The Alive Particle Filter

In the following article we develop a particle filter for approximating Feynman-Kac models with indicator potentials. Examples of such models include approximate Bayesian computation (ABC) posteriors associated with hidden Markov models (HMMs) or rare-event problems. Such models require the use of advanced particle filter or Markov chain Monte Carlo (MCMC) algorithms e.g. Jasra et al. (2012), to perform estimation. One of the drawbacks of existing particle filters, is that they may 'collapse', in that the algorithm may terminate early, due to the indicator potentials. In this article, using a special case of the locally adaptive particle filter in Lee et al. (2013), which is closely related to Le Gland & Oudjane (2004), we use an algorithm which can deal with this latter problem, whilst introducing a random cost per-time step. This algorithm is investigated from a theoretical perspective and several results are given which help to validate the algorithms and to provide guidelines for their implementation. In addition, we show how this algorithm can be used within MCMC, using particle MCMC (Andrieu et al. 2010). Numerical examples are presented for ABC approximations of HMMs

Positional identification and functional analysis of genes regulating autoimmune arthritis

The major histocompatibility complex (MHC) is the most gene-dense and polymorphic region in the human genome with strong associations to many autoimmune disorders, including rheumatoid arthritis (RA). However, even the genetic association between MHC and RA was known more than 40 years ago, we still have not fully explained the functional roles of the MHC genes and identified the underlying specific polymorphisms. This thesis describes some of our research aimed for a better understanding of this topic, which can largely be divided into three parts as follows. First, we made use of a panel of MHC class II (MHC-II) congenic strains to evaluate the functional roles of MHC-II polymorphisms in arthritis. By performing an extensive genetic and functional analysis, we showed that MHC-II RT1-B (the rat orthologs of HLA-DQ) determines the onset and severity of experimental arthritis, possibly due to the amino acid variations in the P1 pocket of RT1-B. In addition, we showed that natural allelic variants in Tap2, another gene in the MHC-II region, regulates the thymic selection of CD8+ T cells. Second, in order to investigate whether other MHC genes also contribute to arthritis susceptibility, we assessed arthritis development in congenic strains mapped to other parts of the MHC region. We identified a second arthritis-regulatory QTL in the MHC class III region, that regulates not only the onset and severity, but also chronicity of arthritis. We subsequently mapped this effect to a conserved, 33-kb large haplotype Ltab-Ncr3 comprising five polymorphic genes. Interestingly, unlike other positionally-identified arthritis genes in rats, Ltab-Ncr3 regulates only adjuvant arthritis models but not autoimmunity triggered by specific tissue antigens, such as type II collagen. Furthermore, we found that gene expression and alternative splicing of the Ltab-Ncr3 genes correlate remarkably with arthritis severity and some of the gene expression differences were reproduced in a cohort of RA patients and healthy controls. Third, the MHC-II gene expression is regulated by class II transactivator (CIITA or C2TA), and in humans, genetic variation in CIITA has been associated with differential expression of MHC-II and susceptibility to autoimmune diseases. Using a congenic mouse strain with an allelic variant in the type I promoter of C2ta, we demonstrate that whereas genetic polymorphisms in C2ta promoter result in differential MHC-II expression and antigen presentation, these do not necessarily have a strong impact on autoimmune diseases such as arthritis. In summary, these studies demonstrate how the congenic approach remains powerful to conclusively identify and characterise genes regulating a complex disease like arthriti

Backpropagation Neural Ensemble for Localizing and Recognizing Non-Standardized Malaysia’s Car Plates

In this paper, we describe a research project that autonomously localizes and recognizes non-standardized Malaysian’s car plates using conventional Backpropagation algorithm (BPP) in combination with Ensemble Neural Network (ENN). We compared the results with the results obtained using simple Feed-Forward Neural Network (FFNN). This research aims to solve four main issues; (1) localization of car plates that has the same colour with the vehicle colour, (2) detection and recognition of car plates with varying sizes, (3) detection and recognition of car plates with different font types, and (4) detection and recognition of non-standardized car plates. The non-standardized Malaysian’s car plates are different from the normal plate as they contain italic characters, a combination of cursive characters, and different font types. The experimental results show that the combination of backpropagation and ENN can be effectively used to solve these four issues. The combination of BPP and ENN’s algorithm achieved a localization rate of 98% and a 97% in recognition rate. On the other hand, the combination of backpropagation and simple FFNN recorded a 96% recognition rate

Backpropagation neural ensemble for localizing and recognizing non-standardized Malaysia’s car plates

In this paper, we describe a research project that autonomously localizes and recognizes non-standardized Malaysian’s car plates using conventional Backpropagation algorithm (BPP) in combination with Ensemble Neural Network (ENN). We compared the results with the results obtained using simple Feed-Forward Neural Network (FFNN). This research aims to solve four main issues; (1) localization of car plates that has the same colour with the vehicle colour, (2) detection and recognition of car plates with varying sizes, (3) detection and recognition of car plates with different font types, and (4) detection and recognition of non-standardized car plates. The non-standardized Malaysian’s car plates are different from the normal plate as they contain italic characters, a combination of cursive characters, and different font types. The experimental results show that the combination of backpropagation and ENN can be effectively used to solve these four issues. The combination of BPP and ENN’s algorithm achieved a localization rate of 98% and a 97% in recognition rate. On the other hand, the combination of backpropagation and simple FFNN recorded a 96% recognition rate

Burkholderia multivorans septicemia in a pediatric liver transplant patient

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148247/1/ajt15065_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148247/2/ajt15065.pd

Carbetocin versus oxytocin for prevention of post-partum haemorrhage at caesarean section in the United Kingdom:An economic impact analysis

OBJECTIVE: To determine the economic impact of the introduction of carbetocin for the prevention of postpartum haemorrhage (PPH) at caesarean section, compared to oxytocin. STUDY DESIGN: The model is a decision tree conducted from a UK National Health Service perspective. 1500 caesarean sections (both elective and emergency) were modelled over a 12 month period. Efficacy data was taken from a published Cochrane meta-analysis, and costs from NHS Reference costs, the British National Formulary and the NHS electronic Medicines Information Tool. A combination of hospital audit data and expert input from an advisory board of clinicians was used to inform resource use estimates. The main outcome measures were the incidence of PPH and total cost over a one year time horizon, as a result of using carbetocin compared to oxytocin for prevention of PPH at caesarean section. RESULTS: The use of carbetocin compared to oxytocin for prevention of PPH at caesarean section was associated with a reduction of 30 (88 vs 58) PPH events (>500ml blood loss), and a cost saving of £27,518. In probabilistic sensitivity analysis, carbetocin had a 91.5% probability of producing better outcomes, and a 69.4% chance of being dominant (both cheaper and more effective) compared to oxytocin. CONCLUSION: At list price, the introduction of carbetocin appears to provide improved clinical outcomes along with cost savings, though this is subject to uncertainty regarding the underlying data in efficacy, resource use, and cost

Immunothrombosis and vascular heterogeneity in cerebral cavernous malformation

Cerebral cavernous malformation (CCM) is a neurovascular disease that results in various neurological symptoms. Thrombi have been reported in surgically resected CCM patient biopsies; but the molecular signatures of these thrombi remain elusive. Here, we investigated the kinetics of thrombi formation in CCM and how thrombi affect the vasculature and contribute to cerebral hypoxia. We used RNA-sequencing to investigate mouse brain endothelial cells with specific Ccm3 gene deletion (Ccm3-iECKO). We found that Ccm3 deficient brain endothelial cells had a higher expression of genes related to the coagulation cascade and hypoxia when compared to wild-type brain endothelial cells. Immunofluorescent assays identified key molecular signatures of thrombi such as fibrin, von Willebrand factor, and activated platelets in Ccm3-iECKO mice and human CCM biopsies. Notably, we identified polyhedrocytes in Ccm3-iECKO mice and human CCM biopsies and report it for the first time. We also found that the parenchyma surrounding CCM lesions is hypoxic and that more thrombi correlate with higher levels of hypoxia. Lastly, we created an in vitro model to study CCM pathology and found that human brain endothelial cells deficient for CCM3, expressed elevated levels of plasminogen activator inhibitor-1 and had a redistribution of von Willebrand factor. With transcriptomics, comprehensive imaging, and an in vitro CCM preclinical model this study provides experimental evidence that genes and proteins related to the coagulation cascade affect the brain vasculature and promote neurological side effects such as hypoxia in CCM. This study supports the concept that antithrombotic therapy may be beneficial for patients with CCM

Multi-Instrument Observations of a Geomagnetic Storm and its Effects on the Arctic Ionosphere: A Case Study of the 19 February 2014 Storm:Observations of a Geomagnetic Storm

We present a multiinstrumented approach for the analysis of the Arctic ionosphere during the 19 February 2014 highly complex, multiphase geomagnetic storm, which had the largest impact on the disturbance storm-time index that year. The geomagnetic storm was the result of two powerful Earth-directed coronal mass ejections (CMEs). It produced a strong long lasting negative storm phase over Greenland with a dominant energy input in the polar cap. We employed global navigation satellite system (GNSS) networks, geomagnetic observatories, and a specific ionosonde station in Greenland. We complemented the approach with spaceborne measurements in order to map the state and variability of the Arctic ionosphere. In situ observations from the Canadian CASSIOPE (CAScade, Smallsat and IOnospheric Polar Explorer) satellite's ion mass spectrometer were used to derive ion flow data from the polar cap topside ionosphere during the event. Our research specifically found that (1) thermospheric O/N2 measurements demonstrated significantly lower values over the Greenland sector than prior to the storm time. (2) An increased ion flow in the topside ionosphere was observed during the negative storm phase. (3) Negative storm phase was a direct consequence of energy input into the polar cap. (4) Polar patch formation was significantly decreased during the negative storm phase. This paper addresses the physical processes that can be responsible for this ionospheric storm development in the northern high latitudes. We conclude that ionospheric heating due to the CME's energy input caused changes in the polar atmosphere resulting in Ne upwelling, which was the major factor in high-latitude ionosphere dynamics for this storm. This research was originally published in Radio Science. © 2017 Wile

Preliminary results of trial NPC-0501 evaluating the therapeutic gain by changing from concurrent-adjuvant to induction-concurrent chemoradiotherapy, changing from fluorouracil to capecitabine, and changing from conventional to accelerated radiotherapy fractionation in patients with locoregionally advanced nasopharyngeal carcinoma

© 2014 American Cancer Society. BACKGROUND A current recommendation for locoregionally advanced nasopharyngeal carcinoma (NPC) is conventional fractionated radiotherapy with concurrent cisplatin plus adjuvant cisplatin and fluorouracil (PF). In this randomized trial, the authors evaluated the potential therapeutic benefit from changing to an induction-concurrent chemotherapy sequence, replacing fluorouracil with oral capecitabine, and/or using accelerated rather than conventional radiotherapy fractionation. METHODS Patients with stage III through IVB, nonkeratinizing NPC were randomly allocated to 1 of 6 treatment arms. The protocol was amended in 2009 to permit confining randomization to the conventional fractionation arms. The primary endpoint was progression-free survival. Secondary endpoints included overall survival and safety. RESULTS In total, 803 patients were accrued, and 706 patients were randomly allocated to all 6 treatment arms. Comparisons of induction PF versus adjuvant PF did not indicate a significant improvement. Unadjusted comparisons of induction cisplatin and capecitabine (PX) versus adjuvant PF indicated a favorable trend in progression-free survival for the conventional fractionation arm (P = .045); analyses that were adjusted for other significant factors and fractionation reflected a significant reduction in the hazards of disease progression (hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.36-0.80) and death (HR, 0.42; 95% CI, 0.25-0.70). Unadjusted comparisons of induction sequences versus adjuvant sequences did not reach statistical significance, but adjusted comparisons indicated favorable improvements by induction sequence. Comparisons of induction PX versus induction PF revealed fewer toxicities (neutropenia and electrolyte disturbance), unadjusted comparisons of efficacy were statistically insignificant, but adjusted analyses indicated that induction PX had a lower hazard of death (HR, 0.57; 95% CI, 0.34-0.97). Changing the fractionation from conventional to accelerated did not achieve any benefit but incurred higher toxicities (acute mucositis and dehydration). CONCLUSIONS Preliminary results indicate that the benefit of changing to an induction-concurrent sequence remains uncertain; replacing fluorouracil with oral capecitabine warrants further validation in view of its convenience, favorable toxicity profile, and favorable trends in efficacy; and accelerated fractionation is not recommended for patients with locoregionally advanced NPC who receive chemoradiotherapy.postprin

Inflammation and neutrophil extracellular traps in cerebral cavernous malformation

Correction: Volume79, Issue7 Article Number: 388 DOI: 10.1007/s00018-022-04418-8Cerebral Cavernous Malformation (CCM) is a brain vascular disease with various neurological symptoms. In this study, we describe the inflammatory profile in CCM and show for the first time the formation of neutrophil extracellular traps (NETs) in rodents and humans with CCM. Through RNA-seq analysis of cerebellum endothelial cells from wild-type mice and mice with an endothelial cell-specific ablation of the Ccm3 gene (Ccm3(iECKO)), we show that endothelial cells from Ccm3(iECKO) mice have an increased expression of inflammation-related genes. These genes encode proinflammatory cytokines and chemokines, as well as adhesion molecules, which promote recruitment of inflammatory and immune cells. Similarly, immunoassays showed elevated levels of these cytokines and chemokines in the cerebellum of the Ccm3(iECKO) mice. Consistently, both flow cytometry and immunofluorescence analysis showed infiltration of different subsets of leukocytes into the CCM lesions. Neutrophils, which are known to fight against infection through different strategies, including the formation of NETs, represented the leukocyte subset within the most pronounced increase in CCM. Here, we detected elevated levels of NETs in the blood and the deposition of NETs in the cerebral cavernomas of Ccm3(iECKO) mice. Degradation of NETs by DNase I treatment improved the vascular barrier. The deposition of NETs in the cavernomas of patients with CCM confirms the clinical relevance of NETs in CCM.Peer reviewe