Ambient Approximation of Functions and Functionals on Embedded Submanifolds

While many problems of approximation theory are already well-understood in Euclidean space and its subdomains, much less is known about problems on submanifolds of that space. And this knowledge is even more limited when the approximation problem presents certain difficulties like sparsity of data samples or noise on function evaluations, both of which can be handled successfully in Euclidean space by minimisers of certain energies. On the other hand, such energies give rise to a considerable amount of techniques for handling various other approximation problems, in particular certain partial differential equations. The present thesis provides a deep going analysis of approximation results on submanifolds and approximate representation of intrinsic functionals: It provides a method to approximate a given function on a submanifold by suitable extension of this function into the ambient space followed by approximation of this extension on the ambient space and restriction of the approximant to the manifold, and it investigates further properties of this approximant. Moreover, a differential calculus for submanifolds via standard calculus on the ambient space is deduced from Riemannian geometry, and various energy functionals are presented and approximately handled by an approximate application of this calculus. This approximate handling of functionals is then employed in several penalty-based methods to solve problems such as interpolation in sparse data sites, smoothing and denoising of function values and approximate solution of certain partial differential equations

Area Deprivation and COVID-19 Incidence and Mortality in Bavaria, Germany: A Bayesian Geographical Analysis

Background: Area deprivation has been shown to be associated with various adverse health outcomes including communicable as well as non-communicable diseases. Our objective was to assess potential associations between area deprivation and COVID-19 standardized incidence and mortality ratios in Bavaria over a period of nearly 2 years. Bavaria is the federal state with the highest infection dynamics in Germany and demographically comparable to several other European countries. Methods: In this retrospective, observational ecological study, we estimated the strength of associations between area deprivation and standardized COVID-19 incidence and mortality ratios (SIR and SMR) in Bavaria, Germany. We used official SARS-CoV-2 reporting data aggregated in monthly periods between March 1, 2020 and December 31, 2021. Area deprivation was assessed using the quintiles of the 2015 version of the Bavarian Index of Multiple Deprivation (BIMD 2015) at district level, analyzing the overall index as well as its single domains. Results: Deprived districts showed higher SIR and SMR than less deprived districts. Aggregated over the whole period, the SIR increased by 1.04 (95% confidence interval (95% CI): 1.01 to 1.07, p = 0.002), and the SMR by 1.11 (95% CI: 1.07 to 1.16, p < 0.001) per BIMD quintile. This represents a maximum difference of 41% between districts in the most and least deprived quintiles in the SIR and 110% in the SMR. Looking at individual months revealed clear linear association between the BIMD quintiles and the SIR and SMR in the first, second and last quarter of 2021. In the summers of 2020 and 2021, infection activity was low. Conclusions: In more deprived areas in Bavaria, Germany, higher incidence and mortality ratios were observed during the COVID-19 pandemic with particularly strong associations during infection waves 3 and 4 in 2020/2021. Only high infection levels reveal the effect of risk factors and socioeconomic inequalities. There may be confounding between the highly deprived areas and border regions in the north and east of Bavaria, making the relationship between area deprivation and infection burden more complex. Vaccination appeared to balance incidence and mortality rates between the most and least deprived districts. Vaccination makes an important contribution to health equality

Exercise training reverses myocardial dysfunction induced by CaMKIIδC overexpression by restoring Ca2+-homeostasis

Several conditions of heart disease, including heart failure and diabetic cardiomyopathy, are associated with upregulation of cytosolic Ca2+/calmodulin-dependent protein kinase II (CaMKIIδC) activity. In the heart, CaMKIIδC isoform targets several proteins involved in intracellular Ca2+ homeostasis. We hypothesized that high-intensity endurance training activates mechanisms that enable a rescue of dysfunctional cardiomyocyte Ca2+ handling and thereby ameliorate cardiac dysfunction despite continuous and chronic elevated levels of CaMKIIδC. CaMKIIδC transgenic (TG) and wild-type (WT) mice performed aerobic interval exercise training over 6 wk. Cardiac function was measured by echocardiography in vivo, and cardiomyocyte shortening and intracellular Ca2+ handling were measured in vitro. TG mice had reduced global cardiac function, cardiomyocyte shortening (47% reduced compared with WT, P < 0.01), and impaired Ca2+ homeostasis. Despite no change in the chronic elevated levels of CaMKIIδC, exercise improved global cardiac function, restored cardiomyocyte shortening, and reestablished Ca2+ homeostasis to values not different from WT. The key features to explain restored Ca2+ homeostasis after exercise training were increased L-type Ca2+ current density and flux by 79 and 85%, respectively (P < 0.01), increased sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a) function by 50% (P < 0.01), and reduced diastolic SR Ca2+ leak by 73% (P < 0.01), compared with sedentary TG mice. In conclusion, exercise training improves global cardiac function as well as cardiomyocyte function in the presence of a maintained high CaMKII activity. The main mechanisms of exercise-induced improvements in TG CaMKIIδC mice are mediated via increased L-type Ca2+ channel currents and improved SR Ca2+ handling by restoration of SERCA2a function in addition to reduced diastolic SR Ca2+ leak

The low acute effectiveness of a high-power short duration radiofrequency current application technique in pulmonary vein isolation for atrial fibrillation

Background: Application of high power radiofrequency (RF) energy for a short duration (HPSD) to isolate pulmonary vein (PV) is an emerging technique. But power and duration settings are very different across different centers. Moreover, despite encouraging preclinical and clinical data, studies measuring acute effectiveness of various HPSD settings are limited.Methods: Twenty-five consecutive patients with symptomatic atrial fibrillation (AF) were treated with pulmonary vein isolation (PVI) using HPSD. PVI was performed with a contact force catheter (Thermocool SF Smart-Touch) and Carto 3 System. The following parameters were used: energy output 50 W, target temperature 43°C, irrigation 15 mL/min, targeted contact force of > 10 g. RF energy was applied for 6–10 s. Required minimal interlesion distance was 4 mm. Twenty minutes after each successful PVI adenosine provocation test (APT) was performed by administrating 18 mg adenosine to unmask dormant PV conduction.Results: All PVs (100 PVs) were successfully isolated. RF lesions needed per patient were 131 ± 41, the average duration for each RF application was 8.1 ± 1.7 s. Procedure time was 138 ± 21 min and average of total RF energy duration was 16.3 ± 5.2 min and average amount of RF energy was 48209 ± 12808 W. APT application time after PVI was 31.1 ± 8.3 min for the left sided PVs and 22.2 ± 4.6 min (p = 0.005) for the right sided PVs. APT was transiently positive in 18 PVs (18%) in 8 (32%) patients.Conclusions: Pulmonary vein isolation with high power for 6–10 s is feasible and shortens the procedure and ablation duration. However, acute effectiveness of the HPSD seems to be lower than expected. Further studies combining other ablation parameters are needed to improve this promising technique

C-terminal phosphorylation of NaV1.5 impairs FGF13-dependent regulation of channel inactivation

International audienceVoltage-gated Na(+) (NaV) channels are key regulators of myocardial excitability, and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)-dependent alterations in NaV1.5 channel inactivation are emerging as a critical determinant of arrhythmias in heart failure. However, the global native phosphorylation pattern of NaV1.5 subunits associated with these arrhythmogenic disorders and the associated channel regulatory defects remain unknown. Here, we undertook phosphoproteomic analyses to identify and quantify in situ the phosphorylation sites in the NaV1.5 proteins purified from adult WT and failing CaMKIIδc-overexpressing (CaMKIIδc-Tg) mouse ventricles. Of 19 native NaV1.5 phosphorylation sites identified, two C-terminal phosphoserines at positions 1938 and 1989 showed increased phosphorylation in the CaMKIIδc-Tg compared with the WT ventricles. We then tested the hypothesis that phosphorylation at these two sites impairs fibroblast growth factor 13 (FGF13)-dependent regulation of NaV1.5 channel inactivation. Whole-cell voltage-clamp analyses in HEK293 cells demonstrated that FGF13 increases NaV1.5 channel availability and decreases late Na(+) current, two effects that were abrogated with NaV1.5 mutants mimicking phosphorylation at both sites. Additional co-immunoprecipitation experiments revealed that FGF13 potentiates the binding of calmodulin to NaV1.5 and that phosphomimetic mutations at both sites decrease the interaction of FGF13 and, consequently, of calmodulin with NaV1.5. Together, we have identified two novel native phosphorylation sites in the C terminus of NaV1.5 that impair FGF13-dependent regulation of channel inactivation and may contribute to CaMKIIδc-dependent arrhythmogenic disorders in failing hearts

The effect of retirement on biomedical and behavioral risk factors for cardiovascular and metabolic disease

Retirement is a major life event potentially associated with changes in relevant risk factors for cardiovascular and metabolic conditions. This study analyzes the effect of retirement on behavioral and biomedical risk factors for chronic disease, together with subjective health parameters using Southern German epidemiological data. We used panel data from the KORA cohort study, consisting of 11,168 observations for individuals 45–80 years old. Outcomes included health behavior (alcohol, smoking, physical activity), biomedical risk factors (BMI, waist-to-hip ratio (WHR), glycosylated hemoglobin (HbA1c), total cholesterol/HDL quotient, systolic/diastolic blood pressure), and subjective health (SF12 mental and physical, self-rated health). We applied a parametric regression discontinuity design based on age thresholds for pension eligibility. Robust results after p-value corrections for multiple testing showed an increase in BMI in early retirees (at the age of 60) [β = 1.11, corrected p-val. < 0.05] and an increase in CHO/HDL in regular retirees (age 65) [β = 0.47, corrected p-val. < 0.05]. Stratified analyses indicate that the increase in BMI might be driven by women and low-educated individuals retiring early, despite increases in the level of physical activity. The increase in CHO/HDL might be driven by men retiring regularly, alongside an increase in subjective physical health. Blood pressure also increased, but the effect differs by retirement timing and sex and is not always robust to sensitivity analysis checks. Our study indicates that retirement has an impact on different risk factors for chronic disease, depending on timing, gender and education. Regular male, early female, and low-educated retirees should be further investigated as potential high-risk groups for worsening risk factors after retirement. Future research should investigate if and how these results are linked: in fact, especially in the last two groups, the increases in leisure time physical activity might not be enough to compensate for the loss of work related physical activity, leading thus to an increase in BMI

Gathering Knowledge from Social Knowledge Management Environments: Validation of an Anticipatory Standard

Knowledge management is more and more happening in social environments, supported by social software. This directly changes the way knowledge workers interact and the way information and communication technology is used. Recent studies, striving to provide a more appropriate support for knowledge work, face challenges when eliciting knowledge from user activities and maintaining its situatedness in context. Corresponding solutions in such social environments are not interoperable due to a lack of appropriate standards. To bridge this gap, we propose and validate a first specification of an anticipatory standard in this field. We illustrate its application and utility analyzing three scenarios. As main result we analyze the lessons learned and provide insights into further research and development of our approach. By that we reach out to stimulate discussion and raise support for this initiative towards establishing standards in the domain of knowledge management

Social Knowledge Environments

Knowledge management represents a key issue for both information systems’ academics and practitioners, including those who have become disillusioned by actual results that fail to deliver on exaggerated promises and idealistic visions. Social software, a tremendous global success story, has prompted similarly high expectations regarding the ways in which organizations can improve their knowledge handling. But can these expectations be met, whether in academic research or the real world? This article seeks to identify current research trends and gaps, with a focus on social knowledge environments. The proposed research agenda features four focal challenges: semi-permeable organizations, social software in professional work settings, crowd knowledge, and crossborder knowledge management. Three solutions emerge as likely methods to address these challenges: designoriented solutions, analytical solutions, and interdisciplinary dialogue