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The history of hemophilia is well documented, yet reports focus heavily on the male perspective and severe forms of the disease. Although hemophilia was initially believed to only affect men with women seen as silent carriers, it is now universally acknowledged that women and girls can also be affected. In this narrative review, we tracked the progression of beliefs about women and hemophilia as documented in the literature from pre-1800s to the present time. We present a timeline of evolving beliefs and testing practices and identified 9 distinct time periods when key shifts occurred related to various scientific discoveries. Our review highlights how women affected by hemophilia experienced complete dismissal of their health issues despite evidence of bleeding symptoms as early as the 1900s. We identified 1990 as a major timepoint for shifting beliefs when large scale acknowledgment that hemophilia also affects women is documented and systematic testing for bleeding risk is first suggested. Women evolve from being seen as unaffected genetic transmitters only, to being recognized as a population affected by hemophilia in unique ways requiring timely testing and effective treatment. Yet, despite this clear progress, recent publications continue to document many persistent issues such as delayed diagnosis, untreated symptoms, and barriers to care. Ongoing research and advocacy efforts are required to improve knowledge translation until real-world outcomes are seen in screening, diagnosis, treatment, and prevention of bleeding., Competing Interests: Declaration of competing interests P.J. has received research funding from Bayer and consultancy with Star/Vega, Band/Guardian, Roche, and Biomarin. D.L. has received research funding from Biomarin, CSL-Behring, and Sanofi and acted in an advisory role for Biomarin, CSL-Behring, Novo Nordisk, Pfizer, and Takeda. M.S. has received research funding from Octapharma and Pfizer (to institution), and honoraria for speaking engagements from Pfizer, Octapharma, Takeda, Sobi, and Medison. All other authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: It is widely acknowledged that haemophilia affects women and girls, yet current testing recommendations for factor level and genetic testing vary and do not universally incorporate updated research. Canadian parents have expressed frustration at inconsistent recommendations and reported instances where delayed testing led to missed diagnosis and preventable bleeding., Aim: Study aim was to explore and describe the practice of haemophilia-related testing of young girls in Canada., Methods: A mixed methods study was carried out with two populations: (1) Nurses working in haemophilia care completed a survey regarding the current testing recommendations of their Haemophilia Treatment Centre (HTC), (2) Parents of obligate or potential haemophilia carriers completed a structured interview with questions about their family experience of haemophilia and testing decisions for daughters., Results: Twenty-six survey responses were received and showed wide variation in the usual recommendations of Canadian HTCs. Different factor level testing recommendations may be given to obligate and potential carriers despite no difference in bleeding risk. Only a minority of HTCs currently recommend an early baseline factor level (< 10 years) to obligate carriers (27%) or potential carriers (15%). For genetic testing of potential carriers, 70% of HTC would approve a family request for genetic testing of a minor with specific conditions. The majority of parents interviewed felt dissatisfied with their testing experience (58%) and highlighted many issues related to delayed testing recommendations., Conclusion: Updated, nationally affirmed testing recommendations are needed that align with research on bleeding in women and girls affected by haemophilia., (© 2024 The Author(s). Haemophilia published by John Wiley & Sons Ltd.)

MoS 2 nanoribbons have attracted increased interest due to their properties, which can be tailored by tuning their dimensions. Herein, the growth of MoS 2 nanoribbons and triangular crystals formed by the reaction between films of MoOx (22 nanoribbons arising from distinct contributions from the single-layer edges and multilayer core. Nanoscale imaging reveals a blue-shifted exciton emission of the monolayer edge compared to the isolated MoS 2 monolayers due to built-in local strain and disorder. We further report on an ultrasensitive photodetector made of a single MoS 2 nanoribbon with a responsivity of 8.72 × 10 2  A W -1 at 532 nm, among the highest reported up-to-date for single-nanoribbon photodetectors. These findings can inspire the design of MoS 2 semiconductors with tunable geometries for efficient optoelectronic devices., (© 2023 The Authors. Advanced Materials published by Wiley-VCH GmbH.)

The renin-angiotensin system (RAS) is one of the main regulatory systems of cardiovascular homeostasis. It is mainly composed of angiotensin-converting enzyme (ACE) and angiotensin II receptors AT1 and AT2. ACE and AT1 are targets of choice for the treatment of hypertension, whereas the AT2 receptor is still not exploited due to the lack of knowledge of its physiological properties. Peptide toxins from venoms display multiple biological functions associated with varied chemical and structural properties. If Brazilian viper toxins have been described to inhibit ACE, no animal toxin is known to act on AT1/AT2 receptors. We screened a library of toxins on angiotensin II receptors with a radioligand competition binding assay. Functional characterization of the selected toxin was conducted by measuring second messenger production, G-protein activation and β-arrestin 2 recruitment using bioluminescence resonance energy transfer (BRET) based biosensors. We identified one original toxin, A-CTX-cMila, which is a 7-residues cyclic peptide from Conus miliaris with no homology sequence with known angiotensin peptides nor identified toxins, displaying a 100-fold selectivity for AT1 over AT2. This toxin shows a competitive antagonism mode of action on AT1, blocking Gαq, Gαi3, GαoA, β-arrestin 2 pathways and ERK 1/2 activation. These results describe the first animal toxin active on angiotensin II receptors.

This work demonstrates the enhancement in plasmonic sensing efficacy resulting from spatially-localized functionalization on nanostructured surfaces, whereby probe molecules are concentrated in areas of high field concentration. Comparison between SERS measurements on nanostructured surfaces (arrays of nanodisks 110 and 220 nm in diameter) with homogeneous and spatially-localized functionalization with thiophenol demonstrates that the Raman signal originates mainly from areas with high field concentration. TERS measurements with 10 nm spatial resolution confirm the field distribution profiles predicted by the numerical modeling. Though this enhancement in plasmonic sensing efficacy is demonstrated with SERS, results apply equally well to any type of optical/plasmonic sensing on functionalized surfaces with nanostructuring.

Background: Hemophilia carriers experience abnormal bleeding symptoms; however, a lack of awareness about this topic coupled with additional knowledge gaps and barriers leads to suboptimal care for this population., Objective: The primary objective was to describe the current knowledge gaps and challenges from the perspective of both hemophilia carriers and their health care providers., Methods: We carried out a mixed methods descriptive study with two population groups between September and December 2020. The hemophilia carrier perspective was obtained through both focus groups and questionnaires, whereas the health care providers perspective obtained via questionnaire sent to the Association of Hemophilia Care Directors of Canada and the Canadian Association of Nurses in Hemophilia Care. Focus groups were analyzed using descriptive thematic analysis and quantitative survey data was also analyzed., Results: Eleven hemophilia carriers participated along with 19 health care providers (11 physicians, eight nurses). Hemophilia carrier focus group discussions identified four areas representing major challenges or knowledge gaps: (1) negative psychosocial impacts; (2) difficulty determining symptom significance; (3) need for self-advocacy; (4) testing concerns. Survey results from both groups were aligned with the most important topics for ongoing education identified as information on abnormal bleeding symptoms, where to seek treatment, and considerations for heavy menstrual bleeding/menstruation. The majority of both study groups believe obligate or potential carriers should have factor levels checked regardless of age if symptoms of abnormal bleeding occur or before an invasive procedure. However, hemophilia carriers were significantly more in favor of genetic testing under the age of consent than health care providers in all scenarios evaluated., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Approach to the patient with bleeding begins with a thorough bleeding, medical, and family history to determine the nature of bleeding and severity of bleeding symptoms. Use of a Bleeding Assessment Tool allows the clinician to obtain a comprehensive bleeding history and ultimately determine the individual bleeding score that reflects bleeding severity and is classifiable as either normal or abnormal. In the absence of significant findings within patient history or presenting symptoms clearly pointing to a specific bleeding pathology, an approach to laboratory investigation is presented that proceeds through first-line, second-line, and third-line testing., Competing Interests: Disclosure P. James has research funding from Bayer., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Graphene nanoribbons (GNRs) fabricated using electron beam lithography are investigated using tip-enhanced Raman spectroscopy (TERS) with a spatial resolution of 5 nm under ambient conditions. High-resolution TERS imaging reveals a structurally modified 5-10 nm strip of disordered graphene at the edge of the GNRs. Furthermore, hyperspectral TERS imaging discovers the presence of nanoscale organic contaminants on the GNRs. These results pave the way for nanoscale chemical and structural characterisation of graphene-based devices using TERS.

One common challenge highlighted in almost every review article on organic resistive memory is the lack of areal switching uniformity. This, in fact, is a puzzle because a molecular switching mechanism should ideally be isotropic and produce homogeneous current switching free from electroforming. Such a demonstration, however, remains elusive to date. The reports attempting to characterize a nanoscopic picture of switching in molecular films show random current spikes, just opposite to the expectation. Here, this longstanding conundrum is resolved by demonstrating 100% spatially homogeneous current switching (driven by molecular redox) in memristors based on Ru-complexes of azo-aromatic ligands. Through a concurrent nanoscopic spatial mapping using conductive atomic force microscopy and in operando tip-enhanced Raman spectroscopy (both with resolution <7 nm), it is shown that molecular switching in the films is uniform from hundreds of micrometers down to the nanoscale and that conductance value exactly correlates with spectroscopically determined molecular redox states. This provides a deterministic molecular route to obtain spatially homogeneous, forming-free switching that can conceivably overcome the chronic problems of robustness, consistency, reproducibility, and scalability in organic memristors., (© 2020 Wiley-VCH GmbH.)

Two-dimensional transition metal dichalcogenides are gaining increasing interest due to their promising optical properties. In particular, molybdenum disulfide (MoS 2 ) which displays a band-gap change from indirect at 1.29 eV for bulk materials to direct at 1.8 eV for the material monolayer. This particular effect can lead to a strong light interaction which can pave the way for a new approach to the next generation of visible light emitting devices. In this work we show the nanoscale variation of light emission properties by tip-enhanced photoluminescence microscopy and spectroscopy in the MoS 2 monolayer, grown by chemical vapour deposition. The variations of the light emission properties are due to different effects depending on the shape of the MoS 2 single layer, for instance, a different concentration of point defect in an irregularly shaped flake and the presence of a nanoscale terrace in a triangular monolayer. Simultaneously, atomic force microscopy reveals indeed the presence of a nanometric terrace, composed of an additional layer of MoS 2 , and tip-enhanced PL intensity imaging shows a localized intensity decrease.

Visualising the distribution of structural defects and functional groups present on the surface of two-dimensional (2D) materials such as graphene oxide challenges the sensitivity and spatial resolution of the most advanced analytical techniques. Here we demonstrate mapping of functional groups on a carboxyl-modified graphene oxide (GO-COOH) surface with a spatial resolution of ≈10 nm using tip-enhanced Raman spectroscopy (TERS). Furthermore, we extend the capability of TERS by measuring local electronic properties in situ, in addition to the surface topography and chemical composition. Our results reveal that the Fermi level at the GO-COOH surface decreases as the I D /I G ratio increases, correlating the local defect density with the Fermi level at nanometre length-scales. The in situ multi-parameter microscopy demonstrated in this work significantly improves the accuracy of nanoscale surface characterisation, eliminates measurement artefacts, and opens up the possibilities for characterising optoelectronic devices based on 2D materials under operational conditions.

The external pallidum (GPe) is a component of the indirect pathway centrally placed in the basal ganglia. Studies already demonstrated that the pharmacological disinhibition of the sensorimotor, associative, and limbic GPe produced dyskinesia, hyperactivity, and compulsive behaviors, respectively. The aim of this study was to investigate the cortical regions altered by the disinhibition of each GPe functional territory. Thus, 5 macaques were injected with bicuculline in sensorimotor, associative, and limbic sites of the GPe producing dyskinesia, hyperactivity, and compulsive behaviors, and underwent in vivo positron tomography with 18 F-2-fluoro-2-deoxy-D-glucose to identify cortical dysfunctions related to GPe disinhibition. Blood cortisol levels were also quantified as a biomarker of anxiety for each condition. Our results showed that pallidal bicuculline injections in anesthetized animals reproducibly modified the activity of specific ipsilateral and contralateral cortical areas depending on the pallidal territory targeted. Bicuculline injections in the limbic GPe led to increased ipsilateral activations in limbic cortical regions (anterior insula, amygdala, and hippocampus). Injections in the associative vs. sensorimotor GPe increased the activity in the ipsilateral midcingulate vs. somatosensory and parietal cortices. Moreover, bicuculline injections increased blood cortisol levels only in animals injected in their limbic GPe. These are the first functional results supporting the model of opened cortico-striato-thalamo-cortical loops where modifications in a functional pallidal territory can impact cortical activities of the same functional territory but also cortical activities of other functional territories. This highlights the importance of the GPe as a crucial node in the top-down control of the cortico-striato-thalamo-cortical circuits from the frontal cortex to influence the perception, attention, and emotional processes at downstream (or non-frontal) cortical levels. Finally, we showed the implication of the ventral pallidum with the amygdala and the insular cortex in a circuit related to aversive processing that should be crucial for the production of anxious disorders., (Copyright © 2016 Elsevier Inc. All rights reserved.)

We report Tip Enhanced Raman Spectroscopy (TERS) mapping and Density Functional (DFT) calculations of aminothiophenol (ATP) grafted on a gold surface. The TERS mapping has demonstrated Raman modes of (ATP) and its dimerised derivative Dimercaptoazobenzene (DMAB). This feature confirms that the plasmon activated chemical reaction of ATP has occurred during TERS measurements. In some specific part of the samples some unidentified Raman modes are observed. We suggest that they could come from intermediate species formed during the conversion of ATP into DMAB. These modes are compared with calculated Raman spectra of some possible intermediate species. These results confirm the high potentiality of TERS measurements for nanochemistry.