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Abstract Background Adeno-associated virus (AAV)-based gene therapy for haemophilia has advanced substantially in the last 13 years; recently, three products have received approvals from regulatory authorities. Although the impact on quality of life seems promising, some limitations remain, such as the presence of pre-existing anti-AAV neutralising antibodies and the occurrence of hepatotoxicity. This review follows the CSL Behring-sponsored symposium at the 27th Congress of the European Hematology Association (EHA) 2022 that examined the haemophilia gene therapy process from a 360-degree multidisciplinary perspective. Here, the faculty (haematologist, nurse and haemophilia patient) summarised their own viewpoints from the symposium, with the aim of highlighting the key considerations required to engage with gene therapy effectively, for both patients and providers, as well as the importance of multidisciplinary collaboration, including with industry. Results When considering these new therapies, patients face a complex decision-making process, which includes whether gene therapy is right for them at their current stage of life. The authors agreed that collaboration and tailored education across the multidisciplinary team (including patients and their carers/families), starting early in the process and continuing throughout the long-term follow-up period, is key for the success of gene therapy. Additionally, patient expectations, which may surround eligibility, follow-up requirements and treatment outcomes, should be continually explored. During these ongoing discussions, transparent communication of the unknown factors, such as anticipated clotting factor levels, long-term factor expression and safety, and psychological changes, is critical. To ensure efficiency and comprehensiveness, clearly‑defined protocols should outline the whole process, which should include the recording and management of long-term effects. Conclusion In order to engage effectively, both patients and providers should be familiar with these key considerations prior to their involvement with the haemophilia gene therapy process. The future after the approval of haemophilia gene therapies remains to be seen and real-world evidence is eagerly awaited.

The emergence of new resistant bacterial strains is a worldwide challenge. A resistant bacterial population can emerge from a single cell that acquires resistance or persistence. Hence, new ways of tackling the mechanism of antibiotic response, such as single cell studies are required. It is necessary to see what happens at the single cell level, in order to understand what happens at the population level. To date, linking the heterogeneity of single-cell susceptibility to the population-scale response to antibiotics remains challenging due to the trade-offs between the resolution and the field of view. Here we present a platform that measures the ability of individual E. coli cells to form small colonies at different ciprofloxacin concentrations, by using anchored microfluidic drops and an image and data analysis pipelines. The microfluidic results are benchmarked against classical microbiology measurements of antibiotic susceptibility, showing an agreement between the pooled microfluidic chip and replated bulk measurements. Further, the experimental likelihood of a single cell to form a colony is used to provide a probabilistic antibiotic susceptibility curve. In addition to the probabilistic viewpoint, the microfluidic format enables the characterization of morphological features over time for a large number of individual cells. This pipeline can be used to compare the response of different bacterial strains to antibiotics with different action mechanisms.

Abstract Primary Sjögren’s syndrome (pSS) is an autoimmune disease with frequent neurological involvement. Memory complaints are common, but their precise patterns remain unclear. We wanted to characterize patterns of neurocognitive profiles in pSS patients with cognitive complaints. Only pSS patients with memory complaints were included, prospectively. Cognitive profiles were compiled through a comprehensive cognitive evaluation by neuropsychologists. Evaluations of anxiety, depression, fatigue, sleep disorders and quality of life were performed for testing their interactions with cognitive profiles. All 32 pSS patients showed at least borderline cognitive impairment, and 17 (53%) exhibited a pathological cognitive profile: a hippocampal profile (37%), a dysexecutive profile (22%), and an instrumental profile (16%) (possible overlap). Regarding the secondary objectives: 37% of patients were depressed, and 48% exhibited a mild-to-severe anxiety trait. Sleep disorders were frequent (excessive daytime sleepiness (55%), high risk for sleep apnea (45%), and insomnia (77%)). Cognitive impairments could not be explained alone by anxiety, depression or sleep disorders. Fatigue level was strongly associated with sleep disorders. Our study highlights that cognitive complaints in pSS patients are supported by measurable cognitive impairments, apart from frequently associated disorders such as depression, anxiety or sleep troubles. Sleep disorders should be screened.

The emergence of new resistant bacterial strains is a worldwide challenge. A resistant bacterial population can emerge from a single cell that acquires resistance or persistence. Hence, new ways of tackling the mechanism of antibiotic response, such as single cell studies are required. It is necessary to see what happens at the single cell level, in order to understand what happens at the population level. To date, linking the heterogeneity of single-cell susceptibility to the population-scale response to antibiotics remains challenging due to the trade-offs between the resolution and the field of view. Here we present a platform that measures the ability of individual E. coli cells to form small colonies at different ciprofloxacin concentrations, by using anchored microfluidic drops and an image and data analysis pipelines. The microfluidic results are benchmarked against classical microbiology measurements of antibiotic susceptibility, showing an agreement between the pooled microfluidic chip and replated bulk measurements. Further, the experimental likelihood of a single cell to form a colony is used to provide a probabilistic antibiotic susceptibility curve. In addition to the probabilistic viewpoint, the microfluidic format enables the characterization of morphological features over time for a large number of individual cells. This pipeline can be used to compare the response of different bacterial strains to antibiotics with different action mechanisms. [ABSTRACT FROM AUTHOR]

Limestones are sedimentary rocks more commonly associated with building stones or sculptures than with millstones. Nevertheless, many examples of limestone saddle querns, rotary querns and millstones are spread across France, at times making up the bulk of the archaeological assemblages in various areas characterized by bedrocks rich of sedimentary stones. These limestone millstones are of different types, sources and geological origins: Eocene sandy or fossiliferous limestones, mainly from the various limestones layers from the Lutetian beds, Quaternary calcareous tufas, and fine Jurassic limestones. To explain the behaviour of these rocks, this study advances a classification of the rocks used for millstones, focused not only on the rock-type but mainly on the topological aspect of the stone surface. (empirical macroscopic surface roughness) This renders it possible to classify the rocks into categories by materials, rather than according to petrographic facies. The pure limestones in this study are essentially vacuolar, whereas sandy limestones or certain biodetritital limestones belong to either the granular rocks category, which also includes sandstones, or to the category of heterogeneous rocks. These limestones appear for the most part to have been used due to their availability. Moreover, they epitomise a very satisfactory compromise between their grinding properties and their ease of carving, even if the hardness of these limestones is lower than those of other rocks used as grindstone (basalts or sandstones).

Abstract Background Neutralizing factor VIII (FVIII) antibodies are a major complication in hemophilia A. Antihemophilic factor VIII (recombinant), porcine sequence (rpFVIII; susoctocog alfa; Baxalta US Inc., a Takeda company) has low cross‐reactivity to anti‐human FVIII antibodies and can provide functional FVIII activity in the presence of FVIII inhibitors. Objectives Evaluate in vitro thrombin generation and clot formation responses to rpFVIII in blood from patients with congenital hemophilia A. Methods In this multicenter study, blood was obtained for in vitro analyses that included human and porcine FVIII inhibitors, low

Sandra Le Quellec1,2 1Unité d’hémostase Clinique – Hôpital Cardiologique Louis Pradel – Hospices Civils de Lyon, Lyon, France; 2Service d’hématologie biologique, Groupement Hospitalier Est – Hospices Civils de Lyon, Lyon, FranceCorrespondence: Sandra Le QuellecUnité d’Hémostase Clinique, Hôpital Cardiologique Louis Pradel, 59, boulevard Pinel, Bron 69677, FranceTel +33 4 72 11 88 10Fax +33 4 72 11 88 17Email sandra.le-quellec@chu-lyon.frAbstract: Emicizumab is a bispecific, humanized, monoclonal antibody mimicking the factor (F) VIII cofactor activity in mediating the generation of FXa by FIXa in patients with hemophilia A (HA). This subcutaneous non-factor agent has been recently extensively approved for the prophylaxis of patients of HA patients with and without FVIII-inhibitors of all ages, although few data are currently available in children. In Phase 3 clinical trials and case series, emicizumab prophylaxis significantly reduced bleeding rates compared to previous treatment in HA adolescents and children with or without FVIII-inhibitors and was generally well tolerated. In addition, subcutaneous administration of emicizumab provided beneficial effects on health-related quality of life, and lessened the burden of the disease in HA patients as well as in their caregivers. However, additional prospective studies are required to evaluate the long-term safety of emicizumab prophylaxis in very young patients, including previously untreated patients. The aim of this paper was to review the limited data available on the use of emicizumab prophylaxis in children and to highlight the need for further studies to address remaining concerns.Keywords: emicizumab, hemophilia A, inhibitors, factor VIII, prophylaxis, subcutaneous

Although known for more than a century and a half, the cave paintings and engravings of the Sahara have not yet provided all the information they contain as witnesses to past societies, of which they are often the only remains. Indeed, on the one hand, the failure of any direct dating has led to the establishment of unsubstantiated chronological sequences ; on the other hand, favoured by this lack of a precise temporal framework, and based on outdated paradigms and methodologies, cultural interpretations of these artefacts, both ideal and material, have often proved to be sterile. However, since the 1990s, and at the initiative of Alfred Muzzolini, a current of thought has been working to restore the full archaeological status of these images, using methods that meet modern scientific requirements, both for establishing the documentation and studying it. Although the current context is not conducive to in situ research, these new approaches have led to significant progress in understanding these images.The emergence of digital imaging has thus generated a considerable contribution to the constitution of Saharan corpuses, by revealing very blurred pictures via image processing software, and then by facilitating the tracings and make them more reliable. In addition, computer databases now allow the permanent archiving of these documents as well as their portability to computer tools adapted to their study.On the basis of these more complete inventories, the use of multivariate statistical analyses made it possible to verifiably reproduce the stylistic classification of paintings and engravings, by deepening the concept of "style nuclei" proposed by Alfred Muzzolini. From the series so obtained, different types of archaeological information can then be studied, in particular by areology and phylomemetics, allowing a better characterization of the author groups.Another innovative aspect that we wish to promote, facilitated by the use of the Internet, is sharing data across geopolitical or institutional boundaries, so that research on these remains can be truly successful.

TERTIA BARNETT. 2019. An engraved landscape: rock carvings in the Wadi al-Ajal, Libya. Volume 1: synthesis. Volume 2: gazetteer. London: The Society for Libyan Studies (The Society for Libyan Studies [...]

The corpus of the myths of the "Devouring Calabash" is here enriched and complemented, as well as that of the diluvial myths, not uncommon in Africa contrary to a widespread opinion. Phylomemetics show that the distribution of the African versions of the Devourer is best explained by assuming the existence of two groups, and areal studies suggest that a Eurasian version would have been introduced in East Africa and that it would have spread by enriching itself with the strictly African development according to which an anthropomorphic Devourer is killed and burned, but resurrects in the form of a monstrous calabash growing on the ashes; then this fruit also begins to devour everyone, and it is therefore necessary to kill anew the Devourer thus "reincarnated". This new variant would have spread to the West and South, giving birth to stories in which there is only the calabash, and these new versions would have been more particularly implanted in the West and enriched by a new motive: the one according to which the winner of this vegetal Devourer is no longer a human, but an animal, and more particularly a ram.

Abstract Background Patients with congenital afibrinogenemia suffer from spontaneous recurrent severe bleeding. While fibrinogen concentrates are known to effectively treat bleeding episodes, thrombotic complications often occur upon replacement therapy, rendering clinical management highly challenging. Case Presentation We hereby report a case of combined afibrinogenemia and congenital antithrombin deficiency manifested by recurrent life-threatening bleeding, as well as spontaneous severe arterial occlusion, such as acute coronary syndrome and stroke, and venous thromboses like pulmonary embolism. Secondary fibrinogen prophylaxis is recommended following any initial life-threatening bleeding episode in patients with afibrinogenemia, yet the high associated risk of thrombosis illustrates the complexity of choosing the most effective prophylaxis strategy combining fibrinogen concentrate with antithrombotic agent for optimal protection against the risk of both severe bleeding and thrombosis. For our patient, the thrombin generation assay objectively confirmed her prothrombotic tendency. Conclusion This case may help us better understand the pathophysiology of arterial thrombosis in afibrinogenemia, while highlighting the difficulty of managing such complications.