Spatio-temporal Models of Lymphangiogenesis in Wound Healing

Several studies suggest that one possible cause of impaired wound healing is failed or insufficient lymphangiogenesis, that is the formation of new lymphatic capillaries. Although many mathematical models have been developed to describe the formation of blood capillaries (angiogenesis), very few have been proposed for the regeneration of the lymphatic network. Lymphangiogenesis is a markedly different process from angiogenesis, occurring at different times and in response to different chemical stimuli. Two main hypotheses have been proposed: 1) lymphatic capillaries sprout from existing interrupted ones at the edge of the wound in analogy to the blood angiogenesis case; 2) lymphatic endothelial cells first pool in the wound region following the lymph flow and then, once sufficiently populated, start to form a network. Here we present two PDE models describing lymphangiogenesis according to these two different hypotheses. Further, we include the effect of advection due to interstitial flow and lymph flow coming from open capillaries. The variables represent different cell densities and growth factor concentrations, and where possible the parameters are estimated from biological data. The models are then solved numerically and the results are compared with the available biological literature.Comment: 29 pages, 9 Figures, 6 Tables (39 figure files in total

Social factors and the prevalence of social isolation in a population-based adult cohort

Purpose Social isolation has negative effects on physical and brain health across the lifespan. However, the prevalence of social isolation, specifically with regard to sociodemographic and socioeconomic factors, is not well known. Methods Database was the Leipzig population-based study of adults (LIFE-Adult Study, n = 10,000). The short form of the Lubben Social Network Scale (LSNS-6) was used to assess social isolation (cutoff < 12 points). Sampling weights were applied to account for differences in sampling fractions. Results Data were available for 9392 study participants; 51.6% were women, the mean age was 45.2 years (SD = 17.3). The prevalence of social isolation was 12.3% (95% CI 11.6–13.0) across ages 18–79 years. Social isolation was more prevalent in men (13.8%, 95% CI 12.8–14.8) compared to women (10.9%, 95% CI 10.0–11.8; (1) = 18.83, p < .001), and it showed an increase with increasing age from 5.4% (95% CI 4.7–6.0) in the youngest age group (18–39 years) to 21.7% (95% CI 19.5–24.0) in the oldest age group (70–79 years; (4) = 389.51, p < .001). Prevalence differed largely with regard to socioeconomic status (SES); showing lower prevalence in high SES (7.2%, 95% CI 6.0–8.4) and higher prevalence in low SES (18.6%, 95% CI 16.9–20.3; (2) = 115.78; p < .001). Conclusion More than one in ten individuals in the adult population reported social isolation, and prevalence varied strongly with regard to sociodemographic and socioeconomic factors. Social isolation was particularly frequent in disadvantaged socioeconomic groups. From a public health perspective, effective prevention of and intervention against social isolation should be a desired target as social isolation leads to poor health. Countermeasures should especially take into account the socioeconomic determinants of social isolation, applying a life-course perspective

A Metabolic Obesity Profile Is Associated With Decreased Gray Matter Volume in Cognitively Healthy Older Adults

Obesity is a risk factor for cognitive decline and gray matter volume loss in aging. Studies have shown that different metabolic factors, e.g., dysregulated glucose metabolism and systemic inflammation, might mediate this association. Yet, even though these risk factors tend to co-occur, they have mostly been investigated separately, making it difficult to establish their joint contribution to gray matter volume structure in aging. Here, we therefore aimed to determine a metabolic profile of obesity that takes into account different anthropometric and metabolic measures to explain differences in gray matter volume in aging. We included 748 elderly, cognitively healthy participants (age range: 60 – 79 years, BMI range: 17 – 42 kg/m2) of the LIFE-Adult Study. All participants had complete information on body mass index, waist-to-hip ratio, glycated hemoglobin, total blood cholesterol, high-density lipoprotein, interleukin-6, C-reactive protein, adiponectin and leptin. Voxelwise gray matter volume was extracted from T1-weighted images acquired on a 3T Siemens MRI scanner. We used partial least squares correlation to extract latent variables with maximal covariance between anthropometric, metabolic and gray matter volume and applied permutation/bootstrapping and cross-validation to test significance and reliability of the result. We further explored the association of the latent variables with cognitive performance. Permutation tests and cross-validation indicated that the first pair of latent variables was significant and reliable. The metabolic profile was driven by negative contributions from body mass index, waist-to-hip ratio, glycated hemoglobin, C-reactive protein and leptin and a positive contribution from adiponectin. It positively covaried with gray matter volume in temporal, frontal and occipital lobe as well as subcortical regions and cerebellum. This result shows that a metabolic profile characterized by high body fat, visceral adiposity and systemic inflammation is associated with reduced gray matter volume and potentially reduced executive function in older adults. We observed the highest contributions for body weight and fat mass, which indicates that factors underlying sustained energy imbalance, like sedentary lifestyle or intake of energy-dense food, might be important determinants of gray matter structure in aging

Are social conflicts at work associated with depressive symptomatology? Results from the population-based LIFE-Adult-Study

Background Psychosocial stressors in the workplace can be detrimental to mental health. Conflicts at work, e.g. aggression, hostility or threats from coworkers, supervisors or customers, can be considered a psychosocial stressor, possibly increasing risk for depressive symptoms. Existing studies, however, differ in the assessment of social conflicts, i.e. as individual- or job-level characteristics. Here, we investigated the association between conflicts at work assessed as objective job characteristics, and depressive symptomatology, using data from a large population-based sample. Additionally, we investigated gender differences and the impact of personality traits and social resources. Methods We used data from the population-based LIFE-Adult-Study from Leipzig, Germany. Information on conflicts at work, assessed as job characteristics, were drawn from the Occupational Information Network, depressive symptoms were assessed via the Center for Epidemiological Studies Depression Scale. Multilevel linear regression models with individuals and occupations as levels of analysis were applied to investigate the association between conflicts at work and depressive symptoms. Results Our sample included 2164 employed adults (age: 18–65 years, mean: 49.3, SD: 7.9) in 65 occupations. No association between conflicts s at work and depressive symptomatology was found (men: b = − 0.14; p = 0.74, women: b = 0.17, p = 0.72). Risk for depression was mostly explained by individual-level factors like e.g. neuroticism or level of social resources. The model showed slightly higher explanatory power in the female subsample. Conclusion Conflicts at work, assessed as objective job characteristics, were not associated with depressive symptoms. Possible links between interpersonal conflict and impaired mental health might rather be explained by subjective perceptions of social stressors and individual coping styles

Social determinants and lifestyle factors for brain health: implications for risk reduction of cognitive decline and dementia

Substantial evidence indicates a huge potential for risk reduction of cognitive decline and dementia based on modifiable health and lifestyle factors. To maximize the chances for risk reduction, it is useful to investigate associations of social determinants and lifestyle for brain health. We computed the “LIfestyle for BRAin health” (LIBRA) score for baseline participants of the Leipzig Research Centre for Civilization Diseases (LIFE) Adult Study, a population-based urban cohort in Germany. LIBRA predicts dementia in midlife and early late life populations, comprising 12 modifiable risk factors (heart disease, kidney disease, diabetes, obesity, hypertension, hypercholesterolemia, alcohol consumption, smoking, physical inactivity, diet, depression, cognitive inactivity). Associations of social determinants (living situation, marital status, social isolation, education, net equivalence income, occupational status, socioeconomic status/SES, employment) with LIBRA were inspected using age- and sex-adjusted multivariable linear regression analysis. Z-standardization and sampling weights were applied. Participants (n = 6203) were M = 57.4 (SD = 10.6, range 40–79) years old and without dementia, 53.0% were women. Except for marital status, all considered social determinants were significantly associated with LIBRA. Beta coefficients for the association with higher LIBRA scores were most pronounced for low SES (β = 0.80, 95% CI [0.72–0.88]; p < 0.001) and middle SES (β = 0.55, 95% CI [0.47–0.62]; p < 0.001). Social determinants, particularly socioeconomic factors, are associated with lifestyle for brain health, and should thus be addressed in risk reduction strategies for cognitive decline and dementia. A social-ecological public health perspective on risk reduction might be more effective and equitable than focusing on individual lifestyle behaviors alone

Memory-related subjective cognitive symptoms in the adult population: prevalence and associated factors – results of the LIFE-Adult-Study

Background Subjectively perceived memory problems (memory-related Subjective Cognitive Symptoms/SCS) can be an indicator of a pre-prodromal or prodromal stage of a neurodegenerative disease such as Alzheimer’s disease. We therefore sought to provide detailed empirical information on memory-related SCS in the dementia-free adult population including information on prevalence rates, associated factors and others. Methods We studied 8834 participants (40–79 years) of the population-based LIFE-Adult-Study. Weighted prevalence rates with confidence intervals (95%-CI) were calculated. Associations of memory-related SCS with participants’ socio-demographic characteristics, physical and mental comorbidity, and cognitive performance (Verbal Fluency Test Animals, Trail-Making-Test, CERAD Wordlist tests) were analyzed. Results Prevalence of total memory-related SCS was 53.0% (95%-CI = 51.9–54.0): 26.0% (95%-CI = 25.1–27.0) of the population had a subtype without related concerns, 23.6% (95%-CI = 22.7–24.5) a subtype with some related concerns, and 3.3% (95%-CI = 2.9–3.7) a subtype with strong related concerns. Report of memory-related SCS was unrelated to participants’ socio-demographic characteristics, physical comorbidity (except history of stroke), depressive symptomatology, and anxiety. Adults with and without memory-related SCS showed no significant difference in cognitive performance. About one fifth (18.1%) of the participants with memory-related SCS stated that they did consult/want to consult a physician because of their experienced memory problems. Conclusions Memory-related SCS are very common and unspecific in the non-demented adult population aged 40–79 years. Nonetheless, a substantial proportion of this population has concerns related to experienced memory problems and/or seeks help. Already available information on additional features associated with a higher likelihood of developing dementia in people with SCS may help clinicians to decide who should be monitored more closely

Depressive Symptomatology in Early Retirees Associated With Reason for Retirement—Results From the Population-Based LIFE-Adult-Study

Background: Transition from employment to retirement is regarded a crucial event. However, there is mixed evidence on associations between retirement and mental health, especially regarding early retirement. In Germany, cases of early retirement due to ill health—particularly, mental ill health—are increasing. Therefore, we investigated the association between early retirement and depressive symptoms, including information on different types of early retirement. Methods: We analyzed data from 4,808 participants of the population-based LIFE-Adult-Study (age: 40–65 years, 654 retired, 4,154 employed), controlling for sociodemographic information, social network, pre-existing health conditions, and duration of retirement. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale. Regression analysis using entropy balancing was applied to achieve covariate balance between retired and employed subjects. Results: We found no overall-differences in depressive symptoms between employed and retired persons (men: b = −.52; p = 0.431; women: b = .05; p = .950). When looking at different types of early retirement, ill-health retirement was linked to increased depressive symptoms in women (b = 4.68, 95% CI = 1.71; 7.65), while voluntary retirement was associated with reduced depressive symptoms in men (b= −1.83, 95% CI = −3.22; −.43) even after controlling for covariates. For women, statutory retirement was linked to lower depressive symptomatology (b = −2.00, 95% CI = −3.99; −.02). Conclusion: Depressive symptomatology among early retirees depends on reason for retirement: For women, ill-health retirement is linked to higher levels of depressive symptoms. Women who retire early due to ill-health constitute a risk group for depressive symptoms that needs specific attention in the health care and social security system

Alterations in rhythmic and non‐rhythmic resting‐state EEG activity and their link to cognition in older age

While many structural and biochemical changes in the brain have previously been associated with older age, findings concerning functional properties of neuronal networks, as reflected in their electrophysiological signatures, remain rather controversial. These discrepancies might arise due to several reasons, including diverse factors determining general spectral slowing in the alpha frequency range as well as amplitude mixing between the rhythmic and non-rhythmic parameters. We used a large dataset (N = 1703, mean age 70) to comprehensively investigate age-related alterations in multiple EEG biomarkers taking into account rhythmic and non-rhythmic activity and their individual contributions to cognitive performance. While we found strong evidence for an individual alpha peak frequency (IAF) decline in older age, we did not observe a significant relationship between theta power and age while controlling for IAF. Not only did IAF decline with age, but it was also positively associated with interference resolution in a working memory task primarily in the right and left temporal lobes suggesting its functional role in information sampling. Critically, we did not detect a significant relationship between alpha power and age when controlling for the 1/f spectral slope, while the latter one showed age-related alterations. These findings thus suggest that the entanglement of IAF slowing and power in the theta frequency range, as well as 1/f slope and alpha power measures, might explain inconsistencies reported previously in the literature. Finally, despite the absence of age-related alterations, alpha power was negatively associated with the speed of processing in the right frontal lobe while 1/f slope showed no consistent relationship to cognitive performance. Our results thus demonstrate that multiple electrophysiological features, as well as their interplay, should be considered for the comprehensive assessment of association between age, neuronal activity, and cognitive performance

HSV Neutralization by the Microbicidal Candidate C5A

Genital herpes is a major risk factor in acquiring human immunodeficiency virus type-1 (HIV-1) infection and is caused by both Herpes Simplex virus type 1 (HSV-1) and HSV-2. The amphipathic peptide C5A, derived from the non-structural hepatitis C virus (HCV) protein 5A, was shown to prevent HIV-1 infection but neither influenza nor vesicular stomatitis virus infections. Here we investigated the antiviral function of C5A on HSV infections. C5A efficiently inhibited both HSV-1 and HSV-2 infection in epithelial cells in vitro as well as in an ex vivo epidermal infection model. C5A destabilized the integrity of the viral HSV membrane. Furthermore, drug resistant HSV strains were inhibited by this peptide. Notably, C5A-mediated neutralization of HSV-1 prevented HIV-1 transmission. An in vitro HIV-1 transmigration assay was developed using primary genital epithelial cells and HSV infection increased HIV-1 transmigration. Treatment with C5A abolished HIV-1 transmigration by preventing HSV infection and by preserving the integrity of the genital epithelium that was severely compromised by HSV infection. In conclusion, this study demonstrates that C5A represents a multipurpose microbicide candidate, which neutralizes both HIV-1 and HSV, and which may interfere with HIV-1 transmission through the genital epithelium

The PRIMED Consortium: Reducing disparities in polygenic risk assessment.

By improving disease risk prediction, polygenic risk scores (PRSs) could have a significant impact on health promotion and disease prevention. Due to the historical oversampling of populations with European ancestry for genome-wide association studies, PRSs perform less well in other, understudied populations, leading to concerns that clinical use in their current forms could widen health care disparities. The PRIMED Consortium was established to develop methods to improve the performance of PRSs in global populations and individuals of diverse genetic ancestry. To this end, PRIMED is aggregating and harmonizing multiple phenotype and genotype datasets on AnVIL, an interoperable secure cloud-based platform, to perform individual- and summary-level analyses using population and statistical genetics approaches. Study sites, the coordinating center, and representatives from the NIH work alongside other NHGRI and global consortia to achieve these goals. PRIMED is also evaluating ethical and social implications of PRS implementation and investigating the joint modeling of social determinants of health and PRS in computing disease risk. The phenotypes of interest are primarily cardiometabolic diseases and cancer, the leading causes of death and disability worldwide. Early deliverables of the consortium include methods for data sharing on AnVIL, development of a common data model to harmonize phenotype and genotype data from cohort studies as well as electronic health records, adaptation of recent guidelines for population descriptors to global cohorts, and sharing of PRS methods/tools. As a multisite collaboration, PRIMED aims to foster equity in the development and use of polygenic risk assessment