Swift Observations of GRB 050603: An afterglow with a steep late time decay slope

We report the results of Swift observations of the Gamma Ray Burst GRB 050603. With a V magnitude V=18.2 about 10 hours after the burst the optical afterglow was the brightest so far detected by Swift and one of the brightest optical afterglows ever seen. The Burst Alert Telescope (BAT) light curves show three fast-rise-exponential-decay spikes with $T_{90}$=12s and a fluence of 7.6$\times 10^{-6}$ ergs cm$^{-2}$ in the 15-150 keV band. With an $E_{\rm \gamma, iso} = 1.26 \times 10^{54}$ ergs it was also one of the most energetic bursts of all times. The Swift spacecraft began observing of the afterglow with the narrow-field instruments about 10 hours after the detection of the burst. The burst was bright enough to be detected by the Swift UV/Optical telescope (UVOT) for almost 3 days and by the X-ray Telescope (XRT) for a week after the burst. The X-ray light curve shows a rapidly fading afterglow with a decay index $\alpha$=1.76$^{+0.15}_{-0.07}$. The X-ray energy spectral index was $\beta_{\rm X}$=0.71\plm0.10 with the column density in agreement with the Galactic value. The spectral analysis does not show an obvious change in the X-ray spectral slope over time. The optical UVOT light curve decays with a slope of $\alpha$=1.8\plm0.2. The steepness and the similarity of the optical and X-ray decay rates suggest that the afterglow was observed after the jet break. We estimate a jet opening angle of about 1-2$^{\circ}$Comment: 14 pages, accepted for publication in Ap

How are health research partnerships assessed? A systematic review of outcomes, impacts, terminology and the use of theories, models and frameworks

BACKGROUND: Accurate, consistent assessment of outcomes and impacts is challenging in the health research partnerships domain. Increased focus on tool quality, including conceptual, psychometric and pragmatic characteristics, could improve the quantification, measurement and reporting partnership outcomes and impacts. This cascading review was undertaken as part of a coordinated, multicentre effort to identify, synthesize and assess a vast body of health research partnership literature. OBJECTIVE: To systematically assess the outcomes and impacts of health research partnerships, relevant terminology and the type/use of theories, models and frameworks (TMF) arising from studies using partnership assessment tools with known conceptual, psychometric and pragmatic characteristics. METHODS: Four electronic databases were searched (MEDLINE, Embase, CINAHL Plus and PsycINFO) from inception to 2 June 2021. We retained studies containing partnership evaluation tools with (1) conceptual foundations (reference to TMF), (2) empirical, quantitative psychometric evidence (evidence of validity and reliability, at minimum) and (3) one or more pragmatic characteristics. Outcomes, impacts, terminology, definitions and TMF type/use were abstracted verbatim from eligible studies using a hybrid (independent abstraction–validation) approach and synthesized using summary statistics (quantitative), inductive thematic analysis and deductive categories (qualitative). Methodological quality was assessed using the Quality Assessment Tool for Studies with Diverse Designs (QATSDD). RESULTS: Application of inclusion criteria yielded 37 eligible studies. Study quality scores were high (mean 80%, standard deviation 0.11%) but revealed needed improvements (i.e. methodological, reporting, user involvement in research design). Only 14 (38%) studies reported 48 partnership outcomes and 55 impacts; most were positive effects (43, 90% and 47, 89%, respectively). Most outcomes were positive personal, functional, structural and contextual effects; most impacts were personal, functional and contextual in nature. Most terms described outcomes (39, 89%), and 30 of 44 outcomes/impacts terms were unique, but few were explicitly defined (9, 20%). Terms were complex and mixed on one or more dimensions (e.g. type, temporality, stage, perspective). Most studies made explicit use of study-related TMF (34, 92%). There were 138 unique TMF sources, and these informed tool construct type/choice and hypothesis testing in almost all cases (36, 97%). CONCLUSION: This study synthesized partnership outcomes and impacts, deconstructed term complexities and evolved our understanding of TMF use in tool development, testing and refinement studies. Renewed attention to basic concepts is necessary to advance partnership measurement and research innovation in the field. Systematic review protocol registration: PROSPERO protocol registration: CRD42021137932 https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=137932. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12961-022-00938-8

Early Increase in Extrasynaptic NMDA Receptor Signaling and Expression Contributes to Phenotype Onset in Huntington's Disease Mice

SummaryN-methyl-D-aspartate receptor (NMDAR) excitotoxicity is implicated in the pathogenesis of Huntington's disease (HD), a late-onset neurodegenerative disorder. However, NMDARs are poor therapeutic targets, due to their essential physiological role. Recent studies demonstrate that synaptic NMDAR transmission drives neuroprotective gene transcription, whereas extrasynaptic NMDAR activation promotes cell death. We report specifically increased extrasynaptic NMDAR expression, current, and associated reductions in nuclear CREB activation in HD mouse striatum. The changes are observed in the absence of dendritic morphological alterations, before and after phenotype onset, correlate with mutation severity, and require caspase-6 cleavage of mutant huntingtin. Moreover, pharmacological block of extrasynaptic NMDARs with memantine reversed signaling and motor learning deficits. Our data demonstrate elevated extrasynaptic NMDAR activity in an animal model of neurodegenerative disease. We provide a candidate mechanism linking several pathways previously implicated in HD pathogenesis and demonstrate successful early therapeutic intervention in mice

CUMYL-4CN-BINACA Is an Efficacious and Potent Pro-Convulsant Synthetic Cannabinoid Receptor Agonist

Synthetic cannabinoid receptor agonists (SCRAs) are the largest class of new psychoactive substances (NPS). New examples are detected constantly, and some are associated with a series of adverse effects, including seizures. CUMYL-4CN-BINACA (1-(4-cyanobutyl)-N-(2-phenylpropan-2-yl)indazole-3-carboxamide) is structurally related to potent, cumylamine-derived SCRAs such as 5F-CUMYL-PINACA, but is unusual due to a terminal aliphatic nitrile group not frequently encountered in SCRAs or pharmaceuticals. We report here that CUMYL-4CN-BINACA is a potent CB1 receptor agonist (Ki = 2.6 nM; EC50 = 0.58 nM) that produces pro-convulsant effects in mice at a lower dose than reported for any SCRA to date (0.3 mg/kg, i.p). Hypothermic and pro-convulsant effects in mice could be reduced or blocked, respectively, by pretreatment with CB1 receptor antagonist SR141716, pointing to at least partial involvement of CB1 receptors in vivo. Pretreatment with CB2 receptor antagonist AM-630 had no effect on pro-convulsant activity. The pro-convulsant properties and potency of CUMYL-4CN-BINACA may underpin the toxicity associated with this compound in humans

Very Early Optical Afterglows of Gamma-Ray Bursts: Evidence for Relative Paucity of Detection

Very early observations with the Swift satellite of gamma-ray burst (GRB) afterglows reveal that the optical component is not detected in a large number of cases. This is in contrast to the bright optical flashes previously discovered in some GRBs (e.g. GRB 990123 and GRB 021211). Comparisons of the X-ray afterglow flux to the optical afterglow flux and prompt gamma-ray fluence is used to quantify the seemingly deficient optical, and in some cases X-ray, light at these early epochs. This comparison reveals that some of these bursts appear to have higher than normal gamma-ray efficiencies. We discuss possible mechanisms and their feasibility for explaining the apparent lack of early optical emission. The mechanisms considered include: foreground extinction, circumburst absorption, Ly-alpha blanketing and absorption due to high redshift, low density environments, rapid temporal decay, and intrinsic weakness of the reverse shock. Of these, foreground extinction, circumburst absorption, and high redshift provide the best explanations for most of the non-detections in our sample. There is tentative evidence of suppression of the strong reverse shock emission. This could be because of a Poynting-flux-dominated flow or a pure non-relativistic hydrodynamical reverse shock.Comment: 22 pages, 5 figures. Accepted for publication in Ap

Homotypic and heterotypic psychopathological continuity: a child cohort study

Background: Heterotypic psychopathological continuity (i.e. one disorder predicting another at a later time point) contradicts the conventional view that psychiatric disorders are discrete, static entities. Studying this phenomenon may help to tease out the complex mechanisms that underpin psychiatric comorbidity. To date, no studies have explicitly compared heterotypic effects within and across higher order dimensions of psychopathology. // Methods: Patterns of homotypic and heterotypic psychopathological continuity were examined using cohort data from the Avon Longitudinal Study of Parents and Children (ALSPAC, N = 4815). Eight common psychiatric disorders were assessed at age 7.5 and again at age 14 years using the maternal report version of the Development and Well-Being Assessment (DAWBA). Cross-lagged models were used to compare patterns of homotypic and heterotypic continuity within and across three higher order dimensions of psychopathology; internalizing-fear, internalizing-distress, and externalizing. // Results: Homotypic continuity was universal. Considerable heterotypic continuity was observed even after controlling for homotypic continuity and the presence of all disorders at baseline. Heterotypic continuity was more common within higher order dimensions, but a number of significant cross-dimension effects were observed, with ADHD acting as a strong predictor of subsequent internalizing disorders. // Conclusions: Heterotypic continuity may reflect elements of shared aetiology, or local-level interactions between disorders

Immunoglobulin gene insertions and deletions in the affinity maturation of HIV-1 broadly reactive neutralizing antibodies.

CAPRISA, 2014.Abstract available in pdf

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised