Artificial Intelligence and Health in Nepal

The growth in information technology and computer capacity has opened up opportunities to deal with much and much larger data sets than even a decade ago. There has been a technological revolution of big data and Artificial Intelligence (AI). Perhaps many readers would immediately think about robotic surgery or self-driving cars, but there is much more to AI. This Short Communication starts with an overview of the key terms, including AI, machine learning, deep learning and Big Data. This Short Communication highlights so developments of AI in health that could benefit a low-income country like Nepal and stresses the need for Nepal’s health and education systems to track such developments and apply them locally. Moreover, Nepal needs to start growing its own AI expertise to help develop national or South Asian solutions. This would require investing in local resources such as access to computer power/ capacity as well as training young Nepali to work in AI

4 million neonatal deaths: an analysis of available cause-of-death data and systematic country estimates with a focus on “birth asphyxia”

BACKGROUND: Of the world’s four million neonatal deaths, 99% occur in low/middleincome countries, but most information relates to the 1% dying in high-income countries. Reliable cause-of-death data are lacking. The aim of this thesis is to develop programmatically-relevant, national estimates for neonatal cause-of-death, focusing on “birth asphyxia” to illustrate specific challenges in the available data and for systematic national estimates. OBJECTIVES: 1. Review estimation methods, giving implications for neonatal cause-of-death estimation. 2. Propose programmatic categories for neonatal cause-of-death, reviewing measurement options for intrapartum-related outcomes (“birth asphyxia”). 3. Identify and analyse existing neonatal cause-of-death data. 4. Estimate intrapartum-related neonatal deaths for all countries, comparing single-cause and multi-cause models. 5. Summarise priorities for improving neonatal cause-of-death estimates and input data. DATA INPUTS: Case definitions were reviewed for neonatal cause-of-death and intrapartumrelated outcomes. Six programmatically relevant cause-of-death categories were defined, plus a residual “other neonatal” category. Two sources of neonatal cause-of-death data were examined: Vital Registration (VR) datasets for countries with high coverage (>90%) based on a new analysis from 83 countries; and published/unpublished studies identified through systematic searches. Inclusion criteria for representativeness and comparability were applied. Data from 44 countries with VR (96,797 neonatal deaths) and from 56 studies (29 countries, 13,685 neonatal deaths) met inclusion criteria, despite screening almost 7,000 abstracts. These data represent <3% of the world’s neonatal deaths. Thus estimation is necessary for global level information. No useable data were identified from Central and North-West Africa, or Central Asia. MODELLING: Methods were developed to estimate intrapartum-related neonatal deaths (single-cause), and then simultaneously estimate seven causes of neonatal death (multi-cause). Applying these proportions to the numbers of neonatal deaths in 192 countries gives a global estimate of intrapartum-related neonatal deaths of 0.90 (0.65-1.17) million using single-cause and 0.91 (0.60-1.08) million using multi-cause methods. DISCUSSION: The multi-cause model has become WHO’s standard method for neonatal cause-of-death estimates. However, complex statistical models are not a panacea. More representative data are required. Simplified case definitions and consistent hierarchical cause-of- death attribution would improve comparability, especially for intrapartum-related deaths

A clinically relevant model and a potential treatment of perinatal hypoxic ischaemic encephalopathy in mice

Hypoxia ischaemia (HI) due to neonatal asphyxia is the most common cause of acute mortality and chronic neurological disability. Currently there is no effective means to repair the damaged brain. The aim of this study was to 1) establish a clinically relevant intrauterine model of perinatal hypoxic ischaemic encephalopathy (HIE) in mice, 2) determine whether lipopolysaccharide (LPS) induced maternal systemic inflammation worsened the outcome of neonates who had previously suffered HIE brain damage and 3) use the mouse HIE model to study whether a docosahexaenoic acid (DHA) enriched maternal diet has the potential to alleviate this harmful clinical condition. This is the first time that the intrauterine HI model has been established in mice. Pups exposed to 15 minutes of HI showed a higher mortality rate at 1 hour and those who survived displayed worse short term outcomes. However, the results were inconsistent with regards to the cellular changes observed such as inflammation and apoptosis, histological evidence and long-term neurocognitive outcomes. LPS-induced maternal systemic inflammation combined with HI showed no difference in survival rates compared to HI alone with a lower hypoxia-inducible factor 1-alpha and higher phospho-p38 and phospho-bad levels in the pup brains being observed. A maternal diet enriched with DHA did not result in a better outcome in the DHA + HI pups. The greater mortality rates in both Caesarean section (CS) and HI groups regardless of DHA in the diet indicated that other factors may influence neonatal death rates. Based on these data, this study concludes that the 15 minutes intrauterine HIE model cannot provide sustained damage observed in the mice brain and that the maternal LPS induced systemic inflammation did not show a clear better or worse outcome in the offspring. In addition, no clear neuroprotective effect was seen for the DHA enriched diet group.Open Acces

Verbal autopsy for stillbirth and neonatal deaths – comparing population cause specific mortality fraction using two methods

Background: Every year 3.2 million infants are stillborn and 3.6 million die within the first month. Up to 98% of these deaths occur in countries with inadequate or non-existent vital registration systems, where cause of death data are sparse and mostly derived from verbal autopsies (VA). It has been advocated that VA are included in routine national statistics. This thesis proposes and compares the strengths and limitations of methodologies to collect and interpret VA data for stillbirths and neonatal deaths. Methods: Data were derived from three research areas in Malawi, Nepal and Mumbai. The development of classifications, diagnostic algorithms and questionnaires for VA, suitable for physician review interpretation is described. A probabilistic method to analyse all age deaths (InterVA) was adapted for stillbirths and neonatal deaths. Cause specific mortality fractions were compared using physicians’ review and InterVA. Results: Neonatal mortality rate in Malawi was 25/1000 livebirths (LB), in Nepal 31/1000 LB and in Mumbai 16/1000 LB. A total of 922 VA including both live and stillbirths were analysed to establish causes of death. Stillbirths accounted for 44-54% of deaths. Of neonatal deaths, in Malawi the majority were attributed to severe infections according to physician review (55%) and InterVA (46%); in Nepal (43%) and Mumbai (61%) perinatal asphyxia was most common according to InterVA. In Nepal however, physician review ascribed the majority of neonatal deaths to severe infections (50%). Kappa statistics for individual agreement comparing both methods was 0.60 (CI 0.567-0.702) in Malawi, 0.62(CI 0.59- 0.65) in Nepal and 0.48(0.40 - 0.50) in Mumbai. Discussion: Different VA interpretation methods exist, however standardised procedures are necessary for international comparison. The role of physician review in interpreting VA is changing while computerised methods are becoming more widespread. The modified InterVA model provides a rapid and consistent method to establish causes of stillbirths and neonatal deaths, however it requires further refinements and ultimately a validation study using a comparison other than physician review

Segmentation of Lung Tomographic Images Using U-Net Deep Neural Networks

Deep Neural Networks (DNNs) are among the best methods of Artificial Intelligence, especially in computer vision, where convolutional neural networks play an important role. There are numerous architectures of DNNs, but for image processing, U-Net offers great performance in digital processing tasks such as segmentation of organs, tumors, and cells for supporting medical diagnoses. In the present work, an assessment of U-Net models is proposed, for the segmentation of computed tomography of the lung, aiming at comparing networks with different parameters. In this study, the models scored 96% Dice Similarity Coefficient on average, corroborating the high accuracy of the U-Net for segmentation of tomographic images

Perinatal and late neonatal mortality in the dog

Pup mortality is reported to be a significant problem in the dog. The purpose of this thesis was to identify the extent and causes of the mortality and the risk factors. Mortality was classified according to the clinical condition of the pup at birth and the pathological investigation was designed to investigate the validity of this classification. Total pup mortality, excluding elective euthanasia for show reasons, was 18.5%. Perinatal mortality, that is, stillbirths and deaths that occurred in the first week, accounted for 90.9% of these losses. Each breed surveyed exhibited a specific mortality pattern and the results of one breed could not be used to anticipate the outcome in another breed. As a consequence of this, there was a marked difference in the predictor variables, or risk factors, identified for each breed. Birth weight and inter-pup whelping intervals were the most consistent variables that increased the odds of a pup dying. The principal cause of pup mortality was attributed to foetal asphyxia, that is, apparently normal pups subjected to excessive hypoxia during the birth process and they were either still born or born in a distressed condition and subsequently died. Death attributed to foetal asphyxia accounted for 7.8% of all pups born and 42.5% of the total mortality. The majority of these pups (82.2%) died during whelping or in the first 24 hours after birth. The death of just over half of these pups could be directly attributed to dystocia. The remaining pups were compromised during what appeared to be a normal whelping. Neonatal atelectasis, pulmonary congestion, inhalation of amniotic fluid and meconium, leptomeningeal and generalised systemic congestion were the principal pathological findings in these pups. Average birth weights, inter-pup whelping intervals, parity, pup presentation and litter position were all significant predictors of mortality due to foetal asphyxia. The abnormal pup was defined as a pup at birth that was mummified, had died prior to birth, was small for date or had gross congenital defects present. These accounted for the death of 4.9% of all pups born and 26.3% of all losses. The only significant predictors of mortality due to the birth of an abnormal pup were the inter-pup interval and birth weight. Since the abnormality occurred in utero and was not related to the birth process this result had no bearing on the outcome. The death of live born, apparently normal pups, in the neonatal period accounted for 5.7% of all pups born and 31.2% of the total mortality. Over half these losses were attributed to fading puppy syndrome. The remainder were due to mismothering / mismanagement and other miscellaneous causes. The majority of fading pups examined were not normal at birth. Growth retardation and the consequent increased susceptibility to foetal hypoxia, lung pathology indicative of foetal asphyxia and intrauterine and/or very early neonatal infections were the principal causes of mortality attributed to fading puppy syndrome identified in this study. The canine perinate is totally dependent on the bitch both in the uterus and in the immediate post partum period. The investigation of pup mortality can not be divorced from the assessment of maternal health, the influence of the whelping process and the post whelping care of the immature pups by the bitch. These factors must be correlated with gross and histological changes identified in dead pups to determine the sequence of events that contributed to the death of the whelp

Study of the Term Neonatal Brain Injury with combined Diffuse Optical Tomography and Electroencephalography

This thesis describes the application of combined diffuse optical tomography (DOT) and electroencephalography (EEG) in the investigation of neonatal term brain injury. With hypoxic ischaemic encephalopathy (HIE) and perinatal stroke being the most frequent contributors to brain injury in the term neonatal population, the first part of the thesis focuses on the description and ongoing requirement for their further investigation. In continuation to that, the characteristics and unique properties of both DOT and EEG are described and explored. The combination of these two modalities was utilised in elucidating the relationship between neuronal activity and cerebral haemodynamics both in physiological processes as well as in disease, by the infant’s cot side. This work differs to previous studies using near-infrared technologies and EEG, as a denser whole head array was used, offering the potential of 3-dimensional image reconstruction of the cortical haemodynamic events in relation to electro-cortical activity. These methods were applied in the study of critically ill infants presenting with seizures in the first few days of life. The relevant results are presented in three separate chapters of the thesis. Distinct neurophysiological phenomena such as seizures and burst suppression were detected and studied in association to underlying HIE. On the grounds of a pre-existing pilot study of our research group, distinct prolonged de-oxygenated cortical areas were identified following electrical seizure activity. Further exploration of infants with seizures provided limited supporting evidence. The investigation of burst suppression in HIE led to the first ever identification of repeated, waveform, cortical haemodynamic events in response to bursts of electrical activity with some spatial correlation to regions of brain injury. Further analysis of the low frequencies within the diffuse optical signal in cases of perinatal stroke, showed a consistent interhemispheric difference between the healthy and stroke-affected brain regions. The limitations, prospects and conclusions are presented in the final chapter. The use of simultaneous DOT and EEG offers a unique neuro-monitoring and neuro-investigating tool in the neonatal intensive care environment, which is safe, portable, and cost-effective, Ongoing research is required for the exploration and development of the methodology and its potential diagnostic properties

Vocal behaviour as an indicator of lamb vigour

The viability and survival of the neonate lamb relies on its ability to communicate and maintain a strong attachment with its dam. To date there has been little concise information available about the role of the lamb's behaviour, and in particular the importance of acoustic cues, in this relationship as greater attention has been focused on maternal attributes important in facilitating the maternal-young bond. In human and rodent neonates, acoustic features of the distress vocalisation are used as indices of neurological deficit and integrity both at birth and in infant acoustic cry analysis. The aim of this thesis was to investigate potential behavioural indicators of lamb vigour, with a particular focus on vocal behaviour, within the first 12 hours of life. Such measures could provide valuable information for development of reproductive breeding objectives, and provide clarity regarding the role of the lamb in failed maternal-young interactions. Delayed vocalisation initiation in response to a separation stimulus was found to be associated with poor vigour-related behaviour reflecting the capacity of the lamb to reunite and follow the dam over 12 hours postpartum. Vocalisation delay was also associated with risk factors related to poor lamb survival including longer parturition duration, male sex, first parity, heavier birth weight and sire-related conformational attributes likely to result in a more difficult birth. Blood assay markers reflecting fetal distress including poor blood oxygenation, and elevated plasma glucose and lactate levels sampled at birth were also demonstrated to be correlated with vocalisation latency. These associations were concluded to reflect impacts on the lamb's neurological system rather than genetic influences because of evidence provided by within-litter comparisons, and to demonstrate neuroregenerative processes over a 12 hour measurement period. An analysis of lamb distress signals modelled on acoustic cry analysis of the human neonate was also undertaken to compare vocalisation characteristics of lambs with delayed responses to those with rapid responses indicating vigour. Signal features of delayed response lambs were more likely to demonstrate acoustic parameters reflecting glottal instability, lower amplitude and reduced repetition rate. These lambs were more likely to emit inefficient or inappropriate signals in the context of isolation. A significantly higher fundamental frequency, an indicator of pathology in the human infant, was not clearly demonstrated to be associated with compromised lambs in this study. It was also found in a two-choice test, where sheep dams were required to demonstrate a preference for signals of their own co-twins, that ewes preferred acoustic signals of lambs correlated with rapid vocalisation response, higher pitch and greater signal stability. The results indicate that delayed vocalisation responsiveness and other acoustic measures are associated with fetal compromise in the neonate lamb, as shown in the human and rodent models. It was concluded that delayed vocal initiation is a marker for poor postnatal outcome characterised by diminished responsiveness to a distress condition. This research has important implications for understanding failed maternal-young relationships and the consequences for survival in mammalian neonates