Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Murine neonates develop vigorous in vivo cytotoxic and Th1/Th2 responses upon exposure to low doses of NIMA-like alloantigens

Early life exposure to noninherited maternal antigens (NIMAs) may occur via transplacental transfer and/or breast milk. There are indications that early life exposure to NIMAs may lead to lifelong tolerance. However, there is mounting evidence that exposure to NIMAs may also lead to immunologic priming. Understanding how these different responses arise could be critical in transplantation with donor cells expressing NIMAs. We recently reported that murine neonates that received a transplant of low doses of NIMA-like alloantigens develop vigorous memory cytotoxic responses, as assessed by in vitro assays. Here, we demonstrate that robust allospecific cytotoxicity is also manifest in vivo. Importantly, at low doses, NIMA-expressing cells induced the development of in vivo cytotoxicity during the neonatal period. NIMA-exposed neonates also developed vigorous primary and memory allospecific Th1/Th2 responses that exceeded the responses of adults. Overall, we conclude that exposure to low doses of NIMA-like alloantigens induces robust in vivo cytotoxic and Th1/Th2 responses in neonates. These findings suggest that early exposure to low levels of NIMA may lead to long-term immunologic priming of all arms of T-cell adaptive immunity, rather than tolerance

The pendulum swings: Tolerance versus priming to NIMA

Fetal and/or perinatal exposure to noninherited maternal antigens (NIMA) has been reported to induce NIMA-specific tolerance. This tolerant state is highly beneficial in transplantation settings; enhanced graft acceptance has been observed when transplanted tissues express NIMA. Reduction in severe graft-vs-host disease has also been noted when bone marrow grafts originate from donors exposed to NIMA in early life. However, there is emerging evidence that exposure to NIMA can alternatively lead to specific priming. The processes regulating tolerance versus priming to NIMA are poorly understood and probably multifactorial. Based on studies in both humans and mice, we propose that both the quality and the quantity of NIMA exposure will be found to be key determinants of these opposing outcomes

Murine neonatal recent thymic emigrants are phenotypically and functionally distinct from adult recent thymic emigrants

In contrast to adults, the murine neonatal CD4+ compartment contains a high frequency of recent thymic emigrants (RTEs). However, the functional capabilities of these cells in neonates are relatively unknown. Moreover, it has not been determined whether RTEs from neonates and adults are comparable. Here we have directly compared neonatal and adult CD4+ RTEs for the first time, using a transgenic mouse strain that allows for the identification and purification of RTEs. Our data demonstrate that RTEs from murine neonates and adults are phenotypically and functionally distinct. In particular, although the magnitude of RTEs cytokine responses from both age groups is dependent on the conditions of activation, neonatal RTEs always exhibited higher levels of effector Th1/Th2 cytokine production than adult RTEs. In addition, neonatal, but not adult, RTEs showed early proliferation in response to stimulation with interleukin-7 alone. This was associated with faster kinetics of interleukin-7Rα down-regulation and higher levels of pSTAT5 in neonatal RTEs. These quantitative and qualitative differences in the neonatal and adult RTEs populations may at least partially explain the diverse responses that are elicited in vivo in neonates in response to different conditions of antigen exposure

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke

Multi-messenger Observations of a Binary Neutron Star Merger

International audienceOn 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of $\sim 1.7\,{\rm{s}}$ with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg(2) at a luminosity distance of ${40}_{-8}^{+8}$ Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 $\,{M}_{\odot }$. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at $\sim 40\,{\rm{Mpc}}$) less than 11 hours after the merger by the One-Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ∼10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position $\sim 9$ and $\sim 16$ days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC 4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta