Economic evaluations of interventions to optimize medication use in older adults with polypharmacy and multimorbidity: A systematic review

Purpose: To conduct a systematic review of the economic impact of interventions intended at optimizing medication use in older adults with multimorbidity and polypharmacy. Methods: We searched Ovid-Medline, Embase, CINAHL, Ageline, Cochrane, and Web of Science, for articles published between 2004 and 2020 that studied older adults with multi-morbidity and polypharmacy. The intervention studied had to be aimed at optimizing medication use and present results on costs. Results: Out of 3,871 studies identified by the search strategy, eleven studies were included. The interventions involved different provider types, with a majority described as a multidisciplinary team involving a pharmacist and a general practitioner, in the decision-making process. Interventions were generally associated with a reduction in medication expenditure. The benefits of the intervention in terms of clinical outcomes remain limited. Five studies were cost-benefit analyses, which had a net benefit that was either null or positive. Cost-utility and cost-effectiveness analyses resulted in incremental cost-effectiveness ratios that were generally within the willingness-to-pay thresholds of the countries in which the studies were conducted. However, the quality of the studies was generally low. Omission of key cost elements of economic evaluations, including intervention cost and payer perspective, limited interpretability. Conclusion: Interventions to optimize medication use may provide benefits that outweigh their implementation costs, but the evidence remains limited. There is a need to identify and address barriers to the scaling-up of such interventions, starting with the current incentive structures for pharmacists, physicians, and patients

Pitchfork and Hopf bifurcation thresholds in stochastic equations with delayed feedback

The bifurcation diagram of a model stochastic differential equation with delayed feedback is presented. We are motivated by recent research on stochastic effects in models of transcriptional gene regulation. We start from the normal form for a pitchfork bifurcation, and add multiplicative or parametric noise and linear delayed feedback. The latter is sufficient to originate a Hopf bifurcation in that region of parameters in which there is a sufficiently strong negative feedback. We find a sharp bifurcation in parameter space, and define the threshold as the point in which the stationary distribution function p(x) changes from a delta function at the trivial state x=0 to p(x) ~ x^alpha at small x (with alpha = -1 exactly at threshold). We find that the bifurcation threshold is shifted by fluctuations relative to the deterministic limit by an amount that scales linearly with the noise intensity. Analytic calculations of the bifurcation threshold are also presented in the limit of small delay tau -> 0 that compare quite favorably with the numerical solutions even for tau = 1

Functional domains of Acinetobacter bacteriophage tail fibers

A rapid increase in antimicrobial resistant bacterial infections around the world is causing a global health crisis. The Gram-negative bacterium Acinetobacter baumannii is categorized as a Priority 1 pathogen for research and development of new antimicrobials by the World Health Organization due to its numerous intrinsic antibiotic resistance mechanisms and ability to quickly acquire new resistance determinants. Specialized phage enzymes, called depolymerases, degrade the bacterial capsule polysaccharide layer and show therapeutic potential by sensitizing the bacterium to phages, select antibiotics, and serum killing. The functional domains responsible for the capsule degradation activity are often found in the tail fibers of select A. baumannii phages. To further explore the functional domains associated with depolymerase activity, tail-associated proteins of 71 sequenced and fully characterized phages were identified from published literature and analyzed for functional domains using InterProScan. Multisequence alignments and phylogenetic analyses were conducted on the domain groups and assessed in the context of noted halo formation or depolymerase characterization. Proteins derived from phages noted to have halo formation or a functional depolymerase, but no functional domain hits, were modeled with AlphaFold2 Multimer, and compared to other protein models using the DALI server. The domains associated with depolymerase function were pectin lyase-like (SSF51126), tailspike binding (cd20481), (Trans)glycosidases (SSF51445), and potentially SGNH hydrolases. These findings expand our knowledge on phage depolymerases, enabling researchers to better exploit these enzymes for therapeutic use in combating the antimicrobial resistance crisis

Predominance of Ehrlichia ewingii in Missouri dogs

To investigate the species distribution of Ehrlichia present in Missouri dogs, we tested 78 dogs suspected of having acute ehrlichiosis and 10 healthy dogs. Blood from each dog was screened with a broad-range 16S rRNA gene PCR assay that detects known pathogenic species of Ehrlichia and Anaplasma. The species was determined by using species-specific PCR assays and nucleotide sequencing. Ehrlichia antibody testing was performed by using an indirect immunofluorescence assay with Ehrlichia chaffeensis as the antigenic substrate. The broad-range assay detected Ehrlichia or Anaplasma DNA in 20 (26%) of the symptomatic dogs and 2 (20%) of the asymptomatic dogs. E. ewingii accounted for 20 (91%), and E. chaffeensis accounted for 1 (5%) of the positives. Anaplasma phagocytophilum DNA was detected in one dog, and the sequences of regions of the 16S rRNA gene and the groESL operon amplified from the blood of this dog matched the published sequences of this organism. Antibodies reactive with E. chaffeensis were detected in 14 (67%) of the 21 PCR-positive dogs and in 12 (19%) of the 64 PCR-negative dogs. Combining the results of PCR and serology indicated that 33 (39%) of 85 evaluable dogs had evidence of past or current Ehrlichia infection. We conclude that E. ewingii is the predominant etiologic agent of canine ehrlichiosis in the areas of Missouri included in this survey. E. canis, a widely recognized agent of canine ehrlichiosis, was not detected in any animal. The finding of E. ewingii in asymptomatic dogs suggests that dogs could be a reservoir for this Ehrlichia species

Pharmacokinetic and pharmacodynamic modelling after subcutaneous, intravenous and buccal administration of a high-concentration formulation of buprenorphine in conscious cats

The aim of this study was to describe the joint pharmacokinetic-pharmacodynamic model and evaluate thermal antinociception of a high-concentration formulation of buprenorphine (Simbadol™) in cats

Development and aetiology of body dissatisfaction in adolescent boys and girls

This longitudinal study aims to describe the development of body dissatisfaction (BD), measured with the Contour Drawing Rating Scale, between the ages of 14 and 18, and to identify factors associated with BD at age 18, among 413 adolescents. Between the ages of 14 and 18, the proportion of girls wanting to be thinner increased, although it remained unchanged among boys. A ratio of 1:2 girls and 1:5 boys reported having seriously tried to lose weight. Factors associated with BD in girls at age 18 were (1) wanting to be thinner, (2) body mass index (BMI), (3) weight control behaviours and (4) negative comments about weight. Factors associated with BD in boys at age 18 were (1) wanting to be thinner or bigger, (2) BMI, (3) having experienced sexual intercourse and (4) negative comments about weight. The high prevalence of BD and weight-related concerns suggest a need for early interventions. © 2014 © 2014 The Author(s). Published by Taylor & Francis

On the reporting and review requirements of ISO 14044

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Involvement of TLR2 in Recognition of Acute Gammaherpesvirus-68 Infection

Toll-like receptors (TLRs) play a crucial role in the activation of innate immunity in response to many viruses. We previously reported the implication of TLR2 in the recognition of Epstein-Barr virus (EBV) by human monocytes. Because murine gammaherpesvirus-68 (MHV-68) is a useful model to study human gammaherpesvirus pathogenesis in vivo, we evaluated the importance of mouse TLR2 in the recognition of MHV-68.In studies using transfected HEK293 cells, MHV-68 lead to the activation of NF-κB reporter through TLR2. In addition, production of interleukin-6 (IL-6) and interferon-α (IFN-α) upon MHV-68 stimulation was reduced in murine embryonic fibroblasts (MEFs) derived from TLR2-/- and MyD88-/- mice as compared to their wild type (WT) counterpart. In transgenic mice expressing a luciferase reporter gene under the control of the mTLR2 promoter, MHV-68 challenge activated TLR2 transcription. Increased expression levels of TLR2 on blood granulocytes (CD115(-)Gr1(+)) and inflammatory monocytes (CD115(+)Gr1(+)), which mobilized to the lungs upon infection with MHV-68, was also confirmed by flow cytometry. Finally, TLR2 or MyD88 deficiency was associated with decreased IL-6 and type 1 IFN production as well as increased viral burden during short-term challenges with MHV-68.TLR2 contributes to the production of inflammatory cytokines and type 1 IFN as well as to the control of viral burden during infection with MHV-68. Taken together, our results suggest that the TLR2 pathway has a relevant role in the recognition of this virus and in the subsequent activation of the innate immune response