First Results in the Search for Dark Sectors at NA64 with the CERN SPS High Energy Muon Beam.

We report the first search for dark sectors performed at the NA64 experiment employing a high energy muon beam and a missing energy-momentum technique. Muons from the M2 beamline at the CERN Super Proton Synchrotron with a momentum of 160 GeV/c are directed to an active target. The signal signature consists of a single scattered muon with momentum <80 GeV/c in the final state, accompanied by missing energy, i.e., no detectable activity in the downstream calorimeters. For a total dataset of (1.98±0.02)×10^{10} muons on target, no event is observed in the expected signal region. This allows us to set new limits on the remaining (m_{Z^{'}},g_{Z^{'}}) parameter space of a new Z^{'} (L_{µ}-L_{τ}) vector boson which could explain the muon (g-2)_{µ} anomaly. Additionally, our study excludes part of the parameter space suggested by the thermal dark matter relic abundance. Our results pave the way to explore dark sectors and light dark matter with muon beams in a unique and complementary way to other experiments.

Genome sequencing identify chromosome 9 inversions disrupting ENG in 2 unrelated HHT families.

Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber disease, is a dominant inherited vascular disorder. The clinical diagnosis is based on the Curaçao criteria and pathogenic variants in the ENG and ACVRL1 genes are responsible for most cases of HHT. Four families with a negative targeted gene panel and selected by a multidisciplinary team were selected and whole-genome sequencing was performed according to the recommendations of the French National Plan for Genomic Medicine. Structural variations were confirmed by standard molecular cytogenetic analysis (FISH). In two families with a definite diagnosis of HHT, we identified two different paracentric inversions of chromosome 9, both disrupting the ENG gene. These inversions are considered as pathogenic and causative for the HHT phenotype of the patients. This is the first time structural variations are reported to cause HHT. As such balanced events are often missed by exon-based sequencing (panel, exome), structural variations may be an under-recognized cause of HHT. Genome sequencing for the detection of these events could be suggested for patients with a definite diagnosis of HHT and in whom no causative pathogenic variant was identified.

Impact of heterozygous ALK1 mutations on the transcriptomic response to BMP9 and BMP10 in endothelial cells from hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension donors.

Heterozygous activin receptor-like kinase 1 (ALK1) mutations are associated with two vascular diseases: hereditary hemorrhagic telangiectasia (HHT) and more rarely pulmonary arterial hypertension (PAH). Here, we aimed to understand the impact of ALK1 mutations on BMP9 and BMP10 transcriptomic responses in endothelial cells. Endothelial colony-forming cells (ECFCs) and microvascular endothelial cells (HMVECs) carrying loss of function ALK1 mutations were isolated from newborn HHT and adult PAH donors, respectively. RNA-sequencing was performed on each type of cells compared to controls following an 18 h stimulation with BMP9 or BMP10. In control ECFCs, BMP9 and BMP10 stimulations induced similar transcriptomic responses with around 800 differentially expressed genes (DEGs). ALK1-mutated ECFCs unexpectedly revealed highly similar transcriptomic profiles to controls, both at the baseline and upon stimulation, and normal activation of Smad1/5 that could not be explained by a compensation in cell-surface ALK1 level. Conversely, PAH HMVECs revealed strong transcriptional dysregulations compared to controls with > 1200 DEGs at the baseline. Consequently, because our study involved two variables, ALK1 genotype and BMP stimulation, we performed two-factor differential expression analysis and identified 44 BMP9-dysregulated genes in mutated HMVECs, but none in ECFCs. Yet, the impaired regulation of at least one hit, namely lunatic fringe (LFNG), was validated by RT-qPCR in three different ALK1-mutated endothelial models. In conclusion, ALK1 heterozygosity only modified the BMP9/BMP10 regulation of few genes, including LFNG involved in NOTCH signaling. Future studies will uncover whether dysregulations in such hits are enough to promote HHT/PAH pathogenesis, making them potential therapeutic targets, or if second hits are necessary.

Search for Light Dark Matter with NA64 at CERN.

Thermal dark matter models with particle χ masses below the electroweak scale can provide an explanation for the observed relic dark matter density. This would imply the existence of a new feeble interaction between the dark and ordinary matter. We report on a new search for the sub-GeV χ production through the interaction mediated by a new vector boson, called the dark photon A^{'}, in collisions of 100 GeV electrons with the active target of the NA64 experiment at the CERN SPS. With 9.37×10^{11} electrons on target collected during 2016-2022 runs NA64 probes for the first time the well-motivated region of parameter space of benchmark thermal scalar and fermionic dark matter models. No evidence for dark matter production has been found. This allows us to set the most sensitive limits on the A^{'} couplings to photons for masses m_{A^{'}}≲0.35 GeV, and to exclude scalar and Majorana dark matter with the χ-A^{'} coupling α_{D}≤0.1 for masses 0.001≲m_{χ}≲0.1 GeV and 3m_{χ}≤m_{A^{'}}.

[Hereditary hemorrhagic telangiectasia]. / La maladie de Rendu-Osler (télangiectasie hémorragique héréditaire).

Hereditary hemorrhagic telangiectasia, also known as Rendu-Osler - Weber disease, is a rare, autosomal dominant vascular disease, with prevalence of 1/5,000. The condition is characterized by muco-cutaneous telangiectasias, which are responsible for a hemorrhagic syndrome of variable severity, as well as arteriovenous malformations (AVMs) appearing in the lungs, the liver, and the nervous system. They can be the source of shunts, which may be associated with high morbidity (neurological ischemic stroke, brain abscess, high-output heart failure, biliary ischemia…). It is therefore crucial to establish a clinical diagnosis using the Curaçao criteria or molecular diagnosis based on genetic analysis of the ENG, ACVRL1, SMAD4 and GDF2 genes. In most cases, multidisciplinary management allows patients to have normal life expectancy. Advances in interventional radiology and better understanding of the pathophysiology of angiogenesis have resulted in improved therapeutic management. Anti-angiogenic treatments, such as bevacizumab (BVZ, an anti-VEGF antibody), have proven to be effective in cases involving bleeding complications and severe liver damage with cardiac repercussions. Other anti-angiogenic agents are currently being investigated, including tyrosine kinase inhibitors.

The European Rare Disease Network for HHT Frameworks for management of hereditary haemorrhagic telangiectasia in general and speciality care.

Hereditary haemorrhagic telangiectasia (HHT) is a complex, multisystemic vascular dysplasia affecting approximately 85,000 European Citizens. In 2016, eight founding centres operating within 6 countries, set up a working group dedicated to HHT within what became the European Reference Network on Rare Multisystemic Vascular Diseases. By launch, combined experience exceeded 10,000 HHT patients, and Chairs representing 7 separate specialties provided a median of 24 years' experience in HHT. Integrated were expert patients who focused discussions on the patient experience. Following a 2016-2017 survey to capture priorities, and underpinned by more than 40 monthly meetings, and new data acquisitions, VASCERN HHT generated position statements that distinguish expert HHT care from non-expert HHT practice. Leadership was by specialists in the relevant sub-discipline(s), and 100% consensus was required amongst all clinicians before statements were published or disseminated. One major set of outputs targeted all healthcare professionals and their HHT patients, and include the new Orphanet definition; Do's and Don'ts for common situations; Outcome Measures suitable for all consultations; COVID-19; and anticoagulation. The second output set span aspects of vascular pathophysiology where greater understanding will assist organ-specific specialist clinicians to provide more informed care to HHT patients. These cover cerebral vascular malformations and screening; mucocutaneous telangiectasia and differential diagnosis; anti-angiogenic therapies; circulatory interplays between anaemia and arteriovenous malformations; and microbiological strategies to counteract loss of normal pulmonary capillary function. Overall, the integrated outputs, and documented current practices, provide frameworks for approaches that augment the health and safety of HHT patients in diverse health-care settings.

Probing the explanation of the muon (g-2) anomaly and thermal light dark matter with the semi-visible dark photon channel.

We report the results of a search for a new vector boson ( A ' ) decaying into two dark matter particles χ 1 χ 2 of different mass. The heavier χ 2 particle subsequently decays to χ 1 and an off-shell Dark Photon A ' ∗ → e + e - . For a sufficiently large mass splitting, this model can explain in terms of new physics the recently confirmed discrepancy observed in the muon anomalous magnetic moment at Fermilab. Remarkably, it also predicts the observed yield of thermal dark matter relic abundance. A detailed Monte-Carlo simulation was used to determine the signal yield and detection efficiency for this channel in the NA64 setup. The results were obtained re-analyzing the previous NA64 searches for an invisible decay A ' → χ χ ¯ and axion-like or pseudo-scalar particles a → γ γ . With this method, we exclude a significant portion of the parameter space justifying the muon g-2 anomaly and being compatible with the observed dark matter relic density for A ' masses from 2 m e up to 390 MeV and mixing parameter ε between 3 × 10 - 5 and 2 × 10 - 2 .

Hunting down the X17 boson at the CERN SPS.

Recently, the ATOMKI experiment has reported new evidence for the excess of e + e - events with a mass ∼ 17 MeV in the nuclear transitions of 4 He, that they previously observed in measurements with 8 Be. These observations could be explained by the existence of a new vector X 17 boson. So far, the search for the decay X 17 → e + e - with the NA64 experiment at the CERN SPS gave negative results. Here, we present a new technique that could be implemented in NA64 aiming to improve the sensitivity and to cover the remaining X 17 parameter space. If a signal-like event is detected, an unambiguous observation is achieved by reconstructing the invariant mass of the X 17 decay with the proposed method. To reach this goal an optimization of the X 17 production target, as well as an efficient and accurate reconstruction of two close decay tracks, is required. A dedicated analysis of the available experimental data making use of the trackers information is presented. This method provides independent confirmation of the NA64 published results [1], validating the tracking procedure. The detailed Monte Carlo study of the proposed setup and the background estimate show that the goal of the proposed search is feasible.

CT dose optimization for the detection of pulmonary arteriovenous malformation (PAVM): A phantom study.

PURPOSE: To determine the lowest suitable dose level for the detection of pulmonary arteriovenous malformation (PAVM) using a task-based image quality assessment. MATERIAL AND METHODS: A phantom was scanned using the standard chest protocol (STD) and 4 other ultra-low dose protocols (ULD) using various kVp. Raw data were reconstructed using level 5 of the hybrid iterative reconstruction algorithm (iDose4) for the STD protocol, and level 6 of iDose4 and levels 1 to 3 of model-based iterative reconstruction (IMR) for the ULD protocols. Both quantitative criteria and qualitative analysis were used to compare protocols. Noise-power-spectrum and Task-based transfer function were computed using imQuest software. The detectability-index (d') was computed for the detection of PAVM. A subjective analysis was performed by 2 chest radiologists to validate the image-quality obtained on the anthropomorphic phantom for all protocols. RESULTS: Similar d' values were found for ULD-140 using iDose4 6 compared to STD protocol. Greater d' values were found for all ULD protocols using IMR compared to STD. Subjective image quality was rated as acceptable to excellent for ULD-140 and ULD-120 for all reconstruction types, for ULD-100 and ULD-80 using IMR2, and for ULD-100 using IMR1. Image smoothing was poor for IMR3 for ULD-100 and ULD-80. Finally, the ULD-80 protocol reconstructed with IMR2 was chosen for the detection of PAVM. With this protocol, the dose (CTDIvol of 0.3mGy) was reduced by 91% compared with the STD protocol. CONCLUSION: A dose level as low as 0.3mGy reconstructed with IMR2 provides an image quality suitable for the detection of PAVM.

Safety of direct oral anticoagulants in patients with hereditary hemorrhagic telangiectasia.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular dysplasia resulting in visceral arteriovenous malformations and smaller mucocutaneous telangiectasia. Most patients experience recurrent nosebleeds and become anemic without iron supplementation. However, thousands may require anticoagulation for conditions such as venous thromboembolism and/or atrial fibrillation. Over decades, tolerance data has been published for almost 200 HHT-affected users of warfarin and heparins, but there are no published data for the newer direct oral anticoagulants (DOACs) in HHT. METHODS: To provide such data, a retrospective audit was conducted across the eight HHT centres of the European Reference Network for Rare Multisystemic Vascular Diseases (VASCERN), in Denmark, France, Germany, Italy, the Netherlands and the UK. RESULTS: Although HHT Centres had not specifically recommended the use of DOACs, 32 treatment episodes had been initiated by other clinicians in 28 patients reviewed at the Centres, at median age 65 years (range 30-84). Indications were for atrial fibrillation (16 treatment episodes) and venous thromboembolism (16 episodes). The 32 treatment episodes used Apixaban (n = 15), Rivaroxaban (n = 14), and Dabigatran (n = 3). HHT nosebleeds increased in severity in 24/32 treatment episodes (75%), leading to treatment discontinuation in 11 (34.4%). Treatment discontinuation was required for 4/15 (26.7%) Apixaban episodes and 7/14 (50%) Rivaroxaban episodes. By a 4 point scale of increasing severity, there was a trend for Rivaroxaban to be associated with a greater bleeding risk both including and excluding patients who had used more than one agent (age-adjusted coefficients 0.61 (95% confidence intervals 0.11, 1.20) and 0.74 (95% confidence intervals 0.12, 1.36) respectively. Associations were maintained after adjustment for gender and treatment indication. Extreme hemorrhagic responses, worse than anything experienced previously, with individual nosebleeds lasting hours requiring hospital admissions, blood transfusions and in all cases treatment discontinuation, occurred in 5/14 (35.7%) Rivaroxaban episodes compared to 3/15 (20%) Apixaban episodes and published rates of ~ 5% for warfarin and heparin. CONCLUSIONS: Currently, conventional heparin and warfarin remain first choice anticoagulants in HHT. If newer anticoagulants are considered, although study numbers are small, at this stage Apixaban appears to be associated with lesser bleeding risk than Rivaroxaban.

Tranexamic acid for epistaxis in hereditary hemorrhagic telangiectasia patients: a European cross-over controlled trial in a rare disease.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder associated with abnormal angiogenesis and disabling epistaxis. Tranexamic acid (TA) has been widely used in the treatment of these severe bleeds but with no properly designed trial. OBJECTIVES: To demonstrate the efficacy of TA in epistaxis in HHT patients and to explore its safety of use. PATIENTS/METHODS: A randomized, placebo-controlled, double-blind, cross-over trial was conducted. Participants were randomized to receive TA (3 g a day) then placebo or the opposite sequence. The main analysis compared intra-individual mean duration of epistaxis under TA vs. placebo on a log scale. The primary outcome was the mean duration of epistaxis per month, assessed with specific grids to be completed by participants. The number of epistaxis episodes was recorded as a secondary outcome. RESULTS: A total of 118 randomized patients contributed to the statistical analysis. The mean duration of epistaxis per month was significantly shorter with TA than placebo (0.19 on the log scale; SD = 0.07; P = 0.005), corresponding to a decrease of 17.3% (15.7 min) in the duration of epistaxis per month (CI 95%, 5.5-27.6). The median number of epistaxis episodes per month was 22.1 episodes in the placebo arm vs. 23.3 episodes in the TA arm. No thrombophlebitis was observed. CONCLUSIONS: In the ATERO study, we demonstrated a significant decrease in the duration of epistaxis in HHT patients taking TA. No safety issues were recorded in our cohort of patients.

Cell viability after osteotomy and bone harvesting: comparison of piezoelectric surgery and conventional bur.

The aim of this study was to evaluate and compare the influence of a piezoelectric device versus a conventional bur on osteocyte viability and osteoblast and osteoclast activity using an in vivo mouse model. Osteotomies were created and bone grafts were harvested using either a conventional bur or a piezoelectric device; the resulting injuries and bone grafts were evaluated over an extended time-course using molecular and cellular assays for cell death (TUNEL assay), cell viability (4',6-diamidino-2-phenylindole (DAPI) staining), the onset of mineralization (alkaline phosphatase activity), and bone remodelling (tartrate-resistant acid phosphatase activity). Osteotomies created with a piezoelectric device showed greater osteocyte viability and reduced cell death. Bone grafts harvested with a piezoelectric device exhibited greater short-term cell viability than those harvested with a bur, and exhibited slightly more new bone deposition and bone remodelling. The difference in response of osteocytes, osteoblasts, and osteoclasts to bone cutting via a bur and via a piezoelectric device is negligible in vivo. Given the improved visibility and the margin of safety afforded by a piezoelectric device, they are the instrument of choice when cutting or harvesting bone to preserve soft tissue.

Immunological abnormalities associated with hereditary haemorrhagic telangiectasia.

OBJECTIVE: Hereditary haemorrhagic telangiectasia (HHT) is a genetic disorder related to mutations in one of the coreceptors to the transforming growth factor-ß superfamily (ALK1 or endoglin). Besides the obvious vascular symptoms (epistaxis and arteriovenous malformations), patients have an unexplained high risk of severe bacterial infections. The aim of the study was to assess the main immunological functions of patients with HHT using the standard biological tests for primary immunodeficiencies. DESIGN, SETTING AND SUBJECTS: A prospective single-centre study of 42 consecutive adult patients with an established diagnosis of HHT was conducted at the National French HHT Reference Center (Lyon). Lymphocyte subpopulations and proliferation capacity, immunoglobulin levels and neutrophil and monocyte phagocytosis, oxidative burst and chemotaxis were assessed. RESULTS: Innate immunity was not altered in patients with HHT. With regard to adaptive immunity, significant changes were seen in immunological parameters: primarily, a lymphopenia in patients with HHT compared with healthy control subjects affecting mean CD4 (642 cells µL(-1) vs. 832 cells µL(-1) , P < 0.001), CD8 (295 cells µL(-1) vs. 501 cells µL(-1) , P < 0.0001) and natural killer (NK) cells (169 cells µL(-1) vs. 221 cells µL(-1) , P < 0.01), associated with increased levels of immunoglobulins G and A. This lymphopenia mainly concerned naïve T cells. Proliferation capacities of lymphocytes were normal. Lymphopenic patients had a higher frequency of iron supplementation but no increase in infection rate. Lower levels of immunoglobulin M and a higher rate of pulmonary arteriovenous malformations were found amongst patients with a history of severe infection. CONCLUSIONS: Patients with HHT exhibit immunological abnormalities including T CD4, T CD8 and NK cell lymphopenia and increased levels of immunoglobulins G and A. The observed low level of immunoglobulin M requires further investigation to determine whether it is a specific risk factor for infection in HHT.

Transverse stability of the proximal segment after bilateral sagittal split ramus osteotomy for mandibular setback surgery.

This study aimed to evaluate the correlation between the transverse displacement of the proximal segment after bilateral sagittal osteotomy for mandibular setback and the amount and design of the mandibular setback. Patients who underwent either bilateral sagittal split ramus osteotomy (BSSRO) alone or two-jaw surgery were selected, and cephalographic postero-anterior (PA) measurements were taken pre-operatively (T1), immediately post-operatively (T2), and at follow-up (T3). The inter-gonal (IG) and inter-ramal (IR) width increased immediately after surgery, but decreased to the initial value during follow-up (P=0.002; IR, P=0.046). Only the immediate IG changes after surgery correlated with the amount of mandibular setback (P=0.009). The IG changes were significant in the symmetric group, but not in the asymmetric group. There was no difference in the IG and IR changes between the symmetric group and the asymmetric group. The immediate IG change in two-jaw patients with symmetric setback showed correlation with the setback amount. The gonial width of the deviated group showed more significant changes than that of the non-deviated group. There was no difference in the unilateral gonial width between the deviated and the non-deviated group, but the difference was significant for the unilateral ramal angle between the two groups. These correlations will be helpful in predicting post-surgical results for patients.

[Pregnancy and Ehlers-Danlos vascular syndrome: patients' care and complications]. / Grossesse et syndrome d'Ehlers-Danlos vasculaire : prise en charge et complications.

INTRODUCTION: Elhers-Danlos vascular syndrome type IV (EDS4) is a hereditary pathology of the connective tissue responsible for an increased risk of lethal arterial, uterine and digestive complications during and after pregnancy. PATIENTS AND METHODS: We describe the obstetrical care, the nature and frequency of complications related to pregnancy of patients with EDS4 and their relatives. RESULTS: Twenty-seven pregnancies were studied including 23 deliveries, 18 vaginal deliveries and five caesarean, no maternal death and two major life-threatening complications (8.7%) were recorded which could be directly linked to EDS4 (rupture of the biscupid valve pillar after vaginal delivery and a rupture of the caecum after a prophylactic caesarean). Ten deliveries underwent epidural anesthesia without complication. Six perineal injuries (33.3%) were observed. CONCLUSION: Pregnancy in patient with EDS4 needs obstetrical cares in a special unit's motivated medical team with intensive care and surgical disponibilities.

Real time atomic force microscopy imaging during nanogap formation by electromigration.

We present real time atomic force microscopy imaging during nanogap fabrication by feedback controlled electromigration of a gold nanowire. The correlated measurements of electrical resistance and atomic force microscopy reveal that the major structural changes appear at the early stage of the process. Moreover, despite important morphological changes, the resistance of the nanowire shows a weak increase of just a few ohms. The detailed analysis of the atomic force microscopy images clearly shows that the electromigration process is strongly influenced by the initial microstructure of the nanowire.

Hereditary hemorrhagic telangiectasia: from molecular biology to patient care.

SUMMARY: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by severe and recurrent nosebleeds, mucocutaneous telangiectases, and, in some cases, life-threatening visceral arteriovenous malformations of various types, including pulmonary, hepatic, cerebral, and spinal. Gastrointestinal telangiectases are frequent and may cause severe bleeding. HHT type 1 results from mutations in ENG on chromosome 9 (coding for endoglin), and HHT type 2 results from mutations in ACVRL1 on chromosome 12 (coding for activin receptor-like kinase 1). Mutations of either of these two genes account for most clinical cases. In addition, mutations in MADH4 (encoding SMAD4), which cause a juvenile polyposis/HHT overlap syndrome, have been described, and recently, an HHT3 locus on chromosome 5 (5q31.3-5q32) has been reported. The mutated genes in HHT encode proteins that modulate transforming growth factor-beta superfamily signaling in vascular endothelial cells. Management of patients has changed considerably in the last 20 years, in terms of both treatment and the prevention of complications. The goal of this review was to describe the underlying molecular and cellular physiopathology, explore clinical and genetic diagnostic strategies for HHT, and present clinical management recommendations in order to treat symptomatic disease and to screen for vascular malformations.

A new highly penetrant form of obesity due to deletions on chromosome 16p11.2.

Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.