IMPORTANCE: Visual function is important for older adults. Interventions to preserve vision, such as cataract extraction, may modify dementia risk. OBJECTIVE: To determine whether cataract extraction ...is associated with reduced risk of dementia among older adults. DESIGN, SETTING, AND PARTICIPANTS: This prospective, longitudinal cohort study analyzed data from the Adult Changes in Thought study, an ongoing, population-based cohort of randomly selected, cognitively normal members of Kaiser Permanente Washington. Study participants were 65 years of age or older and dementia free at enrollment and were followed up biennially until incident dementia (all-cause, Alzheimer disease, or Alzheimer disease and related dementia). Only participants who had a diagnosis of cataract or glaucoma before enrollment or during follow-up were included in the analyses (ie, a total of 3038 participants). Data used in the analyses were collected from 1994 through September 30, 2018, and all data were analyzed from April 6, 2019, to September 15, 2021. EXPOSURES: The primary exposure of interest was cataract extraction. Data on diagnosis of cataract or glaucoma and exposure to surgery were extracted from electronic medical records. Extensive lists of dementia-related risk factors and health-related variables were obtained from study visit data and electronic medical records. MAIN OUTCOMES AND MEASURES: The primary outcome was dementia as defined by Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria. Multivariate Cox proportional hazards regression analyses were conducted with the primary outcome. To address potential healthy patient bias, weighted marginal structural models incorporating the probability of surgery were used and the association of dementia with glaucoma surgery, which does not restore vision, was evaluated. RESULTS: In total, 3038 participants were included (mean SD age at first cataract diagnosis, 74.4 (6.2) years; 1800 women (59%) and 1238 men (41%); and 2752 (91%) self-reported White race). Based on 23 554 person-years of follow-up, cataract extraction was associated with significantly reduced risk (hazard ratio, 0.71; 95% CI, 0.62-0.83; P < .001) of dementia compared with participants without surgery after controlling for years of education, self-reported White race, and smoking history and stratifying by apolipoprotein E genotype, sex, and age group at cataract diagnosis. Similar results were obtained in marginal structural models after adjusting for an extensive list of potential confounders. Glaucoma surgery did not have a significant association with dementia risk (hazard ratio, 1.08; 95% CI, 0.75-1.56; P = .68). Similar results were found with the development of Alzheimer disease dementia. CONCLUSIONS AND RELEVANCE: This cohort study found that cataract extraction was significantly associated with lower risk of dementia development. If validated in future studies, cataract surgery may have clinical relevance in older adults at risk of developing dementia.
Abstract
Climate change adaptation responses are being developed and delivered in many parts of the world in the absence of detailed knowledge of their effects on public health. Here we present the ...results of a systematic review of peer-reviewed literature reporting the effects on health of climate change adaptation responses in low- and middle-income countries (LMICs). The review used the ‘Global Adaptation Mapping Initiative’ database (comprising 1682 publications related to climate change adaptation responses) that was constructed through systematic literature searches in Scopus, Web of Science and Google Scholar (2013–2020). For this study, further screening was performed to identify studies from LMICs reporting the effects on human health of climate change adaptation responses. Studies were categorised by study design and data were extracted on geographic region, population under investigation, type of adaptation response and reported health effects. The review identified 99 studies (1117 reported outcomes), reporting evidence from 66 LMICs. Only two studies were
ex ante
formal evaluations of climate change adaptation responses. Papers reported adaptation responses related to flooding, rainfall, drought and extreme heat, predominantly through behaviour change, and infrastructural and technological improvements. Reported (direct and intermediate) health outcomes included reduction in infectious disease incidence, improved access to water/sanitation and improved food security. All-cause mortality was rarely reported, and no papers were identified reporting on maternal and child health. Reported maladaptations were predominantly related to widening of inequalities and unforeseen co-harms. Reporting and publication-bias seems likely with only 3.5% of all 1117 health outcomes reported to be negative. Our review identified some evidence that climate change adaptation responses may have benefits for human health but the overall paucity of evidence is concerning and represents a major missed opportunity for learning. There is an urgent need for greater focus on the funding, design, evaluation and standardised reporting of the effects on health of climate change adaptation responses to enable evidence-based policy action.
Cognitive impairment is a common and impactful symptom of relapsing-remitting multiple sclerosis (RRMS). Cognitive outcome measures are often used in cross-sectional studies, but their performance as ...longitudinal outcome measures in clinical trials is not widely researched. In this study, we used data from a large clinical trial to describe change on the Symbol Digit Modalities Test (SDMT) and the Paced Auditory Serial Addition Test (PASAT) over up to 144 weeks of follow-up.
We used the data set from DECIDE (clinicaltrials.gov identifier NCT01064401), a large randomized controlled RRMS trial to describe change on the SDMT and PASAT over 144 weeks of follow-up. We compared change on these cognitive outcomes with change on the timed 25-foot walk (T25FW), a well-established physical outcome measure. We investigated several definitions for clinically meaningful change: any change, 4-point change, 8-point change, and 20% change for the SDMT, any change, 4-point change, and 20% change for the PASAT, and 20% change for the T25FW.
DECIDE included 1,814 trial participants. SDMT and PASAT scores steadily improved throughout follow-up: the SDMT from a mean 48.2 (SD, 16.1) points at baseline to 52.6 (SD 15.2) at 144 weeks and the PASAT from 47.0 (SD 11.3) at baseline to 50.0 (SD 10.8) at 144 weeks. This improvement in scores is most likely due to a practice effect. Throughout the trial, participants were more likely to experience improvement than worsening of their SDMT and PASAT performance, whereas the number of worsening events on the T25FW steadily increased. Changing the definition of clinically meaningful change for the SDMT and PASAT or using a 6-month confirmation changed the overall number of worsening or improvement events but did not affect the overall behavior of these measures.
Our findings suggest that the SDMT and PASAT scores do not accurately reflect the steady cognitive decline that people with RRMS experience. Both outcomes show postbaseline increases in scores, which complicates the interpretation of these outcome measures in clinical trials. More research into the size of these changes is needed before recommending a general threshold for clinically meaningful longitudinal change.
To investigate the reliability of clinical outcomes in secondary progressive multiple sclerosis (SPMS) trials, we compared the frequency of progression and improvement events on different clinical ...outcome measures in the placebo arms of 2 large randomized controlled trial (RCT) datasets.
Using original trial data from the placebo arms of IMPACT (International MS Secondary Progressive Avonex Controlled Trial) and ASCEND (A Clinical Study of the Efficacy of Natalizumab on Reducing Disability Progression in Participants With Secondary Progressive Multiple Sclerosis), 2 large RCTs in SPMS, we compared disability progression and similarly defined improvement with and without 3- or 6-month confirmation on the outcome measures Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT), and their combinations.
In both datasets, the EDSS showed the highest rates of improvement over time, and the smallest difference between progression and improvement rates, followed by the T25FW and the 9HPT. For the T25FW and 9HPT, improvement rates were fairly stable over time and remained at below or around the 10% level. For the EDSS, improvement rates increased in parallel with disability progression rates.
All investigated outcome measures in SPMS showed some evidence of random variation and measurement error, the T25FW and 9HPT less so than the more established outcome EDSS. Our findings are relevant for the design and critical appraisal of trials in SPMS.
Fingolimod, a structural analog of sphingosine derived from fungal metabolites, is a functional antagonist of the G-protein-coupled sphingosine 1-phosphate (S1P) receptors S1P
1,3,4,5
. In the ...treatment of relapsing forms of multiple sclerosis (RMS), fingolimod acts by reversibly retaining central memory T cells and naïve T cells in lymph nodes, thereby reducing the recirculation of autoreactive lymphocytes to the central nervous system (CNS). Fingolimod also has differential effects on the trafficking and function of B-cell subtypes and natural killer (NK) cells in peripheral blood and the CNS. Fingolimod also crosses the blood–brain barrier (BBB) and accumulates in the CNS. Experimental evidence increasingly supports a direct action of fingolimod within the CNS on brain cells, providing protection against the neurodegenerative component of RMS. We review the direct influence of this compound on CNS pathogenesis in RMS, including the central effects of fingolimod in animal models of MS and on neural cell types that express S1P receptors, such as astrocytes, BBB endothelial cells, microglia, neurones, and oligodendrocytes, which are all involved in RMS pathology.
IMPORTANCE: Autologous hematopoietic stem cell transplantation (AHSCT) may be effective in aggressive forms of multiple sclerosis (MS) that fail to respond to standard therapies. OBJECTIVE: To ...evaluate the long-term outcomes in patients who underwent AHSCT for the treatment of MS in a large multicenter cohort. DESIGN, SETTING, AND PARTICIPANTS: Data were obtained in a multicenter, observational, retrospective cohort study. Eligibility criteria were receipt of AHSCT for the treatment of MS between January 1995 and December 2006 and the availability of a prespecified minimum data set comprising the disease subtype at baseline; the Expanded Disability Status Scale (EDSS) score at baseline; information on the administered conditioning regimen and graft manipulation; and at least 1 follow-up visit or report after transplant. The last patient visit was on July 1, 2012. To avoid bias, all eligible patients were included in the analysis regardless of their duration of follow-up. Data analysis was conducted from September 1, 2014 to April 27, 2015. EXPOSURES: Demographic, disease-related, and treatment-related exposures were considered variables of interest, including age, disease subtype, baseline EDSS score, number of previous disease-modifying treatments, and intensity of the conditioning regimen. MAIN OUTCOMES AND MEASURES: The primary outcomes were MS progression-free survival and overall survival. The probabilities of progression-free survival and overall survival were calculated using Kaplan-Meier survival curves and multivariable Cox proportional hazards regression analysis models. RESULTS: Valid data were obtained from 25 centers in 13 countries for 281 evaluable patients, with median follow-up of 6.6 years (range, 0.2-16 years). Seventy-eight percent (218 of 281) of patients had progressive forms of MS. The median EDSS score before mobilization of peripheral blood stem cells was 6.5 (range, 1.5-9). Eight deaths (2.8%; 95% CI, 1.0%-4.9%) were reported within 100 days of transplant and were considered transplant-related mortality. The 5-year probability of progression-free survival as assessed by the EDSS score was 46% (95% CI, 42%-54%), and overall survival was 93% (95% CI, 89%-96%) at 5 years. Factors associated with neurological progression after transplant were older age (hazard ratio HR, 1.03; 95% CI, 1.00-1.05), progressive vs relapsing form of MS (HR, 2.33; 95% CI, 1.27-4.28), and more than 2 previous disease-modifying therapies (HR, 1.65; 95% CI, 1.10-2.47). Higher baseline EDSS score was associated with worse overall survival (HR, 2.03; 95% CI, 1.40-2.95). CONCLUSIONS AND RELEVANCE: In this observational study of patients with MS treated with AHSCT, almost half of them remained free from neurological progression for 5 years after transplant. Younger age, relapsing form of MS, fewer prior immunotherapies, and lower baseline EDSS score were factors associated with better outcomes. The results support the rationale for further randomized clinical trials of AHSCT for the treatment of MS.
Glucose Levels and Risk of Dementia Crane, Paul K; Walker, Rod; Hubbard, Rebecca A ...
New England journal of medicine/The New England journal of medicine,
08/2013, Letnik:
369, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Diabetes increases the risk of dementia. In this study, higher levels of glucose, even in persons without clinical diabetes, also increased the risk of dementia.
With the aging of the population, ...dementia has become a major threat to public health worldwide.
1
The rate of obesity is also increasing, with a parallel increase in the rate of diabetes.
2
The results of studies assessing the association between obesity or diabetes and the risk of dementia have been mixed.
3
,
4
It is imperative to understand the potential consequences of the obesity and diabetes epidemics for the incidence of dementia.
5
Any effects that obesity has on the risk of dementia are likely to include effects on metabolism. We evaluated extensive longitudinal clinical data from a prospective cohort with research-quality . . .
Background/Objectives
Longitudinal studies have shown an increase in cognitive decline many years before clinical diagnosis of dementia. We sought to estimate changes, relative to “normal” aging, in ...the trajectory of scores on a global cognitive function test—the Cognitive Abilities Screening Instrument (CASI).
Design
A prospective cohort study.
Setting
Community‐dwelling members of a U.S. health maintenance organization.
Participants
Individuals aged 65 and older who had no dementia diagnosis at baseline and had at least two visits with valid CASI test score (N = 4,315).
Measurements
Average longitudinal trajectories, including changes in trajectory before clinical diagnosis in those who would be diagnosed with dementia, were estimated for CASI item response theory (IRT) scores. The impact of sex, education level, and APOE genotype on cognitive trajectories was assessed.
Results
Increased cognitive decline relative to “normal” aging was evident in CASI IRT at least 10 years before clinical diagnosis. Male gender, lower education, and presence of ≥1 APOE ε4 alleles were associated with lower average IRT scores. In those who would be diagnosed with dementia, a trajectory change point was estimated at an average of 3.1 years (95% confidence interval 3.0‐3.2) before clinical diagnosis, after which cognitive decline appeared to accelerate. The change point did not differ by sex, education level, or APOE ε4 genotype. There were subtle differences in trajectory slopes by sex and APOE ε4 genotype, but not by education.
Conclusion
Decline in average global cognitive function was evident at least 10 years before clinical diagnosis of dementia. The decline accelerated about 3 years before clinical diagnosis.
This study deals with the determination of optimal operation of a wastewater treatment system for minimizing greenhouse gas emissions, operating costs, and pollution loads in the effluent. To do ...this, an integrated performance index that includes three objectives was established to assess system performance. The ASMN_G model was used to perform system optimization aimed at determining a set of operational parameters that can satisfy three different objectives. The complex nonlinear optimization problem was simulated using the Nelder–Mead Simplex optimization algorithm. A sensitivity analysis was performed to identify influential operational parameters on system performance. The results obtained from the optimization simulations for six scenarios demonstrated that there are apparent trade-offs among the three conflicting objectives. The best optimized system simultaneously reduced greenhouse gas emissions by 31%, reduced operating cost by 11%, and improved effluent quality by 2% compared to the base case operation.
•We present a multi-objective optimization of wastewater treatment plant operation.•The optimization considered greenhouse gas emissions, cost, and effluent quality.•The wastewater treatment model predicts all three major greenhouse gas emissions.•The nonlinear optimization problem was solved with the Nelder–Mead Simplex method.•Compared to a base case, the three criteria were reduced by 31%, 11%, and 2%.
Background
It is unclear which cognitive outcome measure is the most useful for clinical trials in multiple sclerosis. To investigate the usefulness of the Symbol Digit Modalities Test (SDMT) as a ...clinical outcome measure in secondary progressive multiple sclerosis (SPMS), we describe the frequency of worsening and improvement events in a large randomized controlled trial (RCT) dataset.
Methods
Using original trial data from the ASCEND trial (n = 889), a recent large RCT in SPMS, we describe worsening and similarly defined improvement with and without 3‐month confirmation on the SDMT in the whole trial cohort and unconfirmed worsening and improvement on the Paced Auditory Serial Addition Test (PASAT) in a smaller subset (n = 107).
Results
Somewhat unexpectedly, SDMT scores steadily increased throughout the 2 years of follow‐up in this trial. There were overall few SDMT worsening events throughout the trial (generally fewer than 10% of participants), but improvement events steadily increased from around 50% of participants with improvement at 12 weeks to more than 70% at 84 weeks and beyond. PASAT scores followed a similar pattern.
Conclusions
In this well‐characterized clinical trial cohort, the SDMT does not reflect the steady cognitive decline that patients with SPMS experience. Both SDMT and PASAT scores improve throughout follow‐up, possibly due to a practice effect. The SDMT may not be a useful outcome measure of disease progression in 2‐year clinical trials in SPMS.
Unexpectedly, Symbol Digit Modalities Test (SDMT) measurements steadily increased during follow‐up in a large clinical trial dataset, likely due to a practice effect. The SDMT does not reflect the steady cognitive decline that patients with secondary progressive multiple sclerosis (SPMS) often experience. The SDMT may not be a useful outcome in SPMS clinical trials.
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