BACKGROUND

Recent technological advances in deep brain stimulation (DBS) (e.g., directional leads, multiple independent current sources) lead to increasing DBS-optimization burden. Techniques to streamline and facilitate programming could leverage these innovations.

OBJECTIVE

We evaluated clinical effectiveness of algorithm-guided DBS-programming based on wearable-sensor-feedback compared to standard-of-care DBS-settings in a prospective, randomized, crossover, double-blind study in two German DBS centers.

METHODS

For 23 Parkinson's disease patients with clinically effective DBS, new algorithm-guided DBS-settings were determined and compared to previously established standard-of-care DBS-settings using UPDRS-III and motion-sensor-assessment. Clinical and imaging data with lead-localizations were analyzed to evaluate characteristics of algorithm-derived programming compared to standard-of-care. Six different versions of the algorithm were evaluated during the study and 10 subjects programmed with uniform algorithm-version were analyzed as a subgroup.

RESULTS

Algorithm-guided and standard-of-care DBS-settings effectively reduced motor symptoms compared to off-stimulation-state. UPDRS-III scores were reduced significantly more with standard-of-care settings as compared to algorithm-guided programming with heterogenous algorithm versions in the entire cohort. A subgroup with the latest algorithm version showed no significant differences in UPDRS-III achieved by the two programming-methods. Comparing active contacts in standard-of-care and algorithm-guided DBS-settings, contacts in the latter had larger location variability and were farther away from a literature-based optimal stimulation target.

CONCLUSION

Algorithm-guided programming may be a reasonable approach to replace monopolar review, enable less trained health-professionals to achieve satisfactory DBS-programming results, or potentially reduce time needed for programming. Larger studies and further improvements of algorithm-guided programming are needed to confirm these results.

In a previous work, we explored zone broadening and the achievable plate numbers in linear drift tube ion mobility-mass spectrometry through developing a plate-height model [1]. On the basis of these findings, the present theoretical study extends the model by exploring peak-to-peak resolution and peak capacity in ion mobility separations. The first part provides a critical overview of chromatography-influenced resolution equations, including refinement of existing formulae. Furthermore, we present exact resolution equations for drift tube ion mobility spectrometry based on first principles. Upon implementing simple modifications, these exact formulae could be readily extended to traveling wave ion mobility separations and to cases when ion mobility spectrometry is coupled to mass spectrometry. The second part focuses on peak capacity. The well-known assumptions of constant plate number and constant peak width form the basis of existing approximate solutions. To overcome their limitations, an exact peak capacity equation is derived for drift tube ion mobility spectrometry. This exact solution is rooted in a suitable physical model of peak broadening, accounting for the finite injection pulse and subsequent diffusional spreading. By borrowing concepts from the theoretical toolbox of chromatography, we believe that the present study will help in integrating ion mobility spectrometry into the unified language of separation science.

The Covid-19 disease has caused a world-wide pandemic with more than 60 million positive cases and more than 1.4 million deaths by the end of November 2020. As long as effective medical treatment and vaccination are not available, non-pharmaceutical interventions such as social distancing, self-isolation and quarantine as well as far-reaching shutdowns of economic activity and public life are the only available strategies to prevent the virus from spreading. These interventions must meet conflicting requirements where some objectives, like the minimization of disease-related deaths or the impact on health systems, demand for stronger counter-measures, while others, such as social and economic costs, call for weaker counter-measures. Therefore, finding the optimal compromise of counter-measures requires the solution of a multi-objective optimization problem that is based on accurate prediction of future infection spreading for all combinations of counter-measures under consideration. We present a strategy for construction and solution of such a multi-objective optimization problem with real-world applicability. The strategy is based on a micro-model allowing for accurate prediction via a realistic combination of person-centric data-driven human mobility and behavior, stochastic infection models and disease progression models including micro-level inclusion of governmental intervention strategies. For this micro-model, a surrogate macro-model is constructed and validated that is much less computationally expensive and can therefore be used in the core of a numerical solver for the multi-objective optimization problem. The resulting set of optimal compromises between counter-measures (Pareto front) is discussed and its meaning for policy decisions is outlined.

Simple Summary: The aim of this analysis was to evaluate the health-related quality of life (HR-QoL) in patients with ovarian cancer using a questionnaire based on patient-reported outcomes (PROs). The HR-QoL for 155 enrolled patients with ovarian cancer was assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) prior to surgery and compared with 501 healthy females in Germany, as well as to the previously published European Organization for Research and Treatment of Cancer (EORTC) reference data for 917 patients with ovarian cancer worldwide. The HR-QoL for the emotional, cognitive, and social functioning scales was lower in patients with ovarian cancer than the healthy female population. Interestingly, the patients with ovarian cancer had no significant differences in the physical functioning scale when compared with the healthy women. Furthermore, the younger patients with ovarian cancer had an even lower HR-QoL for the emotional, social, and cognitive functioning scales, and additionally had more fatigue and financial difficulties.

Abstract: Introduction: The aim of this analysis was to evaluate the health-related quality of life (HR-QoL) in patients with ovarian cancer using a patient-reported outcome (PRO) based questionnaire and to compare it to the healthy female population in Germany and to other ovarian cancer patients worldwide. Additionally, we looked for differences in the HR-QoL with respect to the patients' ages in our cohort. Methods: The HR-QoL for 155 enrolled patients with ovarian cancer was assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) prior to surgery and then compared with 501 healthy females in Germany, as well as to the previously published European Organization for Research and Treatment of Cancer (EORTC) reference data for 917 patients with ovarian cancer worldwide. Moreover, we grouped our cohort by ages 65 years and analyzed them for further differences. To identify the differences, T-tests were applied. Results: Overall, 155 patients were enrolled, and 126 patients had advanced-stage ovarian cancer (FIGO III-IV) (82.4%). Fifty-five (36%) patients were >65 years. Except for the physical functioning scale, all other domains of the functioning scales were significantly lower in our patients with ovarian cancer than in the healthy female population. The emotional (50 points versus 60 points, p = 0.02), cognitive (76 points versus 88 points, p = 0.005), and social functioning scales (68 points versus 81 points, p = 0.006) were lower in the younger subgroup. Further, the younger subgroup exhibited significantly more fatigue (40 points versus 29 points, p = 0.03) and financial difficulties (20 points versus 2 points, p < 0.001) than the older subgroup. Discussion: Interestingly, the patients with ovarian cancer had no significant differences in the physical functioning scale when compared with the healthy women. In contrast, the patients, especially in the younger group, needed special support for the emotional and social areas of their daily lives.

Extravasation can present serious accidental complication of intravenous drug application. While monoclonal antibodies do not show the necrotic potential of cytotoxic chemotherapy drugs, considerable inflammatory toxicity can occur, necessitating standardized operating procedures for the management of their extravasation. Here, we report the clinical course and management of dinutuximab beta extravasation in a 3-year-old child. Dinutuximab beta is a chimeric monoclonal antibody targeting the GD2 disialoganglioside on the surface of neuroblastoma cells that has in recent years gained significant importance in the treatment of high-risk neuroblastoma, now contributing to both first- and second-line therapy protocols. The dinutuximab beta extravasation reported here occurred when the patient received the antibody cycle as a continuous infusion over a 10-day period after haploidentical stem cell transplantation for relapsed high-risk neuroblastoma. The extravasated dinutuximab beta caused local pain, swelling, and hyperemia accompanied by fever and an overall deterioration in the general condition. Laboratory diagnostics demonstrated an increase in C-reactive protein level and total white blood cell count. Clinical complication management consisted of intravenous fluid therapy, local dabbing with dimethyl sulfoxide (DMSO), analgesia with dipyrone, as well as application of intravenous antibiotics to prevent bacterial superinfection in the severely immunocompromised host. The patient considerably improved after six days with this treatment regimen and fully recovered by day 20.

Given its uniformly high expression on plasma cells, CD38 has been considered as a therapeutic target in patients with systemic lupus erythematosus (SLE). Herein, we investigate the distribution of CD38 expression by peripheral blood leukocyte lineages to evaluate the potential therapeutic effect of CD38-targeting antibodies on these immune cell subsets and to delineate the use of CD38 as a biomarker in SLE. We analyzed the expression of CD38 on peripheral blood leukocyte subsets by flow and mass cytometry in two different cohorts, comprising a total of 56 SLE patients. The CD38 expression levels were subsequently correlated across immune cell lineages and subsets, and with clinical and serologic disease parameters of SLE. Compared to healthy controls (HC), CD38 expression levels in SLE were significantly increased on circulating plasmacytoid dendritic cells, CD14(++)CD16(+) monocytes, CD56(+) CD16(dim) natural killer cells, marginal zone-like IgD(+)CD27(+) B cells, and on CD4(+) and CD8(+) memory T cells. Correlation analyses revealed coordinated CD38 expression between individual innate and memory T cell subsets in SLE but not HC. However, CD38 expression levels were heterogeneous across patients, and no correlation was found between CD38 expression on immune cell subsets and the disease activity index SLEDAI-2K or established serologic and immunological markers of disease activity. In conclusion, we identified widespread changes in CD38 expression on SLE immune cells that highly correlated over different leukocyte subsets within individual patients, but was heterogenous within the population of SLE patients, regardless of disease severity or clinical manifestations. As anti-CD38 treatment is being investigated in SLE, our results may have important implications for the personalized targeting of pathogenic leukocytes by anti-CD38 monoclonal antibodies.

A new all-Manganese flow battery (all-MFB) as a non-aqueous hybrid redox-flow battery is reported. The discharged active material [Cat]2[MnIICl4] (Cat = organic cation) utilized in both half-cells supports a long cycle life. The reversible oxidation of [MnIICl4]2− to [MnIIICl5]2− at the positive electrode and manganese metal deposition from [MnIICl4]2− at the negative electrode give a cell voltage of 2.59 V. Suitable electrolytes are prepared and optimized, followed by a characterization in static battery cells and in a pumped flow-cell. Several electrode materials, solvents, and membranes are tested for their feasibility in the all-MFB. An electrolyte consisting of [EMP]2[MnCl4] and some solvent γ-butyrolactone is cycled 500 times, both in a static as well as a flow-cell, over a period of two months, with coulombic efficiencies up to 83%. With the electrolytes prepared in this work, energy densities up to 74 Wh L−1 are possible, exceeding the VRFB benchmark system, using solely the cheap and abundant element manganese as the active material. Although further optimizations are necessary, this system represents a new and promising setup toward sustainable stationary energy storage.

Myocarditis is an inflammatory disease of the heart muscle with a wide range of potential etiological factors and consequently varying clinical patterns across the world. In this review, we address the epidemiology of myocarditis. Myocarditis was considered a rare disease until intensified research efforts in recent decades revealed its true epidemiological importance. While it remains a challenge to determine the true prevalence of myocarditis, studies are underway to obtain better approximations of the proportions of this disease. Nowadays, the prevalence of myocarditis has been reported from 10.2 to 105.6 per 100,000 worldwide, and its annual occurrence is estimated at about 1.8 million cases. This wide range of reported cases reflects the uncertainty surrounding the true prevalence and a potential underdiagnosis of this disease. Since myocarditis continues to be a significant public health issue, particularly in young adults in whom myocarditis is among the most common causes of sudden cardiac death, improved diagnostic and therapeutic procedures are necessary. This manuscript aims to summarize the current knowledge on the epidemiology of myocarditis, new diagnostic approaches and the current epidemiological impact of the COVID-19 pandemic.

The subjective visual vertical (SVV) evaluates the function of the utricle, which, in patients with Meniere's disease (MD), can be affected by endolymphatic hydrops. This study aimed to determine the SVV in MD patients during the chronic phase of illness compared to healthy participants. The second aim was to compare the SVV measurement tools: the analog bucket test, digital bucket test, and C-SVV© goggles. The SVV scores differed significantly between MD patients and the control group for the analog bucket test (p < 0.001) and the C-SVV® goggles (p = 0.028), but no significance was shown when using the digital bucket test (p = 0.062). When comparing the analog bucket test and the C-SVV® goggles applying the calculated threshold (1.125 degrees in analog bucket test, 2.5 degrees in C-SVV® goggles), the bucket test showed higher accuracy (bucket test 73.84%, C-SVV® goggles 69.23%). When examining the influence of betahistine on SVV scores, there were no statistically significant differences in both the analog bucket test and C-SVV© goggles. We conclude that SVV test can be used as an additional tool to evaluate utricle function during the chronic phase of MD and that the analog bucket test produces the most reliable results. The intake of betahistine does not influence the perception of SVV.

The indole alkaloid yohimbine is an alpha-2 receptor antagonist used for its sympathomimetic effects. Several cases of yohimbine intoxication have been reported and the most recent one involved four individuals taking a yohimbine-containing drug powder. All individuals developed severe intoxication symptoms and were admitted to the hospital. Even though all individuals were assumed to have taken the same dose of the drug powder, toxicology analyses revealed yohimbine blood concentrations of 249–5631 ng/mL, amounting to a 22-fold difference. The reason for this high variability remained to be elucidated. We used recently reported knowledge on the metabolism of yohimbine together with state-of-the art nonlinear mixed-effects modelling and simulation and show that a patient’s cytochrome P450 2D6 (CYP2D6) phenotype can explain the large differences observed in the measured concentration after intake of the same yohimbine dose. Our findings can be used both for the identification of safe doses in therapeutic use of yohimbine and for an explanation of individual cases of overdosing.

Salmonella enterica subspecies enterica serovar Derby (S. Derby) is one of the most frequent causes for salmonellosis in humans and animals. Understanding the genetic diversity of S. Derby, as well as the nature and origin of its resistance to antimicrobial treatment are thus the key to epidemiological control and surveillance. Here, we report an analysis of 15 S. Derby strains isolated from pig and cattle in slaughterhouses across Germany (2000–2015), which belonged to multilocus sequence types (ST) ST39, ST40 and ST682. Strains were compared to publicly available S. Derby sequence data of these three STs from Germany, comprising 65 isolates collected between 2004 and 2018 from different sources (i.e., pigs, humans, cattle, wild boar, and poultry). A total of 80 sequences (ST39 = 34, ST40 = 21, and ST682 = 25) were analyzed to assess genetic diversity, to identify virulence-associated and antimicrobial resistance genes (ARGs), and to characterize plasmid content. Strains belonging to all three STs were identified in each source examined. Strains with the same ST were closely related regardless of origin. Altogether, 72.5% of the isolates carried at least one resistance gene, furthermore ST40 carried most of the ARGs and the plasmid replicons. The IncI1 replicon was detected in eleven isolates, four of them carried IncI1 plasmid ST26 with clonal complex 2. The comparison of these four isolates with an IncI1 ST26 plasmid reported in 2010 from a German pig (JX566770), showed only variations in a region carrying different ARGs and mobile genetic elements. The strains of our collection had similar genetic diversity as the strains taken from the public database. Moreover, we found that strains harboring multidrug resistant IncI plasmid were found in different animal species, indicating that S. Derby may be implicated in the spread of antimicrobial resistance among animal species. Results may contribute to the knowledge about the diversity in S. Derby in Germany, which may be useful for the future surveillance and antimicrobial resistance of this serovar.

Incompatible measurements, i.e., measurements that cannot be simultaneously performed, are necessary to observe nonlocal correlations. It is natural to ask, e.g., how incompatible the measurements have to be to achieve a certain violation of a Bell inequality. In this paper, we provide the direct link between Bell nonlocality and the quantification of measurement incompatibility. This includes quantifiers for both incompatible and genuine-multipartite incompatible measurements. Our method straightforwardly generalizes to include constraints on the system's dimension (semi-device-independent approach) and on projective measurements, providing improved bounds on incompatibility quantifiers, and to include the prepare-and-measure scenario.

Metal-sulfur batteries (MSBs) are considered up-and-coming future-generation energy storage systems because of their prominent theoretical energy density. However, the practical applications of MSBs are still hampered by several critical challenges, i.e., the shuttle effects, sluggish redox kinetics, and low conductivity of sulfur species. Recently, benefiting from the high surface area, regulated networks, molecular/atomic-level reactive sites, the metal-organic frameworks (MOFs)-derived nanostructures have emerged as efficient and durable multifaceted electrodes in MSBs. Herein, a timely review is presented on recent advancements in designing MOF-derived electrodes, including fabricating strategies, composition management, topography control, and electrochemical performance assessment. Particularly, the inherent charge transfer, intrinsic polysulfide immobilization, and catalytic conversion on designing and engineering of MOF nanostructures for efficient MSBs are systematically discussed. In the end, the essence of how MOFs’ nanostructures influence their electrochemical properties in MSBs and conclude the future tendencies regarding the construction of MOF-derived electrodes in MSBs is exposed. It is believed that this progress review will provide significant experimental/theoretical guidance in designing and understanding the MOF-derived nanostructures as multifaceted electrodes, thus offering promising orientations for the future development of fast-kinetic and robust MSBs in broad energy fields.

Male frog advertisement calls are species-specific vocalizations used to attract females for breeding. However, it is possible for environmental or biological sounds to overlap these calls in both frequency and duration resulting in signal confusion, influencing female decision and/or location abilities. It is therefore important for vocal species competing for the same acoustic space to partition their calls either spatially or temporally (via call alternation or suppression). However, frog species previously isolated from each other may not have developed appropriate adaptive behaviors, resulting in acoustic competition. This study applied rhythm analysis to track changes in calling behavior, namely changes in calling frequency (as in beats per second), of the wallum sedgefrog and the eastern sedgefrog when vocalizing alone versus in the presence of each other to assess potential acoustic competition. Our main findings demonstrated that both species significantly altered their calling behavior when exposed to each other. While we expected the increased calling activity of one species to inhibit the activity of the other to avoid signal confusion, we instead found that both species greatly increased the beat frequency of their calls when calling in the presence of each other. We also found evidence of beat frequency development in the wallum sedgefrog whereby there was always a strong initial increase in call frequency in reaction to the first vocal interruption by the eastern sedgefrog. These results support the hypothesis that the eastern sedgefrog and the wallum sedgefrog are in competition for the acoustic space in habitats where they occur together. This highlights a new threat to the vulnerable wallum sedgefrog species and may serve to inform future management practices. Using rhythm analyses to track changes in acoustic behavior can help inform on important population dynamics such as health, trajectory, and response to management, and therefore be of great benefit to the conservation of vocal species.

In a green energy economy, electrocatalysis is essential for chemical energy conversion and to produce value added chemicals from regenerative resources. To be widely applicable, an electrocatalyst should comprise the Earth's crust's most abundant elements. The most abundant 3d metal, iron, with its multiple accessible redox states has been manifold applied in chemocatalytic processes. However, due to the low conductivity of FeIIIOxHy phases, its applicability for targeted electrocatalytic oxidation reactions such as water oxidation is still limited. Herein, it is shown that iron incorporated in conductive intermetallic iron silicide (FeSi) can be employed to meet this challenge. In contrast to silicon-poor iron–silicon alloys, intermetallic FeSi possesses an ordered structure with a peculiar bonding situation including covalent and ionic contributions together with conducting electrons. Using in situ X-ray absorption and Raman spectroscopy, it could be demonstrated that, under the applied corrosive alkaline conditions, the FeSi partly forms a unique, oxidic iron(III) phase consisting of edge and corner sharing [FeO6] octahedra together with oxidized silicon species. This phase is capable of driving the oxyge evolution reaction (OER) at high efficiency under ambient and industrially relevant conditions (500 mA cm−2 at 1.50 ± 0.025 VRHE and 65 °C) and to selectively oxygenate 5-hydroxymethylfurfural (HMF).

Background Understanding subnational variation in age-specific fertility rates (ASFRs) and total fertility rates (TFRs), and geographical clustering of high fertility and its determinants in low-income and middle-income countries, is increasingly needed for geographical targeting and prioritising of policy. We aimed to identify variation in fertility rates, to describe patterns of key selected fertility determinants in areas of high fertility.

Methods We did a subnational analysis of ASFRs and TFRs from the most recent publicly available and nationally representative cross-sectional Demographic and Health Surveys and Multiple Indicator Cluster Surveys collected between 2010 and 2016 for 70 low-income, lower-middle-income, and upper-middle-income countries, across 932 administrative units. We assessed the degree of global spatial autocorrelation by using Moran's I statistic and did a spatial cluster analysis using the Getis-Ord Gi* local statistic to examine the geographical clustering of fertility and key selected fertility determinants. Descriptive analysis was used to investigate the distribution of ASFRs and of selected determinants in each cluster.

Findings TFR varied from below replacement (2·1 children per women) in 36 of the 932 subnational regions (mainly located in India, Myanmar, Colombia, and Armenia), to rates of 8 and higher in 14 subnational regions, located in sub-Saharan Africa and Afghanistan. Areas with high-fertility clusters were mostly associated with areas of low prevalence of women with secondary or higher education, low use of contraception, and high unmet needs for family planning, although exceptions existed.

Interpretation Substantial within-country variation in the distribution of fertility rates highlights the need for tailored programmes and strategies in high-fertility cluster areas to increase the use of contraception and access to secondary education, and to reduce unmet need for family planning.

Objectives: selective caries excavation (SE) is recommended for deep carious lesions. Bulk fill composites (BF) may be considered to restore SE-cavities. We compared the susceptibility for secondary caries adjacent to BF versus incrementally filled composites (IF) in SE and non-selectively excavated teeth (NS) in vitro. Methods: in 72 extracted human premolars, artificial caries lesions were induced on pulpo-axial walls of standardized cavities. The lesions were left (SE) or removed (NS), and teeth were restored using two BF, GrandioSO x-tra/Voco (BF-Gra) and SDR/Dentsply (BF-SDR), and an IF, GrandioSO/Voco (IF-Gra) (n = 12/group for SE and NS). After thermo-mechanical cycling (5-55 °C, 8 days), teeth were submitted to a continuous-culture Lactobacillus rhamnosus biofilm model with cyclic loading for 10 days. Mineral loss (ΔZ) of enamel surface lesions (ESL), dentin surface lesions (DSL), and dentin wall lesions (DWL) was analyzed using transversal microradiography. Results: ΔZ was the highest in DSL, followed by ESL, and it was significantly lower in DWL. There were no significant differences in ΔZ between groups in DSL, ESL, and DWL (p > 0.05). Regardless of lesion location, ΔZ did not differ between SE and NS (p > 0.05). Conclusions: BF and IF both showed low risks for DWL (i.e., true secondary caries) after SE in vitro, and surface lesion risk was also not significantly different between materials. SE did not increase secondary caries risk as compared with NS. Clinical Significance: the risk of secondary caries was low after selective excavation in this study, regardless of whether bulk or incrementally filled composites were used

Background In German veterinary education interdisciplinary lectures (ILs) are an important and mandatory part of the curriculum as their merging character builds a useful preparation for the future profession as a veterinarian. These lectures should enable students to work on practically-relevant and interdisciplinary cases, which should ideally be defined jointly by lecturers from different disciplines.

Methods In order to give students the opportunity to work on these cases and at the same time have contact with their lecturers and fellow students, the Faculty of Veterinary Medicine, Freie Universität Berlin, has converted its former in-class ILs (face-to-face delivery format) into a blended learning format. The mandatory lectures comprise 196 curricular hours and are delivered over the course of three semesters within the veterinary curriculum. The new concept was developed over a period of three academic years and extensively evaluated (old-new-comparison) with regard to its acceptance and compliance with national requirements for interdisciplinary teaching.

Results A total of 306 students were asked to evaluate different aspects of the newly implemented format. Overall, more than 79% of the students attending the newly implemented blended learning format responded positively, and the evaluation showed a significant improvement of learning motivation and acceptance when compared to the traditional teaching format.

Conclusion The results indicated that blended learning is a suitable option for teaching mandatory ILs in clinical medicine and veterinary public health.