Tissue Integration and Antimicrobial Effects of Surface-derived Nitric Oxide Release

The analytical performance of glucose sensors is inhibited by the host’s foreign body response (FBR) and risk of bacterial infection. To date, no one strategy has circumvented the physiological reactions to implanted materials. Nitric oxide (NO) is an endogenously produced free radical that acts to initiate events in the FBR and fight bacterial infection. Herein, the potential of NO-releasing surfaces to both mitigate the FBR and bacterial invasion is described. Evaluation of the performance of NO-releasing surfaces to improve glucose sensor performance in vivo was carried out through imparting NO release to microdialysis probes. Perfusion of saturated NO solutions through implanted probes delivered a constant flux of 162 pmol cm-2 s-1 delivering 4.6 μmol cm-2 NO each day. The NO-releasing probes recovered significantly greater concentrations of glucose after 7 d of implantation versus controls. Histological analysis revealed a thinner collagen capsule and decreased inflammation adjacent to NO-releasing probes. To investigate the necessary NO-release properties to achieve the observed histological benefits, NO-releasing polyurethane-coated wires were implanted into a porcine model for up to 6 weeks. Polyurethanes were doped with small molecules or nanoparticles to alter the NO release kinetics, fluxes, and total payloads. Materials with a NO-release duration of 14 d and large NO payload (9.3 μmol cm-2) were most effective at decreasing the collagen encapsulation and inflammation adjacent to the implants. Inflammation was only modulated during active NO release from the implant. While modulation of the FBR is essential for the development of glucose sensors, infection by bacteria is a constant threat. Biomaterial-associated infections most commonly begin through adhesion to the implanted material. Therefore, evaluation of the anti-adhesive properties of NO-releasing surfaces was undertaken by examining the adhesion of six bacterial strains to a wide range of NO fluxes (0.5–50 pmol cm-2 s-1). An average NO flux between 50 pmol cm-2 s-1 reduced surface coverage of all strains by >80% over 1 h. Further, after incubation of adhered bacteria in bacteriostatic conditions for 24 h, large surfacederived NO payloads (1.7 μmol cm-2) decreased viability of adhered bacteria by ≥85%.Doctor of Philosoph

Jupiter’s auroras during the Juno approach phase as observed by the Hubble Space Telescope

We present movies of the Hubble Space Telescope (HST) observations of Jupiter’s FUV auroras observed during the Juno approach phase and first capture orbit, and compare with Juno observations of the interplanetary medium near Jupiter and inside the magnetosphere. Jupiter’s FUV auroras indicate the nature of the dynamic processes occurring in Jupiter’s magnetosphere, and the approach phase provided a unique opportunity to obtain a full set of interplanetary data near to Jupiter at the time of a program of HST observations, along with the first simultaneous with Juno observations inside the magnetosphere. The overall goal was to determine the nature of the solar wind effect on Jupiter’s magnetosphere. HST observations were obtained with typically 1 orbit per day over three intervals: 16 May – 7 June, 22-30 June and 11-18 July, i.e. while Juno was in the solar wind, around the bow shock and magnetosphere crossings, and in the mid-latitude middle-outer magnetospheres. We show that these intervals are characterised by particularly dynamic polar auroras, and significant variations in the auroral power output caused by e.g. dawn storms, intense main emission and poleward forms. We compare the variation of these features with Juno observations of interplanetary compression regions and the magnetospheric environment during the intervals of these observations

Neurodevelopmental and psychosocial risk factors in serial killers and mass murderers

Multiple and serial murders are rare events that have a very profound societal impact. We have conducted a systematic review, following PRISMA guidelines, of both the peer reviewed literature and of journalistic and legal sources regarding mass and serial killings. Our findings tentatively indicate that these extreme forms of violence may be a result of a highly complex interaction of biological, psychological and sociological factors and that, potentially, a significant proportion of mass or serial killers may have had neurodevelopmental disorders such as autism spectrum disorder or head injury. Research into multiple and serial murders is in its infancy: there is a lack of rigorous studies and most of the literature is anecdotal and speculative. Specific future study of the potential role of neurodevelopmental disorders in multiple and serial murders is warranted and, due to the rarity of these events, innovative research techniques may be required

Overview of HST observa7ons of Jupiter’s ultraviolet aurora during Juno orbits 3 to 7

Jupiter’s permanent ultraviolet auroral emissions have been systematically monitored from Earth orbit with the Hubble Space Telescope (HST) during an 8-month period. The Girst part of this HST large program (GO-14634) was meant to support the NASA Juno prime mission during orbits PJ03 through PJ07. The HST program will resume in Feb 2018, in time for Juno’s PJ11 perijove, right after HST’s solar and lunar avoidance periods. HST observations are designed to provide a Jovian auroral activity background for all instruments on-board Juno and for the numerous ground based and space based observatories participating to the Juno mission. In particular, several HST visits were programmed in order to obtain as many simultaneous observations with Juno-UVS as possible, sometimes in the same hemisphere, sometimes in the opposite one. In addition, the timing of some HST visits was set to take advantage of Juno’s multiple crossings of the current sheet and of the magnetic Gield lines threading the auroral emissions. These observations are obtained with the Space Telescope Imaging Spectrograph (STIS) in time-tag mode, they consist in spatially resolved movies of Jupiter’s highly dynamic aurora with timescales ranging from seconds to several days. Here, we present an overview of the present -numerous- HST results. They demonstrate that while Jupiter is always showing the same basic auroral components, it is also displaying an ever-changing auroral landscape. The complexity of the auroral morphology is such that no two observations are alike. Still, in this apparent chaos some patterns emerge. This information is giving clues on magnetospheric processes at play at the local and global scales, the latter being only accessible to remote sensing instruments such as HST

Development of phospho-specific Rab protein antibodies to monitor in vivo activity of the LRRK2 Parkinson’s disease kinase

Mutations that activate the LRRK2 protein kinase, predispose to Parkinson's disease, suggesting that LRRK2 inhibitors might have therapeutic benefit. Recent work has revealed that LRRK2 phosphorylates a subgroup of 14 Rab proteins, including Rab10, at a specific residue located at the centre of its effector binding Switch-II motif. In this study, we analyse the selectivity and sensitivity of polyclonal and monoclonal phospho-specific antibodies raised against 9 different LRRK2 phosphorylated Rab proteins (Rab3A/3B/3C/3D, Rab5A/5B/5C, Rab8A/8B, Rab10, Rab12, Rab29[T71], Rab29[S72], Rab35 and Rab43). We identify rabbit monoclonal phospho-specific antibodies (MJFF-pRAB10) that are exquisitely selective for LRRK2 phosphorylated Rab10, detecting endogenous phosphorylated Rab10 in all analysed cell lines and tissues, including human brain cingulate cortex. We demonstrate that the MJFF-pRAB10 antibodies can be deployed to assess enhanced Rab10 phosphorylation resulting from pathogenic (R1441C/G or G2019S) LRRK2 knock-in mutations as well as the impact of LRRK2 inhibitor treatment. We also identify rabbit monoclonal antibodies displaying broad specificity (MJFF-pRAB8) that can be utilised to assess LRRK2 controlled phosphorylation of a range of endogenous Rab proteins including Rab8A, Rab10 and Rab35. The antibodies described in this study will help with assessment of LRRK2 activity and examination of which Rab proteins are phosphorylated in vivo. These antibodies could also be used to assess impact of LRRK2 inhibitors in future clinical trials

Measuring progress and projecting attainment on the basis of past trends of the health-related Sustainable Development Goals in 188 countries: an analysis from the Global Burden of Disease Study 2016

The UN’s Sustainable Development Goals (SDGs) are grounded in the global ambition of “leaving no one behind”. Understanding today’s gains and gaps for the health-related SDGs is essential for decision makers as they aim to improve the health of populations. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016), we measured 37 of the 50 health-related SDG indicators over the period 1990–2016 for 188 countries, and then on the basis of these past trends, we projected indicators to 2030

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

As mortality rates decline, life expectancy increases, and populations age, non-fatal outcomes of diseases and injuries are becoming a larger component of the global burden of disease. The Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) provides a comprehensive assessment of prevalence, incidence, and years lived with disability (YLDs) for 328 causes in 195 countries and territories from 1990 to 2016