Public health and international drug policy Csete, Joanne, PhD; Kamarulzaman, Adeeba, Prof; Kazatchkine, Michel, Prof ...
The Lancet (British edition),
04/2016, Letnik:
387, Številka:
10026
Journal Article
Recenzirano
Odprti dostop
In September, 2015, the member states of the UN endorsed Sustainable Development Goals (SDGs) for 2030, which aspire to human-rights-centred approaches to ensuring the health and wellbeing of all ...people. The SDGs embody both the UN Charter values of rights and justice for all and the responsibility of states to rely on the best scientific evidence as they seek to better humankind. In April, 2016, these same states will consider control of illicit drugs, an area of social policy that has been fraught with controversy and thought of as inconsistent with human rights norms, and in which scientific evidence and public health approaches have arguably had too limited a role.
Summary Background Cognitive decline is a debilitating manifestation of disease progression in Parkinson's disease. We aimed to develop a clinical–genetic score to predict global cognitive impairment ...in patients with the disease. Methods In this longitudinal analysis, we built a prediction algorithm for global cognitive impairment (defined as Mini Mental State Examination MMSE ≤25) using data from nine cohorts of patients with Parkinson's disease from North America and Europe assessed between 1986 and 2016. Candidate predictors of cognitive decline were selected through a backward eliminated Cox's proportional hazards analysis using the Akaike's information criterion. These were used to compute the multivariable predictor on the basis of data from six cohorts included in a discovery population. Independent replication was attained in patients from a further three independent longitudinal cohorts. The predictive score was rebuilt and retested in 10 000 training and test sets randomly generated from the entire study population. Findings 3200 patients with Parkinson's disease who were longitudinally assessed with 27 022 study visits between 1986 and 2016 in nine cohorts from North America and Europe were assessed for eligibility. 235 patients with MMSE ≤25 at baseline and 135 whose first study visit occurred more than 12 years from disease onset were excluded. The discovery population comprised 1350 patients (after further exclusion of 334 with missing covariates) from six longitudinal cohorts with 5165 longitudinal visits over 12·8 years (median 2·8, IQR 1·6–4·6). Age at onset, baseline MMSE, years of education, motor exam score, sex, depression, and β-glucocerebrosidase ( GBA ) mutation status were included in the prediction model. The replication population comprised 1132 patients (further excluding 14 patients with missing covariates) from three longitudinal cohorts with 19 127 follow-up visits over 8·6 years (median 6·5, IQR 4·1–7·2). The cognitive risk score predicted cognitive impairment within 10 years of disease onset with an area under the curve (AUC) of more than 0·85 in both the discovery (95% CI 0·82–0·90) and replication (95% CI 0·78–0·91) populations. Patients scoring in the highest quartile for cognitive risk score had an increased hazard for global cognitive impairment compared with those in the lowest quartile (hazard ratio 18·4 95% CI 9·4–36·1). Dementia or disabling cognitive impairment was predicted with an AUC of 0·88 (95% CI 0·79–0·94) and a negative predictive value of 0·92 (95% 0·88–0·95) at the predefined cutoff of 0·196. Performance was stable in 10 000 randomly resampled subsets. Interpretation Our predictive algorithm provides a potential test for future cognitive health or impairment in patients with Parkinson's disease. This model could improve trials of cognitive interventions and inform on prognosis. Funding National Institutes of Health, US Department of Defense.
Nonalcoholic steatohepatitis (NASH) is a severe immune-mediated stage of nonalcoholic fatty liver disease that is rapidly becoming the most common etiology requiring liver transplantation (LT), with ...Hispanics bearing a disproportionate burden. This study aimed to uncover the underlying immune mechanisms of the disparities experienced by Hispanic patients undergoing LT for NASH.
We enrolled 164 LT recipients in our institutional review board-approved study, 33 of whom presented with NASH as the primary etiology of LT (20%), with 16 self-reported as Hispanic (48%). We investigated the histopathology of prereperfusion and postreperfusion biopsies, clinical liver function tests, longitudinal soluble cytokines via 38-plex Luminex, and immune cell phenotypes generated by prereperfusion and postreperfusion blood using 14-color flow cytometry and enzyme-linked immunosorbent assay.
Hispanic LT recipients transplanted for NASH were disproportionately female (81%) and disproportionately suffered poor outcomes in the first year posttransplant, including rejection (26%) and death (38%). Clinically, we observed increased pro-inflammatory and apoptotic histopathological features in biopsies, increased AST/international normalized ratio early posttransplantation, and a higher incidence of presensitization to mismatched HLA antigens expressed by the donor allograft. Experimental investigations revealed that blood from female Hispanic NASH patients showed significantly increased levels of leukocyte-attracting chemokines, innate-to-adaptive switching cytokines and growth factors, HMGB1 release, and TLR4/TLR8/TLR9/NOD1 activation, and produced a pro-inflammatory, pro-apoptotic macrophage phenotype with reduced CD14/CD68/CD66a/TIM-3 and increased CD16/CD11b/HLA-DR/CD80.
A personalized approach to reducing immunological risk factors is urgently needed for this endotype in Hispanics with NASH requiring LT, particularly in females.
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