Risk of 30-day hospital readmission associated with medical conditions and drug regimens of polymedicated, older inpatients discharged home: a registry-based cohort study.

OBJECTIVES: The present study analysed 4 years of a hospital register (2015-2018) to determine the risk of 30-day hospital readmission associated with the medical conditions and drug regimens of polymedicated, older inpatients discharged home. DESIGN: Registry-based cohort study. SETTING: Valais Hospital-a public general hospital centre in the French-speaking part of Switzerland. PARTICIPANTS: We explored the electronic records of 20 422 inpatient stays by polymedicated, home-dwelling older adults held in the hospital's patient register. We identified 13 802 hospital readmissions involving 8878 separate patients over 64 years old. OUTCOME MEASURES: Sociodemographic characteristics, medical conditions and drug regimen data associated with risk of readmission within 30 days of discharge. RESULTS: The overall 30-day hospital readmission rate was 7.8%. Adjusted multivariate analyses revealed increased risk of hospital readmission for patients with longer hospital length of stay (OR=1.014 per additional day; 95% CI 1.006 to 1.021), impaired mobility (OR=1.218; 95% CI 1.039 to 1.427), multimorbidity (OR=1.419 per additional International Classification of Diseases, 10th Revision condition; 95% CI 1.282 to 1.572), tumorous disease (OR=2.538; 95% CI 2.089 to 3.082), polypharmacy (OR=1.043 per additional drug prescribed; 95% CI 1.028 to 1.058), and certain specific drugs, including antiemetics and antinauseants (OR=3.216 per additional drug unit taken; 95% CI 1.842 to 5.617), antihypertensives (OR=1.771; 95% CI 1.287 to 2.438), drugs for functional gastrointestinal disorders (OR=1.424; 95% CI 1.166 to 1.739), systemic hormonal preparations (OR=1.207; 95% CI 1.052 to 1.385) and vitamins (OR=1.201; 95% CI 1.049 to 1.374), as well as concurrent use of beta-blocking agents and drugs for acid-related disorders (OR=1.367; 95% CI 1.046 to 1.788). CONCLUSIONS: Thirty-day hospital readmission risk was associated with longer hospital length of stay, health disorders, polypharmacy and drug regimens. The drug regimen patterns increasing the risk of hospital readmission were very heterogeneous. Further research is needed to explore hospital readmissions caused solely by specific drugs and drug-drug interactions.

Transforming a Patient Registry Into a Customized Data Set for the Advanced Statistical Analysis of Health Risk Factors and for Medication-Related Hospitalization Research: Retrospective Hospital Patient Registry Study.

BACKGROUND: Hospital patient registries provide substantial longitudinal data sets describing the clinical and medical health statuses of inpatients and their pharmacological prescriptions. Despite the multiple advantages of routinely collecting multidimensional longitudinal data, those data sets are rarely suitable for advanced statistical analysis and they require customization and synthesis. OBJECTIVE: The aim of this study was to describe the methods used to transform and synthesize a raw, multidimensional, hospital patient registry data set into an exploitable database for the further investigation of risk profiles and predictive and survival health outcomes among polymorbid, polymedicated, older inpatients in relation to their medicine prescriptions at hospital discharge. METHODS: A raw, multidimensional data set from a public hospital was extracted from the hospital registry in a CSV (.csv) file and imported into the R statistical package for cleaning, customization, and synthesis. Patients fulfilling the criteria for inclusion were home-dwelling, polymedicated, older adults with multiple chronic conditions aged ≥65 who became hospitalized. The patient data set covered 140 variables from 20,422 hospitalizations of polymedicated, home-dwelling older adults from 2015 to 2018. Each variable, according to type, was explored and computed to describe distributions, missing values, and associations. Different clustering methods, expert opinion, recoding, and missing-value techniques were used to customize and synthesize these multidimensional data sets. RESULTS: Sociodemographic data showed no missing values. Average age, hospital length of stay, and frequency of hospitalization were computed. Discharge details were recoded and summarized. Clinical data were cleaned up and best practices for managing missing values were applied. Seven clusters of medical diagnoses, surgical interventions, somatic, cognitive, and medicines data were extracted using empirical and statistical best practices, with each presenting the health status of the patients included in it as accurately as possible. Medical, comorbidity, and drug data were recoded and summarized. CONCLUSIONS: A cleaner, better-structured data set was obtained, combining empirical and best-practice statistical approaches. The overall strategy delivered an exploitable, population-based database suitable for an advanced analysis of the descriptive, predictive, and survival statistics relating to polymedicated, home-dwelling older adults admitted as inpatients. More research is needed to develop best practices for customizing and synthesizing large, multidimensional, population-based registries. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1136/bmjopen-2019-030030.

Novel therapeutic strategy for neurodegeneration by blocking Aß seeding mediated aggregation in models of Alzheimer's disease.

Aß accumulation plays a central role in the pathogenesis of Alzheimer's disease (AD). Recent studies suggest that the process of Aß nucleated polymerization is essential for Aß fibril formation, pathology spreading and toxicity. Therefore, targeting this process represents an effective therapeutic strategy to slow or block disease progression. To discover compounds that might interfere with the Aß seeding capacity, toxicity and pathology spreading, we screened a focused library of FDA-approved drugs in vitro using a seeding polymerization assay and identified small molecule inhibitors that specifically interfered with Aß seeding-mediated fibril growth and toxicity. Mitoxantrone, bithionol and hexachlorophene were found to be the strongest inhibitors of fibril growth and protected primary cortical neuronal cultures against Aß-induced toxicity. Next, we assessed the effects of these three inhibitors in vivo in the mThy1-APPtg mouse model of AD (8-month-old mice). We found that mitoxantrone and bithionol, but not hexachlorophene, stabilized diffuse amyloid plaques, reduced the levels of Aß42 oligomers and ameliorated synapse loss, neuronal damage and astrogliosis. Together, our findings suggest that targeting fibril growth and Aß seeding capacity constitutes a viable and effective strategy for protecting against neurodegeneration and disease progression in AD.

The anti-Parkinsonian drug selegiline delays the nucleation phase of α-synuclein aggregation leading to the formation of nontoxic species.

Parkinson's disease (PD) is a movement disorder characterized by the loss of dopaminergic neurons in the substantia nigra and the formation of intraneuronal inclusions called Lewy bodies, which are composed mainly of α-synuclein (α-syn). Selegiline (Sel) is a noncompetitive monoamino oxidase B inhibitor that has neuroprotective effects and has been administered to PD patients as monotherapy or in combination with l-dopa. Besides its known effect of increasing the level of dopamine (DA) by monoamino oxidase B inhibition, Sel induces other effects that contribute to its action against PD. We evaluated the effects of Sel on the in vitro aggregation of A30P and wild-type α-syn. Sel delays fibril formation by extending the lag phase of aggregation. In the presence of Sel, electron microscopy reveals amorphous heterogeneous aggregates, including large annular species, which are innocuous to a primary culture enriched in dopaminergic neurons, while their age-matched counterparts are toxic. The inhibitory effect displayed by Sel is abolished when seeds (small fibril pieces) are added to the aggregation reaction, reinforcing the hypothesis that Sel interferes with early nuclei formation and, to a lesser extent, with fibril elongation. NMR experiments indicate that Sel does not interact with monomeric α-syn. Interestingly, when added in combination with DA (which favors the formation of toxic protofibrils), Sel overrides the inhibitory effect of DA and favors fibrillation. Additionally, Sel blocks the formation of smaller toxic aggregates by perturbing DA-dependent fibril disaggregation. These effects might be beneficial for PD patients, since the sequestration of protofibrils into fibrils or the inhibition of fibril dissociation could alleviate the toxic effects of protofibrils on dopaminergic neurons. In nondopaminergic neurons, Sel might slow the fibrillation, giving rise to the formation of large nontoxic aggregates.

Entacapone and tolcapone, two catechol O-methyltransferase inhibitors, block fibril formation of alpha-synuclein and beta-amyloid and protect against amyloid-induced toxicity.

Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease (AD). There is considerable consensus that the increased production and/or aggregation of alpha-synuclein (alpha-syn) plays a central role in the pathogenesis of PD and related synucleinopathies. Current therapeutic strategies for treating PD offer mainly transient symptomatic relief and aim at the restitution of dopamine levels to counterbalance the loss of dopaminergic neurons. Therefore, the identification and development of drug-like molecules that block alpha-synuclein aggregation and prevent the loss of dopaminergic neurons are desperately needed to treat or slow the progression of PD. Here, we show that entacapone and tolcapone are potent inhibitors of alpha-syn and beta-amyloid (Abeta) oligomerization and fibrillogenesis, and they also protect against extracellular toxicity induced by the aggregation of both proteins. Comparison of the anti-aggregation properties of entacapone and tolcapone with the effect of five other catechol-containing compounds, dopamine, pyrogallol, gallic acid, caffeic acid, and quercetin on the oligomerization and fibrillization of alpha-syn and Abeta, demonstrate that the catechol moiety is essential for the anti-amyloidogenic activity. Our findings present the first characterization of the anti-amyloidogenic properties of tolcapone and entacapone against both alpha-synuclein and Abeta42 and highlight the potential of this class of nitro-catechol compounds as anti-amyloidogenic agents. Their inhibitory properties, mode of action, and structural properties suggest that they constitute promising lead compounds for further optimization.

In vitro screening assays to identify natural or synthetic acetylcholinesterase inhibitors: thin layer chromatography versus microplate methods.

Acetylcholinesterase inhibitors (AChEI) are currently still the best available pharmacotherapy for Alzheimer patients. Successful screening for new AChEI relies on effective and fast assays. Two colorimetric screening assays frequently used to search for new AChEI, namely a thin layer chromatography (TLC) assay with Fast Blue B salt as reagent and a 96-well plate assay based on Ellman's method, were compared. For the majority (83%) of the 138 test compounds of natural and synthetic origin, the results obtained with the two assays converged and both screening assays were considered suitable for the generation of new hits. Fifteen percent of investigated compounds were classified as active with the microplate assay but were shown to be inactive by TLC and about 2% were measured active by TLC but showed to be inactive with the microplate assay. These divergences were not due to the main differences between the experimental protocols of the two screening assays, namely the different colorimetric methods and pre-incubation of test compounds with acetylcholinesterase (AChE). They might be explained by the interaction of either AChE or test compounds with the silica of the TLC plates, resulting in an altered affinity of the enzyme for the compounds.