Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

An experimental challenge model in lactating dairy cows using Streptococcus uberis for antibiotic efficacy testing : a thesis presented in partial fulfilment of the requirements for the degree of Master of Philosophy in Veterinary Science at Massey University, Palmerston North, New Zealand

The aim of this project was to develop a challenge model to test the efficacy of novel intramammary antimicrobial treatments for clinical mastitis. The use of the model, can reduces the costs of testing efficacy and accelerate the process of registration of new products. It provides controlled conditions which safeguard animal welfare. The experimental challenge model using Streptococcus uberis developed in this thesis can provide the pharmaceutical industry and animal health research groups with a cost-effective method to test the efficacy of new antimicrobial products for treatment of mastitis in a safe and controlled environment. Two Cloxacillin-based antimicrobials with different formulations and treatment frequency were tested for their efficacy to cure S. uberis infections after infections were induced using the challenge model developed as described in the third chapter of this thesis. The objective of the first study presented in this thesis was to choose one suitable strain from four strains of S. uberis, to be used in future challenge studies. Four strains were tested for their virulence and susceptibility to antibiotic therapy. A further study objective was to determine the dose (number of pathogens infused, expressed as colony forming units (CFU)) required for the tested strains to produce an acceptable proportion of clinical mastitis cases to enable future studies. The strain which accomplished the desired characteristics was then chosen and was utilised for experimental challenge in further studies (Chapters 4 and 5). The overall incidence of clinical mastitis obtained in this study at a quarter level was 54% (26/48). This study showed significant differences in the ability of different strains of S. uberis to cause clinical mastitis when inoculated via the intramammary route. However, only one of the four strains tested demonstrated favourable characteristics as a strain to be used in experimentally induced clinical mastitis studies. Chapters 4 and 5 describe two challenge studies conducted using the experimental challenge model (Chapter 3) to test the efficacy of different antimicrobial drug formulations. In Chapter 4, the cure rate of one cloxacillin based product applied every 24 hr. was compared with the cure rate of a penicillin-based product applied every 12 hr. During the observation period of this investigation all challenged cows developed clinicalThe aim of this project was to develop a challenge model to test the efficacy of novel intramammary antimicrobial treatments for clinical mastitis. The use of the model, can reduces the costs of testing efficacy and accelerate the process of registration of new products. It provides controlled conditions which safeguard animal welfare. The experimental challenge model using Streptococcus uberis developed in this thesis can provide the pharmaceutical industry and animal health research groups with a cost-effective method to test the efficacy of new antimicrobial products for treatment of mastitis in a safe and controlled environment. Two Cloxacillin-based antimicrobials with different formulations and treatment frequency were tested for their efficacy to cure S. uberis infections after infections were induced using the challenge model developed as described in the third chapter of this thesis. The objective of the first study presented in this thesis was to choose one suitable strain from four strains of S. uberis, to be used in future challenge studies. Four strains were tested for their virulence and susceptibility to antibiotic therapy. A further study objective was to determine the dose (number of pathogens infused, expressed as colony forming units (CFU)) required for the tested strains to produce an acceptable proportion of clinical mastitis cases to enable future studies. The strain which accomplished the desired characteristics was then chosen and was utilised for experimental challenge in further studies (Chapters 4 and 5). The overall incidence of clinical mastitis obtained in this study at a quarter level was 54% (26/48). This study showed significant differences in the ability of different strains of S. uberis to cause clinical mastitis when inoculated via the intramammary route. However, only one of the four strains tested demonstrated favourable characteristics as a strain to be used in experimentally induced clinical mastitis studies. Chapters 4 and 5 describe two challenge studies conducted using the experimental challenge model (Chapter 3) to test the efficacy of different antimicrobial drug formulations. In Chapter 4, the cure rate of one cloxacillin based product applied every 24 hr. was compared with the cure rate of a penicillin-based product applied every 12 hr. During the observation period of this investigation all challenged cows developed clinical mastitis in at least one quarter. The incidence of clinical mastitis at the quarter level was high, with 91.25% (73/80) of challenged quarters being affected. After diagnosis of infections, the cows were randomly allocated to two treatment groups and treated accordingly. Clinical cases in which the quarter did not respond to three applications of the allocated antimicrobial product received an extended treatment of the same product. As the allocation to the extended treatment was not random, clinical and bacteriological cures were statistically evaluated for the short treatment only. Clinical cure rates for the short treatment (3 syringes) were 52.63% and 43.75% for the cloxacillin- and penicillin-based products, respectively. There was no significant difference between the treatments (P = 0.8) in their efficacy for the treatment of experimentally induced S. uberis clinical mastitis. In Chapter 5, two long-acting cloxacillin containing products were compared in their efficacy to cure experimentally induced S. uberis infections. One commercially available product was compared with a novel long acting product (applied every 48 hr.). Out of 80 challenged quarters, 41 quarters developed clinical mastitis after inoculation (51.25%). Treatment with the novel product resulted in a total treatment success rate of 93.1% based on clinical examination, and 96.0% based on the bacteriological cure rate. Treatment with the control product resulted in total treatment success rate of 100% based on clinical and bacteriological cure rate. There was no significant difference between the products (P=0.19) in their efficacy for the treatment of experimentally induced S. uberis clinical mastitis. Results in this thesis showed that experimental challenge models can be a useful tool in animal research to test the efficacy of new products in a safe and cost effective manner

The physiology of the keratin plug formation in the teat canal of dairy cattle and its interaction with current and novel methods for prevention of intramammary infections : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Veterinary Science, Massey University, Turitea, Palmerston North, New Zealand

Chapter 6 was published as an open access article in the Journal of Dairy Science under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 (CC BY-NC-ND) license. Chapter 7 was published as an open access article in Veterinary Sciences under a Creative Commons Attribution (CC BY) license. Both articles are attached.The incidence of intramammary infections (IMI) in dairy cows in the early dry period is the highest of the lactation cycle when methods to prevent IMI are not applied. This high incidence is comparable only with that observed near calving. At the end of lactation, the teat is sealed by a plug formed mainly by keratinised cells, detritus and proteinaceous material. Research suggests that the keratin plug acts as a physicochemical barrier throughout the dry period that impedes the entrance of bacteria. However, the physiological mechanism of keratin plug formation is still uncertain. The main objectives of this thesis were to characterise the physiological functions of the teat canal (TC) during the early dry period and assess how they associate with the presence of IMI. A further objective was to evaluate the modes of action of a current mastitis preventative containing bismuth subnitrate and a novel formulation of micronized keratin that is under investigation as a teat seal for preventing IMI during the early dry period. To address these objectives a novel biopsy method was developed to allow investigation of the physiological characteristics of the epithelial tissues of the TC. A transcriptomic analysis of the TC epithelium after drying off showed that epithelial cells decreased expression of mitotic and immune-response related genes. A Streptococcus uberis strain was used in a challenge study aiming to examine mechanisms of colonization in the TC and the response of the epithelial tissue to progressing infection. This Streptococcus uberis challenge did not result in colonization of the TC nor in IMI with S. uberis. Nevertheless, a reduction in the thickness of the stratum granulosum and the keratin layer of the TC epithelium was observed. This coincided with an increase in TC colonization by non-pathogenic bacteria and a decline in the concentration of certain cytokines after drying off. These changes observed in the TC epithelium support previous reports showing increased incidence of IMI by non-pathogenic bacteria during the early dry period. Antimicrobial effects and neutrophil cell responses were evaluated in vitro in two studies to test previously hypothesised action mechanisms for bismuth subnitrate and a novel keratin-based internal teat sealant (ITS) formulation. Bismuth subnitrate showed an inhibitory effect on bacterial growth, contrary to the current description of ITS as non-pharmacological, inert physical barriers. No activation of a cellular response was observed for keratin or bismuth formulations in vitro. Bismuth subnitrate and keratin were also tested in vivo for their effect on the formation of the keratin plug. The hypothesis of this study was that these treatments induce expression of mitogenic genes that induce a faster sealing of the teat canal. There was no modification of gene expression after treating cows with bismuth subnitrate or the novel keratin-based ITS formulation during the formation of the natural keratin plug, and no modification of the closure status of the teat canal lumen, suggesting that neither of the two treatments induced an improved sealing of the teat canal after drying off through increased keratin production. These findings contribute to the knowledge of keratin plug formation and physiological characteristics of the TC during involution. They align with and partially explain some of the literature-reported events observed during the early dry period. The knowledge gained provides support for future product development aimed to increase protection of the mammary gland during the dry period

Cellular response of neutrophils to bismuth subnitrate and micronized keratin products in vitro

The aim of this study was to assess the effect of bismuth subnitrate and micronized keratin on bovine neutrophils in vitro. We hypothesized that recruitment and activation of neutrophils into the teat canal and sinus are the mechanisms of action of bismuth subnitrate and keratin-based teat sealant formulations. To test this, a chemotaxis assay (Experiment 1) and a myeloperoxidase (MPO) assay (Experiment 2) were conducted in vitro. Blood was sampled from 12 mid-lactation dairy cows of variable ages. Neutrophils were extracted and diluted to obtain cell suspensions of approximately 106 cells/mL. In Experiment 1, test substances were placed in a 96-well plate, separated from the cell suspension by a 3 μm pore membrane and incubated for 3 h to allow neutrophils to migrate through the membrane. In Experiment 2, neutrophils were exposed to the test products and the amount of MPO released was measured by optical density. Results showed that neutrophils were not activated by bismuth or keratin products (p < 0.05) in all of the tests performed. These results suggest that the mechanisms of action of bismuth subnitrate and keratin-based teat sealants do not rely on neutrophil recruitment and activation in the teat canal and sinus after treatment.</p

Cellular response of neutrophils to bismuth subnitrate and micronized keratin products in vitro

The aim of this study was to assess the effect of bismuth subnitrate and micronized keratin on bovine neutrophils in vitro. We hypothesized that recruitment and activation of neutrophils into the teat canal and sinus are the mechanisms of action of bismuth subnitrate and keratin-based teat sealant formulations. To test this, a chemotaxis assay (Experiment 1) and a myeloperoxidase (MPO) assay (Experiment 2) were conducted in vitro. Blood was sampled from 12 mid-lactation dairy cows of variable ages. Neutrophils were extracted and diluted to obtain cell suspensions of approximately 106 cells/mL. In Experiment 1, test substances were placed in a 96-well plate, separated from the cell suspension by a 3 μm pore membrane and incubated for 3 h to allow neutrophils to migrate through the membrane. In Experiment 2, neutrophils were exposed to the test products and the amount of MPO released was measured by optical density. Results showed that neutrophils were not activated by bismuth or keratin products (p <0.05) in all of the tests performed. These results suggest that the mechanisms of action of bismuth subnitrate and keratin-based teat sealants do not rely on neutrophil recruitment and activation in the teat canal and sinus after treatment

Biofilm-Forming Potential of Staphylococcus aureus Isolated from Clinical Mastitis Cases in New Zealand

Biofilm formation is of growing concern in human and animal health. However, it is still unclear how biofilms are related to mastitis infections in dairy cattle. In this study, a comparison between two tests for biofilm formation and the association between biofilm and the presence of genes associated with biofilm formation were investigated for 92 Staphylococcus aureus isolates from clinical mastitis cases. Congo red agar (CRA) and microtitre test assay (MTA) in vitro phenotypic tests were used to evaluate biofilm formation. The presence of icaA, icaD, and bap genes associated with biofilm formation was confirmed using the polymerase chain reaction. Results show that most of the S. aureus isolates, though not possessing one of the biofilm-forming genes, were able to produce biofilms. MTA was more frequently positive in identifying biofilm-forming isolates than CRA