A modular, reversible sealing, and reusable microfluidic device for drug screening.

Preclinical tests for evaluating potential drug candidates using conventional protocols can be exhaustive and high-cost processes. Microfluidic technologies that can speed up this process and allow fast screening of drugs are promising alternatives. This work presents the design, concept, and operational conditions of a simple, modular, and reversible sealing microdevice useful for drug screening. This microdevice allows for the operation of 4 parallel simultaneous conditions and can also generate a diffusive concentration gradient in sextuplicates. We used laminated polydimethylsiloxane (PDMSLAM) and glass as building materials as proof of concept. The PDMSLAM parts can be reused since they can be easily sterilized. We cultured MCF-7 (Michigan Cancer Foundation-7) breast cancer cells. Cells were exposed to a doxorubicin diffusive concentration gradient for 3 h. They were monitored by automated microscopy, and after data processing, it was possible to determine cell viability as a function of doxorubicin concentration. The reversible sealing enabled the recovery of the tested cells and image acquisition. Therefore, this microdevice is a promising tool for drug screening that allows assessing the cellular behavior in dynamic conditions and the recovery of cells for afterward processing and imaging.

Sex differences in mortality: results from a population-based study of 12 longitudinal cohorts.

BACKGROUND: Women generally have longer life expectancy than men but have higher levels of disability and morbidity. Few studies have identified factors that explain higher mortality in men. The aim of this study was to identify potential factors contributing to sex differences in mortality at older age and to investigate variation across countries. METHODS: This study included participants age ≥ 50 yr from 28 countries in 12 cohort studies of the Ageing Trajectories of Health: Longitudinal Opportunities and Synergies (ATHLOS) consortium. Using a 2-step individual participant data meta-analysis framework, we applied Cox proportional hazards modelling to investigate the association between sex and mortality across different countries. We included socioeconomic (education, wealth), lifestyle (smoking, alcohol consumption), social (marital status, living alone) and health factors (cardiovascular disease, diabetes, mental disorders) as covariates or interaction terms with sex to test whether these factors contributed to the mortality gap between men and women. RESULTS: The study included 179 044 individuals. Men had 60% higher mortality risk than women after adjustment for age (pooled hazard ratio [HR] 1.6; 95% confidence interval 1.5-1.7), yet the effect sizes varied across countries (I 2 = 71.5%, HR range 1.1-2.4). Only smoking and cardiovascular diseases substantially attenuated the effect size (by about 22%). INTERPRETATION: Lifestyle and health factors may partially account for excess mortality in men compared with women, but residual variation remains unaccounted for. Variation in the effect sizes across countries may indicate contextual factors contributing to gender inequality in specific settings.

The impact of physical activity on healthy ageing trajectories: evidence from eight cohort studies.

BACKGROUND: Research has suggested the positive impact of physical activity on health and wellbeing in older age, yet few studies have investigated the associations between physical activity and heterogeneous trajectories of healthy ageing. We aimed to identify how physical activity can influence healthy ageing trajectories using a harmonised dataset of eight ageing cohorts across the world. METHODS: Based on a harmonised dataset of eight ageing cohorts in Australia, USA, Mexico, Japan, South Korea, and Europe, comprising 130,521 older adults (Mage = 62.81, SDage = 10.06) followed-up up to 10 years (Mfollow-up = 5.47, SDfollow-up = 3.22), we employed growth mixture modelling to identify latent classes of people with different trajectories of healthy ageing scores, which incorporated 41 items of health and functioning. Multinomial logistic regression modelling was used to investigate the associations between physical activity and different types of trajectories adjusting for sociodemographic characteristics and other lifestyle behaviours. RESULTS: Three latent classes of healthy ageing trajectories were identified: two with stable trajectories with high (71.4%) or low (25.2%) starting points and one with a high starting point but a fast decline over time (3.4%). Engagement in any level of physical activity was associated with decreased odds of being in the low stable (OR: 0.18; 95% CI: 0.17, 0.19) and fast decline trajectories groups (OR: 0.44; 95% CI: 0.39, 0.50) compared to the high stable trajectory group. These results were replicated with alternative physical activity operationalisations, as well as in sensitivity analyses using reduced samples. CONCLUSIONS: Our findings suggest a positive impact of physical activity on healthy ageing, attenuating declines in health and functioning. Physical activity promotion should be a key focus of healthy ageing policies to prevent disability and fast deterioration in health.

Platelet-Rich Plasma Ameliorates Cyclophosphamide-Induced Acute Interstitial Cystitis/Painful Bladder Syndrome in a Rat Model.

BACKGROUND: Interstitial cystitis/painful bladder syndrome (IC/PBS) could be treated to ameliorate urothelial injury. Here, we investigated the efficacy of intravesical instillation with platelet-rich plasma (PRP) and hyaluronic acid for acute IC/PBS. METHODS: The effects of PRP and hyaluronic acid on the proliferation of normal human fibroblast cells (HFCs) were assessed. Additionally, thirty virgin female rats were randomized into five groups: group 1, saline-injected control; group 2, cyclophosphamide (CYP) plus intravesical instillation with normal saline; group 3, CYP plus intravesical instillation with hyaluronic acid (1 mg/mL); group 4, CYP plus intravesical instillation with PRP; and group 5, CYP plus intravesical instillation with PRP plus hyaluronic acid. A cystometry and histological assessments were performed. The expression of cell junction-associated protein zonula occludens-2 (ZO-2) and inflammatory cytokine interleukin 6 (IL-6) was also measured. RESULTS: Low dose PRP increased proliferation in HFCs. The acute IC/PBS rats showed significantly lower voiding interval values. Voiding interval values were significantly higher in the CYP plus intravesical instillation with PRP group than in the CYP-induced acute IC/PBS group. Additionally, the expression of ZO-2 was increased and IL-6 was decreased in the CYP plus intravesical instillation with PRP group compared with the CYP-induced acute IC/PBS group. CONCLUSION: These findings suggest that PRP modulate urothelial repair, which ameliorate the increase in urination frequency in rats treated with CYP. Overall, PRP may confer potential benefits by acting as urothelial repair modulators.

Healthy ageing trajectories and lifestyle behaviour: the Mexican Health and Aging Study.

Projections show that the number of people above 60 years old will triple by 2050 in Mexico. Nevertheless, ageing is characterised by great variability in the health status. In this study, we aimed to identify trajectories of health and their associations with lifestyle factors in a national representative cohort study of older Mexicans. We used secondary data of 14,143 adults from the Mexican Health and Aging Study (MHAS). A metric of health, based on the conceptual framework of functional ability, was mapped onto four waves (2001, 2003, 2012, 2015) and created by applying Bayesian multilevel Item Response Theory (IRT). Conditional Growth Mixture Modelling (GMM) was used to identify latent classes of individuals with similar trajectories and examine the impact of physical activity, smoking and alcohol on those. Conditional on sociodemographic and lifestyle behaviour four latent classes were suggested: high-stable, moderate-stable, low-stable and decliners. Participants who did not engage in physical activity, were current or previous smokers and did not consume alcohol at baseline were more likely to be in the trajectory with the highest deterioration (i.e. decliners). This study confirms ageing heterogeneity and the positive influence of a healthy lifestyle. These results provide the ground for new policies.

Dog ownership supports the maintenance of physical activity during poor weather in older English adults: cross-sectional results from the EPIC Norfolk cohort.

BACKGROUND: Dog ownership has been suggested to encourage physical activity in older adults and may enhance resilience to poor environmental conditions. This study investigates the role of dog ownership and walking as a means of supporting the maintenance of physical activity in older adults during periods of inclement weather. METHODS: The analysis used data from the European Prospective Investigation into Cancer and Nutrition Norfolk cohort. Daily physical activity (counts per minute) and minutes of sedentary behaviour were measured using accelerometers over 7 days. Three types of environmental conditions, day length, precipitation and maximum temperature, were date matched with daily physical activity. A multilevel first-order autoregressive time-series model quantified the moderating effect of self-reported dog ownership and walking on the association between physical activity and weather factors. RESULTS: Among the 3123 participants, 18% reported having a dog in their households and two-thirds of dog owners walked their dogs at least once a day. Regular dog walkers were more active and less sedentary on days with the poorest conditions than non-dog owners were on the days with the best conditions. In days with the worst conditions, those who walked their dogs had 20% higher activity levels than non-dog owners and spent 30 min/day less sedentary. CONCLUSION: Those who walked dogs were consistently more physically active than those who did not regardless of environmental conditions. These large differences suggest that dog walking, where appropriate, can be a component of interventions to support physical activity in older adults.

Weather, day length and physical activity in older adults: Cross-sectional results from the European Prospective Investigation into Cancer and Nutrition (EPIC) Norfolk Cohort.

BACKGROUND: A wide range of environmental factors have been related to active ageing, but few studies have explored the impact of weather and day length on physical activity in older adults. We investigate the cross-sectional association between weather conditions, day length and activity in older adults using a population-based cohort in England, the European Prospective Investigation into Cancer and Nutrition (EPIC) Norfolk study. METHODS: Physical activity was measured objectively over 7 days using an accelerometer and this was used to calculate daily total physical activity (counts per minute), daily minutes of sedentary behaviour and light, moderate and vigorous physical activity (LMVPA). Day length and two types of weather conditions, precipitation and temperature, were obtained from a local weather station. The association between these variables and physical activity was examined by multilevel first-order autoregressive modelling. RESULTS: After adjusting for individual factors, short day length and poor weather conditions, including high precipitation and low temperatures, were associated with up to 10% lower average physical activity (p<0.01) and 8 minutes less time spent in LMVPA but 15 minutes more sedentary time, compared to the best conditions. CONCLUSION: Day length and weather conditions appear to be an important factor related to active ageing. Future work should focus on developing potential interventions to reduce their impact on physical activity behaviours in older adults.

Potentially modifiable lifestyle factors, cognitive reserve, and cognitive function in later life: A cross-sectional study.

BACKGROUND: Potentially modifiable lifestyle factors may influence cognitive health in later life and offer potential to reduce the risk of cognitive decline and dementia. The concept of cognitive reserve has been proposed as a mechanism to explain individual differences in rates of cognitive decline, but its potential role as a mediating pathway has seldom been explored using data from large epidemiological studies. We explored the mediating effect of cognitive reserve on the cross-sectional association between lifestyle factors and cognitive function in later life using data from a population-based cohort of healthy older people. METHODS AND FINDINGS: We analysed data from 2,315 cognitively healthy participants aged 65 y and over in the Cognitive Function and Ageing Study Wales (CFAS-Wales) cohort collected in 2011-2013. Linear regression modelling was used to investigate the overall associations between five lifestyle factors-cognitive and social activity, physical activity, diet, alcohol consumption, and smoking-and cognition, adjusting for demographic factors and chronic conditions. Mediation analysis tested for indirect effects of the lifestyle factors on cognition via cognitive reserve. After controlling for age, gender, and the presence of chronic conditions, cognitive and social activity, physical activity, healthy diet, and light-to-moderate alcohol consumption were positively associated with cognitive function, together accounting for 20% (95% CI 17%-23%) of variance in cognitive test scores. Cognitive reserve was an important mediator of this association, with indirect effects via cognitive reserve contributing 21% (95% CI 15%-27%) of the overall effect on cognition. The main limitations of the study derive from the cross-sectional nature of the data and the challenges of accurately measuring the latent construct of cognitive reserve. CONCLUSIONS: Cross-sectional associations support the view that enhancing cognitive reserve may benefit cognition, and maintenance of cognitive health may be supported by a healthy and active lifestyle, in later life.