Supercharging Prions via Amyloid-Selective Lysine Acetylation.

Repulsive electrostatic forces between prion-like proteins are a barrier against aggregation. In neuropharmacology, however, a prion's net charge (Z) is not a targeted parameter. Compounds that selectively boost prion Z remain unreported. Here, we synthesized compounds that amplified the negative charge of misfolded superoxide dismutase-1 (SOD1) by acetylating lysine-NH3+ in amyloid-SOD1, without acetylating native-SOD1. Compounds resembled a "ball and chain" mace: a rigid amyloid-binding "handle" (benzothiazole, stilbene, or styrylpyridine); an aryl ester "ball"; and a triethylene glycol chain connecting ball to handle. At stoichiometric excess, compounds acetylated up to 9 of 11 lysine per misfolded subunit (ΔZfibril =-8100 per 103 subunits). Acetylated amyloid-SOD1 seeded aggregation more slowly than unacetylated amyloid-SOD1 in vitro and organotypic spinal cord (these effects were partially due to compound binding). Compounds exhibited reactivity with other amyloid and non-amyloid proteins (e.g., fibrillar α-synuclein was peracetylated; serum albumin was partially acetylated; carbonic anhydrase was largely unacetylated).

Design, synthesis and biological evaluation of GPR55 agonists.

GPR55, a G protein-coupled receptor, is an attractive target to alleviate inflammatory and neuropathic pain and treat osteoporosis and cancer. Identifying a potent and selective ligand will aid to further establish the specific physiological roles and pharmacology of the receptor. Towards this goal, a targeted library of 22 compounds was synthesized in a modular fashion to obtain structure-activity relationship information. The general route consisted of coupling a variety of p-aminophenyl sulfonamides to isothiocyanates to form acylthioureas. For the synthesis of a known naphthyl ethyl alcohol motif, route modification led to a shorter and more efficient process. The 22 analogues were analyzed for their ability to serve as agonists at GPR55 and valuable information for both ends of the molecule was ascertained.

Bioinspired Synthesis of a Sedaxane Metabolite Using Catalytic Vanadyl Acetylacetonate and Molecular Oxygen.

A bioinspired synthesis of the sedaxane metabolite 2 from intermediate 3 using catalytic VO(acac)2 and O2 is described. Intermediate 3 was synthesized starting from 2-bromostyrene in four steps. The inner cyclopropyl ring of 3 was assembled with trans geometry using a highly diastereoselective Nishiyama cyclopropanation, and the outer hydroxycyclopropyl ring was installed using the Kulinkovich cyclopropanation. Additionally, conversion of 3 into 2 was demonstrated in in vitro microbial culture experiments consisting of bacteria and fungi.

The Opioid-overdose Reduction Continuum of Care Approach (ORCCA): Evidence-based practices in the HEALing Communities Study.

BACKGROUND: The number of opioid-involved overdose deaths in the United States remains a national crisis. The HEALing Communities Study (HCS) will test whether Communities That HEAL (CTH), a community-engaged intervention, can decrease opioid-involved deaths in intervention communities (n = 33), relative to wait-list communities (n = 34), from four states. The CTH intervention seeks to facilitate widespread implementation of three evidence-based practices (EBPs) with the potential to reduce opioid-involved overdose fatalities: overdose education and naloxone distribution (OEND), effective delivery of medication for opioid use disorder (MOUD), and safer opioid analgesic prescribing. A key challenge was delineating an EBP implementation approach useful for all HCS communities. METHODS: A workgroup composed of EBP experts from HCS research sites used literature reviews and expert consensus to: 1) compile strategies and associated resources for implementing EBPs primarily targeting individuals 18 and older; and 2) determine allowable community flexibility in EBP implementation. The workgroup developed the Opioid-overdose Reduction Continuum of Care Approach (ORCCA) to organize EBP strategies and resources to facilitate EBP implementation. CONCLUSIONS: The ORCCA includes required and recommended EBP strategies, priority populations, and community settings. Each EBP has a "menu" of strategies from which communities can select and implement with a minimum of five strategies required: one for OEND, three for MOUD, and one for prescription opioid safety. Identification and engagement of high-risk populations in OEND and MOUD is an ORCCArequirement. To ensure CTH has community-wide impact, implementation of at least one EBP strategy is required in healthcare, behavioral health, and criminal justice settings, with communities identifying particular organizations to engage in HCS-facilitated EBP implementation.

Use of the SONET score to evaluate Urgent Care Center overcrowding: a prospective pilot study.

OBJECTIVES: To derive a tool to determine Urgent Care Center (UCC) crowding and investigate the association between different levels of UCC overcrowding and negative patient care outcomes. DESIGN: Prospective pilot study. SETTING: Single centre study in the USA. PARTICIPANTS: 3565 patients who registered at UCC during the 21-day study period were included. Patients who had no overcrowding statuses estimated due to incomplete collection of operational variables at the time of registration were excluded in this study. 3139 patients were enrolled in the final data analysis. PRIMARY AND SECONDARY OUTCOME MEASURES: A crowding estimation tool (SONET: Severely overcrowded, Overcrowded and Not overcrowded Estimation Tool) was derived using the linear regression analysis. The average length of stay (LOS) in UCC patients and the number of left without being seen (LWBS) patients were calculated and compared under the three different levels of UCC crowding. RESULTS: Four independent operational variables could affect the UCC overcrowding score including the total number of patients, the number of results pending for patients, the number of patients in the waiting room and the longest time a patient was stationed in the waiting room. In addition, UCC overcrowding was associated with longer average LOS (not overcrowded: 133±76 min, overcrowded: 169±79 min, and severely overcrowded: 196±87 min, p<0.001) and an increased number of LWBS patients (not overcrowded: 0.28±0.69 patients, overcrowded: 0.64±0.98, and severely overcrowded: 1.00±0.97). CONCLUSIONS: The overcrowding estimation tool (SONET) derived in this study might be used to determine different levels of crowding in a high volume UCC setting. It also showed that UCC overcrowding might be associated with negative patient care outcomes.