A Cross-Sectional Survey of the Knowledge, Attitudes, and Practices of Antimicrobial Users and Providers in an Area of High-Density Livestock-Human Population in Western Kenya.

Background: Antimicrobial resistance (AMR) is one of the most important global health crises in recent times and is driven primarily by antimicrobial consumption. In East Africa, there is a paucity of data regarding the knowledge, attitudes, and practices (KAP) related to antimicrobial use (AMU). We investigate the ways in which antimicrobial users in the veterinary sector accessed veterinary antimicrobials, and common behaviors of veterinary antimicrobial users and prescribers associated with AMU and AMR. Methods: In total, 70 farmers, staff at 49 agricultural-veterinary antimicrobial shops (agrovet staff) and 28 veterinary animal healthcare workers or veterinary surgeons (veterinary professionals) were interviewed in Busia county, western Kenya in 2016 using a standard questionnaire as a framework for structured interviews. Data recorded included participant demographics, level of education, access to and sources of veterinary antimicrobials, prescribing patterns, and knowledge of AMR and antimicrobial withdrawal periods. Results: The majority of antimicrobials were accessed through informal means, purchased from agroveterinary shops; more than half of staff did not hold nationally mandated qualifications to advise on or sell veterinary antimicrobials. Approximately 40% of veterinary antimicrobials were sold without a prescription and it was noted that both price and customer preference were important factors when selling antimicrobials in almost all agrovet shops. Knowledge of the dangers associated with AMR and AMU were mostly superficial. Treatment failure occurred often, and there was a lack of differentiation between AMR and simply treatment failure. Conclusion: In this study area in East Africa with high-density human and livestock populations, AMU was primarily for maintenance of livestock health. These findings have highlighted several aspects surrounding inappropriate access to antimicrobials, and as such require attention from policy makers concerned with AMR in both livestock and human medicine sectors. Improving prescribing practices and ensuring a minimum level of general education and awareness of prescribers, as well as expanding the role of agrovet staff in antimicrobial stewardship programmes, may help begin to mitigate the maintenance and transmission of AMR, particularly amongst livestock

A case series of Acceptance and Commitment Therapy (ACT) for reducing symptom interference in functional neurological disorders

There is limited high-quality evidence supporting psychological treatments for functional neurological disorders (FNDs), and what evidence exists suggests that the impact of such treatments could be improved. One way to increase effectiveness is to utilize approaches that can have impact across heterogeneous FND presentations. Acceptance and Commitment Therapy (ACT) targets a transdiagnostic process called psychological flexibility and is used effectively to integrate multidisciplinary treatments in other clinical contexts. Here, we present a consecutive case series (N = 8) of a relatively brief (6 to 10 sessions) ACT intervention, delivered face to face by a clinical psychologist in an outpatient neuropsychology service. Treatment aimed to reduce symptom interference and improve mood via improvements in psychological flexibility. Service users presented with a range of FND symptoms (e.g., syncope, limb paralysis, and paraesthesia). Following treatment, 5 participants showed reliable improvements in symptom interference (Work and Social Adjustment Scale), 2 to the extent of clinical significance; 4 had reliable improvements in mood (Clinical Outcomes in Routine Evaluation—10), and 2 within the range of clinical significance. There were no reliable deteriorations in symptom interference or mood. Marked variation was apparent on the measure of psychological flexibility (Acceptance and Action Questionnaire II), with 4 reliable improvements, 3 within the range of clinical significance, and also 2 reliable deteriorations. These promising results suggest that further investigation of an ACT approach to FND is warranted. Future studies should include measures of psychological flexibility with greater comprehensibility

Trial Designs Likely to Meet Valid Long-Term Alzheimer's Disease Progression Effects: Learning from the Past, Preparing for the Future

The International Society for CNS Clinical Trials and Methodology (ISCTM) held its 4th Annual Autumn Conference in Toronto, Ontario, October 6-7, 2008. The purpose of the present report is to provide an overview of one of the sessions at the conference which focused on the designs and methodologies to be applied in clinical trials of new treatments for Alzheimer's disease (AD) with purported “disease-modifying” effects. The session began with a discussion of how neuroimaging has been applied in multiple sclerosis clinical trials (another condition for which disease modification claims have been achieved). The next two lectures provided a pharmaceutical industry perspective on some of the specific challenges and possible solutions for designing trials to measure disease progression and/or modification. The final lecture provided an academic viewpoint and the closing discussion included additional academic and regulatory perspectives on trial designs, methodologies, and statistical issues relevant to the disease modification concept

Cellular Models of Aggregation-Dependent Template-Directed Proteolysis to Characterize Tau Aggregation Inhibitors for Treatment of Alzheimer's Disease

Copyright © 2015, The American Society for Biochemistry and Molecular Biology. Acknowledgements-We thank Drs Timo Rager and Rolf Hilfiker (Solvias, Switzerland) for polymorph analyses.Peer reviewedPublisher PD

A low-tech, cost-effective and efficient method for safeguarding genetic diversity by direct cryopreservation of poultry embryonic reproductive cells

Chickens are an important resource for smallholder farmers who raise locally adapted, genetically distinct breeds for eggs and meat. The development of efficient reproductive technologies to conserve and regenerate chicken breeds safeguards existing biodiversity and secures poultry genetic resources for climate resilience, biosecurity, and future food production. The majority of the over 1600 breeds of chicken are raised in low and lower to middle income countries under resource-limited, small-scale production systems, which necessitates a low-tech, cost-effective means of conserving diversity is needed. Here, we validate a simple biobanking technique using cryopreserved embryonic chicken gonads. The gonads are quickly isolated, visually sexed, pooled by sex, and cryopreserved. Subsequently, the stored material is thawed and dissociated before injection into sterile host chicken embryos. By using pooled GFP and RFP-labelled donor gonadal cells and Sire Dam Surrogate mating, we demonstrate that chicks deriving entirely from male and female donor germ cells are hatched. This technology will enable ongoing efforts to conserve chicken genetic diversity for both commercial and smallholder farmers, and to preserve existing genetic resources at poultry research facilities

Reduced expression of mitochondrial fumarate hydratase in progressive multiple sclerosis contributes to impaired in vitro mesenchymal stromal cell-mediated neuroprotection

BACKGROUND: Cell-based therapies for multiple sclerosis (MS), including those employing autologous bone marrow-derived mesenchymal stromal cells (MSC) are being examined in clinical trials. However, recent studies have identified abnormalities in the MS bone marrow microenvironment. OBJECTIVE: We aimed to compare the secretome of MSC isolated from control subjects (C-MSC) and people with MS (MS-MSC) and explore the functional relevance of findings. METHODS: We employed high throughput proteomic analysis, enzyme-linked immunosorbent assays and immunoblotting, as well as in vitro assays of enzyme activity and neuroprotection. RESULTS: We demonstrated that, in progressive MS, the MSC secretome has lower levels of mitochondrial fumarate hydratase (mFH). Exogenous mFH restores the in vitro neuroprotective potential of MS-MSC. Furthermore, MS-MSC expresses reduced levels of fumarate hydratase (FH) with downstream reduction in expression of master regulators of oxidative stress. CONCLUSIONS: Our findings are further evidence of dysregulation of the bone marrow microenvironment in progressive MS with respect to anti-oxidative capacity and immunoregulatory potential. Given the clinical utility of the fumaric acid ester dimethyl fumarate in relapsing–remitting MS, our findings have potential implication for understanding MS pathophysiology and personalised therapeutic intervention

Raising argument strength using negative evidence: A constraint on models of induction

Both intuitively, and according to similarity-based theories of induction, relevant evidence raises argument strength when it is positive and lowers it when it is negative. In three experiments, we tested the hypothesis that argument strength can actually increase when negative evidence is introduced. Two kinds of argument were compared through forced choice or sequential evaluation: single positive arguments (e.g., “Shostakovich’s music causes alpha waves in the brain; therefore, Bach’s music causes alpha waves in the brain”) and double mixed arguments (e.g., “Shostakovich’s music causes alpha waves in the brain, X’s music DOES NOT; therefore, Bach’s music causes alpha waves in the brain”). Negative evidence in the second premise lowered credence when it applied to an item X from the same subcategory (e.g., Haydn) and raised it when it applied to a different subcategory (e.g., AC/DC). The results constitute a new constraint on models of induction

In Vivo Emergence of a Novel Protease Inhibitor Resistance Signature in HIV-1 Matrix.

Protease inhibitors (PIs) are the second- and last-line therapy for the majority of HIV-infected patients worldwide. Only around 20% of individuals who fail PI regimens develop major resistance mutations in protease. We sought to explore the role of mutations in gag-pro genotypic and phenotypic changes in viruses from six Nigerian patients who failed PI-based regimens without known drug resistance-associated protease mutations in order to identify novel determinants of PI resistance. Target enrichment and next-generation sequencing (NGS) with the Illumina MiSeq system were followed by haplotype reconstruction. Full-length Gag-protease gene regions were amplified from baseline (pre-PI) and virologic failure (VF) samples, sequenced, and used to construct gag-pro-pseudotyped viruses. Phylogenetic analysis was performed using maximum-likelihood methods. Susceptibility to lopinavir (LPV) and darunavir (DRV) was measured using a single-cycle replication assay. Western blotting was used to analyze Gag cleavage. In one of six participants (subtype CRF02_AG), we found 4-fold-lower LPV susceptibility in viral clones during failure of second-line treatment. A combination of four mutations (S126del, H127del, T122A, and G123E) in the p17 matrix of baseline virus generated a similar 4-fold decrease in susceptibility to LPV but not darunavir. These four amino acid changes were also able to confer LPV resistance to a subtype B Gag-protease backbone. Western blotting demonstrated significant Gag cleavage differences between sensitive and resistant isolates in the presence of drug. Resistant viruses had around 2-fold-lower infectivity than sensitive clones in the absence of drug. NGS combined with haplotype reconstruction revealed that resistant, less fit clones emerged from a minority population at baseline and thereafter persisted alongside sensitive fitter viruses. We used a multipronged genotypic and phenotypic approach to document emergence and temporal dynamics of a novel protease inhibitor resistance signature in HIV-1 matrix, revealing the interplay between Gag-associated resistance and fitness