An update on oral cavity cancer: epidemiological trends, prevention strategies and novel approaches in diagnosis and prognosis.

In the UK, the incidence of oral cavity cancer continues to rise, with an increase of around 60% over the past 10 years. Many patients still present with advanced disease, often resulting in locoregional recurrence and poor outcomes, which has not changed significantly for over four decades. Changes in aetiology may also be emerging, given the decline of smoking in developed countries. Therefore, new methods to better target prevention, improve screening and detect recurrence are needed. High-throughput 'omics' technologies appear promising for future individual-level diagnosis and prognosis. However, given this is a relatively rare cancer with significant intra-tumour heterogeneity and variation in patient response, reliable biomarkers have been difficult to elucidate. From a public health perspective, implementing these novel technologies into current services would require substantial practical, financial and ethical considerations. This may be difficult to justify and implement at present, therefore focus remains on early detection using new patient-led follow-up strategies. This paper reviews the latest evidence on epidemiological trends in oral cavity cancer to help identify at risk groups, population-based approaches for prevention, in addition to potential cutting-edge approaches in the diagnosis and prognosis of this disease.

A meta-analysis comparing the diagnostic performance of abbreviated MRI and a full diagnostic protocol in breast cancer.

AIM: To undertake a meta-analysis of the diagnostic performance of abbreviated (ABB) magnetic resonance imaging (MRI) and full diagnostic protocol MRI (FDP-MRI) in breast cancer. MATERIALS AND METHODS: This meta-analysis was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis for Diagnostic Test Accuracy (PRISMA-DTA) guidelines. The PubMed and EMBASE databases were searched through August 2019 for studies comparing the diagnostic performance of ABB-MRI and FDP-MRI in the breast. Studies were reviewed by two authors independently according to eligibility and exclusion criteria and split into two subgroups (screening population studies and studies using cohorts enriched with known cancers) to avoid bias. Quality assessment and bias for diagnostic accuracy was determined with Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). The diagnostic accuracy for each subgroup was pooled using a bivariate random effects model and summary receiver operating characteristic (sROC) curves produced. Sensitivities and specificities were compared using a paired t-test. RESULTS: Five screening (62/2,588 cancers/patients) and eight enriched cohort (540/1,432 cancers/patients) studies were included in the meta-analysis. QUADAS-2 assessment showed a low risk of bias in most studies. The pooled sensitivity/specificity/area under the receiver operating characteristic curve (AUC) for screening studies was 0.90/0.92/0.94 for ABB-MRI and 0.92/0.95/0.97 for FDP-MRI. The pooled sensitivity/specificity/AUC for enriched cohort studies was 0.93/0.83/0.94 for ABB-MRI and 0.93/0.84/0.95 for FDP-MRI. There was no significant difference in sensitivity or specificity using ABB-MRI or FDP-MRI (p=0.18 and 0.27, p=0.18 and 0.93, respectively). CONCLUSION: The diagnostic performances of the ABB-MRI and FDP-MRI protocols used in either screening or enriched cohorts were comparable. There was a large variation in patient population, study methodology, and abbreviated protocols reported.

"There is a Place": impacts of managed alcohol programs for people experiencing severe alcohol dependence and homelessness.

BACKGROUND: The twin problems of severe alcohol dependence and homelessness are associated with precarious living and multiple acute, social and chronic harms. While much attention has been focused on harm reduction services for illicit drug use, there has been less attention to harm reduction for this group. Managed alcohol programs (MAPs) are harm reduction interventions that aim to reduce the harms of severe alcohol use, poverty and homelessness. MAPs typically provide accommodation, health and social supports alongside regularly administered sources of beverage alcohol to stabilize drinking patterns and replace use of non-beverage alcohol (NBA). METHODS: We examined impacts of MAPs in reducing harms and risks associated with substance use and homelessness. Using case study methodology, data were collected from five MAPs in five Canadian cities with each program constituting a case. In total, 53 program participants, 4 past participants and 50 program staff were interviewed. We used situational analysis to produce a series of "messy", "ordered" and "social arenas" maps that provide insight into the social worlds of participants and the impact of MAPs. RESULTS: Prior to entering a MAP, participants were often in a revolving world of cycling through multiple arenas (health, justice, housing and shelters) where abstinence from alcohol is often required in order to receive assistance. Residents described living in a street-based survival world characterized by criminalization, unmet health needs, stigma and unsafe spaces for drinking and a world punctuated by multiple losses and disconnections. MAPs disrupt these patterns by providing a harm reduction world in which obtaining accommodation and supports are not contingent on sobriety. MAPs represent a new arena that focuses on reducing harms through provision of safer spaces and supply of alcohol, with opportunities for reconnection with family and friends and for Indigenous participants, Indigenous traditions and cultures. Thus, MAPs are safer spaces but also potentially spaces for healing. CONCLUSIONS: In a landscape of limited alcohol harm reduction options, MAPs create a new arena for people experiencing severe alcohol dependence and homelessness. While MAPs reduce precarity for participants, programs themselves remain precarious due to ongoing challenges related to lack of understanding of alcohol harm reduction and insecure program funding.

Hypervelocity collision and water-rock interaction in space preserved in the Chelyabinsk ordinary chondrite.

A comprehensive geochemical study of the Chelyabinsk meteorite reveals further details regarding its history of impact-related fragmentation and melting, and later aqueous alteration, during its transit toward Earth. We support an ∼30 Ma age obtained by Ar-Ar method (Beard et al., 2014) for the impact-related melting, based on Rb-Sr isotope analyses of a melt domain. An irregularly shaped olivine with a distinct O isotope composition in a melt domain appears to be a fragment of a silicate-rich impactor. Hydrogen and Li concentrations and isotopic compositions, textures of Fe oxyhydroxides, and the presence of organic materials located in fractures, are together consistent with aqueous alteration, and this alteration could have pre-dated interaction with the Earth's atmosphere. As one model, we suggest that hypervelocity capture of the impact-related debris by a comet nucleus could have led to shock-wave-induced supercritical aqueous fluids dissolving the silicate, metallic, and organic matter, with later ice sublimation yielding a rocky rubble pile sampled by the meteorite.

Pathogenesis of Vesicular Stomatitis New Jersey Virus Infection in Deer Mice ( Peromyscus maniculatus) Transmitted by Black Flies ( Simulium vittatum).

The natural transmission of vesicular stomatitis New Jersey virus (VSNJV), an arthropod-borne virus, is not completely understood. Rodents may have a role as reservoir or amplifying hosts. In this study, juvenile and nestling deer mice ( Peromyscus maniculatus) were exposed to VSNJV-infected black fly ( Simulium vittatum) bites followed by a second exposure to naive black flies on the nestling mice. Severe neurological signs were observed in some juvenile mice by 6 to 8 days postinoculation (DPI); viremia was not detected in 25 juvenile deer mice following exposure to VSNJV-infected fly bites. Both juvenile and nestling mice had lesions and viral antigen in the central nervous system (CNS); in juveniles, their distribution suggested that the sensory pathway was the most likely route to the CNS. In contrast, a hematogenous route was probably involved in nestling mice, since all of these mice developed viremia and had widespread antigen distribution in the CNS and other tissues on 2 DPI. VSNJV was recovered from naive flies that fed on viremic nestling mice. This is the first report of viremia in a potential natural host following infection with VSNJV via insect bite and conversely of an insect becoming infected with VSNJV by feeding on a viremic host. These results, along with histopathology and immunohistochemistry, show that nestling mice have widespread dissemination of VSNJV following VSNJV-infected black fly bite and are a potential reservoir or amplifying host for VSNJV.

Sympathetic hyper-excitation in obesity and pulmonary hypertension: physiological relevance to the 'obesity paradox'.

BACKGROUND: Within the lung, sympathetic nerve activity (SNA) has an important role in facilitating pulmonary vasodilation. As SNA is elevated in obesity, we aimed to assess the impact of sympathetic hyper-excitation on pulmonary vascular homeostasis in obesity, and its potential role in ameliorating the severity of pulmonary hypertension (PH); the well-documented 'obesity paradox' phenomenon. METHODS: Zucker obese and lean rats were exposed to normoxia or chronic hypoxia (CH-10% O2) for 2 weeks. Subsequently, pulmonary SNA (pSNA) was recorded (electrophysiology), or the pulmonary microcirculation was visualized using Synchrotron microangiography. Acute hypoxic pulmonary vasoconstriction (HPV) was assessed before and after blockade of ß1-adrenergic receptors (ARs) (atenolol, 3 mg kg(-1)) and ß1+ß2-adrenergic (propranolol, 2 mg kg(-1)). RESULTS: pSNA of normoxic obese rats was higher than lean counterparts (2.4 and 0.5 µV s, respectively). SNA was enhanced following the development of PH in lean rats, but more so in obese rats (1.7 and 6.8 µV s, respectively). The magnitude of HPV was similar for all groups (for example, ~20% constriction of the 200-300 µm vessels). Although ß-blockade did not modify HPV in lean rats, it significantly augmented the HPV in normoxic obese rats (ß1 and ß2 blockade), and more so in obese rats with PH (ß2-blockade alone). Western blots showed, while the expression of pulmonary ß1-ARs was similar for all rats, the expression of ß2-ARs was downregulated in obesity and PH. CONCLUSIONS: This study suggests that sympathetic hyper-excitation in obesity may have an important role in constraining the severity of PH and, thus, contribute in part to the 'obesity paradox' in PH.

Direct costs of interferon-based and interferon-free direct-acting antiviral regimens for the treatment of chronic hepatitis C infection.

Given the increasing budget impact of Hepatitis C virus (HCV) treatment, robust real-world cost data are essential for healthcare decision-makers to evaluate and understand the costs and benefits of these treatments. To determine the direct cost of treating HCV infection in a hospital-based ambulatory care setting in Ireland based on available data from the Irish national hepatitis C treatment registry. A microcosting study of the direct costs of patients with hepatitis C treated with interferon-based and interferon-free direct-acting antiviral regimens was conducted. Attendance at the outpatient clinic for clinical assessment, the quantity of resources used per patient, the medication prescribed and the identification and timing of staff involvement was measured and combined to establish a mean cost of treatment per patient and a cost per sustained virological response (SVR). One hundred and sixty-eight patients were included in the analysis; 119 treated with interferon-based direct-acting antiviral regimens and 47 treated with interferon-free regimens. The mean costs of treatment with the interferon-based regimens per patient were €38 286 (95% CI €35 305-€41 061). The cost per SVR was €62 457. The mean cost of treatment with interferon-free regimens per patient was €55 734 (95% CI €50 906-€60 880). The cost per SVR was €81 873. Real-world cost data provide valuable information to enhance reimbursement decisions. While the direct costs associated with hepatitis C treatment in Ireland are substantial, it is reasonable to expect that the mean cost of treatment and the cost per SVR will reduce as patients with less advanced disease are treated with interferon-free therapies.

Baseline abnormal liver function tests are more important than age in the development of isoniazid-induced hepatoxicity for patients receiving preventive therapy for latent tuberculosis infection.

BACKGROUND: One of the cornerstones of Australia's public health programmes to eliminate tuberculosis (TB) is the identification and treatment of latent tuberculosis infection (LTBI). AIMS: The main aim of this study is to determine the demographics, compliance, completion rates and adverse events of patients on preventive therapy (PT) for LTBI at our institution. The secondary aim is to determine the rates of isoniazid (INH) hepatotoxicity and identify any contributory factors. METHODS: The method used was an audit using medical records of 100 consecutive patients (2010-2014) treated with PT for LTBI. RESULTS: Seventy-two patients with confirmed LTBI started 9 months of INH and 22 started 4 months of rifampicin (RIF). The median age was 30 years. Half the patients were born in high TB-prevalence countries. Fifty-six per cent were contacts of index cases with confirmed TB, and 26% were pre-immunosuppression. Seventy-seven per cent completed PT with adequate compliance. Thirty-three per cent on INH and 23% on RIF experienced some liver function test (LFT) abnormality while on treatment. INH was ceased in 3% due to asymptomatic hepatic dysfunction (transaminases >5x upper limit of normal). No patients had permanent liver damage. Significant risk factors for liver dysfunction during PT were risk factors for liver disease (χ(3)(2) = 8.7; P = 0.03) or abnormal pre-therapy LFT (χ(3)(2)= 22.4; P < 0.001). No patients developed active TB. CONCLUSION: The completion rate of 77% and rate of INH-induced hepatic dysfunction of 3% is comparable with the literature. We found no age association with the risk of INH-induced hepatic dysfunction; however, there was a significant and linear association with the degree of liver function abnormality during INH therapy and the presence of abnormal baseline LFT. Routine LFT monitoring allowed early cessation of INH in those with significant but asymptomatic hepatitis who did not meet criteria for ATS/CDC LFT monitoring.

Donor-derived Strongyloides stercoralis infection in solid organ transplant recipients in the United States, 2009-2013.

Infection with Strongyloides stercoralis is typically asymptomatic in immunocompetent hosts, despite chronic infection. In contrast, immunocompromised hosts such as solid organ transplant recipients are at risk for hyperinfection syndrome and/or disseminated disease, frequently resulting in fatal outcomes. Infection in these recipients may result from reactivation of latent infection or infection through transmission from an infected donor. We describe the Centers for Disease Control and Prevention's experience with seven clusters of donor-derived infection from 2009 to 2013. Six of the seven (86%) donors were born in Latin America; donor screening was not performed prior to organ transplantation in any of these investigations. Eleven of the 20 (55%) organ recipients were symptomatic, two of whom died from complications of strongyloidiasis. We also describe the New York Organ Donor Network (NYODN) experience with targeted donor screening from 2010 to 2013. Of the 233 consented potential donors tested, 10 tested positive for Strongyloides antibody; and 18 organs were transplanted. The majority (86%) of the donors were born in Central or South America. Fourteen recipients received prophylaxis after transplantation; no recipients developed strongyloidiasis. The NYODN experience provides evidence that when targeted donor screening is performed prior to transplantation, donor-derived infection can be averted in recipients.

Potency determination of factor VIII and factor IX for new product labelling and postinfusion testing: challenges for caregivers and regulators.

A workshop organized by the European Medicines Agency and the European Directorate for the Quality of Medicines and HealthCare was held in London, UK on November 28-29, 2013, to provide an overview of the current knowledge of the characterization of new factor VIII (FVIII) and factor IX (FIX) concentrates with respect to potency assays and testing of postinfusion material. The objective was to set the basis for regulatory authorities' discussion on the most appropriate potency assay for the individual products, and European Pharmacopoeia (Ph. Eur.) discussion on whether to propose revision of the Ph. Eur. monographs with respect to potency assays in the light of information on new FVIII and FIX concentrates. The workshop showed that for all products valid assays vs. the international concentrate standards were obtained and potency could be expressed in International Units. The Ph. Eur. chromogenic potency assay gave valid assay results which correlate with in vivo functionality of rFVIII products. For some modified rFVIII products and all modified rFIX products, one-stage clotting assay methods result in different potencies depending on the activated partial thromboplastin time reagent. As a consequence, monitoring of patients' postinfusion levels is challenging but it was pointed out that manufacturers are responsible for providing the users with appropriate information for use and laboratory testing of their product. Strategies to avoid misleading determination of patents' plasma levels, e.g. information on suitable assays, laboratory standards or correction factors were discussed.

2013 multistate outbreaks of Cyclospora cayetanensis infections associated with fresh produce: focus on the Texas investigations.

The 2013 multistate outbreaks contributed to the largest annual number of reported US cases of cyclosporiasis since 1997. In this paper we focus on investigations in Texas. We defined an outbreak-associated case as laboratory-confirmed cyclosporiasis in a person with illness onset between 1 June and 31 August 2013, with no history of international travel in the previous 14 days. Epidemiological, environmental, and traceback investigations were conducted. Of the 631 cases reported in the multistate outbreaks, Texas reported the greatest number of cases, 270 (43%). More than 70 clusters were identified in Texas, four of which were further investigated. One restaurant-associated cluster of 25 case-patients was selected for a case-control study. Consumption of cilantro was most strongly associated with illness on meal date-matched analysis (matched odds ratio 19·8, 95% confidence interval 4·0-∞). All case-patients in the other three clusters investigated also ate cilantro. Traceback investigations converged on three suppliers in Puebla, Mexico. Cilantro was the vehicle of infection in the four clusters investigated; the temporal association of these clusters with the large overall increase in cyclosporiasis cases in Texas suggests cilantro was the vehicle of infection for many other cases. However, the paucity of epidemiological and traceback information does not allow for a conclusive determination; moreover, molecular epidemiological tools for cyclosporiasis that could provide more definitive linkage between case clusters are needed.

Reduced axonal motor protein expression in non-lesional grey matter in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a neurological disease characterised by central nervous system inflammation, demyelination, axonal degeneration and neuronal injury. Preventing neuronal and axon damage is of paramount importance in attempts to prevent disease progression. Intact axonal transport mechanisms are crucial to axonal integrity and evidence suggests these mechanisms are disrupted in MS. Anterograde axonal transport is mediated to a large extent through the kinesin superfamily proteins. Recently, certain kinesin superfamily proteins (KIF5A, KIF1B and KIF21B) were implicated in MS pathology. OBJECTIVES: To investigate the expression of KIF5A, KIF21B and KIF1B in MS and control post-mortem grey matter. METHODS: Using both quantitative real-time polymerase chain reaction (PCR) and Immunodot-blots assays, we analysed the expression of kinesin superfamily proteins in 27 MS cases and 13 control cases not linked to neurological disease. RESULTS: We have shown significant reductions in KIF5A, KIF21B and KIF1B messenger ribonucleic acid (mRNA) expression and also KIF5A protein expression in MS grey matter, as compared to control grey matter. CONCLUSION: We have shown significant reductions in mRNA and protein levels of axonal motor proteins in the grey matter of MS cases, which may have important implications for the pathogenesis of neuronal/axonal injury in the disease.

Monitoring of modified factor VIII and IX products.

The dawning era of novel recombinant factor VIII and factor IX concentrates, many of which have been bioengineered to achieve prolonged activity, brings with it the need to consider the most appropriate clinical laboratory approaches for potency assignment, as well as the measurement of postinfusion levels. This session will highlight the known limitations and inconsistencies between existing assay methodologies with respect to currently available products, and discuss some of the early data with respect to the novel agents.

Recombinant factor IX: discrepancies between one-stage clotting and chromogenic assays.

New and modified recombinant factor IX (rFIX) products are in development and accurate potency estimation is important to ensure the consistency of production and efficacy of these therapeutics. Collaborative study data obtained during the replacement of the 3rd International Standard (IS) for FIX concentrate suggested that there was a discrepancy between potency estimates for rFIX using clotting and chromogenic methods, when the rFIX candidate was measured against the plasma-derived FIX (pdFIX) IS. This study explores potential chromogenic and one-stage clotting method discrepancies in more detail. Five batches each of rFIX and pdFIX were assayed against the 4th IS FIX concentrate (a pdFIX) by activated partial thromboplastin time (APTT) one-stage clotting assay and specific functional chromogenic assay. The potency of rFIX by chromogenic assay was consistently around 70% of the one-stage clotting potency (average 78 and 108 IU mL(-1) respectively). These differences were not observed with pdFIX, which had similar potencies (average 96 IU mL(-1) ) by each assay method. In addition, different APTT reagents yielded different potency estimates for rFIX when assayed against the pdFIX IS, with a variation of up to 23%. In all cases, the differences were largely resolved when a rFIX reference was used as the standard. This study highlights some of the challenges associated with assay of rFIX products in the laboratory and that careful consideration needs to be given to the choice of reference material used. This is especially important with the imminent arrival of new and modified rFIX products.

Prevalence of malnutrition in children under five and school-age children in Milot Valley, Haiti.

OBJECTIVES: This research aims to provide child malnutrition prevalence data from Haiti's Milot Valley to inform the design and implementation of local health interventions. STUDY DESIGN: This cross-sectional study measured underweight, stunting, and wasting/thinness using international growth standards. METHODS: Anthropometric measurements (height/length and weight) were taken on a convenience sample of 358 children aged 0-14 years. Participants were recruited through door-to-door field visits at five recruitment sites in the Milot Valley, including individuals in the waiting area of the Pediatric Outpatient Clinic at Hôpital Sacré Coeur. Caregivers were asked questions about the child's health history, including past and current feeding practices. RESULTS: Combining moderate and severe forms of malnutrition, 14.8% of children under five were stunted, 15.3% were wasted, and 16.1% were underweight. Among children 5-14 years of age, 14.1% were stunted, 7.6% were thin (low body mass index (BMI)-for-age), and 14.5% were underweight. For children under five, 42% of mothers ended exclusive breastfeeding before the recommended six months. CONCLUSION: This study illustrates the local magnitude of childhood malnutrition and can serve as a resource for future child health interventions in the Milot Valley. To fight malnutrition, a multipronged, integrated approach is recommended, combining effective community outreach and monitoring, inpatient and outpatient nutrition therapy, and expanded partnerships with nutrition-related organizations in the region.

Circulating pre-treatment T-cell receptor repertoire as a predictive biomarker in advanced or metastatic non-small-cell lung cancer patients treated with pembrolizumab alone or in combination with chemotherapy.

BACKGROUND: The circulating T-cell receptor (TCR) repertoire is a dynamic representation of overall immune responses in an individual. MATERIALS AND METHODS: We prospectively collected baseline blood from patients treated with first-line pembrolizumab monotherapy or in combination with chemotherapy. TCR repertoire metrics were correlated with clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS) and immune-related adverse events (irAEs). We built a logistic regression classifier by fitting all four TCR-ß repertoire metrics to the immune checkpoint inhibitor (ICI) CBR data. In the subsequent receiver operating characteristic (ROC) analysis of the resulting logistic regression model probabilities, the best cut-off value was selected to maximise sensitivity to predict CBR to ICI. RESULTS: We observed an association between reduced number of unique clones and CBR among patients treated with pembrolizumab monotherapy (cohort 1) [risk ratio = 2.86, 95% confidence interval (CI) 1.04-8.73, P = 0.039]. For patients treated with pembrolizumab plus chemotherapy (cohort 2), increased number of unique clones [hazard ratio (HR) = 2.96, 95% CI 1.28-6.88, P = 0.012] and Shannon diversity (HR = 2.73, 95% CI 1.08-6.87, P = 0.033), and reduced evenness (HR = 0.43, 95% CI 0.21-0.90, P = 0.025) and convergence (HR = 0.41, 95% CI 0.19-0.90, P = 0.027) were associated with improved PFS, while only an increased number of unique clones (HR = 4.62, 95% CI 1.52-14.02, P = 0.007) were associated with improved OS. Logistic regression models combining the TCR repertoire metrics improved the prediction of CBR (cohorts 1 and 2) and were strongly associated with PFS (cohort 1, HR = 0.38, 95% CI 0.19-0.78, P = 0.009) and OS (cohort 2, HR = 0.20, 95% CI 0.05-0.76, P < 0.0001). Reduced TCR conversion was associated with increased frequency of irAEs needing systemic steroid treatment. CONCLUSION: Combined pre-treatment circulating TCR metrics might serve as a predictive biomarker for clinical outcomes among patients with advanced non-small-cell lung cancer treated with pembrolizumab alone or in combination with chemotherapy.

Mitochondrial sirtuins--a new therapeutic target for repair and protection in multiple sclerosis.

Given the significant socioeconomic impact of progressive multiple sclerosis (MS) and the paucity of treatment options, there is an urgent need to develop new and effective therapies for this disabling condition. The relatively recent appreciation that progressive disability is largely driven by neuronal loss has focused considerable research attention on neuroprotective strategies. This has coincided with the emergence of oxidative damage as a prominent effector mechanism of axonal damage in studies of MS pathogenesis, which has opened up a new range of putative targets for neuroprotective therapy in MS. Mitochondrial sirtuins are NAD(+)-dependent protein deacetylases associated with the control of metabolism, aging, and stem cell proliferation and differentiation. Their role in inflammatory demyelinating disease has not been fully characterized, and is the subject of ongoing research. Here, we expound the rationale behind selecting mitochondrial sirtuins as a therapeutic target in demyelinating disease, and report preliminary data that warrant further investigation.

Genetics of haemostasis.

Congenital defects of platelets or plasma proteins involved in blood coagulation generally lead to bleeding disorders. In some of these disorders, patients with a severe phenotype are prone to spontaneous bleeds with critical consequences. This situation occurs more commonly in haemophilia A and haemophilia B and to a certain extent in severe forms (type 3) of von Willebrand disease. Defects in other plasma coagulation proteins and platelet factors are relatively rare, with an incidence of ≤ 1: 1-2 million. Molecular genetic studies of the human coagulation factors, especially factors VIII and IX, have contributed to a better understanding of the biology of these genetic disorders, the accurate detection of carriers and genetic counselling, and have also fostered new therapeutic strategies. This article reviews the evolution of genetics over the last five decades as a tool for bleeding disorder investigations, the recent advances in molecular techniques that have contributed to improved genetic diagnosis of this condition, and the development and utility of proficiency testing programmes and reference materials for genetic diagnosis of bleeding disorders.

Average SAR prediction, validation, and evaluation for a compact MR scanner head-sized RF coil.

A recently developed compact 3 T (C3T) MRI scanner with high performance gradients [1, 2] has a dedicated radiofrequency (RF) transmit coil that exposes only the head, neck and a small portion of the upper body region during head-first scanning. Due to the unique coil geometry and patient positioning, the established SAR model used for a conventional whole-body scanner cannot be directly translated to the C3T. Here a specific absorption rate (SAR) estimation and validation framework was developed and used to implement a dedicated and accurate SAR prediction model for the C3T. Two different SAR prediction models for the C3T were defined and evaluated: one based on an anatomically derived exposed mass, and one using a fixed anatomical position located caudally to the RF coil to determine the exposed mass. After coil modeling and virtual human body simulation, the designed SAR prediction model was implemented on the C3T and verified with calorimetry and in vivo scan power monitoring. The fixed-demarcation exposed mass model was selected as appropriate exposed mass region to accurately estimate the SAR deposition in the patient on the C3T.

Nitrogen Incorporation in Potassic and Micro- and Meso-Porous Minerals: Potential Biogeochemical Records and Targets for Mars Sampling.

We measured the N concentrations and isotopic compositions of 44 samples of terrestrial potassic and micro- and meso-porous minerals and a small number of whole-rocks to determine the extent to which N is incorporated and stored during weathering and low-temperature hydrothermal alteration in Mars surface/near-surface environments. The selection of these minerals and other materials was partly guided by the study of altered volcanic glass from Antarctica and Iceland, in which the incorporation of N as NH4+ in phyllosilicates is indicated by correlated concentrations of N and the LILEs (i.e., K, Ba, Rb, Cs), with scatter likely related to the presence of exchanged, occluded/trapped, or encapsulated organic/inorganic N occurring within structural cavities (e.g., in zeolites). The phyllosilicates, zeolites, and sulfates analyzed in this study contain between 0 and 99,120 ppm N and have δ15Nair values of -34‰ to +65‰. Most of these minerals, and the few siliceous hydrothermal deposits that were analyzed, have δ15N consistent with the incorporation of biologically processed N during low-temperature hydrothermal or weathering processes. Secondary ion mass spectrometry on altered hyaloclastites demonstrates the residency of N in smectites and zeolites, and silica. We suggest that geological materials known on Earth to incorporate and store N and known to be abundant at, or near, the surface of Mars should be considered targets for upcoming Mars sample return with the intent to identify any signs of ancient or modern life.