Effect of plasma exchange with albumin replacement on albumin functionality and organ dysfunction in acute-on-chronic liver failure.

Background & Aims: Effective treatments for acute-on-chronic liver failure (ACLF) are a major unmet need. This proof-of-concept pilot study was aimed at evaluating the effects of plasma exchange (PE) with albumin 5% (PE-A5%) on albumin functional capacity and organ dysfunction in patients with ACLF. Methods: Ten adult patients were enrolled in a single-center phase II, prospective, open-label, non-controlled study. Six PE-A5% sessions were performed in 10 days followed by a 1-month follow-up visit. Albumin functional capacity and circulatory function were assessed, as were renal, cerebral, and liver function, and systemic inflammation. The main safety variable was the percentage of PE sessions associated with at least one procedure-related adverse event (AE). Results: Patients with ACLF showed lower albumin binding capacity, lower antioxidant capacity, and lower levels of albumin with preserved structure compared to healthy donors (n = 19). From baseline to day 11, PE-A5% treatment increased albumin levels and improved albumin binding capacity to Sudlow site II (15.3±1.6 mg/ml to 18.9±1.7 mg/ml; p = 0.003), fatty acid-binding capacity (8.2±1.4 µM to 3.1±1.5 µM; p = 0.013) and antioxidant capacity (human mercaptalbumin 9.5±1.5 mg/ml to 14.6±1.6 mg/ml; p = 0.001). Native albumin levels were increased throughout day 1-11 PE-A5% sessions (6.5±1.0 mg/ml to 10.2±1.4 mg/ml; p = 0.035). PE-A5% improved systemic hemodynamics (mean arterial pressure, heart rate, cardiac index), renal function (creatinine level, blood urea nitrogen), cerebral function (hepatic encephalopathy grade), liver parameters (transaminases, bilirubin) and inflammatory parameters (C-reactive protein, leukocyte count). All patients had at least one of the 78 AEs reported, mostly mild (product/procedure-related: 36%). Sixteen serious AEs were reported in eight patients (procedure/product-related: none). Conclusions: PE-A5% was a safe procedure associated with positive effects on albumin functionality, and circulatory, renal, cerebral, and liver function in patients with ACLF. Impact and implications: Acute-on-chronic liver failure (ACLF) is a clinical condition characterized by severe systemic inflammation, organ failure, and high mortality. Plasma exchange removes patient's plasma containing pathogenic substances, replacing it with 5% albumin and fresh frozen plasma (PE-A5%). In this study, cirrhotic patients with ACLF were treated with PE-A5%, which was a safe procedure that increased binding and antioxidant capacity of patients' albumin, while improving circulatory, kidney, brain, and liver functions. These beneficial effects could impact survival in ACLF. ClinicalTrialsgov Identifier: NCT01201720. EudraCT number: 2010-021360-15.

Multimodal spatial availability: A singly-constrained measure of accessibility considering multiple modes.

Place-based accessibility measures communicate the potential interaction with opportunities at a zone that populations can access. Recent research has explored the implications of how opportunities are counted by different accessibility methods. In conventional measures, opportunities are multiply counted if more than one zone offers access to the same opportunity. This multi-count of opportunities leads to values of accessibility that are difficult to interpret. A possible solution to enhance the meaning-making of accessibility results is by constraining the calculations to match a known quantity. This ensures all zonal values sum up to a predetermined quantity (i.e., the total number of opportunities). In this way, each value can be meaningfully related to this total. A recent effort that implements this solution is spatial availability, a singly-constrained accessibility measure. In this paper, we extend spatial availability for use in the case of multiple modes or more generally, heterogeneous population segments with distinct travel behaviors. After deriving a multimodal version of spatial availability, we proceed to illustrate its features using a synthetic example. We then apply it to an empirical example of low emission zones in Madrid, Spain. We conclude with suggestions for future research and its use in evaluating policy interventions.

Well-being implications of immobility during COVID-19: evidence from a student sample in Bangladesh using the satisfaction with life scale.

Immobility is known to impact health and well-being by reducing social contact, activity participation, and changing time use patterns. These unfortunate effects mostly affect specific demographic segments, including older adults, low income families, people who face disabilities, and those living in conflict zones. Emergency measures taken during the COVID-19 pandemic mandated or strongly recommended limitations to mobility, thereby causing this condition for segments of the public not usually characterized by high levels of immobility. In the context of the pandemic, reduced mobility was the non-pharmaceutical intervention of choice, and the evidence suggests that it helped to keep incidences of the disease from exploding. On the other hand, there is also a need to understand how mobility restrictions may have had incidental impacts, including to well-being, in population groups that have not been studied from this perspective before. In this spirit, the present paper uses the items of the Satisfaction with Life Scale to investigate how aspects of well-being changed during the pandemic, using a sample of 400 college and university students in Dhaka, Bangladesh. Analysis is based on multivariate ordered models and the results suggest that being less mobile, less active, and changes in activity time use due COVID-19 had an impact on the satisfaction with life of students. The detrimental effect was more marked for males and students from low-income households. Additionally, perceptions of residential characteristics and sense of belonging also correlate with satisfaction with life in the period under study.

Impact of therapeutic and low volume plasma exchange on clinical laboratory parameters in patients treated for Alzheimer's disease from the AMBAR study.

INTRODUCTION: Little is known about the impact of plasma exchange (PE) on clinical laboratory parameters in Alzheimer's disease (AD) patients. METHODS: AD patients in the AMBAR trial (N = 322) received weekly therapeutic PE (TPE) for 6 weeks followed by monthly low-volume PE (LVPE) for12 months. Treatment were placebo (sham PE), low-albumin, low-albumin + IVIG (i.e., albumin alternated with intravenous immunoglobulin) and high-albumin + IVIG. RESULTS: Coagulation parameters transiently increased post-TPE. Blood calcium, platelets, and albumin levels decreased but remained within the reference range. Leukocyte counts increased. Fibrinogen, hemoglobin, total protein, gamma globulin, and IgG, transiently dipped below the reference range. Hypogammaglobulinemia (7.2 g/L) persisted in pre-TPE measurements. No changes were observed during the LVPE period. Cerebrospinal fluid parameters and vital signs were unchanged throughout. CONCLUSION: Laboratory parameters of AD patients were affected by TPE similarly to effects of PE-treatment for other pathologies. These effects were less pronounced or non-existent for LVPE.

Introducing spatial availability, a singly-constrained measure of competitive accessibility.

Accessibility indicators are widely used in transportation, urban and healthcare planning, among many other applications. These measures are weighted sums of reachable opportunities from a given origin, conditional on the cost of movement, and are estimates of the potential for spatial interaction. Over time, various proposals have been forwarded to improve their interpretability: one of those methodological additions have been the introduction of competition. In this paper we focus on competition, but first demonstrate how a widely used measure of accessibility with congestion fails to properly match the opportunity-seeking population. We then propose an alternative formulation of accessibility with competition, a measure we call spatial availability. This measure relies on proportional allocation balancing factors (friction of distance and population competition) that are equivalent to imposing a single constraint on conventional gravity-based accessibility. In other words, the proportional allocation of opportunities results in a spatially available opportunities value which is assigned to each origin that, when all origin values are summed, equals the total number of opportunities in the region. We also demonstrate how Two-Stage Floating Catchment Area (2SFCA) methods are equivalent to spatial availability and can be reconceptualized as singly-constrained accessibility. To illustrate the application of spatial availability and compare it to other relevant measures, we use data from the 2016 Transportation Tomorrow Survey of the Greater Golden Horseshoe area in southern Ontario, Canada. Spatial availability is an important contribution since it clarifies the interpretation of accessibility with competition and paves the way for future applications in equity analysis (e.g., spatial mismatch, opportunity benchmarking, policy intervention scenario analysis).

Feasibility, safety, and tolerability of two modalities of plasma exchange with albumin replacement to treat elderly patients with Alzheimer's disease in the AMBAR study.

BACKGROUND: In the Alzheimer Management by Albumin Replacement (AMBAR) study, mild-to-moderate Alzheimer's disease (AD) patients were treated with a plasma exchange (PE) program. Feasibility and safety of PE in this specific population are poorly understood and were analyzed in detail in this study. METHODS: Qualified patients were treated with 6 weeks of weekly conventional therapeutic plasma exchange (TPE) with albumin replacement followed by monthly low-volume plasma exchange (LVPE) for 12 months. The patients were divided into four groups: placebo (sham PE treatment), low-albumin (20 g), low-albumin + intravenous immunoglobulin (IVIG) (10 g), and high-albumin (40 g) + IVIG (20 g). Adverse events (AEs) were recorded and analyzed for all PE treatment groups and PE modalities. RESULTS: PE procedure-related AEs were more common in the active treatment groups (16.9% out of 1283 TPE and 12.5% out of 2203 LVPE were associated with at least one AE, a similar rate than in other PE indications) than in the placebo group (0.7% out of 1223 sham PE). Percentage of procedures with at least one AEs was higher with central venous access compared to peripheral venous access in all three active treatment groups (20.1% vs 13.1%, respectively). CONCLUSION: The TPE and LVPE procedures used in the AMBAR study on mild-to-moderate AD population were as safe and feasible as in other therapeutic applications of PE or routine plasmapheresis.

Children's Access to Non-School Destinations by Active or Independent Travel: A Scoping Review.

BACKGROUND: Children's access to non-school destinations is important for their well-being, but this has been overlooked in transport planning. Research on children's access to non-school destinations is growing, and there is a need for a comprehensive overview, examining both quantitative and qualitative studies, of the existing evidence on places that children access by active or independent travel. OBJECTIVES: Identify and summarize quantitative and qualitative research on the topic of active or independent travel to non-school destinations for elementary aged children (6 to 13 years old). METHODS: Papers published in English between 1980 and July 2021 were sourced from: (i) Web of Science Core Collection; (ii) PubMed; and (iii) APA PsycInfo. Three relevant journals related to children and transport were hand searched: (i) Children's Geographies; (ii) Journal of Transport & Health; and (iii) Journal of Transport Geography. The search was limited to peer-reviewed articles published in English between 1980 and July 2021. Covidence, an online software platform for systematic reviews, was used to organize articles during the title and abstract screening stage. PRISMA-Scr is applied for reporting. RESULTS: 27 papers were retained from an initial 1293 identified peer-reviewed articles. The results reveal that children in different geographies travel unsupervised or by active modes to places that support different domains of their well-being such as a friend or relative's home, local parks or green spaces, recreational facilities, and different retail locations (e.g., restaurants). There is evidence that children's ability to reach certain places is constrained, likely due to safety concerns or environmental barriers. CONCLUSIONS: Research on children's diverse destinations is relatively limited as compared to trips to school. Various methodologies have been applied and can be combined to completement each other such as objective GPS tracking and subjective surveys on places children would go if they were available. Future research should clearly report and discuss the non-school destinations that children access to better inform transport planning and policy for all aspects of children's lives.

Neuroimaging analyses from a randomized, controlled study to evaluate plasma exchange with albumin replacement in mild-to-moderate Alzheimer's disease: additional results from the AMBAR study.

PURPOSE: This study was designed to detect structural and functional brain changes in Alzheimer's disease (AD) patients treated with therapeutic plasma exchange (PE) with albumin replacement, as part of the recent AMBAR phase 2b/3 clinical trial. METHODS: Mild-to-moderate AD patients were randomized into four arms: three arms receiving PE with albumin (one with low-dose albumin, and two with low/high doses of albumin alternated with IVIG), and a placebo (sham PE) arm. All arms underwent 6 weeks of weekly conventional PE followed by 12 months of monthly low-volume PE. Magnetic resonance imaging (MRI) volumetric analyses and regional and statistical parametric mapping (SPM) analysis on 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) were performed. RESULTS: MRI analyses (n = 198 patients) of selected subcortical structures showed fewer volume changes from baseline to final visit in the high albumin + IVIG treatment group (p < 0.05 in 3 structures vs. 4 to 9 in other groups). The high albumin + IVIG group showed no statistically significant reduction of right hippocampus. SPM 18FDG-PET analyses (n = 213 patients) showed a worsening of metabolic activity in the specific areas affected in AD (posterior cingulate, precuneus, and parieto-temporal regions). The high-albumin + IVIG treatment group showed the greatest metabolic stability over the course of the study, i.e., the smallest percent decline in metabolism (MaskAD), and least progression of defect compared to placebo. CONCLUSIONS: PE with albumin replacement was associated with fewer deleterious changes in subcortical structures and less metabolic decline compared to the typical of the progression of AD. This effect was more marked in the group treated with high albumin + IVIG. TRIAL REGISTRATION: (AMBAR trial registration: EudraCT#: 2011-001,598-25; ClinicalTrials.gov ID: NCT01561053).

Pharmacokinetic modeling and simulation of subcutaneous and intravenous IgG dosing in patients with primary immunodeficiency diseases.

A population pharmacokinetic (PK) model for comparing the PK of subcutaneously administered immunoglobulin G (IgG) replacement therapy (SCIG) with Gamunex-C 10% or SCIG 20% formulations in patients with primary immunodeficiency diseases was developed using data from 3 clinical trials (N = 95, 69.5% adults, 30.5% <18 years) of intravenous IG (IVIG) 10% and SCIG 10% or SCIG 20%. Serum IgG exposure following switches from IVIG 10% every 3 or 4 weeks to biweekly SCIG 20% (dose adjustment factor 1.0 or 1.37) and from weekly SCIG 20% to biweekly SCIG 20% or SCIG 20% 2-7 times/week was simulated. The PK of IVIG 10% and SCIG 20% were adequately described by a 2-compartment model with first-order absorption rate constant of exogenous IgG from an SC depot compartment into the central compartment and first-order elimination from the central compartment. Switching from IVIG 10% every 4 weeks to biweekly SCIG 20% produced similar serum IgG exposure, with lower peak and higher trough serum IgG concentrations. Switching from IVIG 10% every 3 or 4 weeks to weekly and biweekly SCIG 20% yielded comparable IgG exposure and clinically effective trough IgG concentrations.

Plasma exchange with albumin replacement and disease progression in amyotrophic lateral sclerosis: a pilot study.

BACKGROUND: Plasma exchange (PE) is used to treat a range of neurological disorders. Based on results demonstrated in Alzheimer's disease, we theorized that PE with albumin replacement (PE-A) might alter the metabolic profile of plasma and cerebrospinal fluid in patients with amyotrophic lateral sclerosis (ALS) by removing disease-inducing molecules. The aim of this study was to evaluate the effect of PE-A on disease progression in ALS. METHODS: In this open-label, non-controlled, single-arm, prospective pilot study, 13 adults with ALS had 6 months' treatment with PE-A 5% and 6 months' follow-up. Primary endpoints were changes from baseline in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score and forced vital capacity (FVC) through 48 weeks. A post hoc analysis compared individual patient data with the expected ALSFRS-R progression slope. RESULTS: The median ALSFRS-R score declined throughout the study, although the rate of decline was slower than expected in seven patients at treatment end and in five patients at study end. Six patients remained in the same baseline slope progression category, and four patients improved their slope category at treatment end. Median FVC decreased significantly during the study. Treatment was well tolerated. Of 330 PE-A procedures, 0.9% were associated with potentially related adverse events. CONCLUSION: Although functional impairment progressed, about two-thirds of patients showed a slower than expected rate of decline at treatment end. Most patients had unaltered (54.5%) or reduced (36.4%) ALSFRS-R slope progression at treatment end. Further evaluation of PE-A in controlled studies involving more patients is warranted. EUDRACT NUMBER: 2013-004842-40. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02479802.

Neuropsychological, neuropsychiatric, and quality-of-life assessments in Alzheimer's disease patients treated with plasma exchange with albumin replacement from the randomized AMBAR study.

INTRODUCTION: We report the effects of plasma exchange (PE) with albumin replacement on neuropsychological, neuropsychiatric, and quality-of-life (QoL) outcomes in mild-to-moderate Alzheimer's disease (AD) patients in a phase 2b/3 trial (Alzheimer's Management by Albumin Replacement [AMBAR] study). METHODS: Three hundred forty-seven patients were randomized into placebo (sham-PE) and three PE-treatment arms with low/high doses of albumin, with/without intravenous immunoglobulin (IVIG). Specific test measurements were performed at baseline; month 2 (weekly conventional PE); months 6, 9, and 12 (monthly low-volume PE [LVPE]); and month 14. RESULTS: The PE-treated mild-AD cohort improved their language fluency and processing speed versus placebo at month 14 (effect sizes: >100%; P-values: .03 to .001). The moderate-AD cohort significantly improved short-term verbal memory (effect sizes: 94% to >100%; P-values: .02 to .003). The progression of the neuropsychiatric symptoms of PE-treated was similar to placebo. Mild-AD patients showed improved QoL (P-values: .04 to .008). DISCUSSION: PE-treated AD patients showed improvement in memory, language abilities, processing speed, and QoL-AD. No worsening of their psychoaffective status was observed.

Reproducibility of Research During COVID-19: Examining the Case of Population Density and the Basic Reproductive Rate from the Perspective of Spatial Analysis.

The emergence of the novel SARS-CoV-2 coronavirus and the global COVID-19 pandemic in 2019 led to explosive growth in scientific research. Alas, much of the research in the literature lacks conditions to be reproducible, and recent publications on the association between population density and the basic reproductive number of SARS-CoV-2 are no exception. Relatively few papers share code and data sufficiently, which hinders not only verification but additional experimentation. In this article, an example of reproducible research shows the potential of spatial analysis for epidemiology research during COVID-19. Transparency and openness means that independent researchers can, with only modest efforts, verify findings and use different approaches as appropriate. Given the high stakes of the situation, it is essential that scientific findings, on which good policy depends, are as robust as possible; as the empirical example shows, reproducibility is one of the keys to ensure this.

Changes in accessibility to emergency and community food services during COVID-19 and implications for low income populations in Hamilton, Ontario.

In this paper we analyze the changes in accessibility to emergency and community food services before and during the COVID-19 pandemic in the City of Hamilton, Ontario. Many of these food services are the last line of support for households facing food insecurity; as such, their relevance cannot be ignored in the midst of the economic upheaval caused by the pandemic. Our analysis is based on the application of balanced floating catchment areas and concentrates on households with lower incomes (

Therapeutic plasma exchange with albumin: a new approach to treat Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is a chronic neurodegenerative disease and the most common cause of dementia. It has a complex pathophysiology that is not yet completely understood, where multiple central, systemic, and environmental factors play a key role in disease progression. Understanding the multifactorial nature of AD is paramount to formulate new therapies. AREAS COVERED: The authors reviewed the role of the amyloid-ß-binding, antioxidant, and immunomodulatory properties of albumin in AD and the use of therapeutic plasma exchange (PE) in neurology. The results from the Alzheimer Management By Albumin Replacement (AMBAR) trial that combined the use of PE with albumin replacement in patients with mild-to-moderate AD, are also analyzed. EXPERT OPINION: Findings from the AMBAR study provide encouraging results in the treatment of AD with PE and albumin replacement, especially in patients at the moderate stage of the disease, who showed less cognitive decline from baseline compared with placebo in most of the variables analyzed. Further research is warranted to ascertain the possible mechanisms of action underlying these results. Different cohorts of patients that may also benefit from this treatment, such as those with mild cognitive impairment or other types of dementia, could also be the target of additional studies.

Emerging insights into the role of albumin with plasma exchange in Alzheimer's disease management.

Alzheimer's disease (AD) is a neurodegenerative process that inexorably leads to progressive deterioration of cognition function and, ultimately, death. Central pathophysiologic features of AD include the accumulation of extracellular plaques comprised of amyloid-ß peptide (Aß) and the presence of intraneuronal neurofibrillary tangles. However, a large body of evidence suggests that oxidative stress and inflammation are major contributors to the pathogenesis and progression of AD. To date, available pharmacologic treatments are only symptomatic. Clinical trials focused on amyloid and non-amyloid-targeted treatments with small molecule pharmacotherapy and immunotherapies have accumulated a long list of failures. Considering that around 90 % of the circulating Aß is bound to albumin, and that a dynamic equilibrium exists between peripheral and central Aß, plasma exchange with albumin replacement has emerged as a new approach in a multitargeted AD therapeutic strategy (AMBAR Program). In plasma exchange, a patient's plasma is removed by plasmapheresis to eliminate toxic endogenous substances, including Aß and functionally impaired albumin. The fluid replacement used is therapeutic albumin, which acts not only as a plasma volume expander but also has numerous pleiotropic functions (e.g., circulating Aß- binding capacity, transporter, detoxifier, antioxidant) that are clinically relevant for the treatment of AD. Positive results from the AMBAR Program (phase 1, 2, an 2b/3 trials), i.e., slower decline or stabilization of disease symptoms in the most relevant clinical efficacy and safety endpoints, offer a glimmer of hope to both AD patients and caregivers.

Exploring the determinants of older adults' susceptibility to pedestrians' incidents.

Older pedestrians (65 years and above) are among the most vulnerable road users. As the number and proportion of older adults grows in many countries, and awareness of the benefits of active travel becomes increasingly evident, it behooves researchers to further investigate the safety of older pedestrians. This study contributes to the literature by examining the factors that influence older adults' susceptibility to pedestrian incidents (falls incidents and pedestrian-vehicle collisions). To this end, a sample of older adults living in the Greater Golden Horseshoe, South Ontario, Canada was surveyed. The data were analyzed using descriptive statistics, Confirmatory Factor Analysis (CFA) and Structural Equation Modeling (SEM), to identify several latent factors that are significantly associated with older adults' involvement in pedestrian incidents. The results revealed that the factors that affect older adults' susceptibility to pedestrian incidents are level of difficulty while walking, fear of falling, and crossing evaluation capability. In contrast, level of pedestrian confidence and level of risk-taking crossing behavior are not among the significant factors. It was also found that older pedestrians aged 65-75 years, males, and those who are still working had a greater probability to be involved in pedestrian incidents. These findings shed light on some key constraints of older pedestrians, and the extent to which each factor could improve their safety. This information, in turn, can be used by transportation authorities in prioritizing their plans, policies, and programs towards improving the safety and mobility of older pedestrians.