (AS&R). The two countries have cultural and economic similarities, but differ, for example, in their health care systems, with AS&R having unrestricted access to health services upon arrival in Austria, but not in Germany. This study investigates the determinants of health among refugees in Austria and Germany, and how these determinants differ between the two countries. We analyze comparable and harmonized survey data from both countries for Syrian, Afghan, and Iraqi nationals aged 18 to 59 years who had immigrated between 2013 and 2016 (Germany: n = 2,854; Austria: n = 374). The study adopts a cross-sectional design, and uses propensity score matching to examine comparable AS&R in the two receiving countries. The results reveal that the AS&R in Germany (72%) were significantly less likely to report being in (very) good health than their peers in Austria (89%). Age and education had large impacts on health, whereas the effects of length of stay and length of asylum process were smaller. Compositional differences in terms of age, sex, nationality, education, and partnership situation explained the country differences only in part. After applying propensity score matching to adjust for structural differences and to assess non-confounded country effects, the probability of reporting (very) good health was still 12 percentage points lower in Germany than in Austria. We conclude that many of the determinants of health among AS&R correspond to those in the non-migrant population, and thus call for the implementation of similar health policies. The health disadvantage found among the AS&R in Germany suggests that removing their initially restricted access to health care may improve their health.

Made available in DSpace on 2021-06-25T10:55:22Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-03-01 National Institute of Biological Resources The potential outcome of flavivirus and alphavirus co-infections is worrisome due to the development of severe diseases. Hundreds of millions of people worldwide live under the risk of infections caused by viruses like chikungunya virus (CHIKV, genus Alphavirus), dengue virus (DENV, genus Flavivirus), and zika virus (ZIKV, genus Flavivirus). So far, neither any drug exists against the infection by a single virus, nor against co-infection. The results described in our study demonstrate the inhibitory potential of two flavonoids derived from citrus plants: Hesperetin (HST) against NS2B/NS3pro of ZIKV and nsP2pro of CHIKV and, Hesperidin (HSD) against nsP2pro of CHIKV. The flavonoids are noncompetitive inhibitors and the determined IC50 values are in low µM range for HST against ZIKV NS2B/NS3pro (12.6 ± 1.3 µM) and against CHIKV nsP2pro (2.5 ± 0.4 µM). The IC50 for HSD against CHIKV nsP2pro was 7.1 ± 1.1 µM. The calculated ligand efficiencies for HST were > 0.3, which reflect its potential to be used as a lead compound. Docking and molecular dynamics simulations display the effect of HST and HSD on the protease 3D models of CHIKV and ZIKV. Conformational changes after ligand binding and their effect on the substrate-binding pocket of the proteases were investigated. Additionally, MTT assays demonstrated a very low cytotoxicity of both the molecules. Based on our results, we assume that HST comprise a chemical structure that serves as a starting point molecule to develop a potent inhibitor to combat CHIKV and ZIKV co-infections by inhibiting the virus proteases. Multiuser Center for Biomolecular Innovation Departament of Physics Instituto de Biociências Letras e Ciências Exatas (Ibilce) Universidade Estadual Paulista (UNESP) Institute of Biological Information Processing (IBI-7: Structural Biochemistry) Forschungszentrum Jülich Federal University of Tocantins Instituto de Biociências Letras e Ciências Exatas (Ibilce) Universidade Estadual Paulista (UNESP) FACERES Medical School Faculdade de Medicina de São José do Rio Preto-FAMERP Institute of Physics Federal University of Mato Grosso do Sul Institut für Physikalische Biologie Heinrich-Heine-Universität Düsseldorf JuStruct: Jülich Centre for Structural Biology Forchungszentrum Jülich Multiuser Center for Biomolecular Innovation Departament of Physics Instituto de Biociências Letras e Ciências Exatas (Ibilce) Universidade Estadual Paulista (UNESP) Instituto de Biociências Letras e Ciências Exatas (Ibilce) Universidade Estadual Paulista (UNESP)

Acute graft versus host disease (aGvHD) is an important, life-threatening complication after allogeneic hematopoietic stem cell transplantation (alloHSCT). To investigate the value of multiple simultaneous colon biopsies in improving diagnostic accuracy in patients with aGvHD, we retrospectively analyzed 157 patients after alloHSCT. The biopsies were evaluated individually using three established histological grading systems (Lerner, Sale, and Melson). The maximum, minimum, median, and mean histological aGvHD grades were calculated for each patient, and the results were correlated with the Glucksberg grade of clinical manifestation of GvHD, steroid therapy status, and outcome. We found that multiple colon biopsies enhanced diagnostic sensitivity. Moreover, higher histological grades correlated with steroid therapy initiation and refractoriness; the latter particularly occurred when advanced damage was present in all samples and healthy colon mucosa was reduced or absent. On multivariate analysis, the minimal Lerner and Glucksberg grades for intestinal aGvHD were significantly associated with steroid treatment failure. Ninety-nine patients died. The median survival was 285 days after the biopsies were taken. Fifteen patients died from relapse of their underling disorder and 84 from other causes, mostly infection (53 patients) and GvHD (14 patients). Multivariate analysis revealed a significant association between none-relapse mortality and the mean Lerner grade, minimum Melson grade, Glucksberg organ stage, and platelet counts. Thus, we found the Lerner system to be superior to the other grading methods in most instances and histologic evaluation of multiple simultaneously obtained biopsies from the colon to result in a higher diagnostic yield, which helps plan systemic steroid treatment while predicting treatment response and outcome.

Background The coronavirus disease 2019 (COVID-19) pandemic led to far-reaching restrictions of social and professional life, affecting societies all over the world. To contain the virus, medical schools had to restructure their curriculum by switching to online learning. However, only few medical schools had implemented such novel learning concepts. We aimed to evaluate students’ attitudes to online learning to provide a broad scientific basis to guide future development of medical education. Methods Overall, 3286 medical students from 12 different countries participated in this cross-sectional, web-based study investigating various aspects of online learning in medical education. On a 7-point Likert scale, participants rated the online learning situation during the pandemic at their medical schools, technical and social aspects, and the current and future role of online learning in medical education. Results The majority of medical schools managed the rapid switch to online learning (78%) and most students were satisfied with the quantity (67%) and quality (62%) of the courses. Online learning provided greater flexibility (84%) and led to unchanged or even higher attendance of courses (70%). Possible downsides included motivational problems (42%), insufficient possibilities for interaction with fellow students (67%) and thus the risk of social isolation (64%). The vast majority felt comfortable using the software solutions (80%). Most were convinced that medical education lags behind current capabilities regarding online learning (78%) and estimated the proportion of online learning before the pandemic at only 14%. In order to improve the current curriculum, they wish for a more balanced ratio with at least 40% of online teaching compared to on-site teaching. Conclusion This study demonstrates the positive attitude of medical students towards online learning. Furthermore, it reveals a considerable discrepancy between what students demand and what the curriculum offers. Thus, the COVID-19 pandemic might be the long-awaited catalyst for a new “online era” in medical education.

PLOS ONE 16(2), e0247667 (2021). doi:10.1371/journal.pone.0247667, Published by PLOS, San Francisco, California