The Sleeping Monster: NuSTAR observations of SGR 1806-20, 11 years after the Giant Flare

We report the analysis of 5 NuSTAR observations of SGR 1806-20 spread over a year from April 2015 to April 2016, more than 11 years following its Giant Flare (GF) of 2004. The source spin frequency during the NuSTAR observations follows a linear trend with a frequency derivative $\dot{\nu}=(-1.25\pm0.03)\times10^{-12}$ Hz s$^{-1}$, implying a surface dipole equatorial magnetic field $B\approx7.7\times10^{14}$ G. Thus, SGR 1806-20 has finally returned to its historical minimum torque level measured between 1993 and 1998. The source showed strong timing noise for at least 12 years starting in 2000, with $\dot{\nu}$ increasing one order of magnitude between 2005 and 2011, following its 2004 major bursting episode and GF. SGR 1806-20 has not shown strong transient activity since 2009 and we do not find short bursts in the NuSTAR data. The pulse profile is complex with a pulsed fraction of $\sim8\%$ with no indication of energy dependence. The NuSTAR spectra are well fit with an absorbed blackbody, $kT=0.62\pm0.06$ keV, plus a power-law, $\Gamma=1.33\pm0.03$. We find no evidence for variability among the 5 observations, indicating that SGR 1806-20 has reached a persistent and potentially its quiescent X-ray flux level after its 2004 major bursting episode. Extrapolating the NuSTAR model to lower energies, we find that the 0.5-10 keV flux decay follows an exponential form with a characteristic timescale $\tau=543\pm75$ days. Interestingly, the NuSTAR flux in this energy range is a factor of $\sim2$ weaker than the long-term average measured between 1993 and 2003, a behavior also exhibited in SGR $1900+14$. We discuss our findings in the context of the magnetar model.Comment: 10 pages, 5 figures, accepted for publication in Ap

PEPFAR Public Health Evaluation -Care and Support -Phase I Uganda

Phase 1, a survey of 120 care facilities in Kenya and Uganda, found that over 90% of facilities provided some level of clinical, psychological,and preventive care. Pain control was very limited with paracetamol often the only analgesic. In focus group discussions, patients appreciated free care and positive attitudes from staff, but said that services would be improved by more staff, shorter queues, and reliable drug supplies

PEPFAR Public Health Evaluation - Care and Support - Phase 2 Kenya

Phase 2 consisted of a longitudinal cohort study to measure patient-reported outcomes of care and support, a costing survey, and qualitative interviews to understand patient and carer experiences

PEPFAR Public Health Evaluation-Care and Support -Phase I Kenya

Phase 1, a survey of 120 care facilities in Kenya and Uganda, found that over 90% of facilities provided some level of clinical, psychological,and preventive care. Pain control was very limited with paracetamol often the only analgesic. In focus group discussions, patients appreciated free care and positive attitudes from staff, but said that services would be improved by more staff, shorter queues, and reliable drug supplies

PEPFAR Public Health Evaluation - Care and Support - Phase 2 Uganda

Phase 2 consisted of a longitudinal cohort study to measure patient-reported outcomes of care and support, a costing survey, and qualitative interviews to understand patient and carer experiences

Functional recovery: A mixed methods study of the specific variables within a post-hospital inter-disciplinary brain injury rehabilitation - residential program

The mixed methods explanatory design study examined specific constructs of Post Hospital Interdisciplinary Brain Injury Rehabilitation – Residential (PHIDBIR-R) programs that positively influenced gains in function. The investigation involved exploring the phenomenon of individuals’ experiences while participating in a PHIDBIR-R program as part of recovery from brain injury. The study’ primary purpose was to understand individuals who make the greatest gains in function while participating in these programs, as measured by the Mayo-Portland Adaptability Inventory-4 (MPAI-4) change scores from admission to discharge and what are the components of these programs that may contribute to individuals’ gains in function. Data were collected via repeated measurement of the MPAI-4 to determine top performers and characteristics of those performers, and to understand which components of the MPAI-4’s 29 areas of measurement most contributed to their change scores. Next, semi-structured interviews with 10 of the top performers was completed. Inclusion criteria included: sustained a traumatic brain injury; aged 18 or older; be identified as one of the top performers; agree to participate. Numerous procedures enhanced trustworthiness, including peer reviewers, member checking, and memo-writing. Data were analyzed using constant comparison procedures. Thirteen themes within four major categories were reflected in the data. Themes reflect participants’ understanding of crisis, crisis counseling, crisis supervision, and clinical supervision. The results provided a cogent framework for PHIDBIR-R program development, stakeholder program selection and advocate and legislator consideration for program in inclusion for optimal outcome. Contributions to the literature and future research recommendations are also explored

Transcripts and transcription at an estrogen regulated enhancer of CCND1

Enhancer sequences have been well documented for over a decade, and whilst their function as gene expression regulators is widely appreciated, the mechanism by which they exert their control is not yet understood. Transcription of enhancer regions is linked to enhancer activity, but it is unclear if the enhancer RNA (eRNA) transcript is necessary for cis regulation or merely a by-product of transcription. Through RNA-Sequencing of estradiol (E2) treated MCF7 cells and the use of publicly available sequencing data, we have identified a region neighbouring the CCND1 gene locus which contains at least one enhancer whose bi-directional transcription is upregulated with E2 treatment in estrogen receptor (ER) positive breast cancer cell lines. This enhancer region is known to have cis-regulatory effects on the neighbouring CCND1 gene, whose amplification and overexpression is linked to a poorer prognosis and treatment resistance in ER positive breast cancers. To determine the role of the bi-directionally transcribed eRNAs arising from this enhancer region, we have identified their cellular location and used appropriate siRNA techniques to knockdown both transcripts. We show that siRNA knockdown of either eRNA does not affect regulation of the neighbouring CCND1 gene but premature termination of transcription of the antisense enhancer not only knocks-down the eRNA but also down regulates CCND1 and may have a more global effect on ER regulation. We discuss the challenges encountered in CRISPR/Cas9 mediated knock-in of a polyadenylation signal and compare the resultant effects of knockdown of these eRNA with the premature transcription termination of the enhancer from which they arise and discuss these findings in the context of alternative possible roles for eRNAs.Open Acces

TP53 regulates miRNA association with AGO2 to remodel the miRNA-mRNA interaction network

DNA damage activates TP53-regulated surveillance mechanisms that are crucial in suppressing tumorigenesis. TP53 orchestrates these responses directly by transcriptionally modulating genes, including microRNAs (miRNAs), and by regulating miRNA biogenesis through interacting with the DROSHA complex. However, whether the association between miRNAs and AGO2 is regulated following DNA damage is not yet known. Here, we show that, following DNA damage, TP53 interacts with AGO2 to induce or reduce AGO2's association of a subset of miRNAs, including multiple let-7 family members. Furthermore, we show that specific mutations in TP53 decrease rather than increase the association of let-7 family miRNAs, reducing their activity without preventing TP53 from interacting with AGO2. This is consistent with the oncogenic properties of these mutants. Using AGO2 RIP-seq and PAR-CLIP-seq, we show that the DNA damage–induced increase in binding of let-7 family members to the RISC complex is functional. We unambiguously determine the global miRNA–mRNA interaction networks involved in the DNA damage response, validating them through the identification of miRNA-target chimeras formed by endogenous ligation reactions. We find that the target complementary region of the let-7 seed tends to have highly fixed positions and more variable ones. Additionally, we observe that miRNAs, whose cellular abundance or differential association with AGO2 is regulated by TP53, are involved in an intricate network of regulatory feedback and feedforward circuits. TP53-mediated regulation of AGO2–miRNA interaction represents a new mechanism of miRNA regulation in carcinogenesis

Quality of life and wellbeing among HIV outpatients in East Africa: a multicentre observational study

BACKGROUND: Global health investment has reduced HIV mortality and transmission. However, little is known of patient-reported outcomes alongside ART rollout. This study aimed to measure wellbeing using patient-reported outcome measures (PROMS) among outpatients at PEPFAR-funded facilities. METHODS: In a multicentre 2 country cross-sectional study, adults attending 12 facilities in Kenya and Uganda gave self-reported data on quality of life (physical and mental wellbeing dimensions), functional and a measure of multidimensional problems (physical, psychological, social and spiritual). RESULTS: Among the 1,337 participants, multidimensional problems were more common in psychological, spiritual and social domains than in physical. In multivariable analysis using GEE to adjust for facility effect, the mental health subscale of quality of life was lower for people with limited functional status (B = -5.27, 95% CI -5.99, 1. -4.56 p < 0.001) and higher for wealthier people (B = 0.91, 95% CI 0.48, 1.33, p < 0.001). The physical health subscale of quality of life was lower for those with limited functional status (B = -8.58, 95% CI -9.46 to -7.70, p < 0.001) and those who had a caregiver present (B = -1.97, 95% CI -3.72 to -0.23, p = 0.027), higher for wealthier people (B = 1.14, 95% CI 0.65, 1.64, p < 0.001), and positively associated with CD4 count (B = 1.61, 95% CI 1.08-2.14, p < 0.001). Multidimensional problems were more burdensome for people with limited functional status (B = -2.06, 95% CI -2.46 to -1.66, p < 0.001), and less burdensome with more education (B = 0.63, 95% CI 0.25-1.00, p = 0.001) or ART use (B = 0.94, 95% CI 0.34-1.53, p = 0.002). CONCLUSIONS: Multidimensional problems are highly prevalent, and worse with declining function. Importantly, ART use does not appear to be protective for self-reported physical and mental dimensions of quality of life. Assessment and management of self-reported wellbeing must form part of HIV care and treatment services to ensure maximum benefit from ART investment