Should we screen for the sexually-transmitted infection Mycoplasma genitalium? Evidence synthesis using a transmission-dynamic model

There is increasing concern about Mycoplasma genitalium as a cause of urethritis, cervicitis, pelvic inflammatory disease (PID), infertility and ectopic pregnancy. Commercial nucleic acid amplification tests (NAATs) are becoming available, and their use in screening for M. genitalium has been advocated, but M. genitalium's natural history is poorly-understood, making screening's effectiveness unclear. We used a transmission-dynamic compartmental model to synthesise evidence from surveillance data and epidemiological and behavioural studies to better understand M. genitalium's natural history, and then examined the effects of implementing NAAT testing. Introducing NAAT testing initially increases diagnoses, by finding a larger proportion of infections; subsequently the diagnosis rate falls, due to reduced incidence. Testing only symptomatic patients finds relatively little infection in women, as a large proportion is asymptomatic. Testing both symptomatic and asymptomatic patients has a much larger impact and reduces cumulative PID incidence in women due to M. genitalium by 31.1% (95% range:13.0%-52.0%) over 20 years. However, there is important uncertainty in M. genitalium's natural history parameters, leading to uncertainty in the absolute reduction in PID and sequelae. Empirical work is required to improve understanding of key aspects of M. genitalium's natural history before it will be possible to determine the effectiveness of screening

Contaminants in Commercial Preparations of ‘Purified’ Small Leucine-Rich Proteoglycans May Distort Mechanistic Studies

This paper reports the perplexing results that came about because of seriously impure commercially available reagents. Commercial reagents and chemicals are routinely ordered by scientists and are expected to have been rigorously assessed for their purity. Unfortunately, we found this assumption to be risky. Extensive work was carried out within our laboratory using commercially-sourced preparations of the small leucine-rich proteoglycans, decorin and biglycan, to investigate their influence on nerve cell growth. Unusual results compelled us to analyse the composition and purity of both preparations of these proteoglycans using both mass spectrometry and Western blotting, with and without various enzymatic deglycosylations. Commercial ‘decorin’ and ‘biglycan’ were found to contain a mixture of proteoglycans including not only both decorin and biglycan but also fibromodulin and aggrecan. The unexpected effects of ‘decorin’ and ‘biglycan’ on nerve cell growth could be explained by these impurities. Decorin and biglycan contain either chondroitin or dermatan sulphate glycosaminoglycan chains whilst fibromodulin only contains keratan sulphate and the large (>2,500 kDa), highly glycosylated aggrecan, contains both keratan and chondroitin sulphate. The different structure, molecular weights and composition of these impurities significantly affected our work and any conclusions that could be made. These findings beg the question as to whether scientists need to verify the purity of each commercially obtained reagent used in their experiments. The implications of these findings are vast, since the effects of these impurities may already have led to inaccurate conclusions and reports in the literature with concomitant loss of researchers’ funds and time

Degradation of a quantum directional reference frame as a random walk

We investigate if the degradation of a quantum directional reference frame through repeated use can be modeled as a classical direction undergoing a random walk on a sphere. We demonstrate that the behaviour of the fidelity for a degrading quantum directional reference frame, defined as the average probability of correctly determining the orientation of a test system, can be fit precisely using such a model. Physically, the mechanism for the random walk is the uncontrollable back-action on the reference frame due to its use in a measurement of the direction of another system. However, we find that the magnitude of the step size of this random walk is not given by our classical model and must be determined from the full quantum description.Comment: 5 pages, no figures. Comments are welcome. v2: several changes to clarify the key results. v3: journal reference added, acknowledgements and references update

Trust and transparency in times of crisis: Results from an online survey during the first wave (April 2020) of the COVID-19 epidemic in the UK

BACKGROUND: The success of a government's COVID-19 control strategy relies on public trust and broad acceptance of response measures. We investigated public perceptions of the UK government's COVID-19 response, focusing on the relationship between trust and perceived transparency, during the first wave (April 2020) of the COVID-19 pandemic in the United Kingdom. METHODS: Anonymous survey data were collected (2020-04-06 to 2020-04-22) from 9,322 respondents, aged 20+ using an online questionnaire shared primarily through Facebook. We took an embedded-mixed-methods approach to data analysis. Missing data were imputed via multiple imputation. Binomial & multinomial logistic regression were used to detect associations between demographic characteristics and perceptions or opinions of the UK government's response to COVID-19. Structural topic modelling (STM), qualitative thematic coding of sub-sets of responses were then used to perform a thematic analysis of topics that were of interest to key demographic groups. RESULTS: Most respondents (95.1%) supported government enforcement of behaviour change. While 52.1% of respondents thought the government was making good decisions, differences were apparent across demographic groups, for example respondents from Scotland had lower odds of responding positively than respondents in London. Higher educational levels saw decreasing odds of having a positive opinion of the government response and decreasing household income associated with decreasing positive opinion. Of respondents who thought the government was not making good decisions 60% believed the economy was being prioritised over people and their health. Positive views on government decision-making were associated with positive views on government transparency about the COVID-19 response. Qualitative analysis about perceptions of government transparency highlighted five key themes: (1) the justification of opacity due to the condition of crisis, (2) generalised mistrust of politics, (3) concerns about the role of scientific evidence, (4) quality of government communication and (5) questions about political decision-making processes. CONCLUSION: Our study suggests that trust is not homogenous across communities, and that generalised mistrust, concerns about the transparent use and communication of evidence and insights into decision-making processes can affect perceptions of the government's pandemic response. We recommend targeted community engagement, tailored to the experiences of different groups and a new focus on accountability and openness around how decisions are made in the response to the UK COVID-19 pandemic

Clinical signs of trachoma are prevalent among Solomon Islanders who have no persistent markers of prior infection with Chlamydia trachomatis.

Background: The low population-prevalence of trachomatous trichiasis and high prevalence of trachomatous inflammation-follicular (TF) provide contradictory estimates of the magnitude of the public health threat from trachoma in the Solomon Islands. Improved characterisation of the biology of trachoma in the region may support policy makers as they decide what interventions are required. Here, age-specific profiles of anti-Pgp3 antibodies and conjunctival scarring were examined to determine whether there is evidence of ongoing transmission and pathology from ocularChlamydia trachomatis (Ct)infection.Methods:A total of 1511 individuals aged ≥1 year were enrolled from randomly selected households in 13 villages in which >10% of children aged 1-9 years had TF prior to a single round of azithromycin mass drug administration undertaken six months previously. Blood was collected to be screened for antibodies to theCtantigen Pgp3. Tarsal conjunctival photographs were collected for analysis of scarring severity.Results:Anti-Pgp3 seropositivity was 18% in 1-9 year olds, sharply increasing around the age of sexual debut to reach 69% in those over 25 years. Anti-Pgp3 seropositivity did not increase significantly between the ages of 1-9 years and was not associated with TF (p=0.581) or scarring in children (p=0.472). Conjunctival scars were visible in 13.1% of photographs. Mild (p<0.0001) but not severe (p=0.149) scars increased in prevalence with age.Conclusions:Neither conjunctival scars nor lymphoid follicles were associated with antibodies toCt,suggesting that they are unlikely to be a direct result of ocularCtinfection.Clinical signs of trachoma were prevalent in this population but were not indicative of the underlying rates ofCtinfection. The current World Health Organization guidelines for trachoma elimination indicated that this population should receive intervention with mass distribution of antibiotics, but the data presented here suggest that this may not have been appropriate

Photoproduction of meson pairs: First measurement of the polarization observable I^s

The polarization observable I^s, a feature exclusive to the acoplanar kinematics of multi-meson final states produced via linearly polarized photons, has been measured for the first time. Results for the reaction g p -> p pi0 eta are presented for incoming photon energies between 970 MeV and 1650 MeV along with the beam asymmetry I^c. The comparably large asymmetries demonstrate a high sensitivity of I^s to the dynamics of the reaction. Fits using Bonn-Gatchina partial wave analysis demonstrate that the new polarization observables carry significant information on the contributing partial waves.Comment: 11 pages, 6 figures, v2 to appear in Phys. Lett.

Mach's Principle and the Origin of Inertia

The current status of Mach's principle is discussed within the context of general relativity. The inertial properties of a particle are determined by its mass and spin, since these characterize the irreducible unitary representations of the inhomogeneous Lorentz group. The origin of the inertia of mass and intrinsic spin are discussed and the inertia of intrinsic spin is studied via the coupling of intrinsic spin with rotation. The implications of spin-rotation coupling and the possibility of history dependence and nonlocality in relativistic physics are briefly mentioned.Comment: 14 pages. Dedicated to Carl Brans in honor of his 80th birthday. To appear in the Brans Festschrift; v2: typo corrected, published in: At the Frontier of Spacetime, edited by T. Asselmeyer-Maluga (Springer, 2016), Chapter 10, pp. 177-18

The structure of the PapD-PapGII pilin complex reveals an open and flexible P5 pocket

P pili are hairlike polymeric structures that mediate binding of uropathogenic Escherichia coli to the surface of the kidney via the PapG adhesin at their tips. PapG is composed of two domains: a lectin domain at the tip of the pilus followed by a pilin domain that comprises the initial polymerizing subunit of the 1,000-plus-subunit heteropolymeric pilus fiber. Prior to assembly, periplasmic pilin domains bind to a chaperone, PapD. PapD mediates donor strand complementation, in which a beta strand of PapD temporarily completes the pilin domain's fold, preventing premature, nonproductive interactions with other pilin subunits and facilitating subunit folding. Chaperone-subunit complexes are delivered to the outer membrane usher where donor strand exchange (DSE) replaces PapD's donated beta strand with an amino-terminal extension on the next incoming pilin subunit. This occurs via a zip-in-zip-out mechanism that initiates at a relatively accessible hydrophobic space termed the P5 pocket on the terminally incorporated pilus subunit. Here, we solve the structure of PapD in complex with the pilin domain of isoform II of PapG (PapGIIp). Our data revealed that PapGIIp adopts an immunoglobulin fold with a missing seventh strand, complemented in parallel by the G1 PapD strand, typical of pilin subunits. Comparisons with other chaperone-pilin complexes indicated that the interactive surfaces are highly conserved. Interestingly, the PapGIIp P5 pocket was in an open conformation, which, as molecular dynamics simulations revealed, switches between an open and a closed conformation due to the flexibility of the surrounding loops. Our study reveals the structural details of the DSE mechanism

UNCLES: Method for the identification of genes differentially consistently co-expressed in a specific subset of datasets

Background: Collective analysis of the increasingly emerging gene expression datasets are required. The recently proposed binarisation of consensus partition matrices (Bi-CoPaM) method can combine clustering results from multiple datasets to identify the subsets of genes which are consistently co-expressed in all of the provided datasets in a tuneable manner. However, results validation and parameter setting are issues that complicate the design of such methods. Moreover, although it is a common practice to test methods by application to synthetic datasets, the mathematical models used to synthesise such datasets are usually based on approximations which may not always be sufficiently representative of real datasets. Results: Here, we propose an unsupervised method for the unification of clustering results from multiple datasets using external specifications (UNCLES). This method has the ability to identify the subsets of genes consistently co-expressed in a subset of datasets while being poorly co-expressed in another subset of datasets, and to identify the subsets of genes consistently co-expressed in all given datasets. We also propose the M-N scatter plots validation technique and adopt it to set the parameters of UNCLES, such as the number of clusters, automatically. Additionally, we propose an approach for the synthesis of gene expression datasets using real data profiles in a way which combines the ground-truth-knowledge of synthetic data and the realistic expression values of real data, and therefore overcomes the problem of faithfulness of synthetic expression data modelling. By application to those datasets, we validate UNCLES while comparing it with other conventional clustering methods, and of particular relevance, biclustering methods. We further validate UNCLES by application to a set of 14 real genome-wide yeast datasets as it produces focused clusters that conform well to known biological facts. Furthermore, in-silico-based hypotheses regarding the function of a few previously unknown genes in those focused clusters are drawn. Conclusions: The UNCLES method, the M-N scatter plots technique, and the expression data synthesis approach will have wide application for the comprehensive analysis of genomic and other sources of multiple complex biological datasets. Moreover, the derived in-silico-based biological hypotheses represent subjects for future functional studies.The National Institute for Health Research (NIHR) under its Programme Grants for Applied Research Programme (Grant Reference Number RP-PG-0310-1004)