Medication Profiles at Hospital Discharge Predict Poor Outcomes After Acute Ischemic Stroke.

Objectives: To examine the relationship between medications prescribed during the first 6-months post-stroke and functional outcome. Materials and Methods: A retrospective analysis of ischemic stroke survivors enrolled in an observational stroke recovery study from June-2017 to July-2019 was performed. Survivors with favorable outcomes (modified rankin scale (mRS) score 0-2) were compared to those with unfavorable outcomes (mRS ≥3) 6-months after stroke on the following: discharge medication classes prescribed, achievement of recommended targets for blood pressure control, glycemic control, and LDL ≤70 mg/dL, medication changes, medication interactions, and medication list discrepancies. Results: Unfavorable 6-month outcomes occurred in 36/78 (46.2%) of survivors. Survivors with unfavorable outcomes were more likely to be prescribed a central nervous system-acting agent (97.2% vs 71.4%; P = .0022) and/or an anti-hyperglycemic agent (25.0% vs 9.5%; P = .009) at discharge. After adjustment of baseline covariates, total number of medications prescribed was associated with unfavorable 6-month outcomes (OR 1.13, 95% CI 1.0-1.28). Secondary stroke prevention measures were not achieved in a high proportion of survivors. Medication changes during 6-month follow up were common and survivors with unfavorable outcomes were more likely to have clinically significant drug-drug interactions. Discussion: At 6-months, survivors with unfavorable outcomes were found to be prescribed more medications, particularly central nervous system-acting and anti-hyperglycemic agents. There were also more drug-drug interactions in the medications prescribed compared to those with favorable outcomes. Together, these data suggest the need for enhanced screening of high-risk stroke survivors focused on close monitoring of polypharmacy, drug-drug interactions, and adverse events with pharmacotherapy.

Effects of a pharmacy-driven medication history program on patient outcomes.

PURPOSE: Obtaining an accurate medication history is a vital component of medication reconciliation upon admission to the hospital. Despite the importance of this task, medication histories are often inaccurate and/or incomplete. We evaluated the association of a pharmacy-driven medication history initiative on clinical outcomes of patients admitted to the general medicine service of an academic medical center. METHODS: Comparing patients who received a pharmacy-driven medication history to those who did not, a retrospective stabilized inverse probability treatment weighting propensity score analysis was used to estimate the average treatment effect of the intervention on general medical patients. Fifty-two patient baseline characteristics including demographic, operational, and clinical variables were controlled in the propensity score model. Hospital length of stay, 7-day and 30-day unplanned readmissions, and in-hospital mortality were evaluated. RESULTS: Among 11,576 eligible general medical patients, 2,234 (19.30%) received a pharmacy-driven medication history and 9,342 (80.70%) patients did not. The estimated average treatment effect of receiving a pharmacy-driven medication history was a shorter length of stay (mean, 5.88 days vs 6.53 days; P = 0.0002) and a lower in-hospital mortality rate (2.34% vs 3.72%, P = 0.001), after adjustment for differences in patient baseline characteristics. No significant difference was found for 7-day or 30-day all-cause readmission rates. CONCLUSION: Pharmacy-driven medication histories reduced length of stay and in-hospital mortality in patients admitted to the general medical service at an academic medical center but did not change 7-day and 30-day all-cause readmission rates. Further research via a large, multisite randomized controlled trial is needed to confirm our findings.

Insights From a Short-Term Protein-Calorie Restriction Exploratory Trial in Elective Carotid Endarterectomy Patients.

BACKGROUND: Open vascular surgery interventions are not infrequently hampered by complication rates and durability. Preclinical surgical models show promising beneficial effects in modulating the host response to surgical injury via short-term dietary preconditioning. Here, we explore short-term protein-calorie restriction preconditioning in patients undergoing elective carotid endarterectomy to understand patient participation dynamics and practicalities of robust research approaches around nutritional/surgical interventions. METHODS: We designed a pilot prospective, multicenter, randomized controlled study in patients undergoing carotid endarterectomy. After a 3:2 randomization to a 3-day preoperative protein-calorie restriction regimen (30% calorie/70% protein restriction) or ad libitum group, blood, clinical parameters, and stool samples were collected at baseline, pre-op, and post-op days 1 and 30. Subcutaneous and perivascular adipose tissues were harvested periprocedurally. Samples were analyzed for standard chemistries and cell counts, adipokines. Bacterial DNA isolation and 16S rRNA sequencing were performed on stool samples and the relative abundance of bacterial species was measured. RESULTS: Fifty-one patients were screened, 9 patients consented to the study, 5 were randomized, and 4 completed the trial. The main reason for non-consent was a 3-day in-hospital stay. All 4 participants were randomized to the protein-calorie restriction group, underwent successful endarterectomy, reported no compliance difficulties, nor were there adverse events. Stool analysis trended toward increased abundance of the sulfide-producing bacterial species Bilophila wadsworthia after dietary intervention (P = .08). CONCLUSIONS: Although carotid endarterectomy patients held low enthusiasm for a 3-day preoperative inpatient stay, there were no adverse effects in this small cohort. Multidisciplinary longitudinal research processes were successfully executed throughout the nutritional/surgical intervention. Future translational endeavors into dietary preconditioning of vascular surgery patients should focus on outpatient approaches.

Quorum Sensing Coordinates Cooperative Expression of Pyruvate Metabolism Genes To Maintain a Sustainable Environment for Population Stability.

Quorum sensing (QS) is a microbial cell-cell communication system that regulates gene expression in response to population density to coordinate collective behaviors. Yet, the role of QS in resolving the stresses caused by the accumulation of toxic metabolic by-products at high cell density is not well defined. In response to cell density, QS could be involved in reprogramming of the metabolic network to maintain population stability. Using unbiased metabolomics, we discovered that Vibrio cholerae mutants genetically locked in a low cell density (LCD) QS state are unable to alter the pyruvate flux to convert fermentable carbon sources into neutral acetoin and 2,3-butanediol molecules to offset organic acid production. As a consequence, LCD-locked QS mutants rapidly lose viability when grown with fermentable carbon sources. This key metabolic switch relies on the QS-regulated small RNAs Qrr1-4 but is independent of known QS regulators AphA and HapR. Qrr1-4 dictate pyruvate flux by translational repression of the enzyme AlsS, which carries out the first step in acetoin and 2,3-butanediol biosynthesis. Consistent with the idea that QS facilitates the expression of a common trait in the population, AlsS needs to be expressed cooperatively in a group of cells. Heterogeneous populations with high percentages of cells not expressing AlsS are unstable. All of the cells, regardless of their respective QS states, succumb to stresses caused by toxic by-product accumulation. Our results indicate that the ability of the bacteria to cooperatively control metabolic flux through QS is critical in maintaining a sustainable environment and overall population stability. IMPORTANCE: Our work reveals a novel role for Vibrio cholerae quorum sensing (QS) in relieving the stresses caused by toxic metabolite accumulation when the population becomes crowded through metabolic reprogramming. QS enables V. cholerae switching from a low cell density energy-generating metabolism that is beneficial to individuals at the expense of the environment to a high cell density mode that preserves environmental habitability by sacrificing individual fitness. This cooperative switch provides a stable environment as the common good in maintaining the stability of the community. However, the common good can be exploited by uncooperative mutants that pollute the environment, causing population collapse. Our findings provide insights into the metabolic stress response of a major human pathogen, with implications for our understanding of microbial social biology and cooperation from an ecological and evolutionary perspective.

DNA-binding studies of the natural ß-carboline eudistomin U.

Eudistomin U is a member of the ß-carboline class of heterocyclic amine-containing molecules that are capable of binding to DNA. The structure of eudistomin U is unique since it contains an indole ring at the 1-position of the pyridine ring. While simple ß-carbolines are reported to intercalate DNA, an examination of the mode of binding of eudistomin U has been lacking. We report preliminary spectroscopic (UV-Vis, thermal denaturation, CD) and calorimetric (DSC) data on the binding of eudistomin U to DNA, which suggest that eudistomin U binds weakly according to a mechanism that is more complicated than other members of its class.

Efficient synthesis of eudistomin U and evaluation of its cytotoxicity.

Eudistomin U is a member of a subclass of naturally occurring indole alkaloids known as ß-carbolines. These molecules are reported to have diverse biological activity and high binding affinity to DNA, which make them attractive targets for total synthesis. We describe an efficient, five-step synthesis of eudistomin U by employing two key reactions: a Bischler-Napieralski cyclization and a Suzuki cross coupling. We also describe the cytotoxicity of eudistomin U against various cancer cell lines and human pathogens, in which we observed potent antibacterial activity against Gram-positive bacteria.