Chronic Fatigue Syndrome and Chronic Widespread Pain in Adolescence:Population birth cohort study

Although many studies have investigated the overlap between pain phenotypes and chronic fatigue syndrome (CFS) in adults, little is known about the relationship between these conditions in adolescents. The study's aim was therefore to identify whether a relationship exists between chronic widespread pain (CWP) and CFS in adolescents and investigate whether the two share common associations with a set of covariates. A questionnaire was administered to offspring of the Avon Longitudinal Study of Parents and Children (ALSPAC) at age 17, asking about site, duration, and pain intensity, from which participants with CWP were identified. At the same research clinic, a computer-based Revised Clinical Interview Schedule was filled out, from which a classification of CFS was obtained. The relationship between selected covariates and CFS and CWP was investigated using a variety of logistic, ordinal logistic, and multinomial regressions. We identified 3,214 adolescents with complete data for all outcomes and covariates. There were 82 (2.6%) individuals classified as CFS and 145 (4.5%) as CWP. A classification of CFS resulted in an increased likelihood of having CWP (odds ratio = 3.87; 95% confidence interval, 2.05–7.31). Female adolescents were approximately twice as likely to have CFS or CWP, with multinomial regression revealing a greater sex effect for CWP compared with CFS. Those with exclusive CFS were more likely to report higher levels of pain and greater effect of pain compared with those without CFS, although associations attenuated to the null after adjustment for covariates, which did not occur in those with exclusive CWP. Multinomial regression revealed that relative to having neither CFS nor CWP, a 1-unit increase in the depression and anxiety scales increased the risk of having exclusive CFS and, to a greater extent, the risk of having comorbid CFS and CWP, but not exclusive CWP, which was only related to anxiety. PERSPECTIVE: In this cohort, 14.6% of adolescents with CFS have comorbid CWP. The likely greater proportion of more mild cases observed in this epidemiological study means that prevalence of overlap may be underestimated compared with those attending specialist services. Clinicians should be aware of the overlap between the 2 conditions and carefully consider treatment options offered

Review Essay: Emplacement and everyday use of medications in domestic dwellings

To extend knowledge of relationships between people and domestic settings in the context of medication use, we conducted fieldwork in twenty households in New Zealand. These households contained a range of ‘medicative’ forms, including prescription drugs, traditional remedies, dietary supplements and enhanced foods. The location and use of these substances within domestic dwellings speaks to processes of emplacement and identity in the creation of spaces for care. Our analysis contributes to current understandings of the ways in which objects from ‘outside’ the home come to be woven into relationships, identities and meanings ‘inside’ the home. We demonstrate that, as well as being pharmacological objects, medications are complex, socially embedded objects with histories and memories that are ingrained within contemporary relationships of care and home-making practices

An investigation into the chromatin structure of human telomeres

Telomeres cap the end of eukaryotic chromosomes and prevent the natural end of a chromosome from being recognised as a double-stranded DNA break. Dysfunctional telomeres may trigger replicative senescence, or fuse with other telomeres or with non-telomeric DNA breaks. The length of a telomere plays a key role in telomere function. Relatively little is known about how telomeric chromatin influences telomere length and function. A number of studies in mammalian cells have identified a handful of chromatin remodelling proteins and the chromatin marks they deposit in telomere length regulation. However such examples at human telomeres are scarce. The primary aim of this thesis was to investigate whether the chromatin structure of a telomere is a determinant of its length in human cells. Two approaches were taken to address this issue: Firstly, the chromatin structure of telomeres of differing lengths were directly analysed by measuring enrichment of histone modifications known to be prominent at telomeres in other model organisms. Secondly, selected chromatin remodelling proteins were studied to determine whether they play a role in telomeric chromatin structure and telomere length. Single Telomere Length Analysis (STELA) provides a high resolution method to measure telomere length distributions at individual chromosome ends. STELA assays were previously designed for the 2p, 9p, 11q, 12q, 16p, 17p and 18q telomeres. An allele‐specific STELA assay has also been designed for the XpYp chromosome end. In this study novel telomere and telomeric allele‐specific qPCR assays were developed for the same chromosome ends. These qPCR assays, when used in conjunction with ChIP provide a tool for analysing telomeric chromatin structure at individual chromosome ends. Applying this ChIP‐qPCR approach alongside STELA allows any correlations between telomeric chromatin structure and telomere length to be identified. This approach suggested differences in telomeric chromatin structure between telomeres of different lengths in telomerase‐positive HT1080 fibrosarcoma cells. Shorter HT1080 telomeres were less abundant in H3 and TRF1 and also had lower levels of H4K20me3 and, to a lesser extent, H3K4me3 compared to longer telomeres. Differences in chromatin structure were not observed between telomeres of different lengths in telomerase negative MRC5 fibroblasts. Changes in chromatin structure were observed at individual telomeres/telomere alleles were observed between actively proliferating cells and in cells undergoing senescence. Telomeric enrichment of H3 and TRF1 as well as the histone methylation marks H3K4me3, H3K9me3 and H4K20me3 were reduced in senescent cells. The degree of chromatin structural change as the cells entered senescence differed between chromosome ends. This highlights the benefits of using the telomere-specific ChIP-qPCR approach over the more traditional ChIP-dot blot assays which would not be able to differentiate between the chromatin structure of different chromosome ends. To identify roles for chromatin remodelling proteins in telomere length maintenance siRNA mediated knockdown of selected chromatin remodelers was performed in a clonal population of HT1080 cells followed by STELA analysis. RNAi-depletion of the histone methyltransferase (HMTase) III EHMT2 resulted in an increase in very short 17p telomeres whereas loss of another HMTase, DOT1L caused a divergence in the 17p telomere length distribution suggesting the presence of two subpopulations of cells each with differing telomere length distributions. Subtle changes in mean telomere length was observed after siRNA mediated knockdown of the HMTases MLL and EZH2, the histone deacetylases (HDACs) HDAC1 and SIRT6, the ATP dependent chromatin remodelling complex subunit BAF155 and the H3.3 histone chaperone DAXX. However due to certain limitations of the RNAi screen the validity of these observations is questionable and more work would have to be performed to confirm whether these chromatin remodelers have an effect on telomere length. Finally, dramatic telomere shortening was observed in a keratinocyte holoclone population after siRNA mediated knockdown of DAXX at number of chromosome ends. Prolonged depletion of DAXX also caused an increase in telomere‐to‐telomere fusions. A similarly dramatic loss in telomere length was seen in these cells after knockdown of EHMT2

Realizing a Deterministic Source of Multipartite-Entangled Photonic Qubits

Sources of entangled electromagnetic radiation are a cornerstone in quantum information processing and offer unique opportunities for the study of quantum many-body physics in a controlled experimental setting. While multi-mode entangled states of radiation have been generated in various platforms, all previous experiments are either probabilistic or restricted to generate specific types of states with a moderate entanglement length. Here, we demonstrate the fully deterministic generation of purely photonic entangled states such as the cluster, GHZ, and W state by sequentially emitting microwave photons from a controlled auxiliary system into a waveguide. We tomographically reconstruct the entire quantum many-body state for up to $N=4$ photonic modes and infer the quantum state for even larger $N$ from process tomography. We estimate that localizable entanglement persists over a distance of approximately ten photonic qubits, outperforming any previous deterministic scheme

Telomere length predicts for outcome to FCR chemotherapy in CLL

We have previously shown that dividing patients with CLL into those with telomeres inside the fusogenic range (TL-IFR) and outside the fusogenic range (TL-OFR) is powerful prognostic tool. Here, we used a high-throughput version of the assay (HT-STELA) to establish whether telomere length could predict for outcome to fludarabine, cyclophosphamide, rituximab (FCR)-based treatment using samples collected from two concurrent phase II studies, ARCTIC and ADMIRE (n = 260). In univariate analysis, patients with TL-IFR had reduced progression-free survival (PFS) (P < 0.0001; HR = 2.17) and shorter overall survival (OS) (P = 0.0002; HR = 2.44). Bifurcation of the IGHV-mutated and unmutated subsets according to telomere length revealed that patients with TL-IFR in each subset had shorter PFS (HR = 4.35 and HR = 1.48, respectively) and shorter OS (HR = 3.81 and HR = 2.18, respectively). In addition, the OS of the TL-OFR and TL-IFR subsets were not significantly altered by IGHV mutation status (P = 0.61; HR = 1.24 and P = 0.41; HR = 1.47, respectively). In multivariate modeling, telomere length was the dominant co-variable for PFS (P = 0.0002; HR = 1.85) and OS (P = 0.05; HR = 1.61). Taken together, our data suggest that HT-STELA is a powerful predictor of outcome to FCR-based treatment and could be used to inform the design of future risk-adapted clinical trials

Parallelized and Vectorized Tracking Using Kalman Filters with CMS Detector Geometry and Events

The High-Luminosity Large Hadron Collider at CERN will be characterized by greater pileup of events and higher occupancy, making the track reconstruction even more computationally demanding. Existing algorithms at the LHC are based on Kalman filter techniques with proven excellent physics performance under a variety of conditions. Starting in 2014, we have been developing Kalman-filter-based methods for track finding and fitting adapted for many-core SIMD processors that are becoming dominant in high-performance systems. This paper summarizes the latest extensions to our software that allow it to run on the realistic CMS-2017 tracker geometry using CMSSW-generated events, including pileup. The reconstructed tracks can be validated against either the CMSSW simulation that generated the hits, or the CMSSW reconstruction of the tracks. In general, the code's computational performance has continued to improve while the above capabilities were being added. We demonstrate that the present Kalman filter implementation is able to reconstruct events with comparable physics performance to CMSSW, while providing generally better computational performance. Further plans for advancing the software are discussed

The Nucleotide Excision Repair Pathway Protects Borrelia burgdorferi from Nitrosative Stress in Ixodes scapularis Ticks

The Lyme disease spirochete Borrelia burgdorferi encounters a wide range of environmental conditions as it cycles between ticks of the genus Ixodes and its various mammalian hosts. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are potent antimicrobial molecules generated during the innate immune response to infection, however, it is unclear whether ROS and RNS pose a significant challenge to B. burgdorferi in vivo. In this study, we screened a library of B. burgdorferi strains with mutations in DNA repair genes for increased susceptibility to ROS or RNS in vitro. Strains with mutations in the methyl-directed mismatch repair (MMR) gene mutS1 are hypersensitive to killing by ROS, while strains lacking the nucleotide excision repair (NER) gene uvrB show increased susceptibility to both ROS and RNS. Therefore, mutS1-deficient and uvrB-deficient strains were compared for their ability to complete their infectious cycle in Swiss Webster mice and I. scapularis ticks to help identify sites of oxidative and nitrosative stresses encountered by B. burgdorferi in vivo. Both mutS1¬ and uvrB were dispensable for infection of mice, while uvrB promoted the survival of spirochetes in I. scapularis ticks. The decreased survival of uvrB-deficient B. burgdorferi was associated with the generation of RNS in I. scapularis midguts and salivary glands during feeding. Collectively, these data suggest that B. burgdorferi must withstand cytotoxic levels of RNS produced during infection of I. scapularis ticks