The resonator handbook

The purpose of this work is to extend resonator theory into the region in which the planar mirror is quite small. Results of the theoretical description are then extended to resonator design and experimental arrangements as discussed in further sections of this work. Finally, a discussion of dielectric measurements for small samples is included as a specific application of this work

Discovery and application of colorectal cancer protein markers for disease stratification

Colorectal cancer (CRC) is a major cause of cancer mortality. Whereas some patients respond well to therapy, others do not, and thus more precise methods of CRC stratification are needed. The intracellular protein expression from 28 CRC primary tumours and corresponding normal intestinal mucosa was analysed using saturation-DIGE/MS and Explorer antibody microarrays. Changes in protein abundance were identified at each stage of CRC. Proteins associated with proliferation, glycolysis, reduced adhesion, endoplasmic reticulum stress, angiogenesis, and response to hypoxia represent changes to CRC and its microenvironment during development. Molecular changes in CRC cells and their microenvironment can be incorporated into clinic-pathological data to help sub-classify tumours and personalise treatment. DotScan antibody microarray analysis was used to profile the surface proteome of cells derived from 50 CRC samples and corresponding normal intestinal mucosa. Fluorescence multiplexing enabled the analysis of two different sub-populations of cells from each sample: EpCAM+ cells (CRC cells or normal epithelial cells in normal mucosa) and CD3+ T-cells (tumour-infiltrating lymphocytes). Unsupervised hierarchical clustering of the CRC and T-cell surface profiles defined four clinically relevant clusters, which showed some correlation with histopathological and clinical characteristics such as cancer cell differentiation, peri-tumoural inflammation and stimulation of infiltrating T-cells. The observed relationship between the surface antigen expression profiles of patients’ CRC cells and their corresponding tumour infiltrating T-cells suggests that CRC surface proteins may play a direct role in influencing the activity (and hence surface protein expression) of neighbouring T-cells and/or vice versa. We conclude that the application of surface profiling may provide improved patient stratification, allowing more reliable prediction of disease progression and patient outcome

Semi-solid and solid bolus swallows in high-resolution oesophageal manometry for the detection of motility disorders

Background/Aims: High-resolution oesophageal manometry utilises water swallows to evaluate oesophageal function. However, small volumes of water are not representative of normal eating and as a result often produce normal manometry studies in patients with dysphagia. This study sets out to establish optimal diagnostic thresholds for semi-solid solid swallows and evaluate their ability to uncover motility abnormalities in patients with motility disorders. Method: Manometry was performed using ten 5-mL single water swallows followed by two semi-solid and two solid swallows in the upright position. Normative values for the adjunctive tests were obtained from patient controls while patients with major motility disorders were used to establish the optimal diagnostic thresholds. Diagnostic thresholds identified were prospectively tested in patients with normal water swallows but oesophagus related symptoms and in those with minor and major motility disorders. Results: Normal values for semi-solid and solid were determined in patient controls (n = 100). Development of diagnostic thresholds included 120 patients with major motility disorders. Optimal diagnostic thresholds identified for oesophagogastric junction dysfunction in semi-solid and solid swallows (IRP > 15.5 mmHg). Hypercontractilty and spasm used existing thresholds (>8000 mmHg-s-cm and < 4.5 s, respectively) but modified frequency of ≥50% of adjunctive swallows. Diagnostic thresholds were applied to symptomatic patients with normal water swallows (n = 70) identifying 12/70 (17%) to have abnormal adjunctive swallows. One of 30 patients (3%) with ineffective motility had abnormal adjunctive swallow and 12 patients with oesophageal spasm, oesophagogastric junction obstruction, and hypercontractility had abnormal adjunctive swallows that moved them up the motility disorder hierarchy. Conclusions: Semi-solid and solid challenge increase diagnostic yield of motility disorders

The role of heat shock protein receptor CD91 in initiation of tumor associated immunity

Adaptive immune responses against tumors are routinely detected in hosts bearing the tumors. However, the mechanisms of priming T cell responses which are central to the underlying immunosurveillance for nascent tumors remains unclear, given the limited amount of each unique tumor antigens available for cross-priming during the early stages of tumor development and lack of classical PAMPs in general. I provide evidence here that heat shock proteins (HSPs), when released into the tumor microenvironment under these conditions, is the molecular entity necessary for priming specific tumor-associated immunity. These responses require CD91, the endocytic and signaling receptor for the immunogenic HSPs. In this study, I generated CD11c-specific CD91 knockout mice and showed that tumors grew faster in those knockout mice compared to CD91+/+ mice, due to a lack of priming efficient T cell responses. In addition, I abrogated the interaction of tumor-derived HSP with CD91 in vivo by over-expression of Receptor Associated Protein (RAP), an endogenous inhibitor of CD91. The data showed that: first, tumors expressing RAP grew with significantly faster kinetics than the non-RAP expressing counterparts in wild type mice, although this difference was non-existent in immunocompromised mice; second, RAP-expressing tumors, when used as an immunogen in tumor prophylaxis, were significantly less efficient in priming immune responses; third, inhibition of antigen cross-presentation by RAP reduced T cell proliferation in vivo; last, the competition of RAP and tumor-derived HSP for binding to CD91 was examined in vivo. In the presence of RAP, fewer tumor-derived HSPs were taken up by APCs in draining lymph nodes. In summary, this study demonstrates that early in tumor development, the HSP-CD91 pathway is critical for establishment of anti-tumor immunity. Considering that elevated RAP levels have been reported in colon cancer patients, I propose a novel mechanism of immune evasion for tumors expressing competing ligands for immune receptors such as CD91

New Internet of Medical Things for home-based treatment of anorectal disorders

Home-based healthcare provides a viable and cost-effective method of delivery for resource and labour-intensive therapies, such as rehabilitation therapies, including anorectal biofeedback. However, existing systems for home anorectal biofeedback are not able to monitor patient compliance or assess the quality of exercises performed, and as a result have yet to see wide spread clinical adoption. In this paper, we propose a new Internet of Medical Things (IoMT) system to provide home-based biofeedback therapy, facilitating remote monitoring by the physician. We discuss our user-centric design process and the proposed architecture, including a new sensing probe, mobile app, and cloud-based web application. A case study involving biofeedback training exercises was performed. Data from the IoMT was compared against the clinical standard, high-definition anorectal manometry. We demonstrated the feasibility of our proposed IoMT in providing anorectal pressure profiles equivalent to clinical manometry and its application for home-based anorectal biofeedback therapy

Rheological characteristics of soluble fibres during chemically simulated digestion and their suitability for gastroparesis patients

Dietary fibres are an integral part of a balanced diet. Consumption of a high-fibre diet confers many physiological and metabolic benefits. However, fibre is generally avoided by individuals with gastrointestinal motility disorders like gastroparesis due to increased likelihood of exacerbated symptoms. Low-viscosity soluble fibres have been identified as a possible source of fibre tolerable for these individuals. The aim of this study is to determine the rheological properties of 10 common commercially available soluble fibres in chemically simulated digestive conditions and evaluate their suitability for individuals with mild to moderate gastroparesis, a gastric motility disorder. Rheological testing under neutral condition (distilled water pH 7) and chemically simulated gastric digestion were evaluated to determine the yield point and relative viscosity of each fibre. Our results reveal two rheological categories of soluble fibres; pseudoplastic and dilatant.Simulated digestion was shown to significantly alter the yield-points of psyllium husk, iotacarrageenan, beta-glucan, apple-fibre pectin, and inulin. Gum Arabic and partially hydrolysed guar gum showed the lowest viscosities and were not affected under simulated digestion, characteristics that make them potential candidate fibres for patients with gastroparesis. Altogether, our results demonstrate that digestion can have a significant impact on fibre viscosity and should be taken into consideration when evaluating the suitability of fibres for patients with gastric motility disorders

Prevalence and effects of gastro-oesophageal reflux during spirometry in subjects undergoing reflux assessment

Variability during spirometry can persist despite control of technical and personal factors. We postulate spirometry induces gastro-oesophageal reflux (GOR), which may cause variability and affect results of spirometry. Fifty-eight (58) subjects undergoing GOR investigation with oesophageal manometry and 24hr pH monitoring were recruited. Oesophageal dysmotility and GOR were assessed as part of clinical care. Subjects performed 2 sets of spirometry separated by a 10-minute rest period. The assessment of GOR during spirometry procedure (defined by a lower oesophageal pH<4) started from the first set of spirometry and concluded when the second set of spirometry was completed. We calculated variability (%) of FEV1, FVC and PEFR within each set as well as changes over 10-minutes. Twenty-six subjects (45%) recorded GOR during assessment. Of these, 23 subjects recorded GOR during the 10-minute rest period. Four subjects had GOR recorded only during spirometry tests. We did not find variability of spirometry parameters between the groups with and without GOR during spirometry procedure. However, in subjects with GOR, we found small but significant reductions of PEFR (0.5L/s, 8%, p<0.001) and FEV1 (84 mL, 3%, p = 0.048) in the second set of spirometry compared to the first spirometry set. This pilot study demonstrates that GOR can occur during and following spirometry. Presence of GOR during spirometry in this patient population caused small decreases in PEFR and FEV1 when it is repeated 10-minutes later however not increase variability in a single series of measurements

Simple synthetic data reduces sycophancy in large language models

Sycophancy is an undesirable behavior where models tailor their responses to follow a human user's view even when that view is not objectively correct (e.g., adapting liberal views once a user reveals that they are liberal). In this paper, we study the prevalence of sycophancy in language models and propose a simple synthetic-data intervention to reduce this behavior. First, on a set of three sycophancy tasks (Perez et al., 2022) where models are asked for an opinion on statements with no correct answers (e.g., politics), we observe that both model scaling and instruction tuning significantly increase sycophancy for PaLM models up to 540B parameters. Second, we extend sycophancy evaluations to simple addition statements that are objectively incorrect, finding that despite knowing that these statements are wrong, language models will still agree with them if the user does as well. To reduce sycophancy, we present a straightforward synthetic-data intervention that takes public NLP tasks and encourages models to be robust to user opinions on these tasks. Adding these data in a lightweight finetuning step can significantly reduce sycophantic behavior on held-out prompts. Code for generating synthetic data for intervention can be found at https://github.com/google/sycophancy-intervention

Impact of Cross-Axis Structural Dynamics on Validation of Linear Models for Space Launch System

A feasibility study was performed to examine the advisability of incorporating a set of Programmed Test Inputs (PTIs) during the Space Launch System (SLS) vehicle flight. The intent of these inputs is to provide validation to the preflight models for control system stability margins, aerodynamics, and structural dynamics. During October 2009, Ares I-X program was successful in carrying out a series of PTI maneuvers which provided a significant amount of valuable data for post-flight analysis. The resulting data comparisons showed excellent agreement with the preflight linear models across the frequency spectrum of interest. However unlike Ares I-X, the structural dynamics associated with the SLS boost phase configuration are far more complex and highly coupled in all three axes. This presents a challenge when implementing this similar system identification technique to SLS. Preliminary simulation results show noticeable mismatches between PTI validation and analytical linear models in the frequency range of the structural dynamics. An alternate approach was examined which demonstrates the potential for better overall characterization of the system frequency response as well as robustness of the control design

A HPLC-ESI-Q-ToF-MS method for the analysis of monomer constituents in PHGG, gum arabic and psyllium husk prebiotic dietary fibre supplements

“Soluble” type dietary fibre contains polysaccharides with monomer constituents that play a major role in lowering the glycemic index of food (“low-GI”) and improving colonic health through gut microbiome fermentation. Soluble fibres such as partially hydrolysed guar gum (PHGG), gum Arabic and psyllium husk are of particular interest in gastrointestinal research, exploring their effects in motility disorders such as gastroparesis, constipation, diarrhea and irritable bowel syndrome (IBS) is important. The primary aim of this research was to develop a rapid pre-column derivatized HPLC-ESI-Q-ToF-MS method for the identification and quantification of monomer sugar constituents in commercial dietary fibre supplements of PHGG, gum Arabic and psyllium husk. Polysaccharides in the samples were hydrolysed and derivatized using 1-phenyl-3-methyl-5-pyrazolone (PMP). A rapid 21 min HPLC-ESI-Q-ToF-MS method separated nine different PMP-labelled monomer sugars. Five different sugars (i.e., Galactose, Arabinose, Rhamnose, Mannose and Xylose) were identified and quantified. Standard curve linearity was excellent (R2 > 0.999), with good intra-laboratory precision (< ±5% SD for concentrations, ≤ ±0.02 min peak shifting for retention times). The average three-level (50%, 75% and 100%) spiking recoveries for the analytes was acceptable (96.22–109.49%). Positive scanning mode ESI-MS/MS was used to generate [M + H]+ precursor ions and three (m/z) product ion fragments to provide identity confirmation. The concentrations of monomer sugars in gum Arabic and psyllium husk dietary fibres were consistent with literature reports. In PHGG, the concentration of galactose was unexpectedly higher than mannose, indicating that the commercial hydrolysis process of guar gum during PHGG manufacturing affected monomer composition. The method presented here provides the basis for the standardisation and labelling of commercial PHGG, gum Arabic and psyllium husk supplements. Future research will need to explore the monomer variability in other prebiotic soluble fibres and their efficacy in the production of beneficial short-chain fatty acids (SCFA) in the colonic environment