Developing an intervention to facilitate family communication about inherited genetic conditions, and training genetic counsellors in its delivery.

Many families experience difficulty in talking about an inherited genetic condition that affects one or more of them. There have now been a number of studies identifying the issues in detail, however few have developed interventions to assist families. The SPRinG collaborative have used the UK Medical Research Council's guidance on Developing and Evaluating Complex Interventions, to work with families and genetic counsellors (GCs) to co-design a psycho-educational intervention to facilitate family communication and promote better coping and adaptation to living with an inherited genetic condition for parents and their children (<18 years). The intervention is modelled on multi-family discussion groups (MFDGs) used in psychiatric settings. The MFDG was developed and tested over three phases. First focus groups with parents, young people, children and health professionals discussed whether MFDG was acceptable and proposed a suitable design. Using evidence and focus group data, the intervention and a training manual were developed and three GCs were trained in its delivery. Finally, a prototype MFDG was led by a family therapist and co-facilitated by the three GCs. Data analysis showed that families attending the focus groups and intervention thought MFDG highly beneficial, and the pilot sessions had a significant impact on their family' functioning. We also demonstrated that it is possible to train GCs to deliver the MFDG intervention. Further studies are now required to test the feasibility of undertaking a definitive randomised controlled trial to evaluate its effectiveness in improving family outcomes before implementing into genetic counselling practice.The National Institute of Health Research funded the study but any views expressed do not necessarily reflect those of the Authority. Funded by NIHR reference number: RP-DG-1211-10015

The crystal structure of the Hazara virus nucleocapsid protein

Background: Hazara virus (HAZV) is a member of the Bunyaviridae family of segmented negative stranded RNA viruses, and shares the same serogroup as Crimean-Congo haemorrhagic fever virus (CCHFV). CCHFV is responsible for fatal human disease with a mortality rate approaching 30 %, which has an increased recent incidence within southern Europe. There are no preventative or therapeutic treatments for CCHFV-mediated disease, and thus CCHFV is classified as a hazard group 4 pathogen. In contrast HAZV is not associated with serious human disease, although infection of interferon receptor knockout mice with either CCHFV or HAZV results in similar disease progression. To characterise further similarities between HAZV and CCHFV, and support the use of HAZV as a model for CCHFV infection, we investigated the structure of the HAZV nucleocapsid protein (N) and compared it to CCHFV N. N performs an essential role in the viral life cycle by encapsidating the viral RNA genome, and thus, N represents a potential therapeutic target. Results: We present the purification, crystallisation and crystal structure of HAZV N at 2.7 Å resolution. HAZV N was expressed as an N-terminal glutathione S-transferase (GST) fusion protein then purified using glutathione affinity chromatography followed by ion-exchange chromatography. HAZV N crystallised in the P212121 space group with unit cell parameters a = 64.99, b = 76.10, and c = 449.28 Å. HAZV N consists of a globular domain formed mostly of alpha helices derived from both the N- and C-termini, and an arm domain comprising two long alpha helices. HAZV N has a similar overall structure to CCHFV N, with their globular domains superposing with an RMSD = 0.70 Å, over 368 alpha carbons that share 59 % sequence identity. Four HAZV N monomers crystallised in the asymmetric unit, and their head-to-tail assembly reveals a potential interaction site between monomers. Conclusions: The crystal structure of HAZV N reveals a close similarity to CCHFV N, supporting the use of HAZV as a model for CCHFV. Structural similarity between the N proteins should facilitate study of the CCHFV and HAZV replication cycles without the necessity of working under containment level 4 (CL-4) conditions

Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis:a randomised, double-blind, placebo-controlled, phase 2b trial

Background: Lung delivery of plasmid DNA encoding the CFTR gene complexed with a cationic liposome is a potential treatment option for patients with cystic fibrosis. We aimed to assess the efficacy of non-viral CFTR gene therapy in patients with cystic fibrosis. Methods: We did this randomised, double-blind, placebo-controlled, phase 2b trial in two cystic fibrosis centres with patients recruited from 18 sites in the UK. Patients (aged ≥12 years) with a forced expiratory volume in 1 s (FEV1) of 50–90% predicted and any combination of CFTR mutations, were randomly assigned, via a computer-based randomisation system, to receive 5 mL of either nebulised pGM169/GL67A gene–liposome complex or 0·9% saline (placebo) every 28 days (plus or minus 5 days) for 1 year. Randomisation was stratified by % predicted FEV1 (&lt;70 vs ≥70%), age (&lt;18 vs ≥18 years), inclusion in the mechanistic substudy, and dosing site (London or Edinburgh). Participants and investigators were masked to treatment allocation. The primary endpoint was the relative change in % predicted FEV1. The primary analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT01621867. Findings: Between June 12, 2012, and June 24, 2013, we randomly assigned 140 patients to receive placebo (n=62) or pGM169/GL67A (n=78), of whom 116 (83%) patients comprised the per-protocol population. We noted a significant, albeit modest, treatment effect in the pGM169/GL67A group versus placebo at 12 months' follow-up (3·7%, 95% CI 0·1–7·3; p=0·046). This outcome was associated with a stabilisation of lung function in the pGM169/GL67A group compared with a decline in the placebo group. We recorded no significant difference in treatment-attributable adverse events between groups. Interpretation: Monthly application of the pGM169/GL67A gene therapy formulation was associated with a significant, albeit modest, benefit in FEV1 compared with placebo at 1 year, indicating a stabilisation of lung function in the treatment group. Further improvements in efficacy and consistency of response to the current formulation are needed before gene therapy is suitable for clinical care; however, our findings should also encourage the rapid introduction of more potent gene transfer vectors into early phase trials

Search for Dark Matter Annihilation Signals in the H.E.S.S. Inner Galaxy Survey

The central region of the Milky Way is one of the foremost locations to look for dark matter (DM) signatures. We report the first results on a search for DM particle annihilation signals using new observations from an unprecedented $γ$-ray survey of the Galactic Center (GC) region, i.e., the Inner Galaxy Survey, at very high energies (≳100 GeV) performed with the H.E.S.S. array of five ground-based Cherenkov telescopes. No significant $γ$-ray excess is found in the search region of the 2014–2020 dataset and a profile likelihood ratio analysis is carried out to set exclusion limits on the annihilation cross section $⟨σv⟩$. Assuming Einasto and Navarro-Frenk-White (NFW) DM density profiles at the GC, these constraints are the strongest obtained so far in the TeV DM mass range. For the Einasto profile, the constraints reach $⟨σv⟩$ values of 3.7×10$^{-26}$ cm$^3$ s$^{-1}$ for 1.5 TeV DM mass in the W$^+$W$^-$ annihilation channel, and 1.2×10$^{-26}$ cm$^3$ s$^{-1}$ for 0.7 TeV DM mass in the $τ^+τ^-$ annihilation channel. With the H.E.S.S. Inner Galaxy Survey, ground-based $γ$-ray observations thus probe $⟨σv⟩$ values expected from thermal-relic annihilating TeV DM particles

Search for Dark Matter Annihilation Signals in the H.E.S.S. Inner Galaxy Survey

The central region of the Milky Way is one of the foremost locations to look for dark matter (DM) signatures. We report the first results on a search for DM particle annihilation signals using new observations from an unprecedented $γ$-ray survey of the Galactic Center (GC) region, i.e., the Inner Galaxy Survey, at very high energies (≳100 GeV) performed with the H.E.S.S. array of five ground-based Cherenkov telescopes. No significant $γ$-ray excess is found in the search region of the 2014–2020 dataset and a profile likelihood ratio analysis is carried out to set exclusion limits on the annihilation cross section $⟨σv⟩$. Assuming Einasto and Navarro-Frenk-White (NFW) DM density profiles at the GC, these constraints are the strongest obtained so far in the TeV DM mass range. For the Einasto profile, the constraints reach $⟨σv⟩$ values of 3.7×10$^{-26}$ cm$^3$ s$^{-1}$ for 1.5 TeV DM mass in the W$^+$W$^-$ annihilation channel, and 1.2×10$^{-26}$ cm$^3$ s$^{-1}$ for 0.7 TeV DM mass in the $τ^+τ^-$ annihilation channel. With the H.E.S.S. Inner Galaxy Survey, ground-based $γ$-ray observations thus probe $⟨σv⟩$ values expected from thermal-relic annihilating TeV DM particles

Search for Dark Matter Annihilation Signals in the H.E.S.S. Inner Galaxy Survey

International audienceThe central region of the Milky Way is one of the foremost locations to look for dark matter (DM) signatures. We report the first results on a search for DM particle annihilation signals using new observations from an unprecedented γ-ray survey of the Galactic Center (GC) region, i.e., the Inner Galaxy Survey, at very high energies (≳100  GeV) performed with the H.E.S.S. array of five ground-based Cherenkov telescopes. No significant γ-ray excess is found in the search region of the 2014–2020 dataset and a profile likelihood ratio analysis is carried out to set exclusion limits on the annihilation cross section ⟨σv⟩. Assuming Einasto and Navarro-Frenk-White (NFW) DM density profiles at the GC, these constraints are the strongest obtained so far in the TeV DM mass range. For the Einasto profile, the constraints reach ⟨σv⟩ values of 3.7×10-26  cm3 s-1 for 1.5 TeV DM mass in the W+W- annihilation channel, and 1.2×10-26  cm3 s-1 for 0.7 TeV DM mass in the τ+τ- annihilation channel. With the H.E.S.S. Inner Galaxy Survey, ground-based γ-ray observations thus probe ⟨σv⟩ values expected from thermal-relic annihilating TeV DM particles

Revealing x-ray and gamma ray temporal and spectral similarities in the GRB 190829A afterglow

International audienceGamma-ray bursts (GRBs), which are bright flashes of gamma rays from extragalactic sources followed by fading afterglow emission, are associated with stellar core collapse events. We report the detection of very-high-energy (VHE) gamma rays from the afterglow of GRB 190829A, between 4 and 56 hours after the trigger, using the High Energy Stereoscopic System (H.E.S.S.). The low luminosity and redshift of GRB 190829A reduce both internal and external absorption, allowing determination of its intrinsic energy spectrum. Between energies of 0.18 and 3.3 tera–electron volts, this spectrum is described by a power law with photon index of 2.07 ± 0.09, similar to the x-ray spectrum. The x-ray and VHE gamma-ray light curves also show similar decay profiles. These similar characteristics in the x-ray and gamma-ray bands challenge GRB afterglow emission scenarios.</p

Search for dark matter annihilation in the Wolf-Lundmark-Melotte dwarf irregular galaxy with H.E.S.S.

We search for an indirect signal of dark matter through very high-energy γ rays from the Wolf-Lundmark-Melotte (WLM) dwarf irregular galaxy. The pair annihilation of dark matter particles would produce Standard Model particles in the final state such as γ rays, which might be detected by ground-based Cherenkov telescopes. Dwarf irregular galaxies represent promising targets as they are dark matter dominated objects with well-measured kinematics and small uncertainties on their dark matter distribution profiles. In 2018, the five-telescopes of the high energy stereoscopic system observed the dwarf irregular galaxy WLM for 18 hours. We present the first analysis based on data obtained from an imaging atmospheric Cherenkov telescope for this subclass of dwarf galaxy. As we do not observe any significant excess in the direction of WLM, we interpret the result in terms of constraints on the velocity-weighted cross section for dark matter pair annihilation ⟨σv⟩ as a function of the dark matter particle mass for various continuum channels, as well as the prompt γγ emission. For the τ+τ- channel, the limits reach a ⟨σv⟩ value of about 4×10-22  cm3 s-1 for a dark matter particle mass of 1 TeV. For the prompt γγ channel, the upper limit reaches a ⟨σv⟩ value of about 5×10-24  cm3 s-1 for a mass of 370 GeV. These limits represent an improvement of up to a factor 200, with respect to previous results for the dwarf irregular galaxies for TeV dark matter search

Evidence of 100 TeV gamma-ray emission from HESS J1702-420: A new PeVatron candidate

Aims. The identification of PeVatrons, hadronic particle accelerators reaching the knee of the cosmic ray spectrum (few × 1015 eV), is crucial to understand the origin of cosmic rays in the Galaxy. We provide an update on the unidentified source HESS J1702-420, a promising PeVatron candidate. Methods. We present new observations of HESS J1702-420 made with the High Energy Stereoscopic System (H.E.S.S.), and processed using improved analysis techniques. The analysis configuration was optimized to enhance the collection area at the highest energies. We applied a three-dimensional likelihood analysis to model the source region and adjust non thermal radiative spectral models to the γ-ray data. We also analyzed archival Fermi Large Area Telescope data to constrain the source spectrum at γ-ray energies > 10 GeV. Results. We report the detection of γ-rays up to 100 TeV from a specific region of HESS J1702-420, which is well described by a new source component called HESS J1702-420A that was separated from the bulk of TeV emission at a 5.4σ confidence level. The power law γ-ray spectrum of HESS J1702-420A extends with an index of Γ = 1.53 ± 0.19stat ± 0.20sys and without curvature up to the energy band 64-113 TeV, in which it was detected by H.E.S.S. at a 4.0σ confidence level. This makes HESS J1702-420A a compelling candidate site for the presence of extremely high energy cosmic rays. With a flux above 2 TeV of (2.08 ± 0.49stat ± 0.62sys) × 10-13 cm-2 s-1 and a radius of (0.06 ± 0.02stat ± 0.03sys)°, HESS J1702-420A is outshone - below a few tens of TeV - by the companion HESS J1702-420B. The latter has a steep spectral index of Γ = 2.62 ± 0.10stat ± 0.20sys and an elongated shape, and it accounts for most of the low-energy HESS J1702-420 flux. Simple hadronic and leptonic emission models can be well adjusted to the spectra of both components. Remarkably, in a hadronic scenario, the cut-off energy of the particle distribution powering HESS J1702-420A is found to be higher than 0.5 PeV at a 95% confidence level. Conclusions. For the first time, H.E.S.S. resolved two components with significantly different morphologies and spectral indices, both detected at > 5σ confidence level, whose combined emissions result in the source HESS J1702-420. We detected HESS J1702-420A at a 4.0σ confidence level in the energy band 64-113 TeV, which brings evidence for the source emission up to 100 TeV. In a hadronic emission scenario, the hard γ-ray spectrum of HESS J1702-420A implies that the source likely harbors PeV protons, thus becoming one of the most solid PeVatron candidates detected so far in H.E.S.S. data. However, a leptonic origin of the observed TeV emission cannot be ruled out either

Search for dark matter annihilation signals from unidentified Fermi-LAT objects with H.E.S.S

Cosmological $N$-body simulations show that Milky Way-sized galaxies harbor a population of unmerged dark matter subhalos. These subhalos could shine in gamma-rays and be eventually detected in gamma-ray surveys as unidentified sources. We performed a thorough selection among unidentified Fermi-LAT Objects (UFOs) to identify them as possible TeV-scale dark matter subhalo candidates. We search for very-high-energy (E $\gtrsim$ 100 GeV) gamma-ray emissions using H.E.S.S. observations towards four selected UFOs. Since no significant very-high-energy gamma-ray emission is detected in any dataset of the four observed UFOs nor in the combined UFO dataset, strong constraints are derived on the product of the velocity-weighted annihilation cross section $\langle \sigma v \rangle$ by the $J$-factor for the dark matter models. The 95% C.L. observed upper limits derived from combined H.E.S.S. observations reach $\langle \sigma v \rangle J$ values of 3.7$\times$10$^{-5}$ and 8.1$\times$10$^{-6}$ GeV$^2$cm$^{-2}$s$^{-1}$ in the $W^+W^-$ and $\tau^+\tau^-$ channels, respectively, for a 1 TeV dark matter mass. Focusing on thermal WIMPs, the H.E.S.S. constraints restrict the $J$-factors to lie in the range 6.1$\times$10$^{19}$ - 2.0$\times$10$^{21}$ GeV$^2$cm$^{-5}$, and the masses to lie between 0.2 and 6 TeV in the $W^+W^-$ channel. For the $\tau^+\tau^-$ channel, the $J$-factors lie in the range 7.0$\times$10$^{19}$ - 7.1$\times$10$^{20}$ GeV$^2$cm$^{-5}$ and the masses lie between 0.2 and 0.5 TeV. Assuming model-dependent predictions from cosmological N-body simulations on the $J$-factor distribution for Milky Way-sized galaxies, the dark matter models with masses greater than 0.3 TeV for the UFO emissions can be ruled out at high confidence level