A need to increase von Willebrand disease awareness: vwdtest.com - A global initiative to help address this gap.

Von Willebrand disease (VWD) is an inherited bleeding disorder caused by quantitative or qualitative deficiencies in von Willebrand factor (VWF). People with VWD may experience excessive, recurrent or prolonged bleeding, particularly during menstruation, childbirth, surgery or following trauma. However, many VWD patients are undiagnosed, and therefore inadequately treated. Reasons for the underdiagnosis of VWD include its relatively mild symptoms, complex diagnosis, lack of awareness among non-specialist healthcare providers and the general population, and a lack of prioritisation of disorders disproportionately affecting females. The vwdtest.com platform was launched as part of a global initiative to raise awareness and improve diagnosis of VWD. Besides providing VWD-specific educational resources, the website includes an online bleeding self-assessment tool and offers diagnostic support for individuals, and their providers, who have a score suggestive of a bleeding disorder. vwdtest.com helps to address these unmet needs, especially in regions with limited access to educational and diagnostic resources.

Enhancing the BOADICEA cancer risk prediction model to incorporate new data on RAD51C, RAD51D, BARD1 updates to tumour pathology and cancer incidence.

BACKGROUND: BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) for breast cancer and the epithelial tubo-ovarian cancer (EOC) models included in the CanRisk tool (www.canrisk.org) provide future cancer risks based on pathogenic variants in cancer-susceptibility genes, polygenic risk scores, breast density, questionnaire-based risk factors and family history. Here, we extend the models to include the effects of pathogenic variants in recently established breast cancer and EOC susceptibility genes, up-to-date age-specific pathology distributions and continuous risk factors. METHODS: BOADICEA was extended to further incorporate the associations of pathogenic variants in BARD1, RAD51C and RAD51D with breast cancer risk. The EOC model was extended to include the association of PALB2 pathogenic variants with EOC risk. Age-specific distributions of oestrogen-receptor-negative and triple-negative breast cancer status for pathogenic variant carriers in these genes and CHEK2 and ATM were also incorporated. A novel method to include continuous risk factors was developed, exemplified by including adult height as continuous. RESULTS: BARD1, RAD51C and RAD51D explain 0.31% of the breast cancer polygenic variance. When incorporated into the multifactorial model, 34%-44% of these carriers would be reclassified to the near-population and 15%-22% to the high-risk categories based on the UK National Institute for Health and Care Excellence guidelines. Under the EOC multifactorial model, 62%, 35% and 3% of PALB2 carriers have lifetime EOC risks of <5%, 5%-10% and >10%, respectively. Including height as continuous, increased the breast cancer relative risk variance from 0.002 to 0.010. CONCLUSIONS: These extensions will allow for better personalised risks for BARD1, RAD51C, RAD51D and PALB2 pathogenic variant carriers and more informed choices on screening, prevention, risk factor modification or other risk-reducing options.

Sixth Åland Island Conference on von Willebrand disease.

INTRODUCTION: The sixth Åland Islands Conference on von Willebrand disease (VWD) on the Åland Islands, Finland, was held from 20 to 22 September 2018. AIM: The meeting brought together experts in the field of VWD from around the world to share the latest advances and knowledge in VWD. RESULTS AND DISCUSSION: The topics covered both clinical aspects of disease management, and biochemical and laboratory insights into the disease. The clinical topics discussed included epidemiology, diagnosis and treatment of VWD in different countries, management of children with VWD, bleeding control during surgery, specific considerations for the management of type 3 VWD and bleeding control in women with VWD. Current approaches to the management of acquired von Willebrand syndrome were also discussed. Despite significant advances in the understanding and therapeutic options for VWD, there remain many challenges to be overcome in order to optimise patient care. In comparison with haemophilia A, there are very few registries of VWD patients, which would be a valuable source of data on the condition and its management. VWD is still underdiagnosed, and many patients suffer recurrent or severe bleeding that could be prevented. Awareness of VWD among healthcare practitioners, including non-haematologists, should be improved to allow timely diagnosis and intervention. Diagnosis remains challenging, and the development of fast, simple assays may help to facilitate accurate and rapid diagnosis of VWD.

Time is Blood: The Impact of Diagnostic Delays on Acquired Hemophilia A.

Background and objective Acquired hemophilia A (AHA) is an uncommon autoimmune bleeding disorder caused by the formation of neutralizing antibodies against endogenous factor VIII (FVIII). Delays between the onset of symptoms and the correct diagnosis of the condition lead to poor outcomes and a higher mortality rate. In this study, we aimed to analyze the impact of delays in diagnosis on AHA patients. Methods We conducted a retrospective study at a single hospital system between March 1, 2010, and January 17, 2017, which included six patients meeting the criteria for AHA diagnosis. Results Initial analysis revealed a median age of 79.5 years and a median time to diagnosis from the onset of bleeding of 14 days. Among the six patients, three had cancer (bladder, renal, and prostate) and three had unknown etiologies. One of the patients died prior to the initiation of a bypassing agent. The remaining five patients received recombinant FVIIa (NovoSeven®, Novo Nordisk, Bagsværd, Denmark), and two of those five required a second-line bypassing agent, recombinant porcine sequence FVIII (Obizur®, Takeda Pharmaceutical, Tokyo, Japan) for refractory bleeding. All five patients achieved hemostasis; however, three died within a year, and none of the patients survived for five years. Four of these five patients died directly from bleeding complications. Conclusions Based on our study findings and review of the literature, we propose an algorithm to potentially aid in the early diagnosis and treatment of AHA in emergency and non-specialized settings.

The effects of gender, age, and videogame experience on performance and experiences with a surgical robotic arm: an exploratory study with general public.

Robotic surgery is increasing in prevalence, thanks to its potential benefits for patients (e.g., reduced blood loss) and surgeons (e.g., ergonomics). It is important to know what inherent characteristics of potential surgeons may facilitate robotic surgery training and performance. Findings from previous studies indicate videogames can be inexpensive tools that help improve hand-eye coordination, coordination of 3-D movements with 2-D images, and spatial orientation. In the context of robotic-assisted knee arthroscopy using a MAKO robotic arm, this study explored performance and subjective experiences of novices (N = 104) with a fake bone shaving task at a public event. Participants' performance was measured based on how much of the bone they successfully shaved. Findings showed that duration of videogame play per week was negatively related to performance with the robotic arm. Male and female participants performed similarly on the bone shaving task, and reported similar difficulty with and enjoyment of the task. However, female participants who played videogames performed better than those who did not play videogames. Participants who were younger than 11 had the worst performance and the most difficulty with the robotic arm. Overall, the findings indicate that the effect of videogame experience on the performance with the robotic arm may differ based on gender and age. This has implications on the length of training for surgeons of different gender using videogames and other emerging technologies.

CanRisk Tool-A Web Interface for the Prediction of Breast and Ovarian Cancer Risk and the Likelihood of Carrying Genetic Pathogenic Variants.

BACKGROUND: The CanRisk Tool (https://canrisk.org) is the next-generation web interface for the latest version of the BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) state-of-the-art risk model and a forthcoming ovarian cancer risk model. METHODS: The tool captures information on family history, rare pathogenic variants in cancer susceptibility genes, polygenic risk scores, lifestyle/hormonal/clinical features, and imaging risk factors to predict breast and ovarian cancer risks and estimate the probabilities of carrying pathogenic variants in certain genes. It was implemented using modern web frameworks, technologies, and web services to make it extensible and increase accessibility to researchers and third-party applications. The design of the graphical user interface was informed by feedback from health care professionals and a formal evaluation. RESULTS: This freely accessible tool was designed to be user friendly for clinicians and to boost acceptability in clinical settings. The tool incorporates a novel graphical pedigree builder to facilitate collection of the family history data required by risk calculations. CONCLUSIONS: The CanRisk Tool provides health care professionals and researchers with a user-friendly interface to carry out multifactorial breast and ovarian cancer risk predictions. It is the first freely accessible cancer risk prediction program to carry the CE marking. IMPACT: There have been over 3,100 account registrations, and 98,000 breast and ovarian cancer risk calculations have been run within the first 9 months of the CanRisk Tool launch.

A systematic review and meta-analysis of telephone vs in-person genetic counseling in BRCA1/BRCA2 genetic testing.

Pathogenic variants in the BRCA1 and BRCA2 genes increase the risk of breast and ovarian cancer. Individuals with identified pathogenic variants in the BRCA1 or BRCA2 gene can benefit from cancer risk-reducing strategies. In the recent years, there has been an increase in the demand of genetic services. In light of the ongoing COVID19 pandemic, alternatives to face-to-face consultations have had to be considered and adopted, including telemedicine. Informed consent is necessary for genetic testing. Studies have suggested that increased levels of cancer-specific distress may impair the patient's ability to retain information, therefore, providing informed consent. This systematic review and meta-analysis aimed to answer if telephone genetic counseling for BRCA1 and BRCA2 genetic testing is non-inferior to in-person genetic counseling for the outcomes of cancer-specific distress and genetic knowledge. Databases of Medline, Embase, PsycINFO, CINAHL, SciELO, Web of Science, CENTRAL, ProQuest Dissertation & Theses Database, Clinicaltrials.gov, EU clinical trials register were accessed to identify any published or unpublished relevant literature. Random-effects models were used for the meta-analysis. Four studies were included in the qualitative synthesis of the results. Three studies were included in the quantitative synthesis of the results. Telephone genetic counseling was non-inferior compared to in-person genetic counseling for the outcomes of cancer-specific distress and genetic knowledge. Sensitivity analysis corroborated the main results. Telephone genetic counseling for BRCA1/BRCA2 genetic testing may be an alternative model of delivering genetic services in front of the increased demand/or when required by social context. However, the paucity of the evidence prevents from drawing strong conclusions regarding the generalizability of these results. Further research is needed to strengthen the conclusions.

Evaluation of a Combined HIV and Geriatrics Clinic for Older People Living with HIV: The Silver Clinic in Brighton, UK.

As life expectancy in people living with HIV (PLWH) has increased, the focus of management has shifted to preventing and treating chronic illnesses, but few services exist for the assessment and management of these individuals. Here, we provide an initial description of a geriatric service for people living with HIV and present data from a service evaluation undertaken in the clinic. We conducted an evaluation of the first 52 patients seen in the clinic between 2016 and 2019. We present patient demographic data, assessment outcomes, diagnoses given, and interventions delivered to those seen in the clinic. The average age of attendees was 67. Primary reasons for referral to the clinic included management of complex comorbidities, polypharmacy, and suspected geriatric syndrome (falls, frailty, poor mobility, or cognitive decline). The median (range) number of comorbidities and comedications (non-antiretrovirals) was 7 (2-19) and 9 (1-15), respectively. All attendees had an undetectable viral load. Geriatric syndromes were observed in 26 (50%) patients reviewed in the clinic, with frailty and mental health disease being the most common syndromes. Interventions offered to patients included combination antiretroviral therapy modification, further health investigations, signposting to rehabilitation or social care services, and in-clinic advice. High levels of acceptability among patients and healthcare professionals were reported. The evaluation suggests that specialist geriatric HIV services might play a role in the management of older people with HIV with geriatric syndromes.

A Study of the Cellular Uptake of Magnetic Branched Amphiphilic Peptide Capsules.

Understanding cellular uptake mechanisms of nanoparticles with therapeutic potential has become critical in the field of drug delivery. Elucidation of cellular entry routes can aid in the dissection of the complex intracellular trafficking and potentially allow for the manipulation of nanoparticle fate after cellular delivery (i.e., avoid lysosomal degradation). Branched amphiphilic peptide capsules (BAPCs) are peptide nanoparticles that have been and are being explored as delivery systems for nucleic acids and other therapeutic molecules in vitro and in vivo. In the present study, we determined the cellular uptake routes of BAPCs with and without a magnetic nanobead core (BAPc-MNBs) in two cell lines: macrophages and intestinal epithelial cells. We also studied the influence of size and growth media composition in this cellular process. Substituting the water-filled core with magnetic nanobeads might provide the peptide bilayer nanocapsules with added functionalities, facilitating their use in bio/immunoassays, magnetic field guided drug delivery, and magnetofection among others. Results suggest that BAPc-MNBs are internalized into the cytosol using more than one endocytic pathway. Flow cytometry and analysis of reactive oxygen and nitrogen species (ROS/RNS) demonstrated that cell viability was minimally impacted by BAPc-MNBs. Cellular uptake pathways of peptide vesicles remain poorly understood, particularly with respect to endocytosis and intracellular trafficking. Outcomes from these studies provide a fundamental understanding of the cellular uptake of this peptide-based delivery system which will allow for strengthening of their delivery capabilities and expanding their applications both in vitro and in vivo.

Deep Learning for US Image Quality Assessment Based on Femoral Cartilage Boundary Detection in Autonomous Knee Arthroscopy.

Knee arthroscopy is a complex minimally invasive surgery that can cause unintended injuries to femoral cartilage or postoperative complications, or both. Autonomous robotic systems using real-time volumetric ultrasound (US) imaging guidance hold potential for reducing significantly these issues and for improving patient outcomes. To enable the robotic system to navigate autonomously in the knee joint, the imaging system should provide the robot with a real-time comprehensive map of the surgical site. To this end, the first step is automatic image quality assessment, to ensure that the boundaries of the relevant knee structures are defined well enough to be detected, outlined, and then tracked. In this article, a recently developed one-class classifier deep learning algorithm was used to discriminate among the US images acquired in a simulated surgical scenario on which the femoral cartilage either could or could not be outlined. A total of 38 656 2-D US images were extracted from 151 3-D US volumes, collected from six volunteers, and were labeled as "1" or as "0" when an expert was or was not able to outline the cartilage on the image, respectively. The algorithm was evaluated using the expert labels as ground truth with a fivefold cross validation, where each fold was trained and tested on average with 15 640 and 6246 labeled images, respectively. The algorithm reached a mean accuracy of 78.4% ± 5.0, mean specificity of 72.5% ± 9.4, mean sensitivity of 82.8% ± 5.8, and mean area under the curve of 85% ± 4.4. In addition, interobserver and intraobserver tests involving two experts were performed on an image subset of 1536 2-D US images. Percent agreement values of 0.89 and 0.93 were achieved between two experts (i.e., interobserver) and by each expert (i.e., intraobserver), respectively. These results show the feasibility of the first essential step in the development of automatic US image acquisition and interpretation systems for autonomous robotic knee arthroscopy.

POSTMORTEM DETECTION OF BLUETONGUE AND EPIZOOTIC HEMORRHAGIC DISEASE VIRUSES IN THE BONE MARROW OF WHITE-TAILED DEER (ODOCOILEUS VIRGINIANUS).

We determined the temporal aspects of detecting bluetongue virus (BTV) and epizootic hemorrhagic disease virus (EHDV) in postmortem bone marrow samples of white-tailed deer (Odocoileus virginianus) using molecular and in vitro cell culture techniques. Bone marrow samples from carcasses were collected and assayed on the day of death and at intervals up to 16 wk after death. We recovered BTV and EHDV from fresh bone marrow collected at day 0 by isolation in Vero and BHK-21 cell cultures. However, attempts to replicate the viruses from aged bone marrow in Vero and BHK-21 cell cultures failed. The real-time quantitative reverse transcriptase PCR (qRT-PCR) results confirmed that EHDV and BTV can be detected in aged bone marrow for up to 12 and 16 wk, respectively, after death. The RNA of BTV and EHDV could be detected by qRT-PCR in white-tailed deer bone marrow for extended periods of time postmortem. This technique will provide a useful tool for retrospective determination of BTV or EHDV infection of white-tailed deer at the time of death.

Ultrasound guidance in minimally invasive robotic procedures.

In the past decade, medical robotics has gained significant traction within the surgical field. While the introduction of fully autonomous robotic systems for surgical procedures still remains a challenge, robotic assisted interventions have become increasingly more interesting for the scientific and clinical community. This happens especially when difficulties associated with complex surgical manoeuvres under reduced field of view are involved, as encountered in minimally invasive surgeries. Various imaging modalities can be used to support these procedures, by re-creating a virtual, enhanced view of the intervention site. Among them, ultrasound imaging showed several advantages, such as cost effectiveness, non-invasiveness and real-time volumetric imaging. In this review we comprehensively report about the interventional applications where ultrasound imaging has been used to provide guidance for the intervention tools, allowing the surgeon to visualize intra-operatively the soft tissue configuration in real-time and to compensate for possible anatomical changes. Future directions are also discussed, in particular how the recent developments in 3D/4D ultrasound imaging and the introduction of advanced imaging capabilities (such as elastography) in commercially available systems may fulfil the unmet needs towards fully autonomous robotic interventions.

Orthopaedic surgeon attitudes towards current limitations and the potential for robotic and technological innovation in arthroscopic surgery.

PURPOSE: To determine the perceptions of surgeons at both consultant and resident level to the difficulties of performing knee arthroscopy and to determine their willingness to adopt robotic technology. METHODS: A questionnaire was designed to discern the attitude of orthopaedic consultants and residents to the technical challenges of performing knee arthroscopy and the possible role of robotically enhanced surgery. The questionnaire included 31 questions across five key domains. RESULTS: Iatrogenic damage to articular cartilage was thought to occur in at least 1 in 10 cases by 50% of respondents with 15% believing that it occurred in every case. One hundred or more procedures were thought to be necessary to overcome the learning curve by 40% of respondents and 77.5% believed that 50 procedures or above were necessary. Ninety-nine per cent of respondents agreed that higher technical skills would decrease unintended damage. Despite such difficulties with the procedure and no prior experience with robotic surgery, 47% of respondents see a role for semiautonomous arthroscopic systems in the future. CONCLUSIONS: Surgeons believe that knee arthroscopy is a difficult procedure with a long learning curve and a high incidence of iatrogenic cartilage damage. Many find it ergonomically challenging and have frustration with current tools and technology. CLINICAL RELEVANCE: This is the first study that highlights surgeons' difficulties performing knee arthroscopy despite the commonly held attitudes that it is a straightforward procedure. Systems that are able to decrease these problems should improve patients' outcomes and decrease the risk of harm.

Radioprotective lightweight caps in the interventional cardiology setting: a randomised controlled trial (PROTECT).

AIMS: The aim of this study was to test the radioprotection efficacy and comfort of newer bilayer barium sulphate-bismuth oxide composite (XPF) caps in an interventional cardiology setting. METHODS AND RESULTS: Operators were randomly assigned to wear standard fabric (n=59), 0.3 mm (n=74), or 0.5 mm (n=64) lead-equivalent XPF caps. Radiation doses were measured by using dosimeters placed outside and underneath the caps. Wearing comfort was assessed at the end of each measurement on a visual analogue scale (VAS) (0-100, with 100 indicating optimal comfort). Procedural data did not differ between the XPF and standard groups. Mean standard, XPF 0.3 mm, and XPF 0.5 mm cap weights were 12.5 g, 118.4 g, and 123.7 g, respectively. VAS comfort ratings of the standard and XPF caps did not differ significantly (p=0.272). The mean radiation protection was 12.0%, 95% CI: 4.9-19.1% (standard caps, n=35), 91.5%, 95% CI: 87.4-95.6% (XPF 0.3 mm caps, n=45) and 97.1%, 95% CI: 92.5-100% (XPF 0.5 mm caps, n=44) (p≤0.001 for all group comparisons). Using the XPF caps, a cumulative total radiation dose reduction by almost factor 10 was evident (272 procedures, 22,310 µSv outside the XPF caps, 2,770 µSv inside the caps). CONCLUSIONS: Lightweight XPF caps show comparable comfort to standard fabric caps, but provide substantial radiation protection during fluoroscopy-guided cardiac interventions.

Differential role of P-glycoprotein and breast cancer resistance protein in drug distribution into brain, CSF and peripheral nerve tissues in rats.

1. This study was designed to evaluate how the absence of P-glycoprotein (Pgp, Mdr1a), breast cancer-resistance protein (Bcrp, Abcg2) or both affects drug distribution into sciatic nerves, brain and cerebrospinal fluid (CSF) in rats. 2. Pgp substrate (loperamide), BCRP substrates (dantrolene and proprietary compound X) and dual substrates (imatinib and proprietary compound Y) were well distributed into sciatic nerves with comparable nerve to plasma concentration ratios between wild-type and knockout (KO) rats. 3. Brain exposure increased substantially in Mdr1a(-/-) rats for loperamide and in Mdr1a(-/-)/Abcg2(-/-) rats for imatinib and compound Y, but minimally to modestly in Abcg2(-/-) rats for dantrolene and compound X. The deletion of Mdr1a or Abcg2 alone had little effect on brain distribution of compound Y. 4. While CSF to unbound brain concentration ratio remained ≥3 in the KO animals for dantrolene, compounds X and Y, it was reduced to 1 in the Mdr1a(-/-)/Abcg2(-/-) rats for imatinib. 5. The data indicate that Pgp and Bcrp do not play significant roles in drug distribution into peripheral nerve tissues in rats, while working in concert to regulate brain penetration. Our results further support that CSF concentration may not be a good surrogate for unbound brain concentration of efflux substrates.

Breast-cancer risk in families with mutations in PALB2.

BACKGROUND: Germline loss-of-function mutations in PALB2 are known to confer a predisposition to breast cancer. However, the lifetime risk of breast cancer that is conferred by such mutations remains unknown. METHODS: We analyzed the risk of breast cancer among 362 members of 154 families who had deleterious truncating, splice, or deletion mutations in PALB2. The age-specific breast-cancer risk for mutation carriers was estimated with the use of a modified segregation-analysis approach that allowed for the effects of PALB2 genotype and residual familial aggregation. RESULTS: The risk of breast cancer for female PALB2 mutation carriers, as compared with the general population, was eight to nine times as high among those younger than 40 years of age, six to eight times as high among those 40 to 60 years of age, and five times as high among those older than 60 years of age. The estimated cumulative risk of breast cancer among female mutation carriers was 14% (95% confidence interval [CI], 9 to 20) by 50 years of age and 35% (95% CI, 26 to 46) by 70 years of age. Breast-cancer risk was also significantly influenced by birth cohort (P<0.001) and by other familial factors (P=0.04). The absolute breast-cancer risk for PALB2 female mutation carriers by 70 years of age ranged from 33% (95% CI, 25 to 44) for those with no family history of breast cancer to 58% (95% CI, 50 to 66) for those with two or more first-degree relatives with breast cancer at 50 years of age. CONCLUSIONS: Loss-of-function mutations in PALB2 are an important cause of hereditary breast cancer, with respect both to the frequency of cancer-predisposing mutations and to the risk associated with them. Our data suggest the breast-cancer risk for PALB2 mutation carriers may overlap with that for BRCA2 mutation carriers. (Funded by the European Research Council and others.).