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"Phillips, David R."
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A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa
Coagulation factor Xa is targeted by a new generation of antithrombotic drugs such as rivaroxaban. However, as excessive factor Xa inhibition can cause bleeding, the clinical use of factor Xa inhibitors would be enhanced by the availability of a specific antidote. Uma Sinha and her colleagues devise such an antidote, an inactive form of recombinant factor Xa that can bind to and neutralize factor Xa inhibitors, and demonstrate its efficacy in animal models.
Inhibitors of coagulation factor Xa (fXa) have emerged as a new class of antithrombotics but lack effective antidotes for patients experiencing serious bleeding. We designed and expressed a modified form of fXa as an antidote for fXa inhibitors. This recombinant protein (r-Antidote, PRT064445) is catalytically inactive and lacks the membrane-binding γ-carboxyglutamic acid domain of native fXa but retains the ability of native fXa to bind direct fXa inhibitors as well as low molecular weight heparin–activated antithrombin III (ATIII). r-Antidote dose-dependently reversed the inhibition of fXa by direct fXa inhibitors and corrected the prolongation of
ex vivo
clotting times by such inhibitors. In rabbits treated with the direct fXa inhibitor rivaroxaban, r-Antidote restored hemostasis in a liver laceration model. The effect of r-Antidote was mediated by reducing plasma anti-fXa activity and the non–protein bound fraction of the fXa inhibitor in plasma. In rats, r-Antidote administration dose-dependently and completely corrected increases in blood loss resulting from ATIII-dependent anticoagulation by enoxaparin or fondaparinux. r-Antidote has the potential to be used as a universal antidote for a broad range of fXa inhibitors.
Journal Article
Understanding the Wellbeing of the Oldest-Old in China: A Study of Socio-Economic and Geographical Variations Based on CLHLS Data
Empirical studies of the socio-economic determinants of the wellbeing of the oldest-old in China including the role of geography and spatial factors are rare. This paper applies binary logistic regression analysis to data on the oldest-old aged 80 years old and higher from the 2011 Chinese Longitudinal Healthy Longevity Study (CLHLS). Socioeconomic determinants of the self-reported quality of life (QoL) and self-reported health (SRH) of the oldest-old population are explored, with special attention paid to the role of residence and region. The results indicate that, after controlling for individual demographic and health behavior variables, both economic status and social welfare have a significant effect on self-reported QoL and SRH. There are also significant differences in self-reported QoL among cities, towns and rural areas, with the oldest-old respondents living in Central rural, Western town and Western rural areas being significantly less likely to report good QoL, compared to the oldest-old living in Eastern cities. Significant differences in SRH exist among Eastern China, Western China and Northeastern China, with the oldest-old from Western towns being significantly less likely to report good health, and the oldest-old from Northeastern cities being significantly more likely to report good health than those from Eastern cities. The results of this study indicate that socioeconomic factors that explain self-reported QoL and SRH of the older population are in general factors that explain the self-reported QoL and SRH of the oldest-old cohorts. The interaction effect of residence and region matters more than each of the individual factors, in providing us with more detailed information on the role of geography in explaining QoL and health of the oldest-old. At a time when the oldest-old cohorts in China are at the beginning of their projected growth, these findings are vital for providing policy makers with more information on the urgency of making more geographically targeted policy to improve more effectively the self-reported QoL and SRH of the oldest-old population.
Journal Article
Comparing the Age-Friendliness of Different Neighbourhoods Using District Surveys: An Example from Hong Kong
To address the age-friendliness of living environment in cities, the World Health Organization (WHO) launched the \"Age-friendly cities\" (AFC) initiative in 2005. To date, however, no universal standard tool for assessing age-friendliness of a community has been agreed.
Two quantitative studies on AFC conducted in two Hong Kong districts-Sha Tin and Tuen Mun-were compared. A total of 801 residents aged ≥50 years were interviewed using structured questionnaires based on the WHO's AFC criteria. District-wide differences in age-friendliness were compared on the basis of eight domain scores. Multiple linear regression was used to examine associations with demographic and socio-economic characteristics. The provision of services and amenities was also compared to help explain the difference in domain scores.
Variations in mean domain scores were observed in both districts. Sha Tin showed significantly lower scores in outdoor spaces and buildings, transportation, social participation, respect and social inclusion, civic participation and employment, communication and information, as compared with Tuen Mun. Although a significantly higher score on the housing domain was observed in Sha Tin, differences in community and health services domains were insignificant. Socio-demographic factors, such as age group, gender, area of residence, type of housing, experience of elderly care, employment status, self-rated health and income, were associated with domain scores. However, variations in services and amenities provision appeared not to be strongly associated with district-wide difference in domain scores.
District differences in public opinions towards age-friendly characteristics were observed in this study. Except for two of the eight domains, Sha Tin had significantly lower scores than Tuen Mun. Some socio-demographic indicators seemed predictive to the differences. Paradoxically, Sha Tin had better services and infrastructure and higher socio-economic status, but lower age-friendliness. This warrants detailed research on psychosocial factors that may influence residents' perceptions of local environments.
Journal Article
Physical activity and gender buffer the association of retirement with functional impairment in Ghana
Females on average live longer but with higher rates of functional impairment and lower physical and economic activities than men. However, research linking retirement to functional impairment and the modifying role of gender and physical activity (PA) is limited especially in low- and middle-income countries. This paper examines the association between retirement and functional impairment in Ghana and evaluates the effect modification of the association by gender and PA. The sample included 1201 adults aged ≥ 50 years from a population-based study. Functional impairment was assessed with the activities of daily living scale. Ordinary least squares regression models adjusted for confounding variables and estimated gender-wise and PA heterogeneity effect of retirement on functional impairment. Regressions showed that retirement predicted an increase in functional impairment score in the full sample (
β
= .76,
p
< .001) and in men (
β
= 1.96,
p
< .001), but not in women. Interestingly, retirement significantly increased functional impairment in ≥ 65 age cohort (full sample:
β
= .71,
p
< .005; men:
β
= 1.86,
p
< .001) although not in women. However, the effect was significantly moderated by PA such that retirement × PA predicted a decrease in functional impairment in the full sample (
β
= −.81,
p
< .005) and the ≥ 65 age group (
β
= −.43,
p
< .005). Functional impairment risk of retirement is gender-specific, but PA buffers the relationship. Retirement is generally commonplace, but these findings imply that promoting PA may hold promise for addressing functional impairment in old age. Attending to the physical health needs of men during retirement should be a social policy priority.
Journal Article
Does social capital interact with economic hardships in influencing older adults’ health? A study from China
Background
The importance of social and economic capital as predictors of health is widely documented, yet the complexity of interactions between them and effects on older people’s health is still unclear. Combining the material and psychosocial explanations of health, this study explores the potential interactions between social and economic capital in influencing older adults’ health in urban and rural China.
Methods
Using data from the China Family Panel Survey, physical and mental health in 2018 were regressed on social and economic capital indicators in 2016, controlling for sociodemographic characteristics of 3535 respondents aged 65 and older. Rothman’s synergy index was calculated to investigate potential interaction effects.
Results
Economic hardships were significantly related to both self-reported health and mental health. Neighborhood cohesion and social participation were significantly associated with mental health for all, bonding trust was significantly associated with mental health for urban older people. We found no significant associations between social capital components and self-reported health. There was an interaction effect between low neighborhood cohesion and economic hardships, and between low social participation and economic hardships, creating an increased burden of poor mental health. The interaction effect between low bonding trust and economic hardships on mental health was apparent only among urban older people.
Conclusions
Geographical settings are important factors in the complexity between social and economic capital in affecting older health. Intervention efforts directed towards reducing simultaneously multiple dimensions of deprivation, such as poverty, social exclusion, social isolation, could be helpful in improving older people’s health. In materially deprived places, policies to promote health equity by improving social capital but without eliminating poverty may be less effective.
Journal Article
Social exclusion and health outcomes among empty nest and non-empty nest older people in China
Many existing studies lack a comprehensive picture of the social exclusion statuses and health outcomes of empty nesters and those empty nesters living alone or with a spouse only. Cross-sectional analysis was conducted on representative national data from the 2014 China Longitudinal Aging Social Survey, focusing on respondents aged 60 and above (N = 7,923). Four dimensions of social exclusion (social relationships, subjective feeling of being excluded, social activities and financial products) and three health outcomes (self-reported health (SRH), activities of daily living (ADLs) and depression), were considered. Results show that ‘empty nest’ older people were more likely to be excluded from social relationships and to experience subjective feelings of being excluded, and were less likely to participate in social activities than non-empty nesters. Empty nesters were significantly less likely to report fair SRH and ADL difficulties than non-empty nesters, but they were more likely to report having depression than non-empty nesters. Among ‘empty nest’ older people, empty nesters who were living alone were associated with higher levels of being excluded from social relationships and to experience subjective feelings of being excluded than those who were living with a spouse only. Future research could focus on the development of age-friendly communities which act as health interventions to address relevant situations of social exclusion and depression among empty nesters.
Journal Article
Social support networks and psychological wellbeing in community-dwelling older Ghanaian cohorts
ABSTRACTBackgroundSocial support networks for older persons have been related to health outcomes including differences in psychological wellbeing (PWB). However, the specifics of this relationship remain unclear especially in sub-Saharan Africa. This study investigates the (1) relationship between aspects of social support and PWB among older persons in Ghana and (2) the extent to which this relationship is moderated by their education levels and locational characteristics. MethodThe study included 1,200 community-residing individuals aged 50 years and older who participated in an Aging, Health, Psychological Wellbeing and Health-seeking Behavior Study (AHPWHB) conducted between July 2016 and February 2017. Logistic regression models evaluated the associations of social support and their interactions with education and locational variables in PWB. ResultsSeveral aspects of meaningful social support: family/friends contacts ( β = 0.958, p < 0.05), couple focused ( β = 0.887, p < 0.001), emotional bonds ( β = 0.658, p < 0.005), attending social events ( β = 0.519, p < 0.001) and remittances from children ( β = 0.394, p < 0.005) significantly related to improved PWB in later life. These associations remained robust and largely strengthened after accounting for respondents’ background and health-related factors. Education and locational characteristics substantially influenced the associations between social support and PWB. ConclusionThese findings suggest that especially in terms of PWB, aspects of meaningful social support networks are critical elements in later life. Strengthening opportunities for closer interpersonal relations with older persons may enhance their mental health, quality of life and independence.
Journal Article
CD40L stabilizes arterial thrombi by a β3 integrin–dependent mechanism
CD40L, a member of the tumor necrosis factor family of ligands, plays a major role in immune responses via its receptor, CD40. Recently, CD40L has been detected on the surfaces of activated platelets and shown to activate endothelium. Here we further addressed the function of platelet CD40L. We show that absence of CD40L affects the stability of arterial thrombi and delays arterial occlusion
in vivo
. Infusion of recombinant soluble (rs)CD40L restored normal thrombosis, whereas rsCD40L lacking the KGD integrin-recognition sequence did not. CD40-deficient mice exhibited normal thrombogenesis. rsCD40L specifically bound to purified integrin α
IIb
β
3
and to activated platelets in a β
3
-dependent manner and induced platelet spreading. In addition, rsCD40L promoted the aggregation of either human or mouse platelets under high shear rates. Thus, CD40L appears to be an α
IIb
β
3
ligand, a platelet agonist, and necessary for stability of arterial thrombi.
Journal Article
P2Y12 regulates platelet adhesion/activation, thrombus growth, and thrombus stability in injured arteries
The critical role for ADP in arterial thrombogenesis was established by the clinical success of P2Y12 antagonists, currently used at doses that block 40-50% of the P2Y12 on platelets. This study was designed to determine the role of P2Y12 in platelet thrombosis and how its complete absence affects the thrombotic process. P2Y12-null mice were generated by a gene-targeting strategy. Using an in vivo mesenteric artery injury model and real-time continuous analysis of the thrombotic process, we observed that the time for appearance of first thrombus was delayed and that only small, unstable thrombi formed in P2Y12-/- mice without reaching occlusive size, in the absence of aspirin. Platelet adhesion to vWF was impaired in P2Y12-/- platelets. While adhesion to fibrinogen and collagen appeared normal, the platelets in thrombi from P2Y12-/- mice on collagen were less dense and less activated than their WT counterparts. P2Y12-/- platelet activation was also reduced in response to ADP or a PAR-4-activating peptide. Thus, P2Y12 is involved in several key steps of thrombosis: platelet adhesion/activation, thrombus growth, and stability. The data suggest that more aggressive strategies of P2Y12 antagonism will be antithrombotic without the requirement of aspirin cotherapy and may provide benefits even to the aspirin-nonresponder population.
Journal Article