Novalis's idea of "Experimentalphilosophie" : a study of Romantic science in its context.

PhDThis thesis seeks to examine Novalis's philosophy of practical knowledge and to position it within the context of the work of other Romantic natural philosophers and some aspects of contemporary science. His views on Ritter's galvanism and the latter's significance for his thought in general are treated here for the first time in full. Contrary to most previous views, it is argued that a major part of Novalis's outlook stems from his concept of practical knowledge and his reflection over the term "experiment", which proves to be an extremely complex and central idea in his thought. It is shown how this philosophy of his finds most explicit expression in the idea of a symbolic notation or a "phenomenal" calculus. These notions merge in Novalis's idea of productive "Plastisirung". Particular attention is paid to the symbolic use of phosphorus in the pneumatic debate and Ritter's galvanic interpretation of the nerve. Beyond contemporary science, it is further shown how broad an historical base Novalis channels into his notion of practical knowledge. This should lead to a clearer understanding of Novalis's position within Romantic natural philosophy, his debt to tradition, and his originality. In the light of these findings, it is argued that Novalis's concern for practical knowledge provides the basis for a possible form of consensus in his thought. It is shown that there is an increasing tendency in his writings away from a programme for classifying knowledge in general towards the idea of individual knowledge and the case study, as is exemplified in his reception of Ritter's work. It is also advanced that Novalis's notion of practical knowledge is a significant methodological statement of early Romantic science, which also puts a new perspective on thinkers such as Goethe, Humboldt, Schelling and Ritte

Pressure Ulcer Categorisation and Reporting in Domiciliary Settings using Deep Learning and Mobile Devices: A Clinical Trial to Evaluate End-to-End Performance

Pressure ulcers are a challenge for patients and healthcare professionals. In the UK, pressure ulcers affect 700,000 people each year. Treating them costs the National Health Service £3.8 million every day. Their etiology is complex and multifactorial. However, evidence has shown a strong link between old age, disease-related sedentary lifestyles, and unhealthy eating habits. Direct skin contact with a bed or chair without frequent position changes can cause pressure ulcers. Urinary and faecal incontinence, diabetes, and injuries that restrict body position and nutrition are also known risk factors. Guidelines and treatments exist but their implementation and success vary across different healthcare settings. This is primarily because healthcare practitioners have a) minimal experience in dealing with pressure ulcers, and b) a general lack of understanding of pressure ulcer treatments. Poorly managed, pressure ulcers can lead to severe pain, a poor quality of life, and significant healthcare costs. In this paper, we report the findings of a clinical trial conducted by Mersey Care NHS Foundation Trust that evaluated the performance of a faster region-based convolutional neural network and mobile platform that categorised and documented pressure ulcers automatically. The neural network classifies category I, II, III, and IV pressure ulcers, deep tissue injuries, and pressure ulcers that are unstageable. District nurses used their mobile phones to take pictures of pressure ulcers and transmit them over 4/5G communications to an inferencing server for classification. The approach uses existing deep learning technologies to provide a novel end-to-end pipeline for pressure ulcer categorisation that works in ad hoc domiciliary settings. The strength of the approach resides within MLOPS, model deployment at scale, and the platforms in-situ operation. While solutions exist in the NHS for analysing pressure ulcers none of them automatically classify and report pressure ulcers from a service users’ residential home automatically. We acknowledge that there is a great deal of work to do, but the approach offers a convincing solution to standardise pressure ulcer categorisation and reporting. The results from the study are encouraging and show that using 216 images, collected over an eight-month trial, it was possible to generate a mean average Precision=0.6796, Recall=0.6997, F1-Score=0.6786 with 45 false positives using an @.75 confidence score threshold

Resilience as a Multimodal Dynamic Process

Aim Resilience is rapidly gaining momentum in mental health literature. It provides a new understanding of the highly variable trajectories of mental illness, and has consistently been linked with improved mental health outcomes. The present review aims to clarify the definition of resilience and to discuss new directions for the field. Methods After discussing the definition of resilience, this narrative review synthesizes evidence that identifies the specific protective factors involved in this process. This review also addresses the mechanisms that underlie resilience. Results Recent literature has clarified the three core components of resilience, which are the presence of an adversity or specific risk for mental illness; the influence of protective factors that supersede this risk; and finally, a subsequently more positive outcome than expected. Now that these are largely agreed upon, the field should move on to addressing other topics. Resilience is a dynamic process by which individuals utilize protective factors and resources to their benefit. It can vary within one individual across time and circumstance. It can also refer to good functional outcomes in the context of diagnosable illness. While previous research has focused on psychological resilience, it is essential that resilience is conceptualized across modalities. Conclusions The field should move towards the development of a multimodal model of resilience. Researchers should now focus on producing empirical research which clarifies the specific protective factors and mechanisms of the process, aligning with the core concepts of resilience. This growing, more homogeneous evidence base, can then inform new intervention strategies

Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology

Study of dyadic communication in couples managing prostate cancer: a longitudinal perspective

Objective : Cancer patients and partners often report inadequate communication about illness‐related issues, although it is essential for mutual support and informal caregiving. This study examined the patterns of change in dyadic communication between patients with prostate cancer and their partners, and also determined if certain factors affected their communication over time. Method : Using multilevel modeling, this study analyzed longitudinal data obtained from a randomized clinical trial with prostate cancer patients and their partners, to examine their communication over time. Patients and partners ( N =134 pairs) from the usual‐care control group independently completed baseline demographic assessment and measures of social support, uncertainty, symptom distress, and dyadic communication at baseline, and 4‐, 8‐, and 12‐month follow‐ups. Results : The results indicated that (1) patients and partners reported similar levels of open communication at the time of diagnosis. Communication reported by patients and partners decreased over time in a similar trend, regardless of phase of illness; (2) phase of illness affected couples' open communication at diagnosis but not patterns of change over time; and (3) couples' perceived communication increased as they reported more social support, less uncertainty, and fewer hormonal symptoms in patients. Couples' demographic factors and general symptoms, and patients' prostate cancer‐specific symptoms did not affect their levels of open communication. Conclusions : Perceived open communication between prostate cancer patients and partners over time is affected by certain baseline and time‐varying psychosocial and cancer‐related factors. The results provide empirical evidence that may guide the development of strategies to facilitate couples' interaction and mutual support during survivorship. Copyright © 2010 John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/89519/1/pon1861.pd

Nanostructuring perovskite oxides: The impact of SrTiO3 nanocubes 3D self-assembly on thermal conductivity.

Nanostructuring the perovskite oxide SrTiO3 via 3D assemblage of nanocubes is shown to lower the thermal conductivity over a broad range of temperatures. This is particularly valuable in thermoelectric material applications. The assemblages are composed of pristine perovskite grain interiors confined by SrO or TiO2-rich interfaces resembling Ruddlesden Popper and Magneli phases. The optimum performance in terms of the thermoelectric device applications are predicted to come from SrTiO3 nanocubes synthesised in a Sr-rich environment, although TiO2-rich nanocubes would have an increased strength. The vibrational fingerprint of the assemblages, characterized by a combination of lattice and molecular dynamics, display the characteristic modes of the perovskite structure and significant interface vibrational modes, some at very low frequency. TiO2-rich assemblages display splitting of the active modes similar to anatase providing a way to distinguish them from SrO-rich assemblages. Finally, we show that the IR active low vibrational frequencies are sensitive to the structure and stacking of the nanocubes indicating that it could be an efficient experimental route for identifying and characterizing the material with very low thermal conductivity

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Identification of BRCA1 missense substitutions that confer partial functional activity: potential moderate risk variants?

Introduction: Many of the DNA sequence variants identified in the breast cancer susceptibility gene BRCA1 remain unclassified in terms of their potential pathogenicity. Both multifactorial likelihood analysis and functional approaches have been proposed as a means to elucidate likely clinical significance of such variants, but analysis of the comparative value of these methods for classifying all sequence variants has been limited. Methods: We have compared the results from multifactorial likelihood analysis with those from several functional analyses for the four BRCA1 sequence variants A1708E, G1738R, R1699Q, and A1708V. Results: Our results show that multifactorial likelihood analysis, which incorporates sequence conservation, co-inheritance, segregation, and tumour immunohistochemical analysis, may improve classification of variants. For A1708E, previously shown to be functionally compromised, analysis of oestrogen receptor, cytokeratin 5/6, and cytokeratin 14 tumour expression data significantly strengthened the prediction of pathogenicity, giving a posterior probability of pathogenicity of 99%. For G1738R, shown to be functionally defective in this study, immunohistochemistry analysis confirmed previous findings of inconsistent 'BRCA1-like' phenotypes for the two tumours studied, and the posterior probability for this variant was 96%. The posterior probabilities of R1699Q and A1708V were 54% and 69%, respectively, only moderately suggestive of increased risk. Interestingly, results from functional analyses suggest that both of these variants have only partial functional activity. R1699Q was defective in foci formation in response to DNA damage and displayed intermediate transcriptional transactivation activity but showed no evidence for centrosome amplification. In contrast, A1708V displayed an intermediate transcriptional transactivation activity and a normal foci formation response in response to DNA damage but induced centrosome amplification. Conclusion: These data highlight the need for a range of functional studies to be performed in order to identify variants with partially compromised function. The results also raise the possibility that A1708V and R1699Q may be associated with a low or moderate risk of cancer. While data pooling strategies may provide more information for multifactorial analysis to improve the interpretation of the clinical significance of these variants, it is likely that the development of current multifactorial likelihood approaches and the consideration of alternative statistical approaches will be needed to determine whether these individually rare variants do confer a low or moderate risk of breast cancer