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Influence of Loss Function on Left Ventricular Volume and Ejection Fraction Estimation in Deep Neural Networks
Get PDFQuantification of the left ventricle shape is crucial in evaluating cardiac function from 2D echocardiographic images. This study investigates the applicability of established loss
functions when optimising the U-Net model for 2D echocardiographic left ventricular segmentation. Our results indicate loss functions are a significant component for optimal left ventricle volume measurements when established segmentation metrics could be imperceptible
Fatty acid metabolism of Mycobacterium tuberculosis: a double-edged sword
Get PDFUnlike other heterotrophic bacteria, Mycobacterium tuberculosis (Mtb) can co-catabolize a range of carbon sources simultaneously. Evolution of Mtb within host nutrient environment allows Mtb to consume the host’s fatty acids as a main carbon source during infec- tion. The fatty acid-induced metabolic advantage greatly contributes to Mtb’s pathogenicity and viru- lence. Thus, the identification of key enzymes involved in Mtb’s fatty acid metabolism is urgently needed to aid new drug development. Two fatty acid metabolism enzymes, phosphoenolpyruvate carboxykinase (PEPCK) and isocitrate lyase (ICL) have been intensively studied as promising drug targets, but recently, Quinonez et al. (mBio, doi: 10.1128/mbio.03559-21) highlighted a link between the fatty acid-induced dormancy-like state and drug tolerance. Using metabolomics profiling of a PEPCK-deficient mutant, Quinonez et al. identified that over-accumulation of methylcitrate cycle (MCC) inter- mediates are phenotypically associated with enhanced drug tolerance against first- and second- line TB antibi- otics. This finding was further corroborated by metabolomics and phenotypic characterization of Mtb mutants lacking either ICL or 2-methylcitrate dehydra- tase. Fatty acid metabolism induced drug-tolerance was also recapitulated in wildtype Mtb after treatment with authentic 2-methylisocitrate, an MCC intermedi- ate. Together, the fatty acid-induced dormancy-like state and drug tolerance are attributed to dysregulat- ed MCC activity
On the ability of machine learning methods to discover new scaffolds
No full textThe recent advances in the application of machine learning to drug discovery have made it a "hot topic" for research, with hundreds of academic groups and companies integrating machine learning into their drug discovery projects. Nevertheless, there remains great uncertainty regarding the most appropriate ways to evaluate the relative performance of these powerful methods against more traditional cheminformatics approaches and many pitfalls remain for the unwary. Early in 2020, researchers at MIT (Stokes, et al. [1]) reported the discovery of a new compound with antibacterial activity, halicin, through the use of a neural network machine learning method. A robust ability to identify novel active chemotypes through computational methods would be very useful. In this study, we have used the publicly available halicin dataset to compare the performance of this method to two other approaches, Mapping of Activity Through Dichotomic Scores (MADS) by Todeschini et al. [2] and Random Matrix Theory (RMT) by Lee et al. [3]. We have investigated the impact of dataset composition and standardization on performance. Our results demonstrate that all three methods are capable of predicting halicin as an active antibacterial compound, but that this result is dependent on the dataset composition, pre-processing and the molecular _ngerprint used. Whilst there is no conclusion for the `best' performance overall, MADS is relatively better compared to the other methods based on general predictive performance. Additionally, the prediction analysis of both MADS and RMT is interpretable. We further investigate the sca_old hopping potential of the methods by modifying the dataset by removal of the _-lactam and uoroquinolone chemotypes. MADS and RMT were able to identify actives in the test set that contained these substructures. This ability arises because of high scoring fragments of the withheld chemotypes that are in common with other active antibiotic classes. However, as there is no mechanistic relationship, the generality of the predictive ability of the methods is doubtful. We have further assessed overall performance as determined by several performance metrics
(Safe) sex on my mind: the effects of a safe sex prime and an alcohol prime on sex-related perceptions and behavior
Get PDFObjective:
Previous research suggests that exposure to alcohol primes (i.e., stimuli associated with alcohol) affects drinkers’ perceptions and behaviors. The present study investigated the effects of an environmental alcohol prime (being in a simulated bar setting) and a safe sex message prime (a public health safe sex message) on sexually active alcohol drinkers.
Method:
Participants (n = 80) were assigned to one of four conditions according to priming allocation and engaged in a simulated video chat with a potential partner. They reported their sex-related self-perceptions and perceptions of a potential partner upon procedural completion.
Results:
The alcohol-related environmental prime led participants to rate their potential partner as being significantly less inhibited and more sexual. The safe sex message significantly reduced reported sex-related self-perceptions and perceptions of their partners’ disinhibition. There was a significant effect of primes on participants’ perceptions of their partner's friendliness—participants exposed to either or both prime(s) perceived their partner as being friendlier than participants exposed to no prime.
Conclusions:
Results suggest that environmental alcohol primes may strengthen sexually active drinkers’ perceptions of a potential partner's disinhibition and sexuality even before alcohol consumption begins, and that a safe sex message may moderate these effects. The presence of safe sex messages in alcohol-related environments may positively influence sexual risk decision making among sexually active drinkers
You, me, the BBC and the license fee
Get PDFThis article lays out some of the critical issues about the future of the BBC and public service broadcasting that will be discussed in the mid-term Charter Review starting April 2022. A theme that will be central is the future funding arrangements, with the intention to abolish the license fee already announced by the government minister responsible for the review. The challenge is to ensure that any alternative to license fee funding supports a richer and more relevant public service broadcasting sector
HOX and PBX gene dysregulation as a therapeutic target in glioblastoma multiforme
Get PDFBackground: Glioblastoma multiforme (GBM) is the most common high-grade malignant brain tumour in adults and arises from the glial cells in the brain. The prognosis of treated GBM remains very poor with 5-year survival rates of 5%, a figure which has not improved over the last few decades. Currently, there is a modest 14-month overall median survival in patients undergoing maximum safe resection plus adjuvant chemoradiotherapy. HOX gene dysregulation is now a widely recognised feature of many malignancies.
Methods: In this study we have focused on HOX gene dysregulation in GBM as a potential therapeutic target in a disease with high unmet need.
Results: We show significant dysregulation of these developmentally crucial genes and specifically that HOX genes A9, A10, C4 and D9 are strong candidates for biomarkers and treatment targets for GBM and GBM cancer stem cells. We evaluated a next generation therapeutic peptide, HTL-001, capable of targeting HOX gene over-expression in GBM by disrupting the interaction between HOX proteins and their co-factor, PBX. HTL-001 induced both caspase-dependent and -independent apoptosis in GBM cell lines.
Conclusion: In vivo biodistribution studies confirmed that the peptide was able to cross the blood brain barrier. Systemic delivery of HTL-001 resulted in improved control of subcutaneous murine and human xenograft tumours and improved survival in a murine orthotopic model
A comprehensive framework for risk probability assessment of landfill fire incidents using fuzzy fault tree analysis
Get PDFLandfill fire is the most frequent type of incidents in the waste management complexes. This paper presents a new framework for risk probability evaluation of major fires in landfills using the fuzzy fault tree analysis. The framework starts with construction of the fault tree of landfill fire comprised of 38 basic and 22 intermediate events with the corresponding type of faults under managerial, executive, human, and environmental conditions. Fault tree quantitative analysis is carried out through a combination of fuzzy set theory and experts' judgements to overcome the lack of data limitation. Two new sensitivity analysis approaches are used to identify the critical fault type and critical paths in the fault tree. The proposed framework is demonstrated by its application to a real-world case of a landfill in Iran. The results show the probability of a major "fire incident" is 5.5% in which "fire occurrence" stands for 25% higher than "lack of preparation for controlling fire". In addition, "Waste’s uncontrolled dumping" is recognised as the highest critical event by 6% for probability failure and 24% for importance degree. "Executive fault" also found as the most fault’s critical type by frequency analysis of failure probability. The results also reveal the major impact of the experts’ weights, especially for events related to human or management faults. These results can give decision-makers a profound insight into providing effective intervention strategies for minimising the risk of major landfill fire incidents
Pad cultures: an ethnography of continence care and its consequences for people living with dementia during a hospital admission
Get PDFBackground
There is little research examining how continence care is organised and delivered to people living with dementia across an acute hospital admission, despite the prevalence of this patient population and their vulnerability within these settings.
Objective
To explore how continence care is delivered to people living with dementia during an acute hospital admission.
Design
Ethnographic.
Setting(s)
Acute medical units and wards within three hospitals across England and Wales.
Participants
People living with dementia and ward staff (registered nurses and care assistants) on participating wards.
Methods
Ethnographic fieldwork collected over a period of 12 months (180 days of non-participant observation) focussing on the organisation and delivery of continence care to people living with dementia. Observations were supported with in situ ethnographic interviews (n = 562) with patients, visitors and staff within the six observed wards. Data collection and analysis drew on the theoretical sampling and constant comparison techniques of grounded theory.
Results
The findings comprised of five overall themes: (1) visibility of continence; (2) rationales of continence care; (3) containment and contagion; (4) consequences of continence care and (5) supporting continence.
Conclusions
We introduce the term ‘pad cultures’ to refer to the established routine use of continence pads in the care of a wider group of people living with dementia (regardless of continence status and independence), with the rationale to provide safeguards, ensure containment and prevent ‘accidents’ or incontinent episodes. There was an expectation within acute wards that people living with dementia not only wear continence pads but that they also use them
Involvement of the extracellular matrix and integrin signalling proteins in skeletal muscle glucose uptake
Get PDFWhole-body euglycaemia is partly maintained by two cellular processes that encourage glucose uptake in skeletal muscle; 1) the insulin- and 2) contraction-stimulated pathways, with research suggesting convergence between these two previously separate processes. The normal structural integrity of the skeletal muscle requires an intact actin cytoskeleton as well as integrin-associated proteins, thus those structures are likely fundamental for effective glucose uptake in skeletal muscle. In contrast, excessive extracellular matrix (ECM) remodelling and integrin expression in skeletal muscle may contribute to insulin resistance owing to an increased physical barrier causing reduced nutrient and hormonal flux. This review paper explores the role of the ECM and the actin cytoskeleton in insulin- and contraction-mediated glucose uptake in skeletal muscle. This is a clinically important area of research given that defects in the structural integrity of the ECM and integrin-associated proteins may contribute to loss of muscle function and decreased glucose uptake in type 2 diabetes
Remote sensing measurements for the structural monitoring of historical masonry bridges
Get PDFAdvances in data processing and the availability of larger SAR datasets from various high-resolution (X-Band) satellite missions have consolidated the use of the Multi-Temporal Interferometric Synthetic Aperture Radar (MT-InSAR) technique in the near-real-time assessment of bridges and the health monitoring of transport infrastructures. This research aims to investigate the viability of a novel non-destructive health-monitoring approach based on sat-ellite remote sensing techniques for structural assessment of bridges and the prevention of damage by structural subsidence. To this purpose, commercial high-resolution TerraSAR-X (TSX) products of the German Aerospace Cen-tre (DLR) provided by the European Space Agency (ESA), were acquired and processed by MT-InSAR technique. Analyses were developed to identify and monitor the structural displacements of the historical “Ponte Sisto” masonry bridge located in Rome, Italy, crossing the Tiber River. To this extent, the historical time-series of deformations were processed by Persistent Scatterers (PSs) relevant to critical structural elements of the bridge (i.e., bridge piers and arcs). A novel data interpretation approach is proposed based on the se-lection of several PS data-points with coherent deformation trends and loca-tion on the bridge. The outcomes of this study demonstrate that multi-temporal InSAR remote sensing techniques can be applied to complement non-destructive ground-based analyses (e.g., ground-penetrating radars, laser scanners, accelerometers), paving the way for future integrated approaches in the smart monitoring of infrastructure assets