AbstractObjectivesTo examine the association between the Life Simple 7 cardiovascular health score at age 50 and incidence of dementia.DesignProspective cohort study.SettingCivil service departments ...in London (Whitehall II study; study inception 1985-88).Participants7899 participants with data on the cardiovascular health score at age 50.ExposuresThe cardiovascular health score included four behavioural (smoking, diet, physical activity, body mass index) and three biological (fasting glucose, blood cholesterol, blood pressure) metrics, coded on a three point scale (0, 1, 2). The cardiovascular health score was the sum of seven metrics (score range 0-14) and was categorised into poor (scores 0-6), intermediate (7-11), and optimal (12-14) cardiovascular health.Main outcome measureIncident dementia, identified through linkage to hospital, mental health services, and mortality registers until 2017.Results347 incident cases of dementia were recorded over a median follow-up of 24.7 years. Compared with an incidence rate of dementia of 3.2 (95% confidence interval 2.5 to 4.0) per 1000 person years among the group with poor cardiovascular health, the absolute rate differences per 1000 person years were −1.5 (95% confidence interval −2.3 to −0.7) for the group with intermediate cardiovascular health and −1.9 (−2.8 to −1.1) for the group with optimal cardiovascular health. Higher cardiovascular health score was associated with a lower risk of dementia (hazard ratio 0.89 (0.85 to 0.95) per 1 point increment in the cardiovascular health score). Similar associations with dementia were observed for the behavioural and biological subscales (hazard ratios per 1 point increment in the subscores 0.87 (0.81 to 0.93) and 0.91 (0.83 to 1.00), respectively). The association between cardiovascular health at age 50 and dementia was also seen in people who remained free of cardiovascular disease over the follow-up (hazard ratio 0.89 (0.84 to 0.95) per 1 point increment in the cardiovascular health score).ConclusionAdherence to the Life Simple 7 ideal cardiovascular health recommendations in midlife was associated with a lower risk of dementia later in life.
Summary Background Rejection of allografts has always been the major obstacle to transplantation success. We aimed to improve characterisation of different kidney-allograft rejection phenotypes, ...identify how each one is associated with anti-HLA antibodies, and investigate their distinct prognoses. Methods Patients who underwent ABO-compatible kidney transplantations in Necker Hospital and Saint-Louis Hospital (Paris, France) between Jan 1, 1998, and Dec 31, 2008, were included in our population-based study. We assessed patients who provided biopsy samples for acute allograft rejection, which was defined as the association of deterioration in function and histopathological lesions. The main outcome was kidney allograft loss—ie, return to dialysis. To investigate distinct rejection patterns, we retrospectively assessed rejection episodes with review of graft histology, C4d in allograft biopsies, and donor-specific anti-HLA antibodies. Findings 2079 patients were included in the main analyses, of whom 302 (15%) had acute biopsy-proven rejection. We identified four distinct patterns of kidney allograft rejection: T cell-mediated vascular rejection (26 patients 9%), antibody-mediated vascular rejection (64 21%), T cell-mediated rejection without vasculitis (139 46%), and antibody-mediated rejection without vasculitis (73 24%). Risk of graft loss was 9·07 times (95 CI 3·62–19·7) higher in antibody-mediated vascular rejection than in T cell-mediated rejection without vasculitis (p<0·0001), compared with an increase of 2·93 times (1·1–7·9; P=0·0237) in antibody-mediated rejection without vasculitis and no significant rise in T cell-mediated vascular rejection (hazard ratio HR 1·5, 95% CI 0·33–7·6; p=0·60). Interpretation We have identified a type of kidney rejection not presently included in classifications: antibody-mediated vascular rejection. Recognition of this distinct phenotype could lead to the development of new treatment strategies that could salvage many kidney allografts. Funding None.
Anti-human leukocyte antigen donor-specific antibodies (anti-HLA DSAs) are recognized as a major barrier to patients' access to organ transplantation and the major cause of graft failure. The ...capacity of circulating anti-HLA DSAs to activate complement has been suggested as a potential biomarker for optimizing graft allocation and improving the rate of successful transplantations.
To address the clinical relevance of complement-activating anti-HLA DSAs across all solid organ transplant patients, we performed a meta-analysis of their association with transplant outcome through a systematic review, from inception to January 31, 2018. The primary outcome was allograft loss, and the secondary outcome was allograft rejection. A comprehensive search strategy was conducted through several databases (Medline, Embase, Cochrane, and Scopus). A total of 5,861 eligible citations were identified. A total of 37 studies were included in the meta-analysis. Studies reported on 7,936 patients, including kidney (n = 5,991), liver (n = 1,459), heart (n = 370), and lung recipients (n = 116). Solid organ transplant recipients with circulating complement-activating anti-HLA DSAs experienced an increased risk of allograft loss (pooled HR 3.09; 95% CI 2.55-3.74, P = 0.001; I2 = 29.3%), and allograft rejection (pooled HR 3.75; 95% CI: 2.05-6.87, P = 0.001; I2 = 69.8%) compared to patients without complement-activating anti-HLA DSAs. The association between circulating complement-activating anti-HLA DSAs and allograft failure was consistent across all subgroups and sensitivity analyses. Limitations of the study are the observational and retrospective design of almost all included studies, the higher proportion of kidney recipients compared to other solid organ transplant recipients, and the inclusion of fewer studies investigating allograft rejection.
In this study, we found that circulating complement-activating anti-HLA DSAs had a significant deleterious impact on solid organ transplant survival and risk of rejection. The detection of complement-activating anti-HLA DSAs may add value at an individual patient level for noninvasive biomarker-guided risk stratification.
National Clinical Trial protocol ID: NCT03438058.
AbstractObjectiveTo develop and validate an integrative system to predict long term kidney allograft failure.DesignInternational cohort study.SettingThree cohorts including kidney transplant ...recipients from 10 academic medical centres from Europe and the United States.ParticipantsDerivation cohort: 4000 consecutive kidney recipients prospectively recruited in four French centres between 2005 and 2014. Validation cohorts: 2129 kidney recipients from three centres in Europe and 1428 from three centres in North America, recruited between 2002 and 2014. Additional validation in three randomised controlled trials (NCT01079143, EudraCT 2007-003213-13, and NCT01873157).Main outcome measureAllograft failure (return to dialysis or pre-emptive retransplantation). 32 candidate prognostic factors for kidney allograft survival were assessed.ResultsAmong the 7557 kidney transplant recipients included, 1067 (14.1%) allografts failed after a median post-transplant follow-up time of 7.12 (interquartile range 3.51-8.77) years. In the derivation cohort, eight functional, histological, and immunological prognostic factors were independently associated with allograft failure and were then combined into a risk prediction score (iBox). This score showed accurate calibration and discrimination (C index 0.81, 95% confidence interval 0.79 to 0.83). The performance of the iBox was also confirmed in the validation cohorts from Europe (C index 0.81, 0.78 to 0.84) and the US (0.80, 0.76 to 0.84). The iBox system showed accuracy when assessed at different times of evaluation post-transplant, was validated in different clinical scenarios including type of immunosuppressive regimen used and response to rejection therapy, and outperformed previous risk prediction scores as well as a risk score based solely on functional parameters including estimated glomerular filtration rate and proteinuria. Finally, the accuracy of the iBox risk score in predicting long term allograft loss was confirmed in the three randomised controlled trials.ConclusionAn integrative, accurate, and readily implementable risk prediction score for kidney allograft failure has been developed, which shows generalisability across centres worldwide and common clinical scenarios. The iBox risk prediction score may help to guide monitoring of patients and further improve the design and development of a valid and early surrogate endpoint for clinical trials.Trial registrationClinicaltrials.gov NCT03474003.
Anti-HLA antibodies hamper successful transplantation, and activation of the complement cascade is involved in antibody-mediated rejection. We investigated whether the complement-binding capacity of ...anti-HLA antibodies plays a role in kidney-allograft failure.
We enrolled patients who received kidney allografts at two transplantation centers in Paris between January 1, 2005, and January 1, 2011, in a population-based study. Patients were screened for the presence of circulating donor-specific anti-HLA antibodies and their complement-binding capacity. Graft injury phenotype and the time to kidney-allograft loss were assessed.
The primary analysis included 1016 patients. Patients with complement-binding donor-specific anti-HLA antibodies after transplantation had the lowest 5-year rate of graft survival (54%), as compared with patients with non-complement-binding donor-specific anti-HLA antibodies (93%) and patients without donor-specific anti-HLA antibodies (94%) (P<0.001 for both comparisons). The presence of complement-binding donor-specific anti-HLA antibodies after transplantation was associated with a risk of graft loss that was more than quadrupled (hazard ratio, 4.78; 95% confidence interval CI, 2.69 to 8.49) when adjusted for clinical, functional, histologic, and immunologic factors. These antibodies were also associated with an increased rate of antibody-mediated rejection, a more severe graft injury phenotype with more extensive microvascular inflammation, and increased deposition of complement fraction C4d within graft capillaries. Adding complement-binding donor-specific anti-HLA antibodies to a traditional risk model improved the stratification of patients at risk for graft failure (continuous net reclassification improvement, 0.75; 95% CI, 0.54 to 0.97).
Assessment of the complement-binding capacity of donor-specific anti-HLA antibodies appears to be useful in identifying patients at high risk for kidney-allograft loss.
The benefit of ideal cardiovascular health (CVH) on health-related outcomes in middle-aged patients is firmly established. In the growing elderly population, the high prevalence of comorbidities and ...medications for chronic diseases may offset such benefit.
This study analyzed the association of ideal CVH with mortality, incident coronary heart disease, and stroke events in elderly individuals from the community.
Between 1999 and 2001, 9,294 men and women, noninstitutionalized and aged 65 years and over were examined, and thereafter followed up for the occurrence of vascular events and mortality within the Three-City Study. Hazard ratios (HRs) were estimated by Cox proportional hazard model and compared subjects with 3 to 4 and subjects with 5 to 7 ideal metrics with those with 0 to 2 ideal metrics, respectively.
The mean age was 73.8 ± 5.3 years, and 36.7% were men. Only 5% of the participants had ≥5 metrics at the ideal level. After a median follow-up of 10.9 years and 8.6 years, respectively 1,987 deaths and 680 adjudicated coronary heart disease or stroke events had occurred. In multivariate analysis, the risk of mortality and of vascular events decreased across the categories of ideal metrics. In particular, in subjects with ≥5 metrics at the ideal level (compared with those with ≤2), there was a 29% (hazard ratio HR: 0.71; 95% confidence interval CI: 0.55 to 0.90) decreased risk of all-cause mortality and 67% (HR: 0.33; 95% CI: 0.19 to 0.57) for coronary heart disease and stroke combined (p for trend <0.001).
Even in the elderly, higher CVH status is highly beneficial regarding mortality and vascular event risks.
Kidney allograft rejection can occur in clinically stable patients, but long-term significance is unknown. We determined whether early recognition of subclinical rejection has long-term consequences ...for kidney allograft survival in an observational prospective cohort study of 1307 consecutive nonselected patients who underwent ABO-compatible, complement-dependent cytotoxicity-negative crossmatch kidney transplantation in Paris (2000-2010). Participants underwent prospective screening biopsies at 1 year post-transplant, with concurrent evaluations of graft complement deposition and circulating anti-HLA antibodies. The main analysis included 1001 patients. Three distinct groups of patients were identified at the 1-year screening: 727 (73%) patients without rejection, 132 (13%) patients with subclinical T cell-mediated rejection (TCMR), and 142 (14%) patients with subclinical antibody-mediated rejection (ABMR). Patients with subclinical ABMR had the poorest graft survival at 8 years post-transplant (56%) compared with subclinical TCMR (88%) and nonrejection (90%) groups (P<0.001). In a multivariate Cox model, subclinical ABMR at 1 year was independently associated with a 3.5-fold increase in graft loss (95% confidence interval, 2.1 to 5.7) along with eGFR and proteinuria (P<0.001). Subclinical ABMR was associated with more rapid progression to transplant glomerulopathy. Of patients with subclinical TCMR at 1 year, only those who further developed de novo donor-specific antibodies and transplant glomerulopathy showed higher risk of graft loss compared with patients without rejection. Our findings suggest that subclinical TCMR and subclinical ABMR have distinct effects on long-term graft loss. Subclinical ABMR detected at the 1-year screening biopsy carries a prognostic value independent of initial donor-specific antibody status, previous immunologic events, current eGFR, and proteinuria.
BACKGROUND
How much the association between depressive symptoms (DSs) and all‐cause mortality depends on cardiovascular disease (CVD) events is poorly known. We aimed to prospectively quantify the ...association between DSs at repeated study visits and all‐cause and cause‐specific mortality, and the influence of incident CVD on this association.
METHODS
The Three‐City Study has included adults 65 years and older, who were examined at baseline between 1999 and 2001 and after 2, 4, 7, and 10 years of follow‐up. At each visit, a score of 16 or greater on the 20‐item Center for Epidemiologic Studies Depression Scale defined the presence of DSs. DS status and incident coronary heart disease or stroke events were used as time‐dependent variables in a Cox proportional hazard model of mortality.
RESULTS
We studied 7377 participants (63.7% females) aged 73.8 years (SD = 5.4 years) without a history of CVD at baseline examination. DSs were present in 19% to 22% of subjects at each study visit. During a median follow‐up of 9.4 years, 650 subjects developed a first CVD, and 1255 had died. After adjustment for baseline sociodemographic variables, vascular risk factors, impairment in daily life activities, and antidepressants, time‐dependent DSs were associated with a 28% increased risk of mortality (hazard ratio HR = 1.28; 95% confidence interval CI = 1.06‐1.55), and incident CVD event was associated with a 63% increased risk (HR = 1.63; 95% CI = 1.30‐2.04). However, the association between DSs and mortality was not influenced by the occurrence of CVD (HR for DS and CVD interaction = 1.03; 95% CI = 0.66‐1.61). A mediation analysis confirmed that incident CVD only explained 6.9% of the excess of mortality associated with DSs.
CONCLUSION
In older participants, the increased risk of all‐cause mortality associated with the presence of DSs at baseline and during follow‐up is not modified by and is moderately mediated by incident CVD. J Am Geriatr Soc 67:546–552, 2019.
Objectives
To examine the association between life‐course body silhouette changes and oral conditions in adulthood.
Methods
At study recruitment (2008–2012), 5430 adults underwent a full‐mouth ...clinical examination and recalled their body silhouettes at ages 8, 15, 25, 35 and 45. Life‐course trajectories of body silhouettes were computed using group‐based trajectory modelling. Gingival inflammation, dental plaque, masticatory units, numbers of healthy, missing, decayed and filled teeth at study recruitment were clustered. The associations between body silhouette trajectories and clusters of oral conditions were assessed by multinomial logistic regression.
Results
The final analysis included 4472 participants. Five body silhouette trajectories were established: lean‐stable (30.0%), lean‐increased (19.3%), moderate stable (18.1%), lean‐marked increased (25.8%) and heavy stable (6.7%). Three clusters of oral conditions were identified: optimal oral health and preserved masticatory capacity (70.0%, cluster 1), moderate oral health and moderately impaired masticatory capacity (25.4%, cluster 2) and poor oral health and severely impaired masticatory capacity (4.7%, cluster 3). Participants with a lean‐increased trajectory were 58% more likely than those with a lean‐stable trajectory to be in cluster 3 (aOR 1.58 95% CI 1.07; 2.35) relative to cluster 1, independently of covariates measured at study recruitment and including age, sex, smoking, socioeconomic status, BMI, hypertension, type 2 diabetes, cholesterol and triglycerides.
Conclusions
A life‐course lean‐increased body silhouette trajectory is associated with higher likelihood of poor oral health and severely impaired masticatory capacity in adulthood.
Although such data are available for young competitive athletes, the prevalence, characteristics, and outcome of sports-related sudden death have not been assessed previously in the general ...population.
A prospective and comprehensive national survey was performed throughout France from 2005 to 2010, involving subjects 10 to 75 years of age. Case detection for sports-related sudden death, including resuscitated cardiac arrest, was undertaken via national ambulance service reporting and Web-based screening of media releases. The overall burden of sports-related sudden death was 4.6 cases per million population per year, with 6% of cases occurring in young competitive athletes. Sensitivity analyses used to address suspected underreporting demonstrated an incidence ranging from 5 to 17 new cases per million population per year. More than 90% of cases occurred in the context of recreational sports. The age of subjects was relatively young (mean ± SD 46 ± 15 years), with a predominance of men (95%). Although most cases were witnessed (93%), bystander cardiopulmonary resuscitation was only commenced in 30.7% of cases. Bystander cardiopulmonary resuscitation (odds ratio 3.73, 95% confidence interval 2.19 to 6.39, P<0.0001) and initial use of cardiac defibrillation (odds ratio 3.71, 95% confidence interval 2.07 to 6.64, P<0.0001) were the strongest independent predictors for survival to hospital discharge (15.7%, 95% confidence interval 13.2% to 18.2%).
Sports-related sudden death in the general population is considerably more common than previously suspected. Most cases are witnessed, yet bystander cardiopulmonary resuscitation was only initiated in one third of cases. Given the often predictable setting of sports-related sudden death and that prompt interventions were significantly associated with improved survival, these data have implications for health services planning.
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