Respiratory challenge MRI: practical aspects

Respiratory challenge MRI is the modification of arterial oxygen (PaO2) and/or carbon dioxide (PaCO2) concentration to induce a change in cerebral function or metabolism which is then measured by MRI. Alterations in arterial gas concentrations can lead to profound changes in cerebral haemodynamics which can be studied using a variety of MRI sequences. Whilst such experiments may provide a wealth of information, conducting them can be complex and challenging. In this paper we review the rationale for respiratory challenge MRI including the effects of oxygen and carbon dioxide on the cerebral circulation. We also discuss the planning, equipment, monitoring and techniques that have been used to undertake these experiments. We finally propose some recommendations in this evolving area for conducting these experiments to enhance data quality and comparison between techniques

Eliminating the LIGO bounds on primordial black hole dark matter

Primordial black holes (PBHs) in the mass range $(30$--$100)~M_{\odot}$ are interesting candidates for dark matter, as they sit in a narrow window between microlensing and cosmic microwave background constraints. There are however tight constraints from the binary merger rate observed by the LIGO and Virgo experiments. In deriving these constraints, PBHs were treated as point Schwarzschild masses, while the more careful analysis in an expanding universe we present here, leads to a time-dependent mass. This implies a stricter set of conditions for a black hole binary to form and means that black holes coalesce much more quickly than was previously calculated, namely well before the LIGO/Virgo's observed mergers. The observed binaries are those coalescing within galactic halos, with a merger rate consistent with data. This reopens the possibility for dark matter in the form of LIGO-mass PBHs.Comment: formatting + structure updated, and some arguments have been extended and slightly rewritten for clarity. no changes to the physics or conclusion

Rapid measurement of lactate in exhaled breath condensate: biosensor optimisation and in-human proof-of-concept

Lactate concentration is of increasing interest as a diagnostic for sepsis, septic shock, and trauma. Compared with the traditional blood sample media, the exhaled breath condensate (EBC) has the advantages of non-invasiveness and higher user acceptance. An amperometric biosensor was developed and its application in EBC lactate detection was investigated in this paper. The sensor was modified with PEDOT:PSS-PB, and two different lactate oxidases (LODs). A rotating disk electrode and Koutecky–Levich analysis were applied for the kinetics analysis and gel optimization. The optimized gel formulation was then tested on disposable screen-printed sensors. The disposable sensors exhibited good performance and presented a high stability for both LOD modifications. Finally, human EBC analysis was conducted from a healthy subject at rest and after 30 min of intense aerobic cycling exercise. The sensor coulometric measurements showed good agreement with fluorometric and triple quadrupole liquid chromatography mass spectrometry reference methods. The EBC lactate concentration increased from 22.5 μM (at rest) to 28.0 μM (after 30 min of cycling) and dropped back to 5.3 μM after 60 min of rest

Management of imatinib-resistant CML patients

Imatinib has had marked impact on outcomes in chronic myelogenous leukemia (CML) patients for all stages of the disease and is endorsed by international treatment guidelines as the first line option. Although imatinib is highly effective and well tolerated, the development of resistance represents a clinical challenge. Since the most frequently identified mechanism of acquired imatinib resistance is bcr-abl kinase domain point mutations, periodic hematologic, cytogenetic, and molecular monitoring is critical throughout imatinib therapy. Once cytogenetic remission is achieved, residual disease can be monitored by bcr-abl transcript levels as assayed by reverse transcription polymerase chain reaction (RT-PCR). Detection of bcr-abl mutants prior to and during imatinib therapy can aid in risk stratification as well as in determining therapeutic strategies. Thus, mutation screening is indicated in patients lacking or losing hematologic response. Moreover, search for mutations should also be performed when a 3-log reduction of bcr-abl transcripts is not achieved or there is a reproducible increase of transcript levels. In patients harboring mutations which confer imatinib resistance, novel second line tyrosine kinase inhibitors have demonstrated encouraging efficacy with low toxicity. Only the T315I bcr-abl mutant has proved totally resistant to all clinically available bcr-abl inhibitors. Strategies to further increase the rates of complete molecular remissions represent the next frontier in the targeted therapy of CML patients

Report of the Topical Group on Micro-Pattern Gaseous Detectors for Snowmass 2021

This report summarizes white papers on micro-pattern gaseous detectors (MPGDs) that were submitted to the Instrumentation Frontier Topical Group IF05, as part of the Snowmass 2021 decadal survey of particle physics.Comment: contribution to Snowmass 202

The NRG1 gene is frequently silenced by methylation in breast cancers and is a strong candidate for the 8p tumour suppressor gene.

Neuregulin-1 (NRG1) is both a candidate oncogene and a candidate tumour suppressor gene. It not only encodes the heregulins and other mitogenic ligands for the ERBB family, but also causes apoptosis in NRG1-expressing cells. We found that most breast cancer cell lines had reduced or undetectable expression of NRG1. This included cell lines that had translocation breaks in the gene. Similarly, expression in cancers was generally comparable to or less than that in various normal breast samples. Many non-expressing cell lines had extensive methylation of the CpG island at the principal transcription start site at exon 2 of NRG1. Expression was reactivated by demethylation. Many tumours also showed methylation, whereas normal mammary epithelial fragments had none. Lower NRG1 expression correlated with higher methylation. Small interfering RNA (siRNA)-mediated depletion of NRG1 increased net proliferation in a normal breast cell line and a breast cancer cell line that expressed NRG1. The short arm of chromosome 8 is frequently lost in epithelial cancers, and NRG1 is the most centromeric gene that is always affected. NRG1 may therefore be the major tumour suppressor gene postulated to be on 8p: it is in the correct location, is antiproliferative and is silenced in many breast cancers

Common variants of the TCF7L2 gene are associated with increased risk of type 2 diabetes mellitus in a UK-resident South Asian population

Background Recent studies have implicated variants of the transcription factor 7-like 2 (TCF7L2) gene in genetic susceptibility to type 2 diabetes mellitus in several different populations. The aim of this study was to determine whether variants of this gene are also risk factors for type 2 diabetes development in a UK-resident South Asian cohort of Punjabi ancestry. Methods We genotyped four single nucleotide polymorphisms (SNPs) of TCF7L2 (rs7901695, rs7903146, rs11196205 and rs12255372) in 831 subjects with diabetes and 437 control subjects. Results The minor allele of each variant was significantly associated with type 2 diabetes; the greatest risk of developing the disease was conferred by rs7903146, with an allelic odds ratio (OR) of 1.31 (95% CI: 1.11 – 1.56, p = 1.96 × 10-3). For each variant, disease risk associated with homozygosity for the minor allele was greater than that for heterozygotes, with the exception of rs12255372. To determine the effect on the observed associations of including young control subjects in our data set, we reanalysed the data using subsets of the control group defined by different minimum age thresholds. Increasing the minimum age of our control subjects resulted in a corresponding increase in OR for all variants of the gene (p ≤ 1.04 × 10-7). Conclusion Our results support recent findings that TCF7L2 is an important genetic risk factor for the development of type 2 diabetes in multiple ethnic groups

Defining the challenges for ecodesign implementation in companies:development and consolidation of a framework

This study addresses the problem of the slow take-up of ecodesign in industry by identifying and categorising the implementation challenges faced by practitioners. Case studies from nine manufacturing companies from five different countries are reported based on interviews with key ecodesign personnel. A literature-derived framework is used to analyse each case, allowing for robust cross-case analysis. Challenges are identified in five areas: strategy, tools, collaboration, management and knowledge. The management category of challenges is the most frequently mentioned by the companies sampled. The tools category is not as prominent as might have been expected given the on-going focus on tool development within this field. The main contributions of the study are the updating of the main challenges for ecodesign implementation faced by industry, and the development of a rich framework of challenges, including new challenges not previously mentioned in the literature. It is suggested that the framework can be used (and evolved) by other ecodesign researchers when developing surveys or questions for in-depth case study interviews as this will facilitate more robust comparisons between studies and support the development of a more consolidated body of knowledge in this field