Mechanism-based pharmacokinetic-pharmocodynamic modelling of opioids : role of biophase distribution and target interaction kinetics

The objective of this thesis was the development of a mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) model for the electro-encephalogram (EEG) effects of opioids, with emphasis on biophase distribution and target interaction kinetics. Several in vitro and in vivo studies have been performed to characterize the transport to the site of action in the brain, the receptor interaction and EEG effects. From the transport studies it could be concluded that the efflux transporter P-glycoprotein is involved in the transport of morphine, whereas for the other opioids no interaction could be identified, which was mainly due to the high passive permeability. Population modeling showed that the predicted morphine biophase concentration-time profiles in vivo were distinctly different from the brain ECF concentration-time profiles, as estimated by intracerebral microdialysis. In addition, for morphine, a complex biophase distribution model was required to describe the hysteresis between blood concentration and EEG effect whereas for the other opioids a simple one-compartment distribution model was sufficient. Investigation of the role of target interaction showed that based on the correlation between in vitro and in vivo receptor binding characteristics, two subpopulations existed. In conclusion, for the development of a predictive PK-PD model, the underlying processes should be investigated in great detail and supportive data are essential for model validation and prediction.LEI Universiteit LeidenLACD

Convolutional Neural Networks for Apnea Detection from Smartphone Audio Signals: Effect of Window Size

Although sleep apnea is one of the most prevalent sleep disorders, most patients remain undiagnosed and untreated. The gold standard for sleep apnea diagnosis, polysomnography, has important limitations such as its high cost and complexity. This leads to a growing need for novel cost-effective systems. Mobile health tools and deep learning algorithms are nowadays being proposed as innovative solutions for automatic apnea detection. In this work, a convolutional neural network (CNN) is trained for the identification of apnea events from the spectrograms of audio signals recorded with a smartphone. A systematic comparison of the effect of different window sizes on the model performance is provided. According to the results, the best models are obtained with 60 s windows (sensitivity-0.72, specilicity-0.89, AUROC = 0.88), For smaller windows, the model performance can be negatively impacted, because the windows become shorter than most apnea events, by which sound reductions can no longer be appreciated. On the other hand, longer windows tend to include multiple or mixed events, that will confound the model. This careful trade-off demonstrates the importance of selecting a proper window size to obtain models with adequate predictive power. This paper shows that CNNs applied to smartphone audio signals can facilitate sleep apnea detection in a realistic setting and is a first step towards an automated method to assist sleep technicians. Clinical Relevance- The results show the effect of the window size on the predictive power of CNNs for apnea detection. Furthermore, the potential of smartphones, audio signals, and deep neural networks for automatic sleep apnea screening is demonstrated

Therapeutic Hypothermia for Neonatal Encephalopathy Results in Improved Microstructure and Metabolism in the Deep Gray Nuclei

BACKGROUND AND PURPOSE: Therapeutic hypothermia has reduced morbidity and mortality and is associated with a lower burden of lesions on conventional imaging in NE. However, its effects on brain microstructure and metabolism have not been fully characterized. We hypothesized that therapeutic hypothermia improves measures of brain microstructure and metabolism. MATERIALS AND METHODS: Forty-one neonates with moderate/severe NE (29 treated with hypothermia, 12 nontreated) and 12 healthy neonates underwent MR imaging, DTI, and (1)H-MR spectroscopy. MR imaging scans were scored by the predominant pattern of brain injury: normal, watershed, and BG/thalamus. ADC, FA, Lac:NAA, and NAA:Cho values from bilateral BG and thalamus ROIs were averaged. T test and linear regression analysis were used to determine the association between hypothermia and MR imaging quantitative measures. RESULTS: Conventional MR imaging findings were normal in 41% of treated neonates; all nontreated neonates had brain injury. Values of MR imaging metrics were closer to normal in treated neonates compared with nontreated neonates: ADC was 63% higher in the BG and 116% higher in the thalamus (both P < .05), and Lac:NAA was 76% lower (P = .04) in the BG. Treated neonates with normal MR imaging findings had normal (1)H-MR spectroscopy metabolites, and ADC was higher by 35% in the thalamus (P = .03) compared with healthy neonates. CONCLUSIONS: Therapeutic hypothermia may reduce disturbances of brain metabolism and preserve its microstructure in the setting of NE, possibly by minimizing cytotoxic edema and cell death. Long-term follow-up studies are required to determine whether early post-treatment DTI and (1)H-MR spectroscopy will be useful biomarkers of treatment response

Prediction of fetal and neonatal outcomes after preterm manifestations of placental insufficiency:systematic review of prediction models

Objectives: To identify all prediction models for fetal and neonatal outcomes in pregnancies with preterm manifestations of placental insufficiency (gestational hypertension, pre-eclampsia, HELLP syndrome or fetal growth restriction with its onset before 37 weeks' gestation) and to assess the quality of the models and their performance on external validation. Methods: A systematic literature search was performed in PubMed, Web of Science and EMBASE. Studies describing prediction models for fetal/neonatal mortality or significant neonatal morbidity in patients with preterm placental insufficiency disorders were included. Data extraction was performed using the CHARMS checklist. Risk of bias was assessed using PROBAST. Literature selection and data extraction were performed by two researchers independently. Results: Our literature search yielded 22 491 unique publications. Fourteen were included after full-text screening of 218 articles that remained after initial exclusions. The studies derived a total of 41 prediction models, including four models in the setting of pre-eclampsia or HELLP, two models in the setting of fetal growth restriction and/or pre-eclampsia and 35 models in the setting of fetal growth restriction. None of the models was validated externally, and internal validation was performed in only two studies. The final models contained mainly ultrasound (Doppler) markers as predictors of fetal/neonatal mortality and neonatal morbidity. Discriminative properties were reported for 27/41 models (c-statistic between 0.6 and 0.9). Only two studies presented a calibration plot. The risk of bias was assessed as unclear in one model and high for all other models, mainly owing to the use of inappropriate statistical methods. Conclusions: We identified 41 prediction models for fetal and neonatal outcomes in pregnancies with preterm manifestations of placental insufficiency. All models were considered to be of low methodological quality, apart from one that had unclear methodological quality. Higher-quality models and external validation studies are needed to inform clinical decision-making based on prediction models.</p

Phenobarbital, Midazolam Pharmacokinetics, Effectiveness, and Drug-Drug Interaction in Asphyxiated Neonates Undergoing Therapeutic Hypothermia

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Risk factors for the introduction and within-herd transmission of Mycobacterium avium subspecies paratuberculosis (MAP) infection on 59 Irish dairy herds

Since 1994, Irish cattle have been exposed to greater risks of acquiring Mycobacterium avium subspecies paratuberculosis (MAP) infection as a consequence of the importation of over 70,000 animals from continental Europe. In recent years, there has been an increase in the number of reported clinical cases of paratuberculosis in Ireland. This study examines the prevalence of factors that promote the introduction and within-herd transmission of Mycobacterium avium subspecies paratuberculosis (MAP) on selected Irish dairy farms in the Cork region, and the association between these factors and the results of MAP screening tests on milk sock filter residue (MFR). A total of 59 dairy farms, selected using non-random methods but apparently free of endemic paratuberculosis, were enrolled into the study. A questionnaire was used to collect data about risk factors for MAP introduction and transmission. The MFR was assessed on six occasions over 24 months for the presence of MAP, using culture and immunomagnetic separation prior to polymerase chain reaction (IMS-PCR). Furthermore, blood samples from all entire male and female animals over one year of age in 20 herds were tested by ELISA. Eighteen (31%) farms had operated as closed herds since 1994, 28 (47%) had purchased from multiple sources and 14 (24%) had either direct or indirect (progeny) contact with imported animals. Milk and colostrum were mixed on 51% of farms, while 88% of farms fed pooled milk. Thirty (51%) herds tested negative to MFR culture and IMS-PCR, 12 (20%) were MFR culture positive, 26 (44%) were IMS-PCR positive and seven (12%) were both culture and IMS-PCR positive. The probability of a positive MFR culture was significantly associated with reduced attendance at calving, and with increased use of individual calf pens and increased (but not significantly) if mulitiple suckling was practised. There was poor agreement between MFR culture and MFR IMS-PCR results, but moderate agreement between MFR culture and ELISA test results. This study highlights a lack of awareness among Irish dairy farmers about the effect of inadequate biosecurity on MAP introduction. Furthermore, within-herd transmission will be facilitated by traditional calf rearing and waste management practices. The findings of viable MAP in the presence of known transmission factors in non-clinically affected herds could be a prelude to long-term problems for the Irish cattle and agri-business generally

Normative mammillary body volumes: From the neonatal period to young adult

The mammillary bodies may be small, but they have an important role in encoding complex memories. Mammillary body pathology often occurs following thiamine deficiency but there is increasing evidence that the mammillary bodies are also compromised in other neurological conditions and in younger ages groups. For example, the mammillary bodies are frequently affected in neonates with hypoxic-ischemic encephalopathy. At present, there is no normative data for the mammillary bodies in younger groups making it difficult to identify abnormalities in neurological disorders. To address this, the present study set out to develop a normative dataset for neonates and for children to young adult. A further aim was to determine whether there were laterality or sex differences in mammillary body volumes. Mammillary body volumes were obtained from MRI scans from 506 participants across two datasets. Measures for neonates were acquired from the Developing Human Connectome Project database (156 male; 100 female); volumes for individuals aged 6–24 were acquired from the NICHE database (166 males; 84 females). Volume measurements were acquired using a semi-automated multi-atlas segmentation approach. Mammillary body volumes increased up to approximately 15 years-of-age. The left mammillary body was marginally, but significantly, larger than the right in the neonates with a similar pattern in older children/young adults. In neonates, the mammillary bodies in males were slightly bigger than females but no sex differences were present in older children/young adults. Given the increasing presentation of mammillary body pathology in neonates and children, these normative data will enable better assessment of the mammillary bodies in healthy and at-risk populations

Mammillary body injury in neonatal encephalopathy: a multicentre, retrospective study

Background The mammillary bodies (MBs) have repeatedly been shown to be critical for memory, yet little is known about their involvement in numerous neurological conditions linked to memory impairments, including neonatal encephalopathy. Methods We implemented a multicentre retrospective study, assessing magnetic resonance scans of 219 infants with neonatal encephalopathy who had undergone hypothermia treatment in neonatal intensive care units located in the Netherlands and Italy. Results Abnormal MB signal was observed in similar to 40% of infants scanned; in half of these cases, the brain appeared otherwise normal. MB involvement was not related to the severity of encephalopathy or the pattern/severity of hypoxic-ischaemic brain injury. Follow-up scans were available for 18 cases with abnormal MB signal; in eight of these cases, the MBs appeared severely atrophic. Conclusions This study highlights the importance of assessing the status of the MBs in neonatal encephalopathy; this may require changes to scanning protocols to ensure that the slices are sufficiently thin to capture the MBs. Furthermore, long-term follow-up of infants with abnormal MB signal is needed to determine the effects on cognition, which may enable the use of early intervention strategies. Further research is needed to assess the role of therapeutic hypothermia in MB involvement in neonatal encephalopathy. ImpactThe MBs are particularly sensitive to hypoxia in neonates. Current hypothermia treatment provides incomplete protection against MB injury. MB involvement is likely overlooked as it can often occur when the rest of the brain appears normal. Given the importance of the MBs for memory, it is necessary that this region is properly assessed in neonatal encephalopathy. This may require improvements in scanning protocols.Developmen