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With the rise of immersive media, advertisers have started to use 360° commercials to engage and persuade consumers. Two experiments were conducted to address research gaps and to validate the positive impact of 360° commercials in realistic settings. The first study (N = 62) compared the effects of 360° commercials using either a mobile cardboard head-mounted display (HMD) or a laptop. This experiment was conducted in the participants’ living rooms and incorporated individual feelings of cybersickness as a moderator. The participants who experienced the 360° commercial with the HMD reported higher spatial presence and product evaluation, but their purchase intentions were only increased when their reported cybersickness was low. The second experiment (N = 197) was conducted online and analyzed the impact of 360° commercials that were experienced with mobile (smartphone/tablet) or static (laptop/desktop) devices instead of HMDs. The positive effects of omnidirectional videos were stronger when participants used mobile devices.
Catastrophizing thoughts may contribute to the development of anxiety, but functional emotion regulation may help to improve treatment. No study so far directly compared up- and down-regulation of fear by cognitive reappraisal. Here, healthy individuals took part in a cued fear experiment, in which multiple pictures of faces were paired twice with an unpleasant scream or presented as safety stimuli. Participants (N = 47) were asked (within-subjects) to down-regulate, to up-regulate and to maintain their natural emotional response. Valence and arousal ratings indicated successful up- and down-regulation of the emotional experience, while heart rate and pupil dilation increased during up-regulation, but showed no reduction in down-regulation. State and trait anxiety correlated with evaluations of safety but not threat stimuli, which supports the role of deficient safety learning in anxiety. Reappraisal did not modulate this effect. In conclusion, this study reveals evidence for up-regulation effects in fear, which might be even more efficient than down-regulation on a physiological level and highlights the importance of catastrophizing thoughts for the maintenance of fear and anxiety.
In many real world settings, imbalanced data impedes model performance of learning algorithms, like neural networks, mostly for rare cases. This is especially problematic for tasks focusing on these rare occurrences. For example, when estimating precipitation, extreme rainfall events are scarce but important considering their potential consequences. While there are numerous well studied solutions for classification settings, most of them cannot be applied to regression easily. Of the few solutions for regression tasks, barely any have explored cost-sensitive learning which is known to have advantages compared to sampling-based methods in classification tasks. In this work, we propose a sample weighting approach for imbalanced regression datasets called DenseWeight and a cost-sensitive learning approach for neural network regression with imbalanced data called DenseLoss based on our weighting scheme. DenseWeight weights data points according to their target value rarities through kernel density estimation (KDE). DenseLoss adjusts each data point’s influence on the loss according to DenseWeight, giving rare data points more influence on model training compared to common data points. We show on multiple differently distributed datasets that DenseLoss significantly improves model performance for rare data points through its density-based weighting scheme. Additionally, we compare DenseLoss to the state-of-the-art method SMOGN, finding that our method mostly yields better performance. Our approach provides more control over model training as it enables us to actively decide on the trade-off between focusing on common or rare cases through a single hyperparameter, allowing the training of better models for rare data points.
A reformulation of cardinality-constrained optimization problems into continuous nonlinear optimization problems with an orthogonality-type constraint has gained some popularity during the last few years. Due to the special structure of the constraints, the reformulation violates many standard assumptions and therefore is often solved using specialized algorithms. In contrast to this, we investigate the viability of using a standard safeguarded multiplier penalty method without any problem-tailored modifications to solve the reformulated problem. We prove global convergence towards an (essentially strongly) stationary point under a suitable problem-tailored quasinormality constraint qualification. Numerical experiments illustrating the performance of the method in comparison to regularization-based approaches are provided.
We derive a multi-species BGK model with velocity-dependent collision frequency for a non-reactive, multi-component gas mixture. The model is derived by minimizing a weighted entropy under the constraint that the number of particles of each species, total momentum, and total energy are conserved. We prove that this minimization problem admits a unique solution for very general collision frequencies. Moreover, we prove that the model satisfies an H-Theorem and characterize the form of equilibrium.
In this paper we derive new results on multivariate extremes and D-norms. In particular we establish new characterizations of the multivariate max-domain of attraction property. The limit distribution of certain multivariate exceedances above high thresholds is derived, and the distribution of that generator of a D-norm on R\(^{d}\), whose components sum up to d, is obtained. Finally we introduce exchangeable D-norms and show that the set of exchangeable D-norms is a simplex.
We investigate the convergence of the proximal gradient method applied to control problems with non-smooth and non-convex control cost. Here, we focus on control cost functionals that promote sparsity, which includes functionals of L\(^{p}\)-type for p\in [0,1). We prove stationarity properties of weak limit points of the method. These properties are weaker than those provided by Pontryagin’s maximum principle and weaker than L-stationarity.
Sequential optimality conditions for cardinality-constrained optimization problems with applications
(2021)
Recently, a new approach to tackle cardinality-constrained optimization problems based on a continuous reformulation of the problem was proposed. Following this approach, we derive a problem-tailored sequential optimality condition, which is satisfied at every local minimizer without requiring any constraint qualification. We relate this condition to an existing M-type stationary concept by introducing a weak sequential constraint qualification based on a cone-continuity property. Finally, we present two algorithmic applications: We improve existing results for a known regularization method by proving that it generates limit points satisfying the aforementioned optimality conditions even if the subproblems are only solved inexactly. And we show that, under a suitable Kurdyka–Łojasiewicz-type assumption, any limit point of a standard (safeguarded) multiplier penalty method applied directly to the reformulated problem also satisfies the optimality condition. These results are stronger than corresponding ones known for the related class of mathematical programs with complementarity constraints.
Heart failure with preserved ejection fraction (HFpEF) is highly prevalent in patients on maintenance haemodialysis (HD) and lacks effective treatment. We investigated the effect of spironolactone on cardiac structure and function with a specific focus on diastolic function parameters. The MiREnDa trial examined the effect of 50 mg spironolactone once daily versus placebo on left ventricular mass index (LVMi) among 97 HD patients during 40 weeks of treatment. In this echocardiographic substudy, diastolic function was assessed using predefined structural and functional parameters including E/e'. Changes in the frequency of HFpEF were analysed using the comprehensive 'HFA-PEFF score'. Complete echocardiographic assessment was available in 65 individuals (59.5 ± 13.0 years, 21.5% female) with preserved left ventricular ejection fraction (LVEF > 50%). At baseline, mean E/e' was 15.2 ± 7.8 and 37 (56.9%) patients fulfilled the criteria of HFpEF according to the HFA-PEFF score. There was no significant difference in mean change of E/e' between the spironolactone group and the placebo group (+ 0.93 ± 5.39 vs. + 1.52 ± 5.94, p = 0.68) or in mean change of left atrial volume index (LAVi) (1.9 ± 12.3 ml/m\(^{2}\) vs. 1.7 ± 14.1 ml/m\(^{2}\), p = 0.89). Furthermore, spironolactone had no significant effect on mean change in LVMi (+ 0.8 ± 14.2 g/m\(^{2}\) vs. + 2.7 ± 15.9 g/m\(^{2}\); p = 0.72) or NT-proBNP (p = 0.96). Treatment with spironolactone did not alter HFA-PEFF score class compared with placebo (p = 0.63). Treatment with 50 mg of spironolactone for 40 weeks had no significant effect on diastolic function parameters in HD patients.
Planting non-native tree species, like Douglas fir in temperate European forest systems, is encouraged to mitigate effects of climate change. However, Douglas fir monocultures often revealed negative effects on forest biota, while effects of mixtures with native tree species on forest ecosystems are less well understood. We investigated effects of three tree species (Douglas fir, Norway spruce, native European beech), on ground beetles in temperate forests of Germany. Beetles were sampled in monocultures of each tree species and broadleaf-conifer mixtures with pitfall traps, and environmental variables were assessed around each trap. We used linear mixed models in a two-step procedure to disentangle effects of environment and tree species identity on ground beetle abundance, species richness, functional diversity and species assemblage structure. Contradictory to our expectations, ground beetle abundance and functional diversity was highest in pure Douglas fir stands, while tree mixtures showed intermediate values between pure coniferous and pure beech stands. The main drivers of these patterns were only partially dependent on tree species identity, which highlights the importance of structural features in forest stands. However, our study revealed distinct shifts in assemblage structure between pure beech and pure Douglas fir stands, which were only partially eased through mixture planting. Our findings suggest that effects of planting non-native trees on associated biodiversity can be actively modified by promoting beneficial forest structures. Nevertheless, integrating non-native tree species, even in mixtures with native trees, will invariably alter assemblage structures of associated biota, which can compromise conservation efforts targeted at typical species composition.
The GABA\(_{B}\) receptor agonist baclofen is a medication commonly used for the treatment of muscle spasticity. It is an amino acid and related to the neurotransmitter GABA. In this study, we developed a new, gradient high-performance liquid chromatography (HPLC) method for the impurity assessment of baclofen, which is appropriate for pharmacopoeial purposes. Since the impurities related to the synthesis pathway are acids, zwitterionic, or neutral, the method development is challenging. However, the separation of all components was achieved on a C18 stationary phase using a water–acetonitrile–trifluoroacetic acid gradient. A limit of detection (LOD) of at least 0.02% was registered for all specified impurities. Additionally, CAD detection was performed to detect potential impurities lacking off a chromophore. The baclofen batches analyzed are far more pure than expected. All impurities were found below the specification limit, and thus, they can be regarded as unspecified. Moreover, the required runtime could be significantly reduced compared to the current USP or Ph. Eur. method.
The Mesoproterozoic Aggeneys-Gamsberg ore district, South Africa, is one of the world´s largest sulfidic base metal concentrations and well-known as a prime example of Broken Hill-type base metal deposits, traditionally interpreted as metamorphosed SEDEX deposits. Within this district, the Gamsberg deposit stands out for its huge size and strongly Zn-dominated ore ( >14 Mt contained Zn). New electron microprobe analyses and element abundance maps of sulfides and silicates point to fluid-driven sulfidation during retrograde metamorphism. Differences in the chemistry of sulfide inclusions within zoned garnet grains reflect different degrees of interaction of sulfides with high metal/sulfur-ratio with a sulfur-rich metamorphic fluid. Independent evidence of sulfidation during retrograde metamorphism comes from graphic-textured sulfide aggregates that previously have been interpreted as quenched sulfidic melts, replacement of pyrrhotite by pyrite along micro-fractures, and sulfides in phyllic alteration zones. Limited availability of fluid under retrograde conditions caused locally different degrees of segregation of Fe-rich sphalerite into Zn-rich sphalerite and pyrite, and thus considerable heterogeneity in sphalerite chemistry. The invoked sulfur-rich metamorphic fluids would have been able to sulfidize base metal-rich zones in the whole deposit and thus camouflage a potential pre-metamorphic oxidation. These findings support the recently established hypothesis of a pre-Klondikean weathering-induced oxidation event and challenge the traditional explanation of Broken Hill-type deposits as merely metamorphosed SEDEX deposits. Instead, we suggest that the massive sulfide deposits experienced a complex history, starting with initial SEDEX-type mineralization, followed by near-surface oxidation with spatial metal separation, and then sulfidation of this oxidized ore during medium- to high-grade metamorphism.
During strong El Niño events, below-average rainfall is expected in large parts of southern Africa. The 1992 El Niño season was associated with one of the worst drought episodes in large parts of South Africa. Using reanalysis data set from NCEP-NCAR, this study examined circulation types (CTs) in Africa south of the equator that are statistically related to the El Niño signal in the southwest Indian Ocean and the implication of this relationship during the 1992 drought episode in South Africa. A statistically significant correlation was found between the above-average Nino 3.4 index and a CT that features widespread cyclonic activity in the tropical southwest Indian Ocean, coupled with a weaker state of the south Indian Ocean high-pressure. During the analysis period, it was found that the El Niño signal enhanced the amplitude of the aforementioned CT. The impacts of the El Niño signal on CTs in southern Africa, which could have contributed to the 1992 severe drought episode in South Africa, were reflected in (i) robust decrease in the frequency of occurrence of the austral summer climatology pattern of atmospheric circulation that favors southeasterly moisture fluxes, advected by the South Indian Ocean high-pressure; (ii) modulation of easterly moisture fluxes, advected by the South Atlantic Ocean high-pressure, ridging south of South Africa; (iii) and enhancement of the amplitude of CTs that both enhances subsidence over South Africa, and associated with the dominance of westerlies across the Agulhas current. Under the ssp585 scenario, the analyzed climate models suggested that the impact of radiative heating on the CT significantly related to El Niño might result in an anomalous increase in surface pressure at the eastern parts of South Africa.
Atmospheric circulation is a vital process in the transport of heat, moisture, and pollutants around the globe. The variability of rainfall depends to some extent on the atmospheric circulation. This paper investigates synoptic situations in southern Africa that can be associated with wet days and dry days in Free State, South Africa, in addition to the underlying dynamics. Principal component analysis was applied to the T-mode matrix (variable is time series and observation is grid points at which the field was observed) of daily mean sea level pressure field from 1979 to 2018 in classifying the circulation patterns in southern Africa. 18 circulation types (CTs) were classified in the study region. From the linkage of the CTs to the observed rainfall data, from 11 stations in Free State, it was found that dominant austral winter and late austral autumn CTs have a higher probability of being associated with dry days in Free State. Dominant austral summer and late austral spring CTs were found to have a higher probability of being associated with wet days in Free State. Cyclonic/anti-cyclonic activity over the southwest Indian Ocean, explained to a good extent, the inter-seasonal variability of rainfall in Free State. The synoptic state associated with a stronger anti-cyclonic circulation at the western branch of the South Indian Ocean high-pressure, during austral summer, leading to enhanced low-level moisture transport by southeast winds was found to have the highest probability of being associated with above-average rainfall in most regions in Free State. On the other hand, the synoptic state associated with enhanced transport of cold dry air, by the extratropical westerlies, was found to have the highest probability of being associated with (winter) dryness in Free State.
Iron as the concert master in the pathogenic orchestra playing in sporadic Parkinson's disease
(2021)
About 60 years ago, the discovery of a deficiency of dopamine in the nigro-striatal system led to a variety of symptomatic therapeutic strategies to supplement dopamine and to substantially improve the quality of life of patients with Parkinson's disease (PD). Since these seminal developments, neuropathological, neurochemical, molecular biological and genetic discoveries contributed to elucidate the pathology of PD. Oxidative stress, the consequences of reactive oxidative species, reduced antioxidative capacity including loss of glutathione, excitotoxicity, mitochondrial dysfunction, proteasomal dysfunction, apoptosis, lysosomal dysfunction, autophagy, suggested to be causal for ɑ-synuclein fibril formation and aggregation and contributing to neuroinflammation and neural cell death underlying this devastating disorder. However, there are no final conclusions about the triggered pathological mechanism(s) and the follow-up of pathological dysfunctions. Nevertheless, it is a fact, that iron, a major component of oxidative reactions, as well as neuromelanin, the major intraneuronal chelator of iron, undergo an age-dependent increase. And ageing is a major risk factor for PD. Iron is significantly increased in the substantia nigra pars compacta (SNpc) of PD. Reasons for this finding include disturbances in iron-related import and export mechanisms across the blood-brain barrier (BBB), localized opening of the BBB at the nigro-striatal tract including brain vessel pathology. Whether this pathology is of primary or secondary importance is not known. We assume that there is a better fit to the top-down hypotheses and pathogens entering the brain via the olfactory system, then to the bottom-up (gut-brain) hypothesis of PD pathology. Triggers for the bottom-up, the dual-hit and the top-down pathologies include chemicals, viruses and bacteria. If so, hepcidin, a regulator of iron absorption and its distribution into tissues, is suggested to play a major role in the pathogenesis of iron dyshomeostasis and risk for initiating and progressing ɑ-synuclein pathology. The role of glial components to the pathology of PD is still unknown. However, the dramatic loss of glutathione (GSH), which is mainly synthesized in glia, suggests dysfunction of this process, or GSH uptake into neurons. Loss of GSH and increase in SNpc iron concentration have been suggested to be early, may be even pre-symptomatic processes in the pathology of PD, despite the fact that they are progression factors. The role of glial ferritin isoforms has not been studied so far in detail in human post-mortem brain tissue and a close insight into their role in PD is called upon. In conclusion, "iron" is a major player in the pathology of PD. Selective chelation of excess iron at the site of the substantia nigra, where a dysfunction of the BBB is suggested, with peripherally acting iron chelators is suggested to contribute to the portfolio and therapeutic armamentarium of anti-Parkinson medications.
Depression is a common psychiatric disorder among geriatric patients that decreases the quality of life and increases morbidity and mortality. Vitamin D as a neuro-steroid hormone might play a role in the onset and treatment of depression. In the present study, the association between depressive symptoms and vitamin D concentration in serum was evaluated. 140 patients of a psychogeriatric day-care unit were included. The geriatric depression scale (GDS) and the Hamilton depression rating scale (HDRS) were assessed at the beginning and end of treatment, GDS scores additionally 6 weeks after discharge from the day-care unit. Vitamin D levels were measured at the beginning of the treatment, routinely. Patients with levels below 30 µg/L were treated with 1000 IU vitamin D per day. There was no association between the severity of depressive symptoms and the concentration of vitamin D at the beginning of the treatment. Patients with higher vitamin D levels showed a stronger decline of depressive symptoms measured by the GDS during their stay in the day-care unit. We provide evidence that vitamin D serum levels might influence antidepressant therapy response in a geriatric population. Prospective studies are necessary to determine which patients may profit from add-on vitamin D therapy.
Human induced pluripotent stem cells (hiPSCs) have revolutionized the generation of experimental disease models, but the development of protocols for the differentiation of functionally active neuronal subtypes with defined specification is still in its infancy. While dysfunction of the brain serotonin (5-HT) system has been implicated in the etiology of various neuropsychiatric disorders, investigation of functional human 5-HT specific neurons in vitro has been restricted by technical limitations. We describe an efficient generation of functionally active neurons from hiPSCs displaying 5-HT specification by modification of a previously reported protocol. Furthermore, 5-HT specific neurons were characterized using high-end fluorescence imaging including super-resolution microscopy in combination with electrophysiological techniques. Differentiated hiPSCs synthesize 5-HT, express specific markers, such as tryptophan hydroxylase 2 and 5-HT transporter, and exhibit an electrophysiological signature characteristic of serotonergic neurons, with spontaneous rhythmic activities, broad action potentials and large afterhyperpolarization potentials. 5-HT specific neurons form synapses reflected by the expression of pre- and postsynaptic proteins, such as Bassoon and Homer. The distribution pattern of Bassoon, a marker of the active zone along the soma and extensions of neurons, indicates functionality via volume transmission. Among the high percentage of 5-HT specific neurons (~ 42%), a subpopulation of CDH13 + cells presumably designates dorsal raphe neurons. hiPSC-derived 5-HT specific neuronal cell cultures reflect the heterogeneous nature of dorsal and median raphe nuclei and may facilitate examining the association of serotonergic neuron subpopulations with neuropsychiatric disorders.
In recent years, bumblebees have become a prominent insect model organism for a variety of biological disciplines, particularly to investigate learning behaviors as well as visual performance. Understanding these behaviors and their underlying neurobiological principles requires a clear understanding of brain anatomy. Furthermore, to be able to compare neuronal branching patterns across individuals, a common framework is required, which has led to the development of 3D standard brain atlases in most of the neurobiological insect model species. Yet, no bumblebee 3D standard brain atlas has been generated. Here we present a brain atlas for the buff-tailed bumblebee Bombus terrestris using micro-computed tomography (micro-CT) scans as a source for the raw data sets, rather than traditional confocal microscopy, to produce the first ever micro-CT-based insect brain atlas. We illustrate the advantages of the micro-CT technique, namely, identical native resolution in the three cardinal planes and 3D structure being better preserved. Our Bombus terrestris brain atlas consists of 30 neuropils reconstructed from ten individual worker bees, with micro-CT allowing us to segment neuropils completely intact, including the lamina, which is a tissue structure often damaged when dissecting for immunolabeling. Our brain atlas can serve as a platform to facilitate future neuroscience studies in bumblebees and illustrates the advantages of micro-CT for specific applications in insect neuroanatomy.
Deafness, the most frequent sensory deficit in humans, is extremely heterogeneous with hundreds of genes involved. Clinical and genetic analyses of an extended consanguineous family with pre-lingual, moderate-to-profound autosomal recessive sensorineural hearing loss, allowed us to identify CLRN2, encoding a tetraspan protein, as a new deafness gene. Homozygosity mapping followed by exome sequencing identified a 14.96 Mb locus on chromosome 4p15.32p15.1 containing a likely pathogenic missense variant in CLRN2 (c.494C > A, NM_001079827.2) segregating with the disease. Using in vitro RNA splicing analysis, we show that the CLRN2 c.494C > A variant leads to two events: (1) the substitution of a highly conserved threonine (uncharged amino acid) to lysine (charged amino acid) at position 165, p.(Thr165Lys), and (2) aberrant splicing, with the retention of intron 2 resulting in a stop codon after 26 additional amino acids, p.(Gly146Lysfs*26). Expression studies and phenotyping of newly produced zebrafish and mouse models deficient for clarin 2 further confirm that clarin 2, expressed in the inner ear hair cells, is essential for normal organization and maintenance of the auditory hair bundles, and for hearing function. Together, our findings identify CLRN2 as a new deafness gene, which will impact future diagnosis and treatment for deaf patients.
Purpose
Traditionally, previous wound infection was considered a contraindication to secondary skin closure; however, several case reports describe successful secondary wound closure of wounds "preconditioned" with negative pressure wound therapy (NPWT). Although this has been increasingly applied in daily practice, a systematic analysis of its feasibility has not been published thus far. The aim of this study was to evaluate secondary skin closure in previously infected abdominal wounds following treatment with NPWT.
Methods
Single-center retrospective analysis of patients with infected abdominal wounds treated with NPWT followed by either secondary skin closure referenced to a group receiving open wound therapy. Endpoints were wound closure rate, wound complications (such as recurrent infection or hernia), and perioperative data (such as duration of NPWT or hospitalization parameters).
Results
One hundred ninety-eight patients during 2013-2016 received a secondary skin closure after NPWT and were analyzed and referenced to 67 patients in the same period with open wound treatment after NPWT. No significant difference in BMI, chronic immunosuppressive medication, or tobacco use was found between both groups. The mean duration of hospital stay was 30 days with a comparable duration in both patient groups (29 versus 33 days, p = 0.35). Interestingly, only 7.7% of patients after secondary skin closure developed recurrent surgical site infection and in over 80% of patients were discharged with closed wounds requiring only minimal outpatient wound care.
Conclusion
Surgical skin closure following NPWT of infected abdominal wounds is a good and safe alternative to open wound treatment. It prevents lengthy outpatient wound therapy and is expected to result in a higher quality of life for patients and reduce health care costs.
Purpose
Repeat surgery in patients with primary hyperparathyroidism (pHPT) is associated with an increased risk of complications and failure. This stresses the need for optimized strategies to accurately localize a parathyroid adenoma before repeat surgery is performed. However, evidence on the extent of required diagnostics for a structured approach is sparse.
Methods
A retrospective single-center evaluation of 28 patients with an indication for surgery due to pHPT and previous thyroid or parathyroid surgery was performed. Diagnostic workup, surgical approach, and outcome in terms of complications and successful removement of parathyroid adenoma with biochemical cure were evaluated.
Results
Neck ultrasound, sestamibi scintigraphy, C11-methionine PET-CT, and selective parathyroid hormone venous sampling, but not MRI imaging, effectively detected the presence of a parathyroid adenoma with high positive predictive values. Biochemical cure was revealed by normalization of calcium and parathormone levels 24-48h after surgery and was achieved in 26/28 patients (92.9%) with an overall low rate of complications. Concordant localization by at least two diagnostic modalities enabled focused surgery with success rates of 100%, whereas inconclusive localization significantly increased the rate of bilateral explorations and significantly reduced the rate of biochemical cure to 80%.
Conclusion
These findings suggest that two concordant diagnostic modalities are sufficient to accurately localize parathyroid adenoma before repeat surgery for pHPT. In cases of poor localization, extended diagnostic procedures are warranted to enhance surgical success rates. We suggest an algorithm for better orientation when repeat surgery is intended in patients with pHPT.
The measurement of transepithelial electrical resistance (TEER) is a common technique to determine the barrier integrity of epithelial cell monolayers. However, it is remarkable that absolute TEER values of similar cell types cultured under comparable conditions show an immense heterogeneity. Based on previous observations, we hypothesized that the heterogeneity of absolute TEER measurements can not only be explained by maturation of junctional proteins but rather by dynamics in the absolute length of cell junctions within monolayers. Therefore, we analyzed TEER in epithelial cell monolayers of Caco2 cells during their differentiation, with special emphasis on both changes in the junctional complex and overall cell morphology within monolayers. We found that in epithelial Caco2 monolayers TEER increased until confluency, then decreased for some time, which was then followed by an additional increase during junctional differentiation. In contrast, permeability of macromolecules measured at different time points as 4 kDA fluorescein isothiocyanate (FITC)-dextran flux across monolayers steadily decreased during this time. Detailed analysis suggested that this observation could be explained by alterations of junctional length along the cell borders within monolayers during differentiation. In conclusion, these observations confirmed that changes in cell numbers and consecutive increase of junctional length have a critical impact on TEER values, especially at stages of early confluency when junctions are immature.
Progressive deterioration of the central nervous system (CNS) is commonly associated with aging. An important component of the neurovasculature is the blood-brain barrier (BBB), majorly made up of endothelial cells joined together by intercellular junctions. The relationship between senescence and changes in the BBB has not yet been thoroughly explored. Moreover, the lack of in vitro models for the study of the mechanisms involved in those changes impede further and more in-depth investigations in the field. For this reason, we herein present an in vitro model of the senescent BBB and an initial attempt to identify senescence-associated alterations within.
The aim of this pilot study was to investigate the diagnostic potential of TMEM119 as a useful microglia-specific marker in combination with immunostainings for phagocytic function and infiltrating capacity of monocytes in cases of lethal monosubstance intoxications by morphine (MOR), methamphetamine (METH), and of ethanol-associated death (ETH) respectively. Human brain tissue samples were obtained from forensic autopsies of cases with single substance abuse (MOR, n = 8; ETH, n = 10; METH, n = 9) and then compared to a cohort of cardiovascular fatalities as controls (n = 9). Brain tissue samples of cortex, white matter, and hippocampus were collected and stained immunohistochemically with antibodies against TMEM119, CD68KiM1P, and CCR2. We could document the lowest density of TMEM119-positive cells in MOR deaths with highly significant differences to the control densities in all three regions investigated. In ETH and METH deaths, the expression of TMEM119 was comparable to cell densities in controls. The results indicate that the immunoreaction in brain tissue is different in these groups depending on the drug type used for abuse.
The aim of this study was to investigate if the biomarkers myelin basic protein (MBP) and neurofilament-H (NF-H) yielded informative value in forensic diagnostics when examining cadaveric cerebrospinal fluid (CSF) biochemically via an enzyme-linked immunosorbent assay (ELISA) and comparing the corresponding brain tissue in fatal traumatic brain injury (TBI) autopsy cases by immunocytochemistry versus immunohistochemistry. In 21 trauma and 19 control cases, CSF was collected semi-sterile after suboccipital puncture and brain specimens after preparation. The CSF MBP (p = 0.006) and NF-H (p = 0.0002) levels after TBI were significantly higher than those in cardiovascular controls. Immunohistochemical staining against MBP and against NF-H was performed on cortical and subcortical samples from also biochemically investigated cases (5 TBI cases/5 controls). Compared to the controls, the TBI cases showed a visually reduced staining reaction against MBP or repeatedly ruptured neurofilaments against NF-H. Immunocytochemical tests showed MBP-positive phagocytizing macrophages in CSF with a survival time of > 24 h. In addition, numerous TMEM119-positive microglia could be detected with different degrees of staining intensity in the CSF of trauma cases. As a result, we were able to document that elevated levels of MBP and NF-H in the CSF should be considered as useful neuroinjury biomarkers of traumatic brain injury.
Introduction
In total knee arthroplasty (TKA), the level of conformity, a medial stabilized (MS) implant, needs to restore native (i.e., healthy) knee kinematics without over-tensioning the flexion space when the surgeon chooses to retain the posterior cruciate ligament (PCL) is unknown. Whether an insert with a medial ball-in-socket conformity and lateral flat surface like the native knee or a less than spherical medial conformity restores higher and closer to native internal tibial rotation without anterior lift-off, an over-tension indicator, when implanted with calipered kinematic alignment (KA), is unknown.
Methods and Materials
Two surgeons treated 21 patients with calipered KA and a PCL retaining MS implant. Validated verification checks that restore native tibial compartment forces in passive flexion without release of healthy ligaments were used to select the optimal insert thickness. A goniometer etched onto trial inserts with the ball-in-socket and the less than spherical medial conformity measured the tibial rotation relative to the femoral component at extension and 90° and 120° flexion. The surgeon recorded the incidence of anterior lift-off of the insert.
Results
The insert with the medial ball-in-socket and lateral flat surface restored more internal tibial rotation than the one with less than spherical medial conformity, with mean values of 19° vs. 17° from extension to 90° flexion (p < 0.01), and 23° vs. 20°-120° flexion (p < 0.002), respectively. There was no anterior lift-off of the insert at 90° and 120° flexion.
Conclusion
An MS insert with a medial ball-in-socket and lateral flat surface that matches the native knee's spherical conformity restores native tibial internal rotation when implanted with calipered KA and PCL retention without over-tensioning the flexion space.
Introduction
Epidemiological injury surveillance in professional sports is often based on online media analysis in order to collect necessary data. However, the validation of this study protocol is lacking. Therefore, this study aimed to identify the validity of injury surveillance in men's professional team sports based on media reports.
Methods
In a retrospective cohort study, the validity of media-data-relating injuries was investigated in participating teams of the highest two German divisions in men's professional basketball (BB) and handball (HB) in the season 2018/2019. Injury protocols completed by the team physicians were compared to those of sports media injury reports.
Results
The study population was composed of 133 athletes (54 BB and 79 HB). Of 343 injuries reported by the team physicians, 151 (44%) could be identified by means of sports media reports. Severe injuries (n = 75, 72%) were reported more likely in sports media compared to less severe injuries (n = 76, 32%, p < 0.00001). Odds ratio (OR) was 5.33 (95% CI 3.22-8.82). No differences regarding injury reporting could be seen between the two team sports.
Conclusion
For severe injuries, media analysis may be a sufficient method for data collection in popular men's professional ball sports. An underestimation of true injury prevalence lies within the range of previous reported investigations concerning the validation of injury surveillance methods. Non-severe injuries could not be verified via media analysis in professional handball and basketball.
This expert opinion paper on cardiac imaging after acute ischemic stroke or transient ischemic attack (TIA) includes a statement of the "Heart and Brain" consortium of the German Cardiac Society and the German Stroke Society. The Stroke Unit-Commission of the German Stroke Society and the German Atrial Fibrillation NETwork (AFNET) endorsed this paper. Cardiac imaging is a key component of etiological work-up after stroke. Enhanced echocardiographic tools, constantly improving cardiac computer tomography (CT) as well as cardiac magnetic resonance imaging (MRI) offer comprehensive non- or less-invasive cardiac evaluation at the expense of increased costs and/or radiation exposure. Certain imaging findings usually lead to a change in medical secondary stroke prevention or may influence medical treatment. However, there is no proof from a randomized controlled trial (RCT) that the choice of the imaging method influences the prognosis of stroke patients. Summarizing present knowledge, the German Heart and Brain consortium proposes an interdisciplinary, staged standard diagnostic scheme for the detection of risk factors of cardio-embolic stroke. This expert opinion paper aims to give practical advice to physicians who are involved in stroke care. In line with the nature of an expert opinion paper, labeling of classes of recommendations is not provided, since many statements are based on expert opinion, reported case series, and clinical experience.
Laparoscopic appendectomy versus antibiotic treatment for acute appendicitis-a systematic review
(2021)
Background
Over the last years, laparoscopic appendectomy has progressively replaced open appendectomy and become the current gold standard treatment for suspected, uncomplicated appendicitis. At the same time, though, it is an ongoing discussion that antibiotic therapy can be an equivalent treatment for patients with uncomplicated appendicitis. The aim of this systematic review was to determine the safety and efficacy of antibiotic therapy and compare it to the laparoscopic appendectomy for acute, uncomplicated appendicitis.
Methods
The PubMed database, Embase database, and Cochrane library were scanned for studies comparing laparoscopic appendectomy with antibiotic treatment. Two independent reviewers performed the study selection and data extraction. The primary endpoint was defined as successful treatment of appendicitis. Secondary endpoints were pain intensity, duration of hospitalization, absence from work, and incidence of complications.
Results
No studies were found that exclusively compared laparoscopic appendectomy with antibiotic treatment for acute, uncomplicated appendicitis.
Conclusions
To date, there are no studies comparing antibiotic treatment to laparoscopic appendectomy for patients with acute uncomplicated appendicitis, thus emphasizing the lack of evidence and need for further investigation.
Digital platforms, understood as multi-sided matchmakers, have amassed huge power, reimagining the role of consumers, producers, and even ownership. They increasingly dictate the way the economy and urban life is organized. Yet, despite their influential and far-reaching role in shaping our economic as well as sociocultural world, our understanding of their embeddedness, namely how their activities are embedded in systems of social and societal relationships and how they conceptualize their main functions and actions in relation to their wider setting, remains rudimentary. Consequently, the purpose of this frontier paper is threefold. Firstly, it reveals the need to discuss and evaluate (dis-)embedding processes in platform urbanism in order to understand the underlying dynamics of platform power and urban transformation. Secondly, it aims to reveal the main reasons in regard to the difficulties in pinpointing digital platforms embeddedness. Thirdly, it seeks to propose future research unravelling the (dis-)embeddedness of the platform economy.
This paper argues for three main reasons namely unawareness, unaccountability and non-transparency of digital platforms that drive the lack of embeddedness and reaffirms platform power. This is mainly based on the configuration of new commodities, platforms’ strategic avoidance of labour protections and other regulatory frameworks as well as platforms’ secrecy in which they operate. This frontier paper argues that transferring the concept of embeddedness to the platform economy might serve as a valuable tool to understand and pinpoint essential dynamics and relationships at play, therefore proposing embeddedness as a basis for future research on the platform economy. It strongly argues that a more detailed understanding is urgently needed, in order to be able to understand, accompany and actively influence the development of the platform economy in regulatory terms.
Introduction/Background
Surfing, wind surfing and kite surfing enjoy a growing popularity with a large number of athletes worldwide. The aim of this study was to identify and compare the injury profiles and compare the injury profiles of these three extreme water sports.
Materials and Methods
These data for this retrospective cohort study were collected through an online standardised questionnaire during the 2017–18 season. The questionnaire included questions about anthropometry, skill level, injury diagnosis, injury mechanism, environmental conditions and training regimes.
Results
The 626 athletes included reported 2584 injuries. On average, each athlete sustained 4.12 injuries during the season. The most frequent injury location was in the lower extremity, in particular the foot, with 49 (16.4%) injuries in surfing, 344 (18.3%) in wind surfing and 79 (19.7%) in kite surfing. Surfing demonstrated a particularly high rate of head injuries (n = 37; 12.4%). Other frequent injury types were skin lesions (up to 42.1%) and contusions (up to 40.5%). The most common injury across all surfing sports was skin lesions of the foot (wind surfing: 11.7%; kite surfing: 13.2%; surfing: 12.7%). In surfing, skin lesions of the head were frequently observed (n = 24; 8.0%). In surfing, a ‘too large wave’ (n = 18; 24.7%) was main cause of the injury, while in wind surfing (n = 189; 34.5%) and kite surfing (n = 65; 36.7%) ‘own incompetence’ led to the most injuries.
Conclusion
This unique study compares injury epidemiology and mechanism in the three most popular surfing sports: wind surfing, kite surfing and surfing. Overall, injuries were sustained mainly in the lower extremity, while surfing also demonstrated a high rate of head injuries.
Genetic deficiency for acid sphingomyelinase or its pharmacological inhibition has been shown to increase Foxp3\(^+\) regulatory T-cell frequencies among CD4\(^+\) T cells in mice. We now investigated whether pharmacological targeting of the acid sphingomyelinase, which catalyzes the cleavage of sphingomyelin to ceramide and phosphorylcholine, also allows to manipulate relative CD4\(^+\) Foxp3\(^+\) regulatory T-cell frequencies in humans. Pharmacological acid sphingomyelinase inhibition with antidepressants like sertraline, but not those without an inhibitory effect on acid sphingomyelinase activity like citalopram, increased the frequency of Foxp3\(^+\) regulatory T cell among human CD4\(^+\) T cells in vitro. In an observational prospective clinical study with patients suffering from major depression, we observed that acid sphingomyelinase-inhibiting antidepressants induced a stronger relative increase in the frequency of CD4\(^+\) Foxp3\(^+\) regulatory T cells in peripheral blood than acid sphingomyelinase-non- or weakly inhibiting antidepressants. This was particularly true for CD45RA\(^-\) CD25\(^{high}\) effector CD4\(^+\) Foxp3\(^+\) regulatory T cells. Mechanistically, our data indicate that the positive effect of acid sphingomyelinase inhibition on CD4\(^+\) Foxp3\(^+\) regulatory T cells required CD28 co-stimulation, suggesting that enhanced CD28 co-stimulation was the driver of the observed increase in the frequency of Foxp3+ regulatory T cells among human CD4\(^+\) T cells. In summary, the widely induced pharmacological inhibition of acid sphingomyelinase activity in patients leads to an increase in Foxp3+ regulatory T-cell frequencies among CD4\(^+\) T cells in humans both in vivo and in vitro.
Mutations in the PRKACA gene are the most frequent cause of cortisol-producing adrenocortical adenomas leading to Cushing’s syndrome. PRKACA encodes for the catalytic subunit α of protein kinase A (PKA). We already showed that PRKACA mutations lead to impairment of regulatory (R) subunit binding. Furthermore, PRKACA mutations are associated with reduced RIIβ protein levels; however, the mechanisms leading to reduced RIIβ levels are presently unknown. Here, we investigate the effects of the most frequent PRKACA mutation, L206R, on regulatory subunit stability. We find that Ser\(^{114}\) phosphorylation of RIIβ is required for its degradation, mediated by caspase 16. Last, we show that the resulting reduction in RIIβ protein levels leads to increased cortisol secretion in adrenocortical cells. These findings reveal the molecular mechanisms and pathophysiological relevance of the R subunit degradation caused by PRKACA mutations, adding another dimension to the deregulation of PKA signaling caused by PRKACA mutations in adrenal Cushing’s syndrome.
Background
Even though the international combat against Neglected Tropical Diseases such as schistosomiasis or soil-transmitted helminthiases depends on reliable therapeutics, anthelminthic pharmacovigilance has been neglected on many national African drug markets. Therefore, quality and composition of Albendazole, Mebendazole and Praziquantel locally collected in Burkina Faso, Côte d’Ivoire, Ghana and Tanzania were analysed.
Methods
Samples of 88 different batches were obtained from randomly selected facilities. Sampling took place in Northwest Tanzania, Western Burkina Faso, Southeast Côte d’Ivoire and Southwest Ghana. Visual examination of both packaging and samples was performed according to the WHO ‘Be Aware’ tool. Products were then screened with the GPHF Minilab, consisting of tests of mass uniformity, disintegration times and thin-layer chromatography (TLC). Confirmatory tests were performed according to international pharmacopoeiae, applying assays for dissolution profiles and high-performance liquid chromatography (HPLC).
Findings
Despite minor irregularities, appearance of the products did not hint at falsified medicines. However, 19.6% of the brands collected in Ghana and Tanzania were not officially licensed for sale. Mass uniformity was confirmed in 53 out of 58 brands of tablets. 41 out of 56 products passed disintegration times; 10 out of the 15 failing products did not disintegrate at all. Evaluating TLC results, only 4 out of 83 batches narrowly missed specification limits, 18 batches slightly exceeded them. Not more than 46.3% (31 / 67) of the tablets assayed passed the respective pharmaceutical criteria for dissolution. HPLC findings confirmed TLC results despite shifted specification limits: 10 out of 83 tested batches contained less than 90%, none exceeded 110%.
Conclusion
In the four study countries, no falsified anthelminthic medicine was encountered. The active pharmaceutical ingredient was not found to either exceed or fall below specification limits. Galenic characteristics however, especially dissolution profiles, revealed great deficits.
Coupling N identical emitters to the same field mode is a well-established method to enhance light-matter interaction. However, the resulting √N boost of the coupling strength comes at the cost of a “linearized” (effectively semiclassical) dynamics. Here, we instead demonstrate a new approach for enhancing the coupling constant of a single quantum emitter, while retaining the nonlinear character of the light-matter interaction. We consider a single quantum emitter with N nearly degenerate transitions that are collectively coupled to the same field mode. We show that in such conditions an effective Jaynes-Cummings model emerges with a boosted coupling constant of order √N. The validity and consequences of our general conclusions are analytically demonstrated for the instructive case N=2. We further observe that our system can closely match the spectral line shapes and photon autocorrelation functions typical of Jaynes-Cummings physics, proving that quantum optical nonlinearities are retained. Our findings match up very well with recent broadband plasmonic nanoresonator strong-coupling experiments and will, therefore, facilitate the control and detection of single-photon nonlinearities at ambient conditions.
Perceptual changes that an agent produces by efferent activity can become part of the agent’s minimal self. Yet, in human agents, efferent activities produce perceptual changes in various sensory modalities and in various temporal and spatial proximities. Some of these changes occur at the “biological” body, and they are to some extent conveyed by “private” sensory signals, whereas other changes occur in the environment of that biological body and are conveyed by “public” sensory signals. We discuss commonalties and differences of these signals for generating selfhood. We argue that despite considerable functional overlap of these sensory signals in generating self-experience, there are reasons to tell them apart in theorizing and empirical research about development of the self.
Cone-beam computed tomography is a powerful tool for 3D imaging of the appendicular skeleton, facilitating detailed visualization of bone microarchitecture. This study evaluated various combinations of acquisition and reconstruction parameters for the cone-beam CT mode of a twin robotic x-ray system in cadaveric wrist and elbow scans, aiming to define the best possible trade-off between image quality and radiation dose. Images were acquired with different combinations of tube voltage and tube current–time product, resulting in five scan protocols with varying volume CT dose indices: full-dose (FD; 17.4 mGy), low-dose (LD; 4.5 mGy), ultra-low-dose (ULD; 1.15 mGy), modulated low-dose (mLD; 0.6 mGy) and modulated ultra-low-dose (mULD; 0.29 mGy). Each set of projection data was reconstructed with three convolution kernels (very sharp [Ur77], sharp [Br69], intermediate [Br62]). Five radiologists subjectively assessed the image quality of cortical bone, cancellous bone and soft tissue using seven-point scales. Irrespective of the reconstruction kernel, overall image quality of every FD, LD and ULD scan was deemed suitable for diagnostic use in contrast to mLD (very sharp/sharp/intermediate: 60/55/70%) and mULD (0/3/5%). Superior depiction of cortical and cancellous bone was achieved in FD\(_{Ur77}\) and LD\(_{Ur77}\) examinations (p < 0.001) with LD\(_{Ur77}\) scans also providing favorable bone visualization compared to FD\(_{Br69}\) and FD\(_{Br62}\) (p < 0.001). Fleiss’ kappa was 0.618 (0.594–0.641; p < 0.001), indicating substantial interrater reliability. In this study, we demonstrate that considerable dose reduction can be realized while maintaining diagnostic image quality in upper extremity joint scans with the cone-beam CT mode of a twin robotic x-ray system. Application of sharper convolution kernels for image reconstruction facilitates superior display of bone microarchitecture.
Background
Patients with coronavirus disease 2019 (COVID-19) who undergo surgery have impaired postoperative outcomes and increased mortality. Consequently, elective and semi-urgent operations on the increasing number of patients severely affected by COVID-19 have been indefinitely postponed.in many countries with unclear implications on disease progression and overall survival. The purpose of this study was to evaluate whether the establishment of a standardized screening program for acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is sufficient to ensure high-quality medical and surgical treatment of COVID-19 and non-COVID-19 patients while minimizing in-hospital SARS-CoV-2 transmission.
Methods
The screening program comprised polymerase chain reaction (PCR) testing of nasopharyngeal swabs and a standardized questionnaire about potential symptoms for SARS-CoV-2 infection. All elective and emergency patients admitted to the surgical department of a tertiary-care hospital center in Lower Franconia, Germany, between March and May 2020 were included and their characteristics were recorded.
Results
Out of the study population (n = 657), 509 patients (77.5%) had at least one risk factor for a potentially severe course of COVID-19 and 164 patients (25%) were active smokers. The average 7-day incidence in Lower Franconia was 24.0/100,000 during the observation period. Preoperative PCR testing revealed four asymptomatic positive patients out of the 657 tested patients. No postoperative SARS-CoV-2 infection or transmission could be detected.
Conclusion
The implementation of a standardized preoperative screening program to both COVID-19 and non-COVID-19 patients can ensure high-quality surgical care while minimizing infection risk for healthcare workers and potential in-hospital transmission.
Pilot study on the value of Raman spectroscopy in the entity assignment of salivary gland tumors
(2021)
Background
The entity assignment of salivary gland tumors (SGT) based on histomorphology can be challenging. Raman spectroscopy has been applied to analyze differences in the molecular composition of tissues. The aim of this study was to evaluate the suitability of RS for entity assignment in SGT.
Methods
Raman data were collected in deparaffinized sections of pleomorphic adenomas (PA) and adenoid cystic carcinomas (ACC). Multivariate data and chemometric analysis were completed using the Unscrambler software.
Results
The Raman spectra detected in ACC samples were mostly assigned to nucleic acids, lipids, and amides. In a principal component-based linear discriminant analysis (LDA) 18 of 20 tumor samples were classified correctly.
Conclusion
In this proof of concept study, we show that a reliable SGT diagnosis based on LDA algorithm appears possible, despite variations in the entity-specific mean spectra. However, a standardized workflow for tissue sample preparation, measurement setup, and chemometric algorithms is essential to get reliable results.
Background: Urinary tract infections (UTIs) are a common cause of prescribing antibiotics in family medicine. In Germany, about 40% of UTI-related prescriptions are second-line antibiotics, which contributes to emerging resistance rates. To achieve a change in the prescribing behaviour among family physicians (FPs), this trial aims to implement the guideline recommendations in German family medicine.
Methods/design: In a randomized controlled trial, a multimodal intervention will be developed and tested in family practices in four regions across Germany. The intervention will consist of three elements: information on guideline recommendations, information on regional resistance and feedback of prescribing behaviour for FPs on a quarterly basis. The effect of the intervention will be compared to usual practice. The primary endpoint is the absolute difference in the mean of prescribing rates of second-line antibiotics among the intervention and the control group after 12 months. To detect a 10% absolute difference in the prescribing rate after one year, with a significance level of 5% and a power of 86%, a sample size of 57 practices per group will be needed. Assuming a dropout rate of 10%, an overall number of 128 practices will be required. The accompanying process evaluation will provide information on feasibility and acceptance of the intervention.
Discussion: If proven effective and feasible, the components of the intervention can improve adherence to antibiotic prescribing guidelines and contribute to antimicrobial stewardship in ambulatory care.
Recent advances in the genetics of neurodevelopmental disorders (NDDs) have identified the transcription factor FOXP2 as one of numerous risk genes, e.g. in autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). FOXP2 function is suggested to be involved in GABAergic signalling and numerous studies demonstrate that GABAergic function is altered in NDDs, thus disrupting the excitation/inhibition balance. Interestingly, GABAergic signalling components, including glutamate-decarboxylase 1 (Gad1) and GABA receptors, are putative transcriptional targets of FOXP2. However, the specific role of FOXP2 in the pathomechanism of NDDs remains elusive. Here we test the hypothesis that Foxp2 affects behavioural dimensions via GABAergic signalling using zebrafish as model organism. We demonstrate that foxp2 is expressed by a subset of GABAergic neurons located in brain regions involved in motor functions, including the subpallium, posterior tuberculum, thalamus and medulla oblongata. Using CRISPR/Cas9 gene-editing we generated a novel foxp2 zebrafish loss-of-function mutant that exhibits increased locomotor activity. Further, genetic and/or pharmacological disruption of Gad1 or GABA-A receptors causes increased locomotor activity, resembling the phenotype of foxp2 mutants. Application of muscimol, a GABA-A receptor agonist, rescues the hyperactive phenotype induced by the foxp2 loss-of-function. By reverse translation of the therapeutic effect on hyperactive behaviour exerted by methylphenidate, we note that application of methylphenidate evokes different responses in wildtype compared to foxp2 or gad1b loss-of-function animals. Together, our findings support the hypothesis that foxp2 regulates locomotor activity via GABAergic signalling. This provides one targetable mechanism, which may contribute to behavioural phenotypes commonly observed in NDDs.
Understanding the genetic architecture of complex traits is a major objective in biology. The standard approach for doing so is genome-wide association studies (GWAS), which aim to identify genetic polymorphisms responsible for variation in traits of interest. In human genetics, consistency across studies is commonly used as an indicator of reliability. However, if traits are involved in adaptation to the local environment, we do not necessarily expect reproducibility. On the contrary, results may depend on where you sample, and sampling across a wide range of environments may decrease the power of GWAS because of increased genetic heterogeneity. In this study, we examine how sampling affects GWAS in the model plant species Arabidopsis thaliana. We show that traits like flowering time are indeed influenced by distinct genetic effects in local populations. Furthermore, using gene expression as a molecular phenotype, we show that some genes are globally affected by shared variants, whereas others are affected by variants specific to subpopulations. Remarkably, the former are essentially all cis-regulated, whereas the latter are predominately affected by trans-acting variants. Our result illustrate that conclusions about genetic architecture can be extremely sensitive to sampling and population structure.
Purpose
Patient-specific dosimetry is required to ensure the safety of molecular radiotherapy and to predict response. Dosimetry involves several steps, the first of which is the determination of the activity of the radiopharmaceutical taken up by an organ/lesion over time. As uncertainties propagate along each of the subsequent steps (integration of the time–activity curve, absorbed dose calculation), establishing a reliable activity quantification is essential. The MRTDosimetry project was a European initiative to bring together expertise in metrology and nuclear medicine research, with one main goal of standardizing quantitative \(^{177}\)Lu SPECT/CT imaging based on a calibration protocol developed and tested in a multicentre inter-comparison. This study presents the setup and results of this comparison exercise.
Methods
The inter-comparison included nine SPECT/CT systems. Each site performed a set of three measurements with the same setup (system, acquisition and reconstruction): (1) Determination of an image calibration for conversion from counts to activity concentration (large cylinder phantom), (2) determination of recovery coefficients for partial volume correction (IEC NEMA PET body phantom with sphere inserts), (3) validation of the established quantitative imaging setup using a 3D printed two-organ phantom (ICRP110-based kidney and spleen). In contrast to previous efforts, traceability of the activity measurement was required for each participant, and all participants were asked to calculate uncertainties for their SPECT-based activities.
Results
Similar combinations of imaging system and reconstruction lead to similar image calibration factors. The activity ratio results of the anthropomorphic phantom validation demonstrate significant harmonization of quantitative imaging performance between the sites with all sites falling within one standard deviation of the mean values for all inserts. Activity recovery was underestimated for total kidney, spleen, and kidney cortex, while it was overestimated for the medulla.
Conclusion
This international comparison exercise demonstrates that harmonization of quantitative SPECT/CT is feasible when following very specific instructions of a dedicated calibration protocol, as developed within the MRTDosimetry project. While quantitative imaging performance demonstrates significant harmonization, an over- and underestimation of the activity recovery highlights the limitations of any partial volume correction in the presence of spill-in and spill-out between two adjacent volumes of interests.
Background
Mobile 3-dimensional fluoroscopes are an integral part of modern neurosurgical operating theatres and can also be used in combination with free available image post processing to depict cerebral vessels. In preparation of stereotactic surgery, preoperative Computed Tomography (CT) may be required for image fusion. Contrast CT may be of further advantage for image fusion as it regards the vessel anatomy in trajectory planning. Time-consuming in-hospital transports are necessary for this purpose. Mobile 3D-fluoroscopes may be used to generate a CT equal preoperative data set without an in-hospital transport. This study was performed to determine the feasibility and image quality of intraoperative 3-dimensional fluoroscopy with intravenous contrast administration in combination with stereotactical procedures.
Methods
6 patients were included in this feasibility study. After fixation in a radiolucent Mayfield clamp a rotational fluoroscopy scan was performed with 50 mL iodine contrast agent. The image data sets were merged with the existing MRI images at a planning station and visually evaluated by two observer. The operation times were compared between the frame-based and frameless systems (“skin-to-skin” and “OR entry to exit”).
Results
The procedure proves to be safe. The entire procedure from fluoroscope positioning to the transfer to the planning station took 5–6 min with an image acquisition time of 24 s. In 5 of 6 cases, the fused imaging was able to reproduce the vascular anatomy accurately and in good quality. Both time end-points were significantly shorter compared to frame-based interventions.
Conclusion
The images could easily be transferred to the planning and navigation system and were successfully merged with the MRI data set. The procedure can be completely integrated into the surgical workflow. Preoperative CT imaging or transport under anaesthesia may even be replaced by this technique in the future. Furthermore, hemorrhages can be successfully visualized intraoperatively and might prevent time delays in emergencies.
The macromolecular SMN complex facilitates the formation of Sm-class ribonucleoproteins involved in mRNA processing (UsnRNPs). While biochemical studies have revealed key activities of the SMN complex, its structural investigation is lagging behind. Here we report on the identification and structural determination of the SMN complex from the lower eukaryote Schizosaccharomyces pombe, consisting of SMN, Gemin2, 6, 7, 8 and Sm proteins. The core of the SMN complex is formed by several copies of SMN tethered through its C-terminal alpha-helices arranged with alternating polarity. This creates a central platform onto which Gemin8 binds and recruits Gemins 6 and 7. The N-terminal parts of the SMN molecules extrude via flexible linkers from the core and enable binding of Gemin2 and Sm proteins. Our data identify the SMN complex as a multivalent hub where Sm proteins are collected in its periphery to allow their joining with UsnRNA.
Muscle cuff in distal pedicled adipofascial sural artery flaps: a retrospective case control study
(2021)
Background:
Amputation after open tibial fracture occurs in 3% of cases. The rate increases when flap reconstruction is required. The standard care involves microsurgical tissue transfer although the pedicled reverse sural artery adipofascial flap (PRSAF) is a local alternative in patients endangered by a prolonged operative time. Incorporation of a gastrocnemius muscle cuff in this flap can be used to fill dead space and increase healing potential. Literature shows superior survival rates for both PRSAF and inclusion of a muscle cuff in comparison with the cutaneous version. The aim of the study was to compare the outcome of the PRSAF and the musculoadipofascial version (PRSMAF). We hypothesize that the PRSMAF provides similar lap viability and flap-related complication rates as does the adipofascial version. The muscle component may reduce the long-term osteomyelitis rate.
Methods:
Patients were evaluated retrospectively after reconstruction with either PRSAF or PRSMAF. Preoperative osteomyelitis, flap survival, complications and osteomyelitis clearance were analyzed.
Results:
The study shows preliminary results supporting the potential use of the PRSMAF. We compare either 23 PRSMAF or 20 PRSAF flaps. We found no statistically significant differences in flap survival or in complication rate.
Conclusions:
Although the anatomical situation may sometimes dictate the use of a free flap, a technically less-complicated option may in some cases offer a viable alternative. This study shows that the PRSMAF can serve as an alternative for complex bone defects in the limb, though it does not provide statistical improvement to the PRSAF.
In Staphylococcus aureus, de novo methionine biosynthesis is regulated by a unique hierarchical pathway involving stringent-response controlled CodY repression in combination with a T-box riboswitch and RNA decay. The T-box riboswitch residing in the 5′ untranslated region (met leader RNA) of the S. aureus metICFE-mdh operon controls downstream gene transcription upon interaction with uncharged methionyl-tRNA. met leader and metICFE-mdh (m)RNAs undergo RNase-mediated degradation in a process whose molecular details are poorly understood. Here we determined the secondary structure of the met leader RNA and found the element to harbor, beyond other conserved T-box riboswitch structural features, a terminator helix which is target for RNase III endoribonucleolytic cleavage. As the terminator is a thermodynamically highly stable structure, it also forms posttranscriptionally in met leader/ metICFE-mdh read-through transcripts. Cleavage by RNase III releases the met leader from metICFE-mdh mRNA and initiates RNase J-mediated degradation of the mRNA from the 5′-end. Of note, metICFE-mdh mRNA stability varies over the length of the transcript with a longer lifespan towards the 3′-end. The obtained data suggest that coordinated RNA decay represents another checkpoint in a complex regulatory network that adjusts costly methionine biosynthesis to current metabolic requirements.
The dense variant surface glycoprotein (VSG) coat of African trypanosomes represents the primary host-pathogen interface. Antigenic variation prevents clearing of the pathogen by employing a large repertoire of antigenically distinct VSG genes, thus neutralizing the host’s antibody response. To explore the epitope space of VSGs, we generate anti-VSG nanobodies and combine high-resolution structural analysis of VSG-nanobody complexes with binding assays on living cells, revealing that these camelid antibodies bind deeply inside the coat. One nanobody causes rapid loss of cellular motility, possibly due to blockage of VSG mobility on the coat, whose rapid endocytosis and exocytosis are mechanistically linked to Trypanosoma brucei propulsion and whose density is required for survival. Electron microscopy studies demonstrate that this loss of motility is accompanied by rapid formation and shedding of nanovesicles and nanotubes, suggesting that increased protein crowding on the dense membrane can be a driving force for membrane fission in living cells.
Fluorogenic RNA aptamers are synthetic functional RNAs that specifically bind and activate conditional fluorophores. The Chili RNA aptamer mimics large Stokes shift fluorescent proteins and exhibits high affinity for 3,5-dimethoxy-4-hydroxybenzylidene imidazolone (DMHBI) derivatives to elicit green or red fluorescence emission. Here, we elucidate the structural and mechanistic basis of fluorescence activation by crystallography and time-resolved optical spectroscopy. Two co-crystal structures of the Chili RNA with positively charged DMHBO+ and DMHBI+ ligands revealed a G-quadruplex and a trans-sugar-sugar edge G:G base pair that immobilize the ligand by π-π stacking. A Watson-Crick G:C base pair in the fluorophore binding site establishes a short hydrogen bond between the N7 of guanine and the phenolic OH of the ligand. Ultrafast excited state proton transfer (ESPT) from the neutral chromophore to the RNA was found with a time constant of 130 fs and revealed the mode of action of the large Stokes shift fluorogenic RNA aptamer.