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The effects in-utero exposure to influenza on mental health and mortality risk throughout the life-course
No full textStudies examining the later-life health consequences of in-utero exposure to influenza have typically estimated effects on physical health conditions, with little evidence of effects on mental health outcomes or mortality. Previous studies have also relied primarily on reduced-form estimates of the effects of exposure to influenza pandemics, meaning they are unlikely to recover effects of influenza exposure at an individual-level. This paper uses inverse probability of treatment weighting and “doubly-robust” methods alongside rare mother-reported data on in-utero influenza exposure to estimate the individual-level effect of in-utero influenza exposure on mental health and mortality risk throughout childhood and adulthood. We find that in-utero exposure to influenza is associated with small reductions in mental health in mid-childhood, driven by increases in internalising symptoms, and increases in depressive symptoms in mid-life for males. There is also evidence that in-utero influenza exposure is associated with substantial increases in mortality, although these effects are primarily driven by a 75% increase in the probability of being stillborn, with limited evidence of additional survival disadvantages at later ages. The potential for mortality selection implies that estimated effects on mental health outcomes are likely to represent a lower bound
Hereditary Alpha-Tryptasemia:UK Prevalence and Variability in Disease Expression
No full textBACKGROUND: Hereditary alpha-tryptasemia (HAT) is a genetic trait caused by an increased alpha-tryptase tryptase alpha/beta 1 gene copy number. Basal serum mast cell tryptase (MCT) level is typically greater than or equal to 8.0 ng/mL.OBJECTIVES: To study the clinical disease spectrum of HAT and determine its UK prevalence.METHODS: Droplet digital PCR was used to determine tryptase alpha/beta 1 copy number in 432 DNA samples from an unselected UK birth cohort and in 70 patients referred with a basal MCT level greater than 8 ng/mL. Baseline MCT concentrations and clinical presentation were also assessed in 4283 samples sent to a regional immunology laboratory.RESULTS: Duplication in alpha copy number was present in 5% of the unselected British birth cohort, with all affected individuals having a basal MCT level of greater than or equal to 8.0 ng/mL. Basal MCT levels of greater than or equal to 8.0 ng/mL were also found in 5% of the 4283 individuals referred for MCT testing because of clinical symptoms. In 70 patients confirmed to have HAT (79% with a duplication; 21% with a higher alpha gene copy number), urticaria/angioedema (51%), skin flushing (41%), food intolerances (39%), and altered bowel habits (36%) were common presenting complaints. However, clinical manifestations were not more common in patients with gene triplications or quintuplications than in those with duplications. Some immediate family members with the same genetic trait and high basal MCT levels were asymptomatic.CONCLUSIONS: Five percent of people in the United Kingdom may have HAT. The diagnosis should be considered when basal MCT level is greater than or equal to 8 ng/mL. HAT has variable clinical penetrance. It may modify the expression of multifactorial allergic diseases rather than directly cause specific phenotypes.</p
Respiratory infections in children: an appropriateness study of when to seek help
No full textBackground: Children with respiratory tract infections (RTIs) use more primary care appointments than any other group, but many parents are unsure when to seek medical help, and report existing guidance is unclear. Aim: To develop symptom-based criteria to support parental medical help seeking for children with RTIs. Design and setting: A RAND/UCLA appropriateness study to obtain consensus on children’s RTI symptoms appropriate for home, primary or secondary health care. Methods: A multidisciplinary panel of 12 healthcare professionals (six general practitioners (GPs), two pharmacists, two NHS 111 nurses and two emergency paediatric consultants) rated the appropriateness of care setting for 1,134 scenarios in children aged >12 months Results: Panellists agreed that home care would be appropriate for children with up to one week of ‘normal’ infection symptoms (cough, sore throat, ear pain and/or runny nose, with or without eating adequately and normal conscious level). The presence of two or more additional symptoms generally indicated the need for a same-day GP consultation, as did the presence of shortness of breath. Assessment in the Emergency Department (ED) was considered appropriate when three symptoms were present and included shortness of breath or wheeze. Conclusions: We have defined the respiratory tract infection symptoms that parents might regard as ‘normal’ and therefore suitable for care at home. These results could help parents decide when to home care and when to seek medical help for children with RTIs
Single pulse modeling and the bi-drifting subpulses of radio pulsar B1839-04
No full textWe study the bi-drifting pulsar B1839-04, where the observed subpulse drift direction in the two leading pulse components is opposite from that in the two trailing components. Such diametrically opposed apparent motions challenge our understanding of an underlying structure. We find that for the geometry spanned by the observer and the pulsar magnetic and rotation axes, the observed bi-drifting in B1839-04 can be reproduced assuming a non-dipolar configuration of the surface magnetic field. Acceptable solutions are found to either have relatively weak (∼ 1012 G) or strong (∼ 1014 G) surface magnetic fields. Our single pulse modeling shows that a global electric potential variation at the polar cap that leads to a solid-body-like rotation of spark forming regions is favorable in reproducing the observed drift characteristics. This variation of the potential additionally ensures that the variability is identical in all pulse components resulting in the observed phase locking of subpulses. Thorough and more general studies of pulsar geometry show that a low ratio of impact factor to opening angle (β/ρ) increases the likelihood of bi-drifting to be observed. We thus conclude that bi-drifting is visible when our line of sight crosses close to the magnetic pole
FIGHT-302: First-line pemigatinib vs gemcitabine + cisplatin for advanced cholangiocarcinoma with FGFR2 rearrangements
No full textFibroblast growth factor receptor (FGFR) 2 rearrangements resulting in dysregulated signaling are drivers of cholangiocarcinoma tumorigenesis, and occur almost exclusively in intrahepatic cholangiocarcinoma. Pemigatinib, a selective, potent, oral inhibitor of FGFR 1–3, has demonstrated efficacy and safety in a phase 2 study of patients with previously treated locally advanced/metastatic cholangiocarcinoma harboring FGFR2 fusions/rearrangements. We describe the study design of FIGHT-302, an open-label, randomized, active-controlled, multicenter, global, phase 3 study comparing the efficacy and safety of first-line pemigatinib versus gemcitabine plus cisplatin in patients with advanced cholangiocarcinoma with FGFR2 rearrangements (NCT03656536). The primary endpoint is progression-free survival; secondary endpoints are objective response rate, overall survival, duration of response, disease control rate, safety, and quality of life
Betelgeuse fainter in the sub-millimetre too: an analysis of JCMT and APEX monitoring during the recent optical minimum
No full textBetelgeuse, the nearest Red Supergiant star to us underwent an unusually deep minimum at optical wavelengths during its most recent pulsation cycle. We present submillimetre observations taken by the James Clerk Maxwell Telescope and Atacama Pathfinder Experiment over a time span of 13 years including the optical dimming. We find that Betelgeuse has also dimmed by ∼ 20% at these longer wavelengths during this optical minimum. Using radiative-transfer models, we show that this is likely due to changes in the photosphere (luminosity) of the star as opposed to the surrounding dust as was previously suggested in the literature
Mystery-driven institutionalism: the Jesuit Spiritual Exercises as a book of practices leading nowhere
No full textThis paper discusses how mystery was imprinted into the Jesuit Spiritual Exercises, supporting their diffusion across space and time. It shows that the book of the Spiritual Exercises is a practice in itself and fosters a practice or set of practices. The book is more than an object: it is an action, unleashed not by the specification of what actions it dictates but by the mystery the ‘book-as-practice’ carries. The paper contributes to the literature on practice driven institutionalism, namely by showing how mystery furthers our understanding of the mutual constitution of practices and institutions. The Spiritual Exercises have been practiced for more than four centuries, even though their meaning is not stable and they are never fully understood. Therefore, our paper asks: how do the Jesuits understand what they have to do if the book does not prescribe everything? We argue that it is indeed this mystery that distinguishes religious practices, explaining their endurance across time and space and, henceforth, their institutionalisation. We show that the Spiritual Exercises are to be practiced and it is this practicing that allows them to diffuse and institutionalise a new understanding of how the individual relates to God. ‘God’s will’ is searched through the practicing, without ever being determined by the practice. It is by practicing the book that the mystery of ‘God’s will’ reveals itself. Moreover, ‘God’s will’ is never known or knowable. Instead, it is embodied and felt while practicing the book of the Exercises. Emotions thus reconcile, through mystery, the new logics and the practicing of it. Our paper contributes to practice-driven institutionalism by showing how mystery can drive institutionalisation processes
How the Ligand Field in Lanthanide Coordination Complexes Determines Magnetic Susceptibility Anisotropy, Paramagnetic NMR Shift and Relaxation Behaviour
No full textA Low Jitter, Low Cost Optical Chopper
No full textAn optical chopper is described that has comparable performance to commercially available units. The new chopper is built within the frame of a hard disk drive, and uses the existing motor and its disk for operation. The rotation speed is measured using a photointerrupter and adjusted with a microcontroller. Chopping frequencies from 150 Hz to 1650 Hz with phase jitter less than 0.38 degrees per revolution have been demonstrated. The hardware design and control algorithm are described, and results showing the phase jitter characteristics are presented. The performance of this new design is comparable to that of commercial optical choppers, and can be built for a fraction of their cost
Characterization of permissive and non-permissive peptide insertion sites in chloramphenicol acetyltransferase
No full textThe growing prevalence of antibiotic resistance in numerous pathogenic bacteria is a major public health concern and urgently requires the development of new therapeutic approaches. Multidrug resistant species that remain sensitive to chloramphenicol (CAM) treatment have engendered renewed interest in using this drug as a modern day antimicrobial agent. High-level resistance to CAM commonly is mediated by chloramphenicol acetyltransferase (CAT) which catalyzes the acetylation of CAM and renders the drug inactive. Of the three main types (CATI, CATII and CATIII), CATI is of broad clinical significance. Despite this importance, understanding of the catalytic mechanism of CATI largely is extrapolated from studies of CATIII. Here, pentapeptide scanning mutagenesis was used to generate a library of random insertions in CATI to gain a better understanding of structure-function relationships in the enzyme. Pentapeptide insertions in secondary structure elements which contain residues that form part of the CATI active site abolished CAM resistance in Escherichia coli. Insertions in secondary structures that have key roles in protein folding and CAM binding led to a reduction in resistance. In contrast, insertions in loop regions between the major secondary structure features exerted modest, if any, effects on CAM resistance. The analysis pinpoints regions of CATI that may serve as targets for the design of novel inhibitors that prevent the spread of CAM-resistant pathogens thereby enabling the drug to be re-deployed as a broad range antimicrobial agent. Moreover, regions of CATI that are tolerant of insertions may be suitable for the construction of bifunctional enzymes in which peptides, mini-proteins or amino acid tags are introduced at the permissive sites