The Papua New Guinea national health and HIV research agenda.

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Dependence of antibody gene diversification on uracil excision

Activation-induced deaminase (AID) catalyses deamination of deoxycytidine to deoxyuridine within immunoglobulin loci, triggering pathways of antibody diversification that are largely dependent on uracil-DNA glycosylase (uracil-N-glycolase [UNG]). Surprisingly efficient class switch recombination is restored to ung−/− B cells through retroviral delivery of active-site mutants of UNG, stimulating discussion about the need for UNG's uracil-excision activity. In this study, however, we find that even with the overexpression achieved through retroviral delivery, switching is only mediated by UNG mutants that retain detectable excision activity, with this switching being especially dependent on MSH2. In contrast to their potentiation of switching, low-activity UNGs are relatively ineffective in restoring transversion mutations at C:G pairs during hypermutation, or in restoring gene conversion in stably transfected DT40 cells. The results indicate that UNG does, indeed, act through uracil excision, but suggest that, in the presence of MSH2, efficient switch recombination requires base excision at only a small proportion of the AID-generated uracils in the S region. Interestingly, enforced expression of thymine-DNA glycosylase (which can excise U from U:G mispairs) does not (unlike enforced UNG or SMUG1 expression) potentiate efficient switching, which is consistent with a need either for specific recruitment of the uracil-excision enzyme or for it to be active on single-stranded DNA

H0LiCOW XII. Lens mass model of WFI2033-4723 and blind measurement of its time-delay distance and H0H_0

We present the lens mass model of the quadruply-imaged gravitationally lensed quasar WFI2033-4723, and perform a blind cosmographical analysis based on this system. Our analysis combines (1) time-delay measurements from 14 years of data obtained by the COSmological MOnitoring of GRAvItational Lenses (COSMOGRAIL) collaboration, (2) high-resolution $\textit{Hubble Space Telescope}$ imaging, (3) a measurement of the velocity dispersion of the lens galaxy based on ESO-MUSE data, and (4) multi-band, wide-field imaging and spectroscopy characterizing the lens environment. We account for all known sources of systematics, including the influence of nearby perturbers and complex line-of-sight structure, as well as the parametrization of the light and mass profiles of the lensing galaxy. After unblinding, we determine the effective time-delay distance to be $4784_{-248}^{+399}~\mathrm{Mpc}$, an average precision of $6.6\%$. This translates to a Hubble constant $H_{0} = 71.6_{-4.9}^{+3.8}~\mathrm{km~s^{-1}~Mpc^{-1}}$, assuming a flat $\Lambda$CDM cosmology with a uniform prior on $\Omega_\mathrm{m}$ in the range [0.05, 0.5]. This work is part of the $H_0$ Lenses in COSMOGRAIL's Wellspring (H0LiCOW) collaboration, and the full time-delay cosmography results from a total of six strongly lensed systems are presented in a companion paper (H0LiCOW XIII).Comment: Version accepted by MNRAS. 29 pages including appendix, 17 figures, 6 tables. arXiv admin note: text overlap with arXiv:1607.0140

Storylines of UK drought based on the 2010–2012 event

Spatially extensive multi-year hydrological droughts cause significant environmental stress. The UK is expected to remain vulnerable to future multi-year droughts under climate change. Existing approaches to quantify hydrological impacts of climate change often rely solely on global climate model (GCM) projections following different emission scenarios. This may miss out low-probability events with significant impacts. As a means of exploring such events, physical climate storyline approaches aim to quantify physically coherent articulations of how observed events could hypothetically have unfolded in alternative ways. This study uses the 2010–2012 drought, the most recent period of severe hydrological drought in the UK, as a basis and analyses storylines based on changes to (1) precondition severity, (2) temporal drought sequence, and (3) climate change. Evidence from multiple storylines shows that the maximum intensity, mean deficit, and duration of the 2010–2012 drought were highly influenced by its meteorological preconditions prior to drought inception, particularly for northern catchments at shorter timescales. The influence of progressively drier preconditions reflects both the spatial variation in drought preconditions and the role of physical catchment characteristics, particularly hydrogeology in the propagation of multi-year droughts. There are two plausible storylines of an additional dry year with dry winter conditions repeated either before the observed drought or replacing the observed dramatic drought termination confirm the vulnerability of UK catchments to a “third dry winter” storyline. Applying the UKCP18 climate projections, we find that drought conditions worsen with global warming with a mitigation of drought conditions by wetter winters in northern catchments at high warming levels. Comparison of the storylines with a benchmark drought (1975–1976) and a protracted multi-year drought (1989–1993) shows that, for each storyline (including the climate change storylines), drought conditions could have matched and exceeded those experienced during the past droughts at catchments across the UK, particularly for southern catchments. The construction of storylines based on observed events can complement existing methods to stress test UK catchments against plausible unrealised droughts

A Highly Magnified Gravitationally Lensed Red QSO at z = 2.5 with a Significant Flux Ratio Anomaly

We present the discovery of a gravitationally lensed dust-reddened QSO at z = 2.517, identified in a survey for QSOs by infrared selection. Hubble Space Telescope imaging reveals a quadruply lensed system in a cusp configuration, with a maximum image separation of ~1.8\arcsec. We find that compared to the central image of the cusp, the neighboring brightest image is anomalous by a factor of ~ 7 - 10, which is the largest flux anomaly measured to date in a lensed QSO. Incorporating high-resolution Jansky Very Large Array radio imaging and sub-mm imaging with the Atacama Large (sub-)Millimetre Array, we conclude that a low-mass perturber is the most likely explanation for the anomaly. The optical through near-infrared spectrum reveals that the QSO is moderately reddened with E(B - V) = 0.7 - 0.9. We see an upturn in the ultraviolet spectrum due to ~ 1% of the intrinsic emission being leaked back into the line of sight, which suggests that the reddening is intrinsic and not due to the lens. The QSO may have an Eddington ratio as high as L/L_Edd ~ 0.2. Consistent with previous red QSO samples, this source exhibits outflows in its spectrum as well as morphological properties suggestive of it being in a merger-driven transitional phase. We find a host-galaxy stellar mass of log M_*/M_Sun = 11.4, which is higher than the local M_BH vs. M_* relation, but consistent with other high redshift QSOs. When de-magnified, this QSO is at the knee of the luminosity function, allowing for the detailed study of a more typical moderate-luminosity infrared-selected QSO at high redshift.Comment: Accepted for publication in ApJ; 29 pages, 18 figures, 8 tables. arXiv admin note: text overlap with arXiv:1807.0543

Comparison of magnetic resonance imaging and computed tomography for breast target volume delineation in prone and supine positions

Purpose To\ua0determine whether T2-weighted MRI improves seroma cavity (SC) and whole breast (WB) interobserver conformity for radiation therapy purposes, compared with the gold standard of CT, both in the prone and supine positions. Methods and Materials Eleven observers (2 radiologists and 9 radiation oncologists) delineated SC and WB clinical target volumes (CTVs) on T2-weighted MRI and CT supine and prone scans (4 scans per patient) for 33 patient datasets. Individual observer's volumes were compared using the Dice similarity coefficient, volume overlap index, center of mass shift, and Hausdorff distances. An average cavity visualization score was also determined. Results Imaging modality did not affect interobserver variation for WB CTVs. Prone WB CTVs were larger in volume and more conformal than supine CTVs (on both MRI and CT). Seroma cavity volumes were larger on CT than on MRI. Seroma cavity volumes proved to be comparable in interobserver conformity in both modalities (volume overlap index of 0.57\ua0(95% Confidence Interval (CI) 0.54-0.60) for CT supine and 0.52\ua0(95% CI 0.48-0.56) for MRI supine, 0.56\ua0(95% CI 0.53-0.59) for CT prone and 0.55\ua0(95% CI 0.51-0.59) for MRI prone); however, after registering modalities together the intermodality variation (Dice similarity coefficient of 0.41\ua0(95% CI 0.36-0.46) for supine and 0.38\ua0(0.34-0.42) for prone) was larger than the interobserver variability for SC, despite the location typically remaining constant. Conclusions Magnetic resonance imaging interobserver variation was comparable to CT for the WB CTV and SC delineation, in both prone and supine positions. Although the cavity visualization score and interobserver concordance was not significantly higher for MRI than for CT, the SCs were smaller on MRI, potentially owing to clearer SC definition, especially on T2-weighted MR images

Is telomere length socially patterned? Evidence from the West of Scotland Twenty-07 study

Lower socioeconomic status (SES) is strongly associated with an increased risk of morbidity and premature mortality, but it is not known if the same is true for telomere length, a marker often used to assess biological ageing. The West of Scotland Twenty-07 Study was used to investigate this and consists of three cohorts aged approximately 35 (N = 775), 55 (N = 866) and 75 years (N = 544) at the time of telomere length measurement. Four sets of measurements of SES were investigated: those collected contemporaneously with telomere length assessment, educational markers, SES in childhood and SES over the preceding twenty years. We found mixed evidence for an association between SES and telomere length. In 35-year-olds, many of the education and childhood SES measures were associated with telomere length, i.e. those in poorer circumstances had shorter telomeres, as was intergenerational social mobility, but not accumulated disadvantage. A crude estimate showed that, at the same chronological age, social renters, for example, were nine years (biologically) older than home owners. No consistent associations were apparent in those aged 55 or 75. There is evidence of an association between SES and telomere length, but only in younger adults and most strongly using education and childhood SES measures. These results may reflect that childhood is a sensitive period for telomere attrition. The cohort differences are possibly the result of survival bias suppressing the SES-telomere association; cohort effects with regard different experiences of SES; or telomere possibly being a less effective marker of biological ageing at older ages

Risk factors to predict the incidence of surgical adverse events following open or laparoscopic surgery for apparent early stage endometrial cancer: Results from a randomised controlled trial

Aims: To identify risk factors for major Adverse Events (AEs) and to develop a nomogram to predict the probability of such AEs in individual patients who have surgery for apparent early stage endometrial cancer. Methods: We used data from 753 patients who were randomized to either total laparoscopic hysterectomy or total abdominal hysterectomy in the LACE trial. Serious adverse events that prolonged hospital stay or postoperative adverse events (using common terminology criteria 3+, CTCAE V3) were considered major AEs. We analyzed pre-surgical characteristics that were associated with the risk of developing major AEs by multivariate logistic regression. We identified a parsimonious model by backward stepwise logistic regression. The six most significant or clinically important variables were included in the nomogram to predict the risk of major AEs within 6 weeks of surgery and the nomogram was internally validated. Results: Overall, 132 (17.5%) patients had at least one major AE. An open surgical approach (laparotomy), higher Charlson’s medical co-morbidities score, moderately differentiated tumours on curettings, higher baseline ECOG score, higher body mass index and low haemoglobin levels were associated with AE and were used in the nomogram. The bootstrap corrected concordance index of the nomogram was 0.63 and it showed good calibration. Conclusions: Six pre-surgical factors independently predicted the risk of major AEs. This research might form the basis to develop risk reduction strategies to minimize the risk of AEs among patients undergoing surgery for apparent early stage endometrial cancer

Polyurethane scaffold with in situ swelling capacity for nucleus pulposus replacement

Nucleus pulposus (NP) replacement offers a minimally invasive alternative to spinal fusion or total disc replacement for the treatment of intervertebral disc (IVD) degeneration. This study aimed to develop a cytocompatible {NP} replacement material, which is feasible for non-invasive delivery and tunable design, and allows immediate mechanical restoration of the IVD. A bi-phasic polyurethane scaffold was fabricated consisting of a core material with rapid swelling property and a flexible electrospun envelope. The scaffold was assessed in a bovine whole {IVD} organ culture model under dynamic load for 14 days. Nucleotomy was achieved by incision through the endplate without damaging the annulus fibrosus. After implantation of the scaffold and in situ swelling, the dynamic compressive stiffness and disc height were restored immediately. The scaffold also showed favorable cytocompatibility for native disc cells. Implantation of the scaffold in a partially nucleotomized {IVD} down-regulated catabolic gene expression, increased proteoglycan and type {II} collagen intensity and decreased type I collagen intensity in remaining {NP} tissue, indicating potential to retard degeneration and preserve the {IVD} cell phenotype. The scaffold can be delivered in a minimally invasive manner, and the geometry of the scaffold post-hydration is tunable by adjusting the core material, which allows individualized design. Keywords : Intervertebral disc degeneratio