A new experimental rodent model of cerebral palsy and foregut dysmotility

Background: Children with cerebral palsy often suffer from inability to tolerate enteral feeds. This may manifest as retching, vomiting, abdominal pain and faltering weight (previously referred to as failure to thrive). This study has three stages the aim of the first stage was to develop and establish an animal model of cerebral palsy (CP) and foregut dysmotility so as to better understand the clinical association seen in paediatric practice and to develop new therapies for this condition in the future. The second stage involved performing an experimental technique of splanchnectomy to assess whether this could be used as a surgical tool for such patients who fail to respond to conventional therapy. The third and final stage involved an examination of human biopsies from children with CP and known foregut dysmotility. Methods: Ethical approval was obtained in accordance with the Animals (Scientific Procedures) Act 1986 (PPL 60/4262). In phase one neonatal Sprague-Dawley rat pups aged postnatal days 5-6 (P5-6) underwent midline craniotomies under anaesthesia to allow either unilateral or bilateral brain injections of the neurotoxin, ibotenic acid (IBA), in the medial prefrontal (MPFC) or insular cortex (IC) using a digital stereotaxic frame. P5-6 was chosen as this has been shown to correspond to the stage of white matter vulnerability and that neurotoxin injections at this stage can mimic lesions that appear histologically similar to human peri-ventricular white matter injury as seen in cerebral palsy. A further group underwent sham injections with normal saline. All animals were monitored with a modified APGAR score post-operatively. Gastric emptying studies were then performed between 7 and 21 days postoperatively to look for any delay in gastric emptying times (GET) and animals were weighed regularly. GET was recorded by gavaging water soluble contrast and performing time lapsed x-rays. The pups were perfused on day 28 of life and their brains and foregut were examined. Phase two then involved repeating the creation of our CP model and performing unilateral splanchnectomy via a midline laparotomy to investigate whether we could improve the GET in our model. In both phase 1 and phase 2 immunohistochemistry was performed looking at several antibodies to compounds implicated in the pathogenesis of dysmotility. In phase three, a retrospective analysis of archived human biopsies from children with CP and dysmotility was performed. Main results: In Phase 1 forty-five pups were injected in total (28 male and 17 female). The median weight at time of operation was 13.5 grams (range 7.5-21 grams). Four pups died at the start of the study two intra-operatively from haemorrhage and two in the immediate post-operative period presumably from anaesthetic complications. GET was significantly prolonged in each IBA group compared to shams, and interestingly 5 out of 6 of those with bilateral MPFC lesions demonstrated reflux during their contrast studies. In Phase 2, twenty-six rat pups were injected (14 female and 12 male). 13 pups underwent IBA injection and 13 sham injections. One pup died post brain injection from postoperative apnoea, the remainder progressed to splanchnectomy. Two pups, one from each group, died post laparotomy from intraoperative bleeding. The median GET was significantly longer in the CP model 58 minutes compared to 45 minutes (p=0.0024). Splanchnectomy reduced the GET in the CP group to 40.5 minutes (p<0.0001) Our results from phase 3 revealed that we were unable to compare our animal specimens to our cohort of archived human biopsies. The reasons for this are discussed in detail. Conclusion: In conclusion, we have developed a new and reproducible animal model of cerebral palsy and foregut dysmotility. We have shown that lesions in the brain cortex can lead to structural changes in villous and crypt architecture in the gut and that splanchnectomy improves gastric emptying in our model. Further work needed is needed to explore the mechanistic pathways and provide insight into the pathogenesis of impaired gastrointestinal motility in cerebral palsy and may lead to much needed development of new treatments

Deep Learning-based Solutions to Improve Diagnosis in Wireless Capsule Endoscopy

[eng] Deep Learning (DL) models have gained extensive attention due to their remarkable performance in a wide range of real-world applications, particularly in computer vision. This achievement, combined with the increase in available medical records, has made it possible to open up new opportunities for analyzing and interpreting healthcare data. This symbiotic relationship can enhance the diagnostic process by identifying abnormalities, patterns, and trends, resulting in more precise, personalized, and effective healthcare for patients. Wireless Capsule Endoscopy (WCE) is a non-invasive medical imaging technique used to visualize the entire Gastrointestinal (GI) tract. Up to this moment, physicians meticulously review the captured frames to identify pathologies and diagnose patients. This manual process is time- consuming and prone to errors due to the challenges of interpreting the complex nature of WCE procedures. Thus, it demands a high level of attention, expertise, and experience. To overcome these drawbacks, shorten the screening process, and improve the diagnosis, efficient and accurate DL methods are required. This thesis proposes DL solutions to the following problems encountered in the analysis of WCE studies: pathology detection, anatomical landmark identification, and Out-of-Distribution (OOD) sample handling. These solutions aim to achieve robust systems that minimize the duration of the video analysis and reduce the number of undetected lesions. Throughout their development, several DL drawbacks have appeared, including small and imbalanced datasets. These limitations have also been addressed, ensuring that they do not hinder the generalization of neural networks, leading to suboptimal performance and overfitting. To address the previous WCE problems and overcome the DL challenges, the proposed systems adopt various strategies that utilize the power advantage of Triplet Loss (TL) and Self-Supervised Learning (SSL) techniques. Mainly, TL has been used to improve the generalization of the models, while SSL methods have been employed to leverage the unlabeled data to obtain useful representations. The presented methods achieve State-of-the-art results in the aforementioned medical problems and contribute to the ongoing research to improve the diagnostic of WCE studies.[cat] Els models d’aprenentatge profund (AP) han acaparat molta atenció a causa del seu rendiment en una àmplia gamma d'aplicacions del món real, especialment en visió per ordinador. Aquest fet, combinat amb l'increment de registres mèdics disponibles, ha permès obrir noves oportunitats per analitzar i interpretar les dades sanitàries. Aquesta relació simbiòtica pot millorar el procés de diagnòstic identificant anomalies, patrons i tendències, amb la conseqüent obtenció de diagnòstics sanitaris més precisos, personalitzats i eficients per als pacients. La Capsula endoscòpica (WCE) és una tècnica d'imatge mèdica no invasiva utilitzada per visualitzar tot el tracte gastrointestinal (GI). Fins ara, els metges revisen minuciosament els fotogrames capturats per identificar patologies i diagnosticar pacients. Aquest procés manual requereix temps i és propens a errors. Per tant, exigeix un alt nivell d'atenció, experiència i especialització. Per superar aquests inconvenients, reduir la durada del procés de detecció i millorar el diagnòstic, es requereixen mètodes eficients i precisos d’AP. Aquesta tesi proposa solucions que utilitzen AP per als següents problemes trobats en l'anàlisi dels estudis de WCE: detecció de patologies, identificació de punts de referència anatòmics i gestió de mostres que pertanyen fora del domini. Aquestes solucions tenen com a objectiu aconseguir sistemes robustos que minimitzin la durada de l'anàlisi del vídeo i redueixin el nombre de lesions no detectades. Durant el seu desenvolupament, han sorgit diversos inconvenients relacionats amb l’AP, com ara conjunts de dades petits i desequilibrats. Aquestes limitacions també s'han abordat per assegurar que no obstaculitzin la generalització de les xarxes neuronals, evitant un rendiment subòptim. Per abordar els problemes anteriors de WCE i superar els reptes d’AP, els sistemes proposats adopten diverses estratègies que aprofiten l'avantatge de la Triplet Loss (TL) i les tècniques d’auto-aprenentatge. Principalment, s'ha utilitzat TL per millorar la generalització dels models, mentre que els mètodes d’autoaprenentatge s'han emprat per aprofitar les dades sense etiquetar i obtenir representacions útils. Els mètodes presentats aconsegueixen bons resultats en els problemes mèdics esmentats i contribueixen a la investigació en curs per millorar el diagnòstic dels estudis de WCE

A study of molecular forms of the cholinesterases with particular reference to Hirschsprung's disease and neural tube defects

PhD ThesisAcetylcholinesterase [ACNE) and butyrylcholinesterase [EChE) were studied in amniotic fluid in relation to the detection of neural tube defects CNTD), and in rectal tissue in the diagnosis of Hirschsprung's disease. An automated assay is described for measurement of AChE and BChE activity in amniotic Fluid, and an increase in both is found in the presence of NTD. Analysis of AChE molecular forms by sucrose density sedimentation revealed three species with differing sedimentation coefficients and molecular masses: monomeric G1[4. OS, 78KOa), dimeric G2[5.5S, 126KOa) and tetrameric G4(10.35,256KDa). The tetramer, G4 is NTD specific and is largely responsible for the increase in activity seen in the quantitative assessment of'total AChE and for the abnormal band identifiable by polyacrylamide gel electrophoresis in pregnancies affected by NTO. Evidence is presented which indicates that G4 is a soluble species secreted from nerve trunks exposed as a result of the lesion. SChE activity, the likely source of which is fetal plasma is shown to be a less specific indicator of NTD. These results represent the first description of the structural molecular heterogeneity of AChE and SChE forms in amniotic fluid. AChE activity was measured in rectal biopsy specimens from 213 patients in whom a diagnosis of Hirschsprung's disease was suspected. The results from this, the largest study so far reported, indicate the value of AChE measurement in the detection of the disease. The molecular forms of AChE and SChE were investigated in resected bowel segments from patients with Hirschsprung's disease. Four species of AChE were identified: G1[3.55,74KOa), G2[S. OS, 131KDa), 64(9.23,275KOa] and the asymmetric form A12(16.83,811KDa). In all cases there was an increase (4-14 fold] in G4-AChE activity in the aganglionic cola-rectum. The evidence indicates that this is derived from hypertrophied nerve trunks present in the affected zone. The increase in G4-AChE was largely responsible for the increase in total AChE activity in rectal biopsy specimens from patients with Hirschsprung's disease. BChE molecular forms showed no consistent changes in Hirschsprung's disease. Characterisation of the molecular forms of AChE by gel filtration and with respect to their thermal stability, sensitivity to Triton X-100 and response to substrate inhibition is also investigated.Mr J Wagget, Fleming Memorial Hospital

Frequency of significant steatosis in various chronic liver diseases: an evaluation with Transient Elastography (TE)

INTRODUCTION: TE was developed as a non-invasive method to assess liver fibrosis and steatosis using shear wave velocity. Many studies have proven its’ effectiveness as a method for evaluating liver fibrosis and steatosis.1-2 OBJECTIVE: To determine the prevalence and aetiology of steatosis in our local population. METHOD: This study was conducted as a retrospective review on all patients who had TE performed at UMMC from 1 January 2013 to 31 December 2021. Their demographics, clinical characteristics and TE findings were charted. RESULTS: A total of 3066 patients were included. 51.7% were males and 48.3% were females. The median CAP value was 271 dB/m. The median E value was 6.5kPa. 61.2% of patients had steatosis, with a staggering number of of these patients having significant steatosis (51.8%). 6.3% of patients had S2 steatosis whereas 45.5% of patients had severe (S3) steatosis. Interestingly, in those with S2 steatosis, 34.7% had chronic hepatitis B (CHB), 31.5% had non-alcoholic fatty liver disease (NAFLD), 5.2% with chronic hepatitis C (CHC) and 1% had alcoholic liver disease (ALD). In the S3 steatosis group, 66.7% had NAFLD, followed by ALD (36.6%), CHB (30.1%) and CHC (27.7%). 221 DISCUSSION: It is important to highlight that a large proportion of our patients has significant steatosis. This is likely in keeping with the global rise of obesity and sedentary lifestyle.3 NAFLD is a 4-decades old nomenclature that does not appropriately address the heterogenous pathogenicity of fatty liver disease. Our study reflects this heterogeneity, as it shows that steatosis often co-exists with other diverse aetiologies. CONCLUSION: Whilst NAFLD clearly has the greatest frequency of severe steatosis, it is also present in other aetiologies. These findings support the new terminology of metabolic associated fatty liver disease (MAFLD), which reflects the fact that NAFLD commonly co-exists with other aetiologies

Biomedical Engineering

Biomedical engineering is currently relatively wide scientific area which has been constantly bringing innovations with an objective to support and improve all areas of medicine such as therapy, diagnostics and rehabilitation. It holds a strong position also in natural and biological sciences. In the terms of application, biomedical engineering is present at almost all technical universities where some of them are targeted for the research and development in this area. The presented book brings chosen outputs and results of research and development tasks, often supported by important world or European framework programs or grant agencies. The knowledge and findings from the area of biomaterials, bioelectronics, bioinformatics, biomedical devices and tools or computer support in the processes of diagnostics and therapy are defined in a way that they bring both basic information to a reader and also specific outputs with a possible further use in research and development

Examining the impact of a novel integrated care pathway for faecal incontinence on patients and within a National Health Service organisation

Background: Faecal incontinence (FI) is a common healthcare problem. The management of FI patients is widely reported as being disjointed. In response to this and governmental guidance, an integrated care pathway (ICP) was implemented at a local NHS trust. Aim: To assess how the implementation of a community-based ICP affects the key stakeholders and to observe the process of organisational change within the trust using normalization process theory (NPT). Methods: Mixed methodology combining semi-structured interviews of key stakeholders, narrative interviews with patients, focus group discussion, observational work and clinical quantitative data. Qualitative data was analysed using thematic analysis and the Framework Method, with NPT being used to structure the qualitative findings. Results: Key facilitators to the implementation of the ICP included clinical leadership, staff commitment, teamwork, adequate clinical capacity and good clinical outcomes. There was a delay in the implementation due to lack of organisational management input and key stakeholder time From a patient perspective, benefits were identified such as improved access to the service and symptom improvement. Conclusions: An ICP for FI could provide an answer to the long-standing issues that have blighted continence services. Patients report satisfaction based on improved access to the service alongside good clinical outcomes