The principal risk factor for developing most adult onset neurodegenerative diseases is aging, with incidence rising significantly after age 50. Despite research efforts, the causes of Parkinson's disease (PD) remain unknown. As neurons age, they show signs of diminished lysosomal and mitochondrial function, including increased oxidative stress and accumulation of misfolded proteins, and these changes become exacerbated PD. We show that activity of the lysosomal hydrolase glucocerebrosidase gradually diminishes with age in the substantia nigra and putamen of healthy controls. This reduction is comparable to glucocerebrosidase activity in GBA1-mutation carrier PD patients. These data, demonstrate for the first time that an age-dependent reduction in glucocerebrosidase activity may lower the threshold for developing PD.

Aims: Loss-of-function mutations in GBA1, which cause the autosomal recessive lysosomal storage disease, Gaucher disease (GD), are also a key genetic risk factor for the α-synucleinopathies, including Parkinson's disease (PD) and dementia with Lewy bodies. GBA1 encodes for the lysosomal hydrolase glucocerebrosidase and reductions in this enzyme result in the accumulation of the glycolipid substrates glucosylceramide and glucosylsphingosine. Deficits in autophagy and lysosomal degradation pathways likely contribute to the pathological accumulation of α-synuclein in PD. In this report we used conduritol-β-epoxide (CBE), a potent selective irreversible competitive inhibitor of glucocerebrosidase, to model reduced glucocerebrosidase activity in vivo, and tested whether sustained glucocerebrosidase inhibition in mice could induce neuropathological abnormalities including α-synucleinopathy, and neurodegeneration. Results: Our data demonstrate that daily systemic CBE treatment over 28 days caused accumulation of insoluble α-synuclein aggregates in the substantia nigra, and altered levels of proteins involved in the autophagy lysosomal system. These neuropathological changes were paralleled by widespread neuroinflammation, upregulation of complement C1q, abnormalities in synaptic, axonal transport and cytoskeletal proteins, and neurodegeneration. Innovation: A reduction in brain GCase activity has been linked to sporadic PD and normal aging, and may contribute to the susceptibility of vulnerable neurons to degeneration. This report demonstrates that systemic reduction of GCase activity using chemical inhibition, leads to neuropathological changes in the brain reminiscent of α-synucleinopathy. Conclusions: These data reveal a link between reduced glucocerebrosidase and the development of α-synucleinopathy and pathophysiological abnormalities in mice, and support the development of GCase therapeutics to reduce α-synucleinopathy in PD and related disorders. Antioxid. Redox Signal. 23, 550–564.

Diminished lysosomal function can lead to abnormal cellular accumulation of specific proteins, including α-synuclein, contributing to disease pathogenesis of vulnerable neurons in Parkinson's disease (PD) and related α-synucleinopathies. GBA1 encodes for the lysosomal hydrolase glucocerebrosidase (GCase), and mutations in GBA1 are a prominent genetic risk factor for PD. Previous studies showed that in sporadic PD, and in normal aging, GCase brain activity is reduced and levels of corresponding glycolipid substrates are increased. The present study tested whether increasing GCase through AAV-GBA1 intra-cerebral gene delivery in two PD rodent models would reduce the accumulation of α-synuclein and protect midbrain dopamine neurons from α-synuclein-mediated neuronal damage. In the first model, transgenic mice overexpressing wildtype α-synuclein throughout the brain (ASO mice) were used, and in the second model, a rat model of selective dopamine neuron degeneration was induced by AAV-A53T mutant α-synuclein. In ASO mice, intra-cerebral AAV-GBA1 injections into several brain regions increased GCase activity and reduced the accumulation of α-synuclein in the substantia nigra and striatum. In rats, co-injection of AAV-GBA1 with AAV-A53T α-synuclein into the substantia nigra prevented α-synuclein-mediated degeneration of nigrostriatal dopamine neurons by 6 months. These neuroprotective effects were associated with altered protein expression of markers of autophagy. These experiments demonstrate, for the first time, the neuroprotective effects of increasing GCase against dopaminergic neuron degeneration, and support the development of therapeutics targeting GCase or other lysosomal genes to improve neuronal handling of α-synuclein.

No abstract

The Hospital Readmissions Reduction Program (HRRP), a part of the US Patient Protection and Affordable Care Act, requires the Centers for Medicare and Medicaid Services to penalize hospitals with excess readmissions. We take an economic and operational (patient flow) perspective to analyze the effectiveness of this policy in encouraging hospitals to reduce readmissions. We introduce a single-hospital model to capture the dependence of a hospital's readmission-reduction decision on various hospital characteristics. We derive comparative statics that predict how changes in hospital characteristics impact the hospital's readmissionreduction decision. We then proceed to develop a game-theoretic model that captures the competition between hospitals introduced by the HRRP policy's benchmarking mechanism. We provide bounds that apply to any equilibrium of the game and show that the comparative statics derived from the single-hospital model remain valid after the introduction of competition. Importantly, the comparison of the single-hospitals and multi-hospital models shows that, while the competition among hospitals often encourages more hospitals to reduce readmissions, it can only increase the number of "worst offenders," which are hospitals that prefer paying penalties over reducing readmissions in any equilibrium. We calibrate our model with a dataset of hospitals in California which allows us to quantify the results and insights derived from the model. Last, we validate our model with recent hospitals' performance data collected since the policy was implemented.

No abstract

Since 2004, NASA has been working to return to the Moon. In contrast to the Apollo missions, two key objectives of the current exploration program is to establish significant infrastructure and an outpost. Achieving these objectives will enable long-duration stays and long-distance exploration of the Moon. To do this, robotic systems will be needed to perform tasks which cannot, or should not, be performed by crew alone. In this paper, we summarize our work to develop "utility robots" for lunar surface operations, present results and lessons learned from field testing, and discuss directions for future research.

Emergency departments (EDs) typically use a triage system to classify patients into priority levels. However, most triage systems do not specify how exactly to route patients across and within the assigned triage levels. Therefore decision makers in EDs often have to use their own discretion to route patients. Also, how patient waiting is perceived and accounted for in ED operations is not clearly understood. In this paper, using patient-level ED visit data, we structurally estimate the waiting cost structure of ED patients as perceived by the decision makers who make ED patient routing decisions. We derive policy implications and make suggestions for improving triage systems. We analyze the patient routing behaviors of ED decision makers in four EDs in the metro Vancouver, British Columbia area. They all use the Canadian Triage and Acuity Scale (CTAS), which has a wait timerelated target service level objective. We propose a general discrete choice framework, consistent with queueing literature, as a tool to analyze prioritization behaviors in multi-class queues under mild assumptions. We nd that the decision makers in all four EDs 1) apply a delay-dependent prioritization across dierent triage levels; 2) have a perceived marginal ED patient waiting cost that is best t by a piece-wise linear concave function in wait time; 3) generally follow, in the same triage level, the rst-come rst-served (FCFS) principle, but their adherence to the principle decreases for patients who wait past a certain threshold; and 4) do not use patient-complexity as a major criterion in prioritization decisions.