Search

More than twelve million US adults ages forty and older are affected by vision impairment, and projections suggest that this number will double by 2050. Although most vision impairment can be eliminated with corrective lenses, many adults lack access to routine eye care. In this study, we analyzed detailed state-by-state Medicaid policies for 2022 and documented variability in coverage for adult vision services. Most fee-for-service Medicaid programs covered routine eye exams, although many did not cover glasses (twenty states) or low vision aids (thirty-five states), and about two-thirds of states with routine coverage required enrollee cost sharing. Managed care plans generally provided consistent or enhanced coverage relative to fee-for-service programs, although coverage sometimes varied between plans within a state. We estimated that about 6.5 million and 14.6 million adult enrollees resided in states without comprehensive coverage for routine eye exams and glasses, respectively. These findings reveal important gaps and opportunities for states to increase access to routine vision care.

Low-income Medicare beneficiaries rely on Medicaid for supplemental coverage but must meet income and asset tests to qualify. We examined states' income and asset tests for full-benefit Medicaid during the period 2006-18 and examined how alternative asset tests would affect eligibility for community-dwelling Medicare beneficiaries ages sixty-five and older. Most states have not updated the dollar limit of Medicaid's asset test since 1989, making the asset test increasingly restrictive in inflation-adjusted terms. We estimated that increasing Medicaid's asset limit by the Consumer Price Index, to Medicare Savings Program levels, or to $10,000 for individuals and $20,000 for couples would increase Medicaid eligibility by 1.7 percent, 4.4 percent, and 7.5 percent, respectively. Simplifying Medicaid's asset test to focus only on certain high-value assets would increase eligibility by 20.5 percent. Increasing asset limits would lessen restrictions on Medicaid eligibility that arise from stagnant asset tests, broadening eligibility for certain low-income Medicare beneficiaries and allowing them to retain higher, yet still modest, savings.

Objective: Molecular dynamics (MD) simulations provide an in silico method to study the structure of lipid-based formulations (LBFs) and the incorporation of poorly water-soluble drugs within such formulations. In order to validate the ability of MD to effectively model the properties of LBFs, this work investigates the well-known cyclosporine A formulations, Sandimmune® and Neoral®. Sandimmune® exhibits poor dispersibility and its absorption from the gastrointestinal tract is enhanced when administered after food, whereas Neoral® disperses comparatively well and shows no food effect., Methods: MD simulations were performed of both LBFs to investigate the differences observed in fasted and fed conditions. These conditions were also tested using an in vitro experimental model of dispersion and digestion., Results: These MD simulations were able to show that the food effect observed for Sandimmune® can be explained by large changes in drug solubilization on addition of bile. In contrast, Neoral® is well dispersed in water or in simulated fasted conditions, and this dispersion is relatively unchanged on moving to fed conditions. These differences were confirmed using dispersion and digestion in vitro experimental model., Conclusions: The current data suggests that MD simulations are a potential method to model the fate of LBFs in the gastrointestinal tract, predict their dispersion and digestion, investigate behaviour of APIs within the formulations, and provide insights into the clinical performance of LBFs., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Successful oral peptide delivery faces two major hurdles: low enzymatic stability in the gastro-intestinal lumen and poor intestinal membrane permeability. While lipid-based formulations (LBF) have the potential to overcome these barriers, effective formulation of peptides remains challenging. Lipophilic salt (LS) technology can increase the apparent lipophilicity of peptides, making them more suitable for LBF., Methods: As a model therapeutic peptide, octreotide (OCT) was converted to the docusate LS (OCT.DoS 2 ), and compared to the commercial acetate salt (OCT.OAc 2 ) in oral absorption studies and related in vitro studies, including parallel artificial membrane permeability assay (PAMPA), Caco-2, in situ intestine perfusion, and simulated digestion in vitro models. The in vivo oral absorption of OCT.DoS 2 and OCT.OAc 2 formulated in self-emulsifying drug delivery systems (SEDDS) was studied in rats., Results: LS formulation improved the solubility and loading of OCT in LBF excipients and OCT.DoS 2 in combination with SEDDS showed higher OCT absorption than the acetate comparator in the in vivo studies in rats. The Caco-2 and in situ intestine perfusion models indicated no increases in permeability for OCT.DoS 2 . However, the in vitro digestion studies showed reduced enzymatic degradation of OCT.DoS 2 when formulated in the SEDDS formulations. Further in vitro dissociation and release studies suggest that the enhanced bioavailability of OCT from SEDDS-incorporating OCT.DoS 2 is likely a result of higher partitioning into and prolonged retention within lipid colloid structures., Conclusion: The combination of LS and LBF enhanced the in vivo oral absorption of OCT primarily via the protective effect of LBF sheltering the peptide from gastrointestinal degradation.

Previous studies have demonstrated that the ionophore clioquinol (CQ), in conjunction with the biometals copper and zinc, increases the expression of P-glycoprotein (P-gp) in human cerebral microvascular endothelial (hCMEC/D3) cells. As P-gp expression and function at the blood-brain barrier (BBB) is of great interest regarding CNS drug access and endogenous toxin trafficking (e.g., amyloid beta), the present study assessed the in vivo translation of these previous in vitro findings. Swiss outbred mice received an 11-day treatment of CQ (30 mg/kg) by oral gavage, after which brain microvessel-enriched fractions (MEFs) and surrounding interfaces (subcortical brain tissue and plasma) were extracted. P-gp expression was quantified in the MEF, and biometal concentrations in all 3 compartments were assessed via inductively coupled plasma mass spectrometry. CQ treatment did not modify the expression of P-gp, nor copper or zinc concentrations in the brain MEF under this treatment regime. Metallomic analysis revealed, however, that CQ reduced potassium and magnesium levels in the brain MEF and also lowered brain iron levels. This study has shown that under this dosing regimen, CQ does not increase BBB P-gp expression in Swiss outbred mice, but that CQ facilitates redistribution of certain metal ions within the brain MEF, plasma, and brain parenchyma., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Purpose: Biometals such as zinc and copper have been shown to affect tight junction expression and subsequently blood-brain barrier (BBB) integrity. Whether these biometals also influence the expression and function of BBB transporters such as P-glycoprotein (P-gp) however is currently unknown., Methods: Using the immortalised human cerebral microvascular endothelial (hCMEC/D3) cell line, an in-cell western assay (alongside western blotting) assessed relative P-gp expression after treatment with the metal ionophore clioquinol and biometals zinc and copper. The fluorescent P-gp substrate rhodamine-123 was employed to observe functional modulation, and inductively coupled plasma mass spectrometry (ICP-MS) provided information on biometal trafficking., Results: A 24-h treatment with clioquinol, zinc and copper (0.5, 0.5 and 0.1 μM) induced a significant upregulation of P-gp (1.7-fold) assessed by in-cell western and this was confirmed with western blotting (1.8-fold increase). This same treatment resulted in a 23% decrease in rhodamine-123 accumulation over a 1 h incubation. ICP-MS demonstrated that while t8his combination treatment had no effect on intracellular zinc concentrations, the treatment significantly enhanced bioavailable copper (4.6-fold)., Conclusions: Enhanced delivery of copper to human brain microvascular endothelial cells is associated with enhanced expression and function of the important efflux pump P-gp, which may provide therapeutic opportunities for P-gp modulation.

An in-cell western (ICW) protocol detecting the relative expression of P-glycoprotein (P-gp) in human cerebro-microvascular endothelial cells (hCMEC/D3) was developed and optimized, with the intention of improving throughput relative to western blotting (WB). For validation of the ICW protocol, hCMEC/D3 cells were incubated with known P-gp upregulators (10 μM rifampicin and 5 μM SR12813) and treated with siRNA targeted against MDR1, before measuring changes in P-gp expression, using both ICW and WB in parallel. To confirm a relationship between the detected P-gp expression and function, the uptake of the P-gp substrate rhodamine-123 was assessed following SR12813 treatment. Rifampicin and SR12813 significantly upregulated P-gp expression (1.5-fold and 1.9-fold, respectively) compared to control, as assessed by the ICW protocol. WB analysis of the same treatments revealed 1.4-fold and 1.5-fold upregulations. MDR1 siRNA reduced P-gp abundance by 20% and 35% when assessed by ICW and WB, respectively. SR12813 treatment reduced rhodamine-123 uptake by 18%, indicating that the observed changes in P-gp expression by ICW were associated with comparable functional changes. The correlation of P-gp upregulation by WB, rhodamine-123 uptake, and the ICW protocol provide validation of a new ICW method as an alternative method for quantification of P-gp in hCMEC/D3 cells., (Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.)

Despite a century of steady and incremental progress toward understanding the underlying biochemical mechanisms, Alzheimer's disease (AD) remains a complicated and enigmatic disease, and greater insight will be necessary before substantive clinical success is realised. Over the last decade in particular, a large body of work has highlighted the cerebral microvasculature as an anatomical region with an increasingly apparent role in the pathogenesis of AD. The causative interplay and temporal cascade that manifest between the brain vasculature and the wider disease progression of AD are not yet fully understood, and further inquiry is required to properly characterise these relationships. The purpose of this review is to highlight the recent advancements in research implicating neurovascular factors in AD, at both the molecular and anatomical levels. We begin with a brief introduction of the biochemical and genetic aspects of AD, before reviewing the essential concepts of the blood-brain barrier (BBB) and the neurovascular unit (NVU). In detail, we then examine the evidence demonstrating involvement of BBB dysfunction in AD pathogenesis, highlighting the importance of neurovascular components in AD. Lastly, we include within this review research that focuses on how altered properties of the BBB in AD impact upon CNS exposure of therapeutic agents and the potential clinical impact that this may have on people with this disease.

The frequency of polymyxin-resistant pathogenic Gram-negative bacteria appearing in the clinic is increasing, and the consequences are largely mediated by modification of lipopolysaccharide (LPS) in the outer membrane. As polymyxins exert their antibacterial effect by binding to LPS, understanding their mode of binding will prove highly valuable for new antibiotic discovery. In this study, we assess the potential of MIPS-9451, a fluorescent polymyxin analogue designed for imaging studies, as a fluorescent reporter molecule, titrating it against 17 different Gram-negative species and/or strains of LPS. MIPS-9451 bound to the various species and/or strains of LPS with a dissociation constant ranging between 0.14 ± 0.01 μM (Escherichia coli) and 0.90 ± 0.42 μM (Porphyromonas gingivalis; mean ± standard error). Furthermore, we assessed the applicability of MIPS-9451 to rank affinities of polymyxin B to different LPS species in a displacement assay which yielded inhibition constants of 6.2 μM ± 33%, 7.2 μM ± 30%, and 0.95 μM ± 13% for Klebsiella pneumoniae, Pseudomonas aeruginosa, and Salmonella enterica, respectively (mean ± coefficient of variation). The results from this study are concordant with those observed with similarly structured polymyxin probes, confirming the potential of MIPS-9451 for quantitation of polymyxin-LPS affinities in discovery programs of novel polymyxin antibiotics., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

During the US recession of 2007-09, overall health care spending growth fell, but Medicare spending growth increased. Using state-level data from the period 1991-2009, we show that these divergent trends were also observed within states. Furthermore, increases in state unemployment rates were associated with higher Medicare spending per capita and increased hospital use by Medicare beneficiaries. For example, a one-percentage-point point rise in the unemployment rate was associated with a $40 (0.7 percent) increase in Medicare spending per capita. Our results suggest that economic downturns contribute to Medicare spending and use. One of many possible explanations may be that health care providers have greater capacity, inclination, and financial incentive to treat Medicare patients during recessions as a result of slackening demand from the non-Medicare population.