Outcomes in Clinical Subgroups of Patients With Alcohol-Related Hospitalizations.

Importance: Alcohol-related hospitalizations are common and associated with significant cost to the health care system. We have a limited understanding of the characteristics of individuals who experience alcohol-related hospitalizations, which limits our capacity to prioritize those at the highest risk of postdischarge harm. Objective: To identify and characterize the clinical subgroups of individuals who are hospitalized for alcohol-related harms. Design, Setting, and Participants: This cohort study used latent class analysis (LCA) to identify clinical subgroups of individuals experiencing alcohol-related hospitalizations in 2 provinces in Canada. All individuals between ages 10 and 105 years who were hospitalized for an alcohol-related harm between January 2017 and December 2018 (ie, the index hospitalization) were eligible. Data were analyzed between June 2023 and August 2023. Exposures: The exposure of interest was the clinical subgroup that an individual belonged to. These subgroups were identified using an LCA based on (1) the characteristics of the index hospitalization and (2) the history of alcohol-related health service use. Main Outcomes and Measures: In-hospital mortality, alcohol-related hospital readmission, and all-cause mortality in the year following discharge from the index hospitalization. The association between subgroup membership and the risk of in-hospital and postdischarge outcomes was evaluated using multivariable regression. Results: A total of 34 043 individuals were included in analysis, 4753 from Manitoba (median [IQR] age, 49 [40-58] years; 1786 female [37.6%]) and 29 290 from Ontario (median [IQR] age, 57 [45-67] years; 8527 female [29.1%]). Seven subgroups were identified following a gradient from low-frequency service use for acute intoxication to high-frequency service use for severe alcohol use disorder and liver disease. In Ontario, there were 4431 individuals in the liver disease subgroup representing 15.5% of the cohort who were at the highest risk of 1-year mortality (1382 [31.2%]) relative to the acute intoxication subgroup (42 [4.0%]) (adjusted hazard ratio [aHR], 3.83; 95% CI, 2.80-5.24). There was also a small subgroup (10.6%) of individuals with high-frequency alcohol-related health service use who had a much higher hazard of readmission following the index hospitalization (1-year readmission: 703 of 1526 [46.1%] vs 104 of 1058 [9.8%] in the acute intoxication subgroup; aHR, 5.09; 95% CI, 4.11-6.31). Conclusions and Relevance: In this population-based cohort study of individuals experiencing alcohol-related hospitalizations, we identified several small, clinically distinct subgroups that were at a disproportionately high risk of readmission and mortality. These groups could merit prioritization in strategies aimed at reducing the risk of adverse outcomes following alcohol-related hospitalizations.

Prevalence of Mental Health and Addiction Service use Prior to and During Incarceration in Provincial Jails in Ontario, Canada: A Retrospective Cohort Study.

OBJECTIVE: Individuals with mental illness and addiction are overrepresented in prisons. Few studies have assessed mental health and addiction (MHA)-related service use among individuals experiencing incarceration using health administrative data and most focus on service use after prison release. The objective of this study was to determine the prevalence of MHA-related service use in the 5 years prior to and during incarceration. METHODS: We used linked correctional and administrative health data for people released from Ontario provincial jails in 2010. MHA-related service use in the 5 years prior to the index incarceration was categorized hierarchically into four mutually exclusive categories based on the type of service use: psychiatric hospitalization, MHA-related emergency department (ED) visit, MHA-related outpatient visit (from psychiatrist or primary care physician), and no MHA-related service use. Demographic, diagnostic, and incarceration characteristics were compared across the four service use categories. MHA-related service use during the index incarceration was assessed by category and length of incarceration. RESULTS: A total of 48,917 individuals were included. Prior to incarceration, 6,116 (12.5%) had a psychiatric hospitalization, 8,837 (18.1%) had an MHA-related ED visit, and 15,866 (32.4%) had an MHA-related outpatient visit. Of the individuals with any MHA-related service prior to incarceration, 60.4% did not receive outpatient care from a psychiatrist prior to incarceration and 65.6% did not receive MHA-related care during incarceration. CONCLUSION: Despite a high prevalence of mental illness and addiction among people experiencing incarceration, access to and use of MHA-related care prior to and during incarceration is poor. Increasing the accessibility and use of MHA-related services throughout the criminal justice pathway is warranted.

BAG5 Promotes Alpha-Synuclein Oligomer Formation and Functionally Interacts With the Autophagy Adaptor Protein p62.

Molecular chaperones are critical to maintaining intracellular proteostasis and have been shown to have a protective role against alpha-synuclein-mediated toxicity. Co-chaperone proteins regulate the activity of molecular chaperones and connect the chaperone network to protein degradation and cell death pathways. Bcl-2 associated athanogene 5 (BAG5) is a co-chaperone that modulates proteostasis by inhibiting the activity of Heat shock protein 70 (Hsp70) and several E3 ubiquitin ligases, resulting in enhanced neurodegeneration in models of Parkinson's disease (PD). Here we identify a novel interaction between BAG5 and p62/sequestosome-1 (SQSTM1), suggesting that BAG5 may bridge the chaperone network to autophagy-mediated protein degradation. We found that BAG5 enhanced the formation of pathogenic alpha-synuclein oligomers and regulated the levels and subcellular distribution of p62. These results extend the role of BAG5 in alpha-synuclein processing and intracellular proteostasis.

Bcl-2-associated athanogene 5 (BAG5) regulates Parkin-dependent mitophagy and cell death.

As pathogenic Parkin mutations result in the defective clearance of damaged mitochondria, Parkin-dependent mitophagy is thought to be protective against the dopaminergic neurodegeneration observed in Parkinson's disease. Recent studies, however, have demonstrated that Parkin can promote cell death in the context of severe mitochondrial damage by degrading the pro-survival Bcl-2 family member, Mcl-1. Therefore, Parkin may act as a 'switch' that can shift the balance between protective or pro-death pathways depending on the degree of mitochondrial damage. Here, we report that the Parkin interacting protein, Bcl-2-associated athanogene 5 (BAG5), impairs mitophagy by suppressing Parkin recruitment to damaged mitochondria and reducing the movement of damaged mitochondria into the lysosomes. BAG5 also enhanced Parkin-mediated Mcl-1 degradation and cell death following severe mitochondrial insult. These results suggest that BAG5 may regulate the bi-modal activity of Parkin, promoting cell death by suppressing Parkin-dependent mitophagy and enhancing Parkin-mediated Mcl-1 degradation.

Parkinsonism due to A53E α-synuclein gene mutation: Clinical, genetic, epigenetic, and biochemical features.

BACKGROUND: SNCA mutations cause autosomal dominant parkinsonism and inform our understanding of the molecular underpinnings of synucleinopathies. The most recently identified mutation, p.Ala53Glu (A53E), has only been observed in Finland. The objectives of this study were to examine clinical, genetic, epigenetic, and biochemical features of the first family outside Finland with A53E. METHODS: We examined a Canadian family with parkinsonism because of A53E using haplotype and DNA methylation analyses. We assessed aggregation properties of A53E α-synuclein in vitro. RESULTS: Family members with parkinsonism shared a common haplotype distinct from Finnish patients with A53E. Increased acceleration of DNA methylation age was accompanied by earlier age at onset in the family members. We demonstrate that A53E α-synuclein has a propensity to form oligomers and phosphorylation promotes fibrillation. CONCLUSIONS: A53E as a cause of parkinsonism is not restricted to Finnish individuals. DNA methylation may contribute to disease age at onset. A53E enriches α-synuclein oligomers and fibrils dependent on the phosphorylation state. © 2018 International Parkinson and Movement Disorder Society.

Chaperone-Based Therapies for Disease Modification in Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder and is characterized by the presence of pathological intracellular aggregates primarily composed of misfolded α-synuclein. This pathology implicates the molecular machinery responsible for maintaining protein homeostasis (proteostasis), including molecular chaperones, in the pathobiology of the disease. There is mounting evidence from preclinical and clinical studies that various molecular chaperones are downregulated, sequestered, depleted, or dysfunctional in PD. Current therapeutic interventions for PD are inadequate as they fail to modify disease progression by ameliorating the underlying pathology. Modulating the activity of molecular chaperones, cochaperones, and their associated pathways offers a new approach for disease modifying intervention. This review will summarize the potential of chaperone-based therapies that aim to enhance the neuroprotective activity of molecular chaperones or utilize small molecule chaperones to promote proteostasis.