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The ongoing global crisis of suicide underscores the imperative for effective prevention measures addressing the mental health struggles of individuals, offering hope, and facilitating access to essential services. Research is vast when considering suicide in general; however, the gap in research lies in understanding the perceptions of pastors and congregant members regarding the topic. Pastors, by integrating the topic of suicide into their sermons, can play a crucial role in prevention through messages of hope and encouragement. This approach fosters open dialogue and reduces stigma within congregations. The purpose of this qualitative case study was to gain a deeper understanding of those perceptions. Participants included pastors and congregant members of a diversity of religious denominations who volunteered to participate in interviews. Participants were asked to provide information regarding their knowledge of risk factors, interventions, perceptions of how scripture addresses the topic of suicide, and thoughts on the inclusion of the topic in sermons. A thematic analysis produced 12 themes: (a) mental health, (b) physical health, (c) God’s word/Bible, (d) professional resources, (e) healthy relationships, (f) God does not provide specific parameters on suicide, but some scripture may be relatable, (g) God is final judge, (h) due to prevalence, most all had some sort of experience with suicide, (i) supports inclusion within certain parameters, (j) should do from a Biblical background, (k) appropriate age, and (l) topic publicized prior. The information obtained allowed for a deeper understanding of the perspectives of pastors and congregant members surrounding the topic of suicide.

Three experiments were conducted to determine how dietary lipid sources influence lipid and polyunsaturated fatty acid (PUFA) metabolism when fed to young, growing chickens. In the first experiment, commercial meat-type chickens were fed one of four dietary lipids: 1) linseed oil (LO); 2) menhaden oil (MO); 3) soybean oil (SBO); or 4) chicken fat (CF). Chickens fed the polyunsaturated lipids, LO, MO, and SBO all had similar very low density lipoprotein + low density lipoprotein (VLDL + LDL) triacylglycerol concentrations which were lower than those for chickens fed CF. Tissue lipids from chickens fed LO contained more 20:5n3 compared with those fed SBO or CF. The amounts of 20:5n3 in tissues from chickens fed LO approached those found in tissues from chickens fed MO. Tissue lipids from LO and MO treatments exhibited decreased 20:4n6 concentrations compared with SBO or CF treatments. The data indicate that dietary n-3 lipid sources influence the fatty acid compositions of tissues and can be effectively used to enrich edible chicken tissues. The second experiment examined the effects of varying combinations of CF and MO on plasma triacylglycerols in broiler chickens. As the amount of dietary n-3 fatty acids and the polyunsaturate:saturate ratio increased, the concentration of triacylglycerols in plasma and the plasma VLDL + LDL fraction decreased. On the other hand, plasma triacylglycerol levels increased as the dietary n-6 fatty acids increased. The dietary n-3 fatty acids in the MO treatment led to higher levels of PUFA in the tissues evaluated. In the third experiment, female chickens from two genetic lines, high body weight (HW) and low body weight (LW), were fed SBO (rich in n-6 polyunsaturates) or MO (rich in n-3 polyunsaturates). The amounts of triacylglycerols in the plasma VLDL + LDL fractions were elevated in the LW chickens compared with the HW groups. Amounts of 18:1 isomers and total monounsaturates were highest in the livers and hearts of HW chickens. Feeding MO enriched the plasma, liver and heart tissues with n-3 polyunsaturates in both genetic lines. Plasma triacylglycerol concentrations were decreased in chickens fed MO at 56, but not at 84 days of age. The data suggest differences in lipid metabolism between the HW and LW lines which were not greatly affected by dietary n-6 or n-3 polyunsaturated fatty acids.

The aim of this thesis is to describe how the use of pharmacokinetic and pharmacodynamic techniques can provide a better understanding of the optimal use of antimicrobial agents. In vivo animal experimental models and clinical PK-PD datasets for three systemically administered antifungal agents, isavuconazonium sulfate (active moiety isavuconazole), micafungin, and VL-2397, are used to accomplish this goal.

Nosocomial bloodstream infection (BSI) is the most common type of hospital-acquired infection in paediatric patients and a major cause of morbidity and mortality worldwide. Methicillin-resistant staphylococci (CoNS and MRSA) are a leading cause of hospital-acquired neonatal sepsis and BSI. Glycopeptides (vancomycin and teicoplanin) constitute the current mainstay of therapy. There is limited antimicrobial PK-PD data available for neonates and children and optimal drug exposures resulting in maximal efficacy and suppression of resistance are not known. A translational pharmacological approach can be used to build the evidence required to optimize the current use of antimicrobial therapy in children. Pre-clinical experimental (in vitro and in vivo) and clinical PK-PD work was conducted throughout this thesis to improve our understanding of the PK-PD relationships of vancomycin and teicoplanin against CoNS and MRSA. The in vitro HFIM defined the relevant PD indexes and free drug exposures associated with maximal bacterial killing and suppression of resistance. The in vivo models (a rabbit central-line associated BSI and a mouse neutropenic thigh infection model) validated the in vitro findings. CRP concentrations were incorporated as an in vivo PD input. A clinical PK study of teicoplanin in 57 patients (neonates, infants and older children) was conducted and the population PK parameters estimated. PK-PD modelling techniques were used to analyse the PK-PD data and bridge the experimental results to human patients by means of Monte Carlo (MC) simulations. Vancomycin and teicoplanin displayed a concentration-dependent pattern of activity. An AUC:MIC ratio was associated with maximal antibacterial activity and suppression of resistance. Based on MC simulations, the probability of the in vivo target attainment with currently used teicoplanin dosage regimens results insufficient to treat a majority of patients with MRSA infection. High teicoplanin PK variability was identified in children. Weight, age and renal function were the best explanatory covariates of PK variability. Wider drug exposure distribution is observed in the paediatric population with respect to adults. A patient-tailored TDM approach with the aid of a Bayesian feedback adaptive control tool is required to ensure individual patients achieve optimal drug exposures in a precise and safe manner. The defined pre-clinical optimal targets of exposure for vancomycin-CoNS and teicoplanin-MRSA now need to be prospectively evaluated in patients. Currently used teicoplanin dosage regimens in both, adults and children, may be insufficient to treat a high proportion of patients with serious MRSA infection. Current EUCAST clinical breakpoint may need to be revised for teicoplanin against MRSA. The current strategy of using teicoplanin fixed population-based antibiotic regimens results in a wide range of drug exposures in neonates and children. An individualised dosing and TDM approach can ensure optimal target attainment at the individual level and in real-time.

Severe infection due to Gram-negative bacteraemia increases mortality and long term consequences of morbidity. In Liverpool Women’s NHS FT neonatal unit mortality increased from 20% for the more premature babies to 44%. Ciprofloxacin is a synthetic fluoroquinolone prescribed for suspected or proven Gram-negative infection in many neonatal units throughout Europe (25%). At present this drug is not authorised for this population and is prescribed off label. The optimal drug regimen is unknown resulting in a wide range of regimens (5 to 60 mg/kg/day) prescribed internationally. The TINN Consortium ‘Treat Infection in Neonates’ were funded by a European Union FP7 grant to develop a Paediatric Investigation Plan in line with the EU Paediatric Regulations and European Medicines Agency requirements. This thesis describes a prospective population PK clinical trial as part of the work of TINN, a retrospective clinical outcome study in neonates and infants with late onset Gram-negative sepsis and a framework to facilitate PK-PD research. The pharmacokinetic (PK) clinical trial of ciprofloxacin recruited 64 babies including a minimum of seven recruits representing every four weeks of development. The median post menstrual age in weeks was 35.7 (6.5) (range 24.9 - 47.9). Blood samples (n = 265) were collected at pre-defined informative time points in addition to 165 samples scavenged from clinically indicated blood tests, in total 430. A two compartment model with first-order elimination fitted the data. PK parameters included maximum concentration, clearance, area under the curve (0-tau), apparent volume of distribution and half-life and selected covariates with their inter-individual variability (CV%). Based on adult PD targets the minimum area under the curve /minimum inhibitory concentration (AUC/MIC) ratio 125 was achieved by 85% of this population. Higher AUC24 hour/MIC targets >250 may be required for serious infections yet few (42%) of this population achieved this. The optimal AUC/MIC ratio for neonates is unknown. Clearance increased with post-natal age yet the combined effect of PMA at birth and corrected gestational age had a greater effect on clearance. Clearance reduced by 29% with co-administration of inotropes associated with underlying renal compromise. Monte Carlo simulation demonstrated that the AUC24/MIC 125 was achieved by 90% of neonates < 34 weeks PMA administered 7.5 mg/kg/day and 84% of those ≥34 PMA administered 12.5 mg/kg/day. Ciprofloxacin is lipophilic and has good tissue penetration. CSF concentrations achieved a ratio of 0.33 of the serum plasma concentrations. Pharmacodynamic data included a retrospective cohort study over a six year period of neonates with confirmed Gram-negative organisms in blood cultures. Organisms retrieved from the clinical laboratory (n=88) were re-cultured and the MIC ciprofloxacin determined using an E Test. A sub-group were administered ciprofloxacin (n=33); each organism’s MIC was compared with the same neonate’s clinical outcome. Relatively higher MICs within the susceptible range were associated with a greater risk of treatment failure. These data were not statistically significant due to the low incidence of confirmed Gram-negative bacteraemia (1.3%). The clinical implications are that more intensive dosage regimens may be required or a lower clinical breakpoint subject to further PD and safety data. Too few organisms were available to determine if the MIC increased annually but the incidence of ciprofloxacin resistance in surveillance surface swabs was no higher than for gentamicin. To prepare for a future pharmacogenomic study, DNA scavenged from clinical blood samples were compared to a buccal scrape to evaluate whether this less invasive method is reliable. A substantially larger quantity and higher quality of DNA was obtained from scavenged blood. A sub-group were transfused with leukocyte depleted products for their clinical care prior to DNA sampling. The genotyping of allelic polymorphisms were not affected by the donor’s blood sufficiently to affect the genetic fingerprint. This indicates that prior blood transfusions should not be a contra-indication to scavenging blood for pharmacogenetic purposes. The challenges of PK/PD trials in this vulnerable population were explored. The majority were recruited in intensive care and had comorbidity and extreme prematurity. Due to the complexity of critical illness there are limitations to interpreting clinical outcome or safety data from a PK clinical trial design. There were no suspected unexpected serious adverse reactions. Arthralgia was not reported but is difficult to assess in non-weight bearing non-vocal neonates and young infants. A proportionate regulatory model of neonatal PK clinical trials was developed with the Medicines and Health Care Products Regulatory Agency. A framework for pharmacovigilance reporting during critical illness which avoided nuisance reporting was developed. The impact was assessed by an observational case study and review of discharge letters to illustrate the challenge of attributing causality. Individualised therapy may be required in critical illness. The correct dose of an antimicrobial may change daily during the sepsis episode. The inter- and intra-individual variability in parameters is associated with dynamic changes during neonatal development and the effects of critical illness. Further outcome and safety data are required to determine the optimal AUC24/MIC ratio. Paediatric clinical breakpoints specific to each sub-age group of children are required. Individualised therapy may be required to optimise clinical outcome and minimise resistance.