title: Preformulation and Formulation of Steroids and Assessment of an Electronically Modulated Intravaginal Device for Induced Calving or Oestrous synchronization of Cattle.

authors: Ismail, Ali Abdi

subjects: steroids

abstract: Drug delivery technology is currently advancing faster than at any time in biotechnology history. The challenge of drug delivery is to achieve a controlled release of therapeutic agents over an extended period. Controlled release potentially offers significant advantages over conventional dosage forms, by eliminating both under- and overdosing while maintaining a desired range of drug concentrations. An existing drug regimen for induced calving produces a declining blood profile that does not mimic the naturally occurring, gradually increasing, cortisol blood level around parturition effectively, causing animal health issues.  Likewise, while the existing progesterone controlled release systems for oestrous control successfully synchronise oestrus, it is however, associated with reduced fertility and as such other drugs have to be administered to improve the fertility during oestrus. Therefore, there is a need for a drug delivery system that is capable of delivering multiple drugs at various times and patterns. This research aimed to investigate, characterize, identify steroids with high absorption rates through vaginal mucosa and evaluate the potential of an electronic drug delivery system for the delivery of steroids for either the control of the bovine oestrous cycle or induced calving.
In order to identify steroids with high absorption rates across the vaginal mucosa, an in vitro permeation method was developed to screen selected steroids for their ability to permeate artificial and biological membranes. The steroids were pre-formulated to enhance their solubility and permeation through these membranes. Analytical UV and HPLC assays to characterise the pure and formulated steroidal compounds were also developed and validated. An assessment of an intravaginal Electronically Modulated Intravaginal Device (EMID) for the control of the bovine oestrous cycle or induced calving was carried out. Five different release assessment methods were investigated and critically evaluated in order to identify the most appropriate release assessment method for the EMID. These were: 1) the Drug Dissolution Test, 2) a weight loss method, 3) the dispensed weight method, 4) the determination of piston travel distance method, and 5) the rod expulsion from the EMID method. The methods investigated were critically evaluated in terms of ease of use and automation, reproducibility and cost/time savings. Optimisation of various components and construction materials of the EMID were also investigated. Animal trials were carried out using the original EMID (manufactured from polypropylene polymer) and modified inserts (manufactured from high density polyethylene polymer) to determine their retention rate in the animals. Accelerated stability testing of progesterone in suspension, oestradiol-17 tablets, cloprostenol as a powder blend and the driving mechanism of the EMID were examined.
The flux of the steroids was evaluated through poly-&-caprolactone and excised cow mucosa membranes using side-by-side permeation cells. 
Results indicated that progesterone followed by dexamethasone acetate and dexamethasone valerate showed higher permeability values through vaginal mucosa compared to dexamethasone or its other analogues. The weight loss method of the EMID proved to be an easy and appropriate method to measure the release rate from the EMID. A high density polyethylene polymer was identified as the most ideal body material for the insert compared to polypropylene body. Also double O-ring silicone, Elastollan WYO 1388-5 and solid silicone pistons were found to be amongst the best pistons tested and all performed well compared to other piston materials. There was a low retention rate with either the original EMID or the modified inserts. Further modification of retention wings of the EMID did not improve the retention rate, but a good blood profile response was obtained from cows treated with the complete EMID containing formulated progesterone. The formulations and driving mechanism were found to be stable under the tested conditions.  
Therefore, the EMID has potential for commercial application of induced calving or oestrous control per vaginum administration, reliant on improvement of its retention mechanism.

text: Preformulation and Formulation of Steroids and Assessment of an Electronically Modulated Intravaginal Device for Induced Calving or Oestrous synchronization of Cattle. Drug delivery technology is currently advancing faster than at any time in biotechnology history. The challenge of drug delivery is to achieve a controlled release of therapeutic agents over an extended period. Controlled release potentially offers significant advantages over conventional dosage forms, by eliminating both under- and overdosing while maintaining a desired range of drug concentrations. An existing drug regimen for induced calving produces a declining blood profile that does not mimic the naturally occurring, gradually increasing, cortisol blood level around parturition effectively, causing animal health issues.  Likewise, while the existing progesterone controlled release systems for oestrous control successfully synchronise oestrus, it is however, associated with reduced fertility and as such other drugs have to be administered to improve the fertility during oestrus. Therefore, there is a need for a drug delivery system that is capable of delivering multiple drugs at various times and patterns. This research aimed to investigate, characterize, identify steroids with high absorption rates through vaginal mucosa and evaluate the potential of an electronic drug delivery system for the delivery of steroids for either the control of the bovine oestrous cycle or induced calving.
In order to identify steroids with high absorption rates across the vaginal mucosa, an in vitro permeation method was developed to screen selected steroids for their ability to permeate artificial and biological membranes. The steroids were pre-formulated to enhance their solubility and permeation through these membranes. Analytical UV and HPLC assays to characterise the pure and formulated steroidal compounds were also developed and validated. An assessment of an intravaginal Electronically Modulated Intravaginal Device (EMID) for the control of the bovine oestrous cycle or induced calving was carried out. Five different release assessment methods were investigated and critically evaluated in order to identify the most appropriate release assessment method for the EMID. These were: 1) the Drug Dissolution Test, 2) a weight loss method, 3) the dispensed weight method, 4) the determination of piston travel distance method, and 5) the rod expulsion from the EMID method. The methods investigated were critically evaluated in terms of ease of use and automation, reproducibility and cost/time savings. Optimisation of various components and construction materials of the EMID were also investigated. Animal trials were carried out using the original EMID (manufactured from polypropylene polymer) and modified inserts (manufactured from high density polyethylene polymer) to determine their retention rate in the animals. Accelerated stability testing of progesterone in suspension, oestradiol-17 tablets, cloprostenol as a powder blend and the driving mechanism of the EMID were examined.
The flux of the steroids was evaluated through poly-&-caprolactone and excised cow mucosa membranes using side-by-side permeation cells. 
Results indicated that progesterone followed by dexamethasone acetate and dexamethasone valerate showed higher permeability values through vaginal mucosa compared to dexamethasone or its other analogues. The weight loss method of the EMID proved to be an easy and appropriate method to measure the release rate from the EMID. A high density polyethylene polymer was identified as the most ideal body material for the insert compared to polypropylene body. Also double O-ring silicone, Elastollan WYO 1388-5 and solid silicone pistons were found to be amongst the best pistons tested and all performed well compared to other piston materials. There was a low retention rate with either the original EMID or the modified inserts. Further modification of retention wings of the EMID did not improve the retention rate, but a good blood profile response was obtained from cows treated with the complete EMID containing formulated progesterone. The formulations and driving mechanism were found to be stable under the tested conditions.  
Therefore, the EMID has potential for commercial application of induced calving or oestrous control per vaginum administration, reliant on improvement of its retention mechanism.

year: 2007

title: Predictive Risk Modelling for Hospital Readmissions

authors: Forsythe, Claire Elizabeth

subjects: Logistic regression

abstract: This thesis is concerned with developing a predictive risk model to identify patients that are at high risk of readmission to hospital. Such a model should have a desirable level of predictive accuracy but also, should be financially beneficial to the DHB. Logistic regression and Naive Bayes probabilistic classification methods were both considered to build the predictive model. Performance measures such as the positive predictive value (PPV) and cost savings analysis were used to find the optimal days between initial admission and readmission and the optimal threshold for prediction of high risk patients. This study is concerned with Waikato District Health Board (DHB) domiciled patients discharged between 1 July 2009 and 31 October 2013. The dataset includes information about the patients initial admission and the response variable is whether a readmission occurred or not. 

Using logistic regression, this study found the model that fits the data best includes 21 variables that contain information about the patients initial admission. The two classification methods used produce a risk probability between 0 and 1 for each patient in the study. The logistic regression model performance was better than Naive Bayes as shown by the PPV (the proportion of patients correctly identified as at risk over the total at risk). The 56 day readmission data PPV at a risk threshold of 0.5 for the logistic regression was 48.4% and 30.8% for Naive Bayes. Analysis of the PPV identifies the risk threshold level of 0.5 and readmission period of 56 days as optimal predictive criteria in this study. Cost savings analysis also supports the 56 day model with an intervention cost of $500. The 0.5 cut off point in the 56 day model identifies a reasonable number of patients at risk for intervention, approximately 3,000, which equates to about 2 patients at risk per day over the period of this analysis.

This analysis found the optimal model for predicting patients at risk of readmission is a logistic regression model using 56 day readmission data and a risk threshold of 0.5. A key recommendation of this study is that the DHB needs to introduce a method that correctly flags patient admissions. The model should be used on a trial basis at the DHB to see how accurate it performs.

text: Predictive Risk Modelling for Hospital Readmissions This thesis is concerned with developing a predictive risk model to identify patients that are at high risk of readmission to hospital. Such a model should have a desirable level of predictive accuracy but also, should be financially beneficial to the DHB. Logistic regression and Naive Bayes probabilistic classification methods were both considered to build the predictive model. Performance measures such as the positive predictive value (PPV) and cost savings analysis were used to find the optimal days between initial admission and readmission and the optimal threshold for prediction of high risk patients. This study is concerned with Waikato District Health Board (DHB) domiciled patients discharged between 1 July 2009 and 31 October 2013. The dataset includes information about the patients initial admission and the response variable is whether a readmission occurred or not. 

Using logistic regression, this study found the model that fits the data best includes 21 variables that contain information about the patients initial admission. The two classification methods used produce a risk probability between 0 and 1 for each patient in the study. The logistic regression model performance was better than Naive Bayes as shown by the PPV (the proportion of patients correctly identified as at risk over the total at risk). The 56 day readmission data PPV at a risk threshold of 0.5 for the logistic regression was 48.4% and 30.8% for Naive Bayes. Analysis of the PPV identifies the risk threshold level of 0.5 and readmission period of 56 days as optimal predictive criteria in this study. Cost savings analysis also supports the 56 day model with an intervention cost of $500. The 0.5 cut off point in the 56 day model identifies a reasonable number of patients at risk for intervention, approximately 3,000, which equates to about 2 patients at risk per day over the period of this analysis.

This analysis found the optimal model for predicting patients at risk of readmission is a logistic regression model using 56 day readmission data and a risk threshold of 0.5. A key recommendation of this study is that the DHB needs to introduce a method that correctly flags patient admissions. The model should be used on a trial basis at the DHB to see how accurate it performs.

year: 2014

title: A literary and linguistic critique of a Māori lullaby

authors: August, Tipene

subjects: waiata Māori

abstract: Māori song poems surviving from pre-colonial times can provide a valuable source of information about the artistic and cultural heritage of Māoridom. However, they present a number of challenges for the contemporary analyst. On the basis of a stylistic analysis of a Māori lullaby, a number of hypotheses about Māori song poems in general, and the lullaby in particular, are put forward and it is suggested that these hypotheses could be tested in relation to a corpus of song poems. It is hoped that the approach to stylistic analysis adopted here will be of use to scholars of Māori song poems and, perhaps, also to others who are interested in indigenous art forms more generally.

text: A literary and linguistic critique of a Māori lullaby Māori song poems surviving from pre-colonial times can provide a valuable source of information about the artistic and cultural heritage of Māoridom. However, they present a number of challenges for the contemporary analyst. On the basis of a stylistic analysis of a Māori lullaby, a number of hypotheses about Māori song poems in general, and the lullaby in particular, are put forward and it is suggested that these hypotheses could be tested in relation to a corpus of song poems. It is hoped that the approach to stylistic analysis adopted here will be of use to scholars of Māori song poems and, perhaps, also to others who are interested in indigenous art forms more generally.

year: 2001-02