The RAG Model: a new paradigm for genetic risk stratification in multiple myeloma

Molecular studies have shown that multiple myeloma is a highly genetically heterogonous disease which may manifest itself as any number of diverse subtypes each with variable clinicopathological features and outcomes. Given this genetic heterogeneity, a universal approach to treatment of myeloma is unlikely to be successful for all patients and instead we should strive for the goal of personalised therapy using rationally informed targeted strategies. Current DNA sequencing technologies allow for whole genome and exome analysis of patient myeloma samples that yield vast amounts of genetic data and provide a mutational overview of the disease. However, the clinical utility of this information currently lags far behind the sequencing technology which is increasingly being incorporated into clinical practice. This paper attempts to address this shortcoming by proposing a novel genetically based “traffic-light” risk stratification system for myeloma, termed the RAG (Red, Amber, Green) model, which represents a simplified concept of how complex genetic data may be compressed into an aggregate risk score. The model aims to incorporate all known clinically important trisomies, translocations, and mutations in myeloma and utilise these to produce a score between 1.0 and 3.0 that can be incorporated into diagnostic, prognostic, and treatment algorithms for the patient

General practitioner perception of prostate-specific antigen testing has improved, but more awareness of prostate cancer risk in younger patients is still awaited.

BACKGROUND: In 2006, a county-wide survey of general practitioners (GPs) in the United Kingdom (UK) identified a reluctance to refer younger men with abnormal prostate specific antigen (PSA) levels. Younger men have the most to gain from early-detection of prostate cancer (PCa), which remains a national government priority in the UK and around the world. We sought to assess changes in perception of abnormal PSA-values amongst UK GPs over the past 10 years. MATERIALS AND METHODS: A total of 500 self-administered paper questionnaires were distributed to individually named GPs. One hundred and forty two responded (28.4%), representing a patient population of ∼600,000. A series of visual analogue questions assessed referral thresholds and understanding of risk factors related to the development of PCa. RESULTS: GPs with a median of 23-years experience responded. Although mean PSA threshold for referral to urology did fall between 2006 and 2016 in both the 45-year (5.42 ng/mL vs. 4.61 ng/mL P = 0.0003) and 55-year (5.81 ng/mL vs. 5.30 ng/mL P = 0.0164) age groups, the median referral values were unchanged. Significantly, referral thresholds quoted for younger men (<65 years) were considerably higher than recommended UK maximum PSA-levels. Using case-based scenarios, practitioners appeared more likely to refer older men with abnormal PSA values, with GPs reporting an average 56.2% likelihood of referring an asymptomatic 55-year-old with elevated age-adjusted PSA of 4.6 ng/mL. A total of 95.1% recognised a family history of PCa to be a potential risk factor but other at-risk categories were not so clearly understood. CONCLUSION: Awareness of abnormal PSA values in UK primary care is improving, but continues to lag behind the evidence. Strategies to disseminate knowledge of maximum PSA-values to GPs should focus especially on those for younger patients

Prevalence and influence of cys407* Grm2 mutation in Hannover-derived Wistar rats:mGlu2 receptor loss links to alcohol intake, risk taking and emotional behaviour

AbstractModulation of metabotropic glutamate 2 (mGlu2) receptor function has huge potential for treating psychiatric and neurological diseases. Development of drugs acting on mGlu2 receptors depends on the development and use of translatable animal models of disease. We report here a stop codon mutation at cysteine 407 in Grm2 (cys407*) that is common in some Wistar rats. Therefore, researchers in this field need to be aware of strains with this mutation. Our genotypic survey found widespread prevalence of the mutation in commercial Wistar strains, particularly those known as Han Wistar. Such Han Wistar rats are ideal for research into the separate roles of mGlu2 and mGlu3 receptors in CNS function. Previous investigations, unknowingly using such mGlu2 receptor-lacking rats, provide insights into the role of mGlu2 receptors in behaviour. The Grm2 mutant rats, which dominate some selectively bred lines, display characteristics of altered emotionality, impulsivity and risk-related behaviours and increased voluntary alcohol intake compared with their mGlu2 receptor-competent counterparts. In addition, the data further emphasize the potential therapeutic role of mGlu2 receptors in psychiatric and neurological disease, and indicate novel methods of studying the role of mGlu2 and mGlu3 receptors

Ice fabric in an Antarctic ice stream interpreted from seismic anisotropy

Here we present new measurements of an anisotropic ice fabric in a fast moving (377 ma−1) ice stream in West Antarctica. We use ∼6000 measurements of shear wave splitting observed in microseismic signals from the bed of Rutford Ice Stream, to show that in contrast to large-scale ice flow models, which assume that ice is isotropic, the ice in Rutford Ice Stream is dominated by a previously unobserved type of partial girdle fabric. This fabric has a strong directional contrast in mechanical properties, shearing 9.1 times more easily along the ice flow direction than across flow. This observed fabric is likely to be widespread and representative of fabrics in other ice streams and large glaciers, suggesting it is essential to consider anisotropy in data-driven models to correctly predict ice loss and future flow in these regions. We show how passive microseismic monitoring can be effectively used to provide these data

'Hidden hot springs' as a source of groundwater fluoride and severe dental fluorosis in Malawi

Hidden hot springs likely impact rural water supplies in Malawi's Rift Valley with excess dissolved fluoride leading to localised endemic severe dental fluorosis. Predicting their occurrence is a challenge; Malawi's groundwater data archive is sporadic and incomplete which prevents the application of standard modelling techniques. A creative alternative method to predict hidden hot spring locations was developed using a synthesis of proxy indicators (geological, geochemical, dental) and is shown to be at least 75% effective. An exciting collaboration between geoscientists and dentists allowed corroboration of severe dental fluorosis with hydrogeological vulnerability. Thirteen hidden hot springs were identified based on synthesised proxy indicators. A vulnerability prediction map for the region was developed and is the first of its kind in Malawi. It allows improved groundwater fluoride prediction in Malawi's rift basin which hosts the majority of hot springs. Moreover, it allows dentists to recognise geological control over community oral health. Collaborative efforts have proven mutually beneficial, allowing both disciplines to conduct targeted research to improve community wellbeing and health and inform policy development in their respective areas. This work contributes globally in developing nations where incomplete groundwater data and vulnerability to groundwater contamination from hydrothermal fluoride exist in tandem

Diagnostic accuracy of pulmonary host inflammatory mediators in the exclusion of ventilator-acquired pneumonia.

BACKGROUND: Excessive use of empirical antibiotics is common in critically ill patients. Rapid biomarker-based exclusion of infection may improve antibiotic stewardship in ventilator-acquired pneumonia (VAP). However, successful validation of the usefulness of potential markers in this setting is exceptionally rare. OBJECTIVES: We sought to validate the capacity for specific host inflammatory mediators to exclude pneumonia in patients with suspected VAP. METHODS: A prospective, multicentre, validation study of patients with suspected VAP was conducted in 12 intensive care units. VAP was confirmed following bronchoscopy by culture of a potential pathogen in bronchoalveolar lavage fluid (BALF) at >10(4) colony forming units per millilitre (cfu/mL). Interleukin-1 beta (IL-1β), IL-8, matrix metalloproteinase-8 (MMP-8), MMP-9 and human neutrophil elastase (HNE) were quantified in BALF. Diagnostic utility was determined for biomarkers individually and in combination. RESULTS: Paired BALF culture and biomarker results were available for 150 patients. 53 patients (35%) had VAP and 97 (65%) patients formed the non-VAP group. All biomarkers were significantly higher in the VAP group (p<0.001). The area under the receiver operator characteristic curve for IL-1β was 0.81; IL-8, 0.74; MMP-8, 0.76; MMP-9, 0.79 and HNE, 0.78. A combination of IL-1β and IL-8, at the optimal cut-point, excluded VAP with a sensitivity of 100%, a specificity of 44.3% and a post-test probability of 0% (95% CI 0% to 9.2%). CONCLUSIONS: Low BALF IL-1β in combination with IL-8 confidently excludes VAP and could form a rapid biomarker-based rule-out test, with the potential to improve antibiotic stewardship

Rac1 Deletion Causes Thymic Atrophy

The thymic stroma supports T lymphocyte development and consists of an epithelium maintained by thymic epithelial progenitors. The molecular pathways that govern epithelial homeostasis are poorly understood. Here we demonstrate that deletion of Rac1 in Keratin 5/Keratin 14 expressing embryonic and adult thymic epithelial cells leads to loss of the thymic epithelial compartment. Rac1 deletion led to an increase in c-Myc expression and a generalized increase in apoptosis associated with a decrease in thymic epithelial proliferation. Our results suggest Rac1 maintains the epithelial population, and equilibrium between Rac1 and c-Myc may control proliferation, apoptosis and maturation of the thymic epithelial compartment. Understanding thymic epithelial maintenance is a step toward the dual goals of in vitro thymic epithelial cell culture and T cell differentiation, and the clinical repair of thymic damage from graft-versus-host-disease, chemotherapy or irradiation

Comparison of the caries-protective effect of fluoride varnish with treatment as usual in nursery school attendees receiving preventive oral health support through the Childsmile oral health improvement programme - the Protecting Teeth@3 Study:a randomised controlled trial

Background: The Scottish Government set out its policy on addressing the poor oral health of Scottish children in 2005. This led to the establishment of Childsmile, a national programme designed to improve the oral health of children in Scotland. One element of the programme promotes daily tooth brushing in all nurseries in Scotland (Childsmile Core). A second targeted component (Childsmile Nursery) offers twice-yearly application of fluoride varnish to children attending nurseries in deprived areas. Studies suggest that fluoride varnish application can reduce caries in both adult and child populations. This trial aims to explore the effectiveness and cost-effectiveness of additional preventive value fluoride varnish application compared to Childsmile Core. Methods/Design: The Protecting Teeth@3 Study is an ongoing 2 year parallel group randomised treatment as usual controlled trial. Three-year-old children attending the ante pre-school year are randomised (1:1) to the intervention arm (fluoride varnish &#38; treatment as usual) or the control arm (treatment as usual). Children in the intervention arm will have Duraphat® fluoride varnish painted on the primary tooth surfaces and will continue to receive treatment as usual: the core Childsmile Nursery intervention. Children in the treatment as usual arm will receive the same series of contacts, without the application of varnish and will also continue with the Childsmile Core intervention. Interventions are undertaken by Childsmile trained extended duty dental nurses at six-monthly intervals. Participants receive a baseline dental inspection in nursery and an endpoint inspection in Primary 1 at the age of 5 years old. We will use primary and secondary outcome measures to compare the effectiveness of Duraphat® fluoride varnish plus treatment as usual with treatment as usual only in preventing any further dental decay. We will also undertake a full economic evaluation of the trial

Locomotor changes in length and EMG activity of feline medial gastrocnemius muscle following paralysis of two synergists

The mechanism of the compensatory increase in electromyographic activity (EMG) of a cat ankle extensor during walking shortly after paralysis of its synergists is not fully understood. It is possible that due to greater ankle flexion in stance in this situation, muscle spindles are stretched to a greater extent and, thus, contribute to the EMG enhancement. However, also changes in force feedback and central drive may play a role. The aim of the present study was to investigate the short-term (1- to 2-week post-op) effects of lateral gastrocnemius (LG) and soleus (SO) denervation on muscle fascicle and muscle–tendon unit (MTU) length changes, as well as EMG activity of the intact medial gastrocnemius (MG) muscle in stance during overground walking on level (0%), downslope (−50%, presumably enhancing stretch of ankle extensors in stance) and upslope (+50%, enhancing load on ankle extensors) surfaces. Fascicle length was measured directly using sonomicrometry, and MTU length was calculated from joint kinematics. For each slope condition, LG-SO denervation resulted in an increase in MTU stretch and peak stretch velocity of the intact MG in early stance. MG muscle fascicle stretch and peak stretch velocity were also higher than before denervation in downslope walking. Denervation significantly decreased the magnitude of MG fascicle shortening and peak shortening velocity during early stance in level and upslope walking. MG EMG magnitude in the swing and stance phases was substantially greater after denervation, with a relatively greater increase during stance of level and upslope walking. These results suggest that the fascicle length patterns of MG muscle are significantly altered when two of its synergists are in a state of paralysis. Further, the compensatory increase in MG EMG is likely mediated by enhanced MG length feedback during downslope walking, enhanced feedback from load-sensitive receptors during upslope walking and enhanced central drive in all walking conditions