Understanding the Impact of Active-to-Passive Area Ratio on Deformation in One-Dimensional Dielectric Elastomer Actuators with Uniaxial Strain State.

There is increasing interest in the use of novel elastomers with inherent or modified advanced dielectric and mechanical properties, as components of dielectric elastomer actuators (DEA). This requires corresponding techniques to assess their electro-mechanical performance. A common way to test dielectric materials is the fabrication of actuators with pre-stretch fixed by a stiff frame. This results in the problem that the electrode size has an influence on the achievable actuator displacement and strain, which is detrimental to the comparability of experiments. This paper presents an in-depth study of the active-to-passive ratio with the aim of investigating the influence of the coverage ratio on uniaxial actuator displacement and strain. To model the effect, a simple lumped-parameter model is proposed. The model shows that the coverage ratio for maximal displacement is 50%. To validate the model results, experiments are carried out. For this, a rectangular, fiber-reinforced DEA is used to assess the relation of the coverage ratio and deformation. Due to the stiffness of the fibers, highly anisotropic mechanical properties are achieved, leading to the uniaxial strain behavior of the actuator, which allows the validation of the one-dimensional model. To consider the influence of the simplifications in the lumped-parameter model, the results are compared to a hyperelastic model. In summary, it is shown that the ratio of the active-to-passive area has a significant influence on the actuator deformation. Both the model and experiments confirm that an active-to-passive ratio of 50% is particularly advantageous in most cases.

Systemic Evidence for Mitochondrial Dysfunction in Age-Related Macular Degeneration as Revealed by mtDNA Copy Number Measurements in Peripheral Blood.

Mitochondrial dysfunction is a common occurrence in the aging process and is observed in diseases such as age-related macular degeneration (AMD). Increased levels of reactive oxygen species lead to damaged mitochondrial DNA (mtDNA), resulting in dysfunctional mitochondria, and, consequently, mtDNA causes further harm in the retinal tissue. However, it is unclear whether the effects are locally restricted to the high-energy-demanding retinal pigment epithelium or are also systematically present. Therefore, we measured mtDNA copy number (mtDNA-CN) in peripheral blood using a qPCR approach with plasmid normalization in elderly participants with and without AMD from the AugUR study (n = 2262). We found significantly lower mtDNA-CN in the blood of participants with early (n = 453) and late (n = 170) AMD compared to AMD-free participants (n = 1630). In regression analyses, we found lower mtDNA-CN to be associated with late AMD when compared with AMD-free participants. Each reduction of mtDNA-CN by one standard deviation increased the risk for late AMD by 24%. This association was most pronounced in geographic atrophy (OR = 1.76, 95% CI 1.19-2.60, p = 0.004), which has limited treatment options. These findings provide new insights into the relationship between mtDNA-CN in blood and AMD, suggesting that it may serve as a more accessible biomarker than mtDNA-CN in the retina.

Genetic Risk Score Analysis Supports a Joint View of Two Classification Systems for Age-Related Macular Degeneration.

Purpose: The purpose of this study was to evaluate the utility of combining the Clinical Classification (CC) and the Three Continent age-related macular degeneration (AMD) Consortium Severity Scale (3CACSS) for classification of AMD. Methods: In two independent cross-sectional datasets of our population-based AugUR study (Altersbezogene Untersuchungen zur Gesundheit der Universität Regensburg), we graded AMD via color fundus images applying two established classification systems (CC and 3CACSS). We calculated the genetic risk score (GRS) across 50 previously identified variants for late AMD, its association via logistic regression, and area under the curve (AUC) for each AMD stage. Results: We analyzed 2188 persons aged 70 to 95 years. When comparing the two classification systems, we found a distinct pattern: CC "age-related changes" and CC "early AMD" distinguished individuals with 3CACSS "no AMD"; 3CACSS "mild/moderate/severe early AMD" stages, and distinguished CC "intermediate AMD". This suggested a 7-step scale combining the 2 systems: (i) "no AMD", (ii) "age-related changes", (iii) "very early AMD", (i.e. CC "early"), (iv) "mild early AMD", (v) "moderate early AMD", (vi) "severe early AMD", and (vii) "late AMD". GRS association and diagnostic accuracy increased stepwise by increased AMD severity in the 7-step scale and by increased restriction of controls (e.g. for CC "no AMD without age-related changes": AUC = 55.1%, 95% confidence interval [CI] = 51.6, 58.6, AUC = 62.3%, 95% CI = 59.1, 65.6, AUC = 63.8%, 95% CI = 59.3, 68.3, AUC = 78.1%, 95% CI = 73.6, 82.5, AUC = 82.2%, 95% CI = 78.4, 86.0, and AUC = 79.2%, 95% CI = 75.4, 83.0). A stepwise increase was also observed by increased drusen size and area. Conclusions: The utility of a 7-step scale is supported by our clinical and GRS data. This harmonization and full data integration provides an immediate simplification over using either CC or 3CACSS and helps to sharpen the control group.

A multilocus genetic risk score for obesity: Association with BMI and metabolic alterations in a cohort with severe obesity.

Genome wide association studies have identified numerous single nucleotide polymorphisms (SNPs) associated with obesity, yet effect sizes of individual SNPs are small. Therefore, the aim of our study was to investigate whether a genetic risk score (GRS) comprising risk alleles of SNPs identified in the GIANT consortium meta-analyses shows association with body mass index (BMI) and other BMI related metabolic alterations in a cohort with an extreme phenotype. Genotyping of 93 SNPs was performed in 314 obese individuals (mean BMI 40.5 ± 7.8 kg/m², aged 45 ± 12 years), participating in a standardized weight reduction program, and in 74 lean controls (mean BMI 24.6 ± 3.3 kg/m², aged 41.7 ± 13.4 years). Allele numbers of all 93 SNPs were added to a GRS. Anthropometric parameters, parameters of glucose/insulin and lipid metabolism were assessed standardized after a 12 hours fast. GRS was significantly different between controls and obese individuals (unweighted GRS: 86.6 vs 89.0, P = .002; weighted GRS: 84.9 vs 88.3, P = .005). Furthermore, linear regression analysis showed significant associations of GRS with BMI ( P < .0001), weight ( P = .0005), waist circumference ( P = .0039), fat mass ( P < .0001) and epicardial fat thickness ( P = .0032), yet with small effect sizes ( r ² < 0.06). In conclusion, in our study GRS could differentiate between extreme obese and lean individuals, and was associated with BMI and its related traits, yet with small effect sizes.

Polygenic scores for estimated glomerular filtration rate in a population of general adults and elderly - comparative results from the KORA and AugUR study.

BACKGROUND: Polygenic scores (PGSs) combining genetic variants found to be associated with creatinine-based estimated glomerular filtration rate (eGFRcrea) have been applied in various study populations with different age ranges. This has shown that PGS explain less eGFRcrea variance in the elderly. Our aim was to understand how differences in eGFR variance and the percentage explained by PGS varies between population of general adults and elderly. RESULTS: We derived a PGS for cystatin-based eGFR (eGFRcys) from published genome-wide association studies. We used the 634 variants known for eGFRcrea and the 204 variants identified for eGFRcys to calculate the PGS in two comparable studies capturing a general adult and an elderly population, KORA S4 (n = 2,900; age 24-69 years) and AugUR (n = 2,272, age ≥ 70 years). To identify potential factors determining age-dependent differences on the PGS-explained variance, we evaluated the PGS variance, the eGFR variance, and the beta estimates of PGS association on eGFR. Specifically, we compared frequencies of eGFR-lowering alleles between general adult and elderly individuals and analyzed the influence of comorbidities and medication intake. The PGS for eGFRcrea explained almost twice as much (R2 = 9.6%) of age-/sex adjusted eGFR variance in the general adults compared to the elderly (4.6%). This difference was less pronounced for the PGS for eGFRcys (4.7% or 3.6%, respectively). The beta-estimate of the PGS on eGFRcrea was higher in the general adults compared to the elderly, but similar for the PGS on eGFRcys. The eGFR variance in the elderly was reduced by accounting for comorbidities and medication intake, but this did not explain the difference in R2-values. Allele frequencies between general adult and elderly individuals showed no significant differences except for one variant near APOE (rs429358). We found no enrichment of eGFR-protective alleles in the elderly compared to general adults. CONCLUSIONS: We concluded that the difference in explained variance by PGS was due to the higher age- and sex-adjusted eGFR variance in the elderly and, for eGFRcrea, also by a lower PGS association beta-estimate. Our results provide little evidence for survival or selection bias.

Cardiovascular Risk Factor Control in 70- to 95-Year-Old Individuals: Cross-Sectional Results from the Population-Based AugUR Study.

Cardiovascular risk factors such as high glucose, LDL-cholesterol, blood pressure, and impaired kidney function are particularly frequent in old-aged individuals. However, population-based data on the extent of cardiovascular risk factor control in the old-aged population is limited. AugUR is a cohort of the mobile "70+"-year-old population of/near Regensburg, recruited via population registries. We conducted cross-sectional analyses assessing the proportion of AugUR participants with LDL-cholesterol, HbA1c, or blood pressure beyond recommended levels and their association with impaired creatinine- and cystatin-based estimated glomerular filtration rate (eGFR, <60 mL/min/1.73 m2) or urine albumin-creatinine ratio (UACR, ≥30 mg/g). Among 2215 AugUR participants, 74.7% were taking lipid-, glucose-, blood-pressure-lowering, or diuretic medication. High LDL-cholesterol at ≥116 mg/dL was observed for 76.1% (51.1% among those with prior cardiovascular events). We found HbA1c ≥ 7.0% for 6.3%, and high or low systolic blood pressure for 6.8% or 26.5%, respectively (≥160, <120 mmHg). Logistic regression revealed (i) high HbA1c levels associated with increased risk for impaired kidney function among those untreated, (ii) high blood pressure with increased UACR, and (iii) low blood pressure with impaired eGFR, which was confined to individuals taking diuretics. Our results provide important insights into cardiovascular risk factor control in individuals aged 70-95 years, which are understudied in most population-based studies.

Single-Center Experience in Detecting Influenza Virus, RSV and SARS-CoV-2 at the Emergency Department.

Reverse transcription polymerase chain reaction (RT-PCR) on respiratory tract swabs has become the gold standard for sensitive and specific detection of influenza virus, respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this retrospective analysis, we report on the successive implementation and routine use of multiplex RT-PCR testing for patients admitted to the Internal Medicine Emergency Department (ED) at a tertiary care center in Western Austria, one of the hotspots in the early coronavirus disease 2019 (COVID-19) pandemic in Europe. Our description focuses on the use of the Cepheid® Xpert® Xpress closed RT-PCR system in point-of-care testing (POCT). Our indications for RT-PCR testing changed during the observation period: From the cold season 2016/2017 until the cold season 2019/2020, we used RT-PCR to diagnose influenza or RSV infection in patients with fever and/or respiratory symptoms. Starting in March 2020, we used the RT-PCR for SARS-CoV-2 and a multiplex version for the combined detection of all these three respiratory viruses to also screen subjects who did not present with symptoms of infection but needed in-hospital medical treatment for other reasons. Expectedly, the switch to a more liberal RT-PCR test strategy resulted in a substantial increase in the number of tests. Nevertheless, we observed an immediate decline in influenza virus and RSV detections in early 2020 that coincided with public SARS-CoV-2 containment measures. In contrast, the extensive use of the combined RT-PCR test enabled us to monitor the re-emergence of influenza and RSV detections, including asymptomatic cases, at the end of 2022 when COVID-19 containment measures were no longer in place. Our analysis of PCR results for respiratory viruses from a real-life setting at an ED provides valuable information on the epidemiology of those infections over several years, their contribution to morbidity and need for hospital admission, the risk for nosocomial introduction of such infection into hospitals from asymptomatic carriers, and guidance as to how general precautions and prophylactic strategies affect the dynamics of those infections.

Photostress Recovery Time as a Potential Predictive Biomarker for Age-Related Macular Degeneration.

Purpose: The purpose of this study was to assess recovery time following photostress and its association with age-related macular degeneration (AMD) cross-sectionally and longitudinally in an elderly population-based cohort. Methods: We analyzed photostress recovery time (PRT) and AMD in >1800 AugUR study participants aged 70+ years. On color fundus images from baseline and 3-year follow-up, presence of AMD was graded manually (Three Continent AMD Consortium Severity Scale). Visual acuity (VA) was assessed via Early Treatment Diabetic Retinopathy Study (ETDRS) charts. After a 30-second bleaching of the macular region via direct ophthalmoscope, PRT was measured as the seconds to regain VA. Results: First, we analyzed 1208 AugUR participants cross-sectionally (288 with early AMD, and 78 with late AMD). Prolonged PRT was associated with early and late AMD versus no AMD (median PRT = 119.5, 198.0 versus 80.0 seconds, respectively; logistic regression odds ratio [OR] = 1.109-1.165 per 10 seconds, P values < 0.0001). Sensitivity analyses using alternative models or restricting to participants after cataract surgery revealed similar ORs. Second, the association was confirmed in an independent cross-sectional AugUR sample (n = 486). Third, in longitudinal analysis of 233 AugUR participants without AMD, prolonged PRT was associated with incident AMD ascertained 3 years later (follow-up time = 3.2 ± 0.2 years, OR = 1.112-1.162 per 10 seconds, P < 0.05). Overall, we demonstrate a significant association of prolonged PRT with AMD cross-sectionally and longitudinally in elderly individuals. Conclusions: Prolonged PRT might capture retinal function impairment after cell damage before early AMD is visible via color fundus imaging. Translational Relevance: Our results suggest PRT as quantitative predictive biomarker for incident AMD, making it potentially worthwhile also for clinical care.

DNA extraction from clotted blood in genotyping quality.

DNA extraction from frozen blood clots is challenging. Here, the authors applied QIAGEN Clotspin Baskets and the Gentra Puregene Blood Kit for DNA extraction to cellular fraction of 5.5 ml whole blood without anticoagulating additives. The amount and quality of extracted DNA were assessed via spectrophotometer and gel electrophoresis. Results from array-based genotyping were analyzed. All steps were compared with DNA isolated from anticoagulated blood samples from a separate study. The quality and concentration of DNA extracted from clotted blood were comparable to those of DNA extracted from anticoagulated blood. DNA yield was on average 27 µg per ml clotted blood, with an average purity of 1.87 (A260/A280). Genotyping quality was similar for both DNA sources (call rate: 99.56% from clotted vs 99.49% from anticoagulated blood).

Deformation-Induced Martensitic Transformation in Laser Cladded 304 Stainless Steel Coatings.

There are only a few cost-effective solutions for coating applications in combined mechanical loading and corrosive environments. Stainless steel AISI 304 has the potential to fill this niche, showing excellent corrosion resistance while utilizing the deformation-induced phase transformation from γ-austenite to α'-martensite, which results in an increase in strength. However, it is not known whether this can occur in laser cladded material. Therefore, laser cladded AISI 304 coatings in as-cladded condition and after heat treatment at 1100 °C for 60 min were investigated before and after bending deformation, by means of light microscopy, energy-dispersive X-ray spectroscopy and electron backscatter diffraction. It was shown that due to the dendritic microstructure accompanied by an inhomogeneous distribution of the main alloying elements (Cr and Ni), no deformation-induced phase transformation occurred in the as-cladded coating. The applied approach with subsequent solution heat treatment at 1100 °C for 60 min resulted in a homogeneous γ-austenite microstructure, so that a deformation-induced martensitic transformation (DIMT) could occur in the coatings. However, the volume fraction of martensite that had been formed locally at individual shear bands was rather low, which can be possibly attributed to the high Ni content of the feedstock, stabilizing the γ-austenite microstructure. This study shows the possibility of exploiting the DIMT mechanism in heat-treated laser-cladded AISI 304 coatings.

Self-report of chronic diseases in old-aged individuals: extent of agreement with general practitioner medical records in the German AugUR study.

BACKGROUND: To estimate prevalence and incidence of diseases through self-reports in observational studies, it is important to understand the accuracy of participant reports. We aimed to quantify the agreement of self-reported and general practitioner-reported diseases in an old-aged population and to identify socio-demographic determinants of agreement. METHODS: This analysis was conducted as part of the AugUR study (n=2449), a prospective population-based cohort study in individuals aged 70-95 years, including 2321 participants with consent to contact physicians. Self-reported chronic diseases of participants were compared with medical data provided by their respective general practitioners (n=589, response rate=25.4%). We derived overall agreement, over-reporting/under-reporting, and Cohen's kappa and used logistic regression to evaluate the dependency of agreement on participants' sociodemographic characteristics. RESULTS: Among the 589 participants (53.1% women), 96.9% reported at least one of the evaluated chronic diseases. Overall agreement was >80% for hypertension, diabetes, myocardial infarction, stroke, cancer, asthma, bronchitis/chronic obstructive pulmonary disease and rheumatoid arthritis, but lower for heart failure, kidney disease and arthrosis. Cohen's kappa was highest for diabetes and cancer and lowest for heart failure, musculoskeletal, kidney and lung diseases. Sex was the primary determinant of agreement on stroke, kidney disease, cancer and rheumatoid arthritis. Agreement for myocardial infarction and stroke was most compromised by older age and for cancer by lower educational level. CONCLUSION: Self-reports may be an effective tool to assess diabetes and cancer in observational studies in the old and very old aged. In contrast, self-reports on heart failure, musculoskeletal, kidney or lung diseases may be substantially imprecise.

Informal dementia care: The carer's lived experience at the divides between policy and practice.

Support for informal dementia care at a local community level is not working for most carers today. Carers looking after a person with dementia have long lamented the absence of an empowered named support and an effectively actioned care plan. Drawing on literary writing and social research, we argue in this article that these challenges have existed since dementia emerged as a major condition in the West during the 1980s. Based on this historical context, we ask: Why has this issue persisted over the last four decades? How have healthcare politics and policy initiatives responded to these requests? And what can we learn from this for the current, COVID-19 exacerbated crisis of care? This article focuses on the English context, to discuss these ongoing challenges in the light of a series of policy papers, and to ask what is hampering the implementation of such policy initiatives. In England, local authorities are responsible for dementia support. This article focuses on the situation in a county in the Midlands where one of us (AB) has been lobbying local government for over a decade. The discussion contextualises the lived experience of dementia care within the situation exacerbated by the COVID-19 pandemic, ensuing politics of crises and persistent emphasis on cure over care. We find that the absence on two points centrally challenges care: a joined-up approach between health and social care and adequate information on available care support services, accessible through an empowered named contact. To enhance the lived experience of dementia care, consistent provision of individual named support and professional care support, as and when required, should become essential to local implementation of the care policy.

Relative Telomere Length Is Associated With Age-Related Macular Degeneration in Women.

Purpose: Relative telomere length (RTL) is a biomarker for physiological aging. Premature shortening of telomeres is associated with oxidative stress, which is one possible pathway that might contribute to age-related macular degeneration (AMD). We therefore aimed to investigate the association between RTL and AMD in a well-characterized group of elderly individuals. Methods: We measured RTL in participants of the AugUR study using a multiplex quantitative PCR-based assay determining the ratio between the telomere product and a single-copy gene product (T/S ratio). AMD was assessed by manual grading of color fundus images using the Three Continent AMD Consortium Severity Scale. Results: Among the 2262 individuals 70 to 95 years old (627 with AMD and 1635 without AMD), RTL was significantly shorter in individuals with AMD compared to AMD-free participants. In age- and sex-adjusted logistic regression analyses, we observed an 8% higher odds for AMD per 0.1 unit shorter RTL (odds ratio [OR] = 1.08; 95% confidence interval [CI], 1.02-1.14; P = 0.005). The estimates remained stable when adjusted for smoking, high-density lipoprotein cholesterol, cardiovascular disease, diabetes, and hypertension. Interestingly, this association was only present in women (OR = 1.14; 95% CI, 1.06-1.23; P < 0.001), but not in men (OR = 1.01; 95% CI, 0.93-1.10; P = 0.76). A significant sex-by-RTL interaction on AMD was detected (P = 0.043). Conclusions: Our results show an association of RTL with AMD that was restricted to women. This is in line with altered reactive oxygen species levels and higher telomerase activity in women and provides an indication for a sex-differential pathway for oxidative stress and AMD.

Quantity of IgG response to SARS-CoV-2 spike glycoprotein predicts pulmonary recovery from COVID-19.

The CovILD study is a prospective, multicenter, observational cohort study to systematically follow up patients after coronavirus disease-2019 (COVID-19). We extensively evaluated 145 COVID-19 patients at 3 follow-up visits scheduled for 60, 100, and 180 days after initial confirmed diagnosis based on typical symptoms and a positive reverse transcription-polymerase chain reaction (RT-PCR) for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We employed comprehensive pulmonary function and laboratory tests, including serum concentrations of IgG against the viral spike (S) glycoprotein, and compared the results to clinical data and chest computed tomography (CT). We found that at the 60 day follow-up, 131 of 145 (90.3%) participants displayed S-specific serum IgG levels above the cut-off threshold. Notably, the highly elevated IgG levels against S glycoprotein positively correlated with biomarkers of immune activation and negatively correlated with pulmonary function and the extent of pulmonary CT abnormalities. Based on the association between serum S glycoprotein-specific IgG and clinical outcome, we generated an S-specific IgG-based recovery score that, when applied in the early convalescent phase, accurately predicted delayed pulmonary recovery after COVID-19. Therefore, we propose that S-specific IgG levels serve as a useful immunological surrogate marker for identifying at-risk individuals with persistent pulmonary injury who may require intensive follow-up care after COVID-19.

Incidence, progression and risk factors of age-related macular degeneration in 35-95-year-old individuals from three jointly designed German cohort studies.

OBJECTIVE: To estimate age-related macular degeneration (AMD) incidence/progression across a wide age range. METHODS AND ANALYSIS: AMD at baseline and follow-up (colour fundus imaging, Three Continent AMD Consortium Severity Scale, 3CACSS, clinical classification, CC) was assessed for 1513 individuals aged 35-95 years at baseline from three jointly designed population-based cohorts in Germany: Kooperative Gesundheitsforschung in der Region Augsburg (KORA-Fit, KORA-FF4) and Altersbezogene Untersuchungen zur Gesundheit der Universität Regensburg (AugUR) with 18-year, 14-year or 3-year follow-up, respectively. Baseline assessment included lifestyle, metabolic and genetic markers. We derived cumulative estimates, rates and risk factor association for: (1) incident early AMD, (2) incident late AMD among no AMD at baseline (definition 1), (3) incident late AMD among no/early AMD at baseline (definition 2), (4) progression from early to late AMD. RESULTS: Incidence/progression increased by age, except progression in 70+-year old. We observed 35-55-year-old with 3CACSS-based early AMD who progressed to late AMD. Predominant risk factor for incident late AMD definition 2 was early AMD followed by genetics and smoking. When separating incident late AMD definition 1 from progression (instead of combined as incident late AMD definition 2), estimates help judge an individual's risk based on age and (3CACSS) early AMD status: for example, for a 65-year old, 3-year late AMD risk with no or early AMD is 0.5% or 7%, 3-year early AMD risk is 3%; for an 85-year old, these numbers are 0.5%, 21%, 12%, respectively. For CC-based 'early/intermediate' AMD, incidence was higher, but progression was lower. CONCLUSION: We provide a practical guide for AMD risk for ophthalmology practice and healthcare management and document a late AMD risk for individuals aged <55 years.

Changes in healthcare seeking and lifestyle in old aged individuals during COVID-19 lockdown in Germany: the population-based AugUR study.

BACKGROUND: Containment measures in the COVID-19 pandemic protected individuals at high risk, particularly individuals at old age, but little is known about how these measures affected health-related behavior of old aged individuals. We aimed to investigate the impact of the spring 2020 lockdown in Germany on healthcare-seeking and health-related lifestyle in the old aged and to identify susceptible subgroups. METHODS: We conducted a follow-up survey among the pre-pandemically well-characterized participants of our AugUR cohort study, residents in/around Regensburg aged 70+ years and relatively mobile. A self-completion questionnaire on current behavior, perceived changes, and SARS-Cov-2 infection was mailed in May 2020, shortly before contact restrictions ended. Pre-pandemic lifestyle and medical conditions were derived from previous study center visits. RESULTS: Among 1850 survey participants (73-98 years; net-response 89%), 74% were at increased risk for severe COVID-19 according to medical conditions; four participants reported SARS-CoV-2 infection (0.2%). Participants reported changes in behavior: 29% refrained from medical appointments, 14% increased TV consumption, 26% reported less physical activity, but no systematic increase of smoking or alcohol consumption. When comparing during- and pre-lockdown reports of lifestyle within participant, we found the same pattern as for the reported perceived changes. Women and the more educated were more susceptible to changes. Worse QOL was perceived by 38%. CONCLUSIONS: Our data suggest that the spring 2020 lockdown did not affect the lifestyle of a majority of the mobile old aged individuals, but the substantial proportions with decreased physical activity and healthcare-seeking are markers of collateral damage.

Design procedure for triply periodic minimal surface based biomimetic scaffolds.

Cellular additively manufactured metallic structures for load-bearing scaffolds in the context of bone tissue engineering (BTE) have emerged as promising candidates. Due to many advantages in terms of morphology, stiffness, strength and permeability compared to conventional truss structures, lattices based on triply periodic minimal surfaces (TPMS) have recently attracted increasing interest for this purpose. In addition, the finite element method (FEM) has been proven to be suitable for accurately predicting the deformation behavior as well as the mechanical properties of geometric structures after appropriate parameter validation based on experimental data. Numerous publications have examined many individual aspects, but conceptual design procedures that consider at least the essential requirements for cortical and trabecular bone simultaneously are still rare. Therefore, this paper presents a numerical approach to first determine the actual admissible design spaces for a choice of TPMS based lattices with respect to key parameters and then weight them with respect to further benefit parameters. The admissible design spaces are limited by pore size, strut size and volume fraction, and the subsequent weighting is based on Young's modulus, cell size and surface area. Additively manufactured beta-Ti-42Nb with a strain stiffness of 60.5GPa is assumed as material. In total, the procedure considers twelve lattice types, consisting of six different TPMS, each as network solid and as sheet solid. The method is used for concrete prediction of suitable TPMS based lattices for cortical bone and trabecular bone. For cortical bone a lattice based on the Schwarz Primitive sheet solid with 67.572µm pore size, 0.5445 volume fraction and 18.758GPa Young's modulus shows to be the best choice. For trabecular bone a lattice based on the Schoen Gyroid network solid with 401.39µm pore size, 0.3 volume fraction and 4.6835GPa Young's modulus is the identified lattice. Finally, a model for a long bone scaffold is generated from these two lattices using functional grading methods in terms of volume fraction, cell size and TPMS type. In particular, the presented procedure allows an efficient estimation for a likely suitable biometric TPMS-based scaffolds. In addition to medical applications, however, the method can also be transferred to numerous other applications in mechanical, civil and electrical engineering.

Distribution and specificity of high-sensitivity cardiac troponin T in older adults without acute cardiac conditions: cross-sectional results from the population-based AugUR study.

OBJECTIVE: European guidelines recommended a uniform upper reference limit of high-sensitivity cardiac troponin T (hsTnT) to rule out non-ST segment elevation myocardial infarction. Our study aimed to provide a hsTnT reference distribution and to assess the specificity of the 14 ng/L cut-off value in the mobile population ≥70 years of age. DESIGN: A cross-sectional analysis was performed in the German AugUR study (Altersbezogene Untersuchungen zur Gesundheit der University of Regensburg). SETTING: Study population was the mobile population aged 70+ years living in the city and county of Regensburg, Germany. PARTICIPANTS: A random sample was derived from the local population registries of residence. Of the 5644 individuals invited, 1133 participated (response ratio=20.1%). All participants came to the study centre and were mentally and physically mobile to conduct the protocol (face-to-face interview, blood draw and standardised transthoracic echocardiography). None of the participants was in an acute state of myocardial infarction. RESULTS: Among the 1129 individuals with hsTnT measurements (overall median=10.0 ng/L(25th, 75th percentile)=(7.0, 15.0 ng/L)), hsTnT was higher among the older individuals and higher among men (men 70-74 years median=9.6 ng/L (7.2, 13.1 ng/L); men 90-95 years median=21.2 ng/L (14.6, 26.0 ng/L); women 70-74 years median=6.3 ng/L (4.7, 8.7 ng/L); and women 90-95 years median=18.0 ng/L (11.0, 21.0 ng/L)). In participants with impaired kidney function (eGFRcrea <60 mL/min/1.73 m2), hsTnT was elevated (median=13.6 ng/L (9.4, 20.6 ng/L)).Specificity of recommended upper reference limit, 14 ng/L, is 68%. Most false positives were among men aged >79 years (specificity=34%). In a healthy subgroup (n=96, none of the following: overt heart disease, impaired renal function, blood pressure >160/100 mm Hg, left ventricular hypertrophy and diastolic/systolic dysfunction), specificity was 90%. CONCLUSION: In the elderly population without acute myocardial infarction, hsTnT further increases with age showing different levels for men and women. The specificity of the 14 ng/L cut-off is considerably lower than 99%, even in healthy subjects.

Half-life extension of efficiently produced DARPin serum albumin fusions as a function of FcRn affinity and recycling.

Serum albumin shows slow clearance from circulation due to neonatal Fc receptor (FcRn)-mediated recycling and has been used for half-life extension. We report here fusions to a high-affinity DARPin, binding to Epithelial Cell Adhesion Molecule (EpCAM). We developed a novel, efficient expression system for such fusion proteins in Pichia pastoris with titers above 300 mg/L of lab-scale shake-flask culture. Since human serum albumin (HSA) does not bind to the murine FcRn, half-lives of therapeutic candidates are frequently measured in human FcRn transgenic mice, limiting useable tumor models. Additionally, serum albumins with extended half-life have been designed. We tested HSA7, motivated by its previously claimed extraordinarily long half-life in mice, which we could not confirm. Instead, we determined a half-life of only 29 h for HSA7, comparable to MSA. The fusion of HSA7 to a DARPin showed a similar half-life. To rationalize these findings, we measured binding kinetics and affinities to murine and human FcRn. Briefly, HSA7 showed affinity to murine FcRn only in the micromolar range, comparable to MSA to its cognate murine FcRn, and an affinity in the nanomolar range only to the human FcRn. This explains the comparable half-life of MSA and HSA7 in mice, while wild-type-HSA has a half-life of only 21 h, as it does not bind the murine FcRn and is not recycled. Thus, HSA-fusions with improved FcRn-affinity, such as HSA7, can be used for preclinical experiments in mice when FcRn transgenes cannot be used, as they reflect better the complex FcRn-mediated recycling and distribution mechanisms.

S-Sulfocysteine - Investigation of cellular uptake in CHO cells.

For the generation of therapeutic proteins in cell culture, high producing clones are used. These clones have a high demand in amino acids to support cell growth and productivity. l-cysteine (Cys) is critical in highly concentrated feeds due to low stability of Cys and low solubility of the oxidation product cystine at neutral pH. S-sulfocysteine (SSC) was developed to substitute the Cys source and fed-batch experiments using SSC showed good cellular performance regarding viable cell density and titer, indicating uptake and metabolization of SSC by Chinese hamster ovary cells. However, the responsible transporter allowing cellular uptake remains unclear and was studied in this work. Due to the structure similarity of SSC with cystine and glutamate, it was proposed that the cystine/glutamate antiporter (xc-) allows cellular uptake of SSC. The uptake was assessed via transporter inhibition using sulfasalazine and transporter overexpression using either sulforaphane or sulforaphane-N-acetylcysteine during fed-batch experiments. Following daily addition of 50 µM and 100 µM sulfasalazine, the extracellular SSC concentration was increased by 65 % and 177 % respectively, suggesting a reduced uptake due to xc- inhibition. In contrast, enhanced transporter activity through 15 µM sulforaphane and sulforaphane-N-acetylcysteine treatment, induced a 60 % and 52 % reduced extracellular SSC concentration, respectively. These inverse uptake results strongly suggest that xc- is facilitating the transport of SSC.