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Frailty and delirium are important conditions in an ageing population, but there is little evidence exploring medical students’ conceptualisation of, or attitudes towards these subjects. We investigated how students’ concepts of frailty and delirium changed following a new geriatric medicine module at Manchester medical school. Semi-structured interviews were used with students before and after the new teaching week to explore changes in attitude towards frailty and delirium and their conceptualisation. Final year students who had not completed the module were interviewed as a comparison group. Grounded theory and content clouds were employed for data analysis. Ten 4th year and 11 final year students were interviewed. After the teaching week, 4th year students had a richer conceptualisation of frailty and delirium. Students described structured assessments such as comprehensive geriatric assessment and expressed confidence in their use. Their frameworks were more developed than the final year students who had not had such teaching. Attitudes towards older people, frailty, delirium, and the specialty of geriatric medicine improved following the teaching week. This study shows that geriatric medicine teaching improves students’ conceptualisation of frailty and delirium and their understanding of the importance of structured assessments and management plans.

The UK population is ageing with increases in both the median age and the numbers and proportion of older people. Fastest growth has been in those aged 85 years and over with percentages of the total UK population increasing from 1–2% between 1985 and 2010. It is projected that by 2035, this figure will rise to 5% of the total UK population (3.5 million people) [1]. In the last 25 years, numbers of in-patient hospital beds have reduced by a third, while numbers of emergency admissions have increased annually, with older people accounting for the largest increase. Historically, hospitals have coped with this demand by reducing length of stay (LOS) for patients. However, in the over 85s, LOS has plateaued and more recently started to rise [2]. Sixty-five percent of people admitted to hospital are over the age of 65 years, with increasing numbers frail or with a diagnosis of dementia [3]. Multimorbidity, the presence of two or more chronic medical conditions, is more common in older people and is associated with functional decline, decreased quality of life and increased healthcare utilization (including emergency admissions) [4,5]. A R T I C L E I N F O

Frailty and delirium are important conditions in an ageing population, but there is little evidence exploring medical students' conceptualisation of, or attitudes towards these subjects. We investigated how students' concepts of frailty and delirium changed following a new geriatric medicine module at Manchester medical school.Semi-structured interviews were used with students before and after the new teaching week to explore changes in attitude towards frailty and delirium and their conceptualisation. Final year students who had not completed the module were interviewed as a comparison group. Grounded theory and content clouds were employed for data analysis.Ten 4th year and 11 final year students were interviewed. After the teaching week, 4th year students had a richer conceptualisation of frailty and delirium. Students described structured assessments such as comprehensive geriatric assessment and expressed confidence in their use. Their frameworks were more developed than the final year students who had not had such teaching. Attitudes towards older people, frailty, delirium, and the specialty of geriatric medicine improved following the teaching week.This study shows that geriatric medicine teaching improves students' conceptualisation of frailty and delirium and their understanding of the importance of structured assessments and management plans.

Summary Background TargomiRs are minicells (EnGeneIC Dream Vectors) loaded with miR-16-based mimic microRNA (miRNA) and targeted to EGFR that are designed to counteract the loss of the miR-15 and miR-16 family miRNAs, which is associated with unsuppressed tumour growth in preclinical models of malignant pleural mesothelioma. We aimed to assess the safety, optimal dosing, and activity of TargomiRs in patients with malignant pleural mesothelioma. Methods In this first-in-man, open-label, dose-escalation phase 1 trial at three major cancer centres in Sydney (NSW, Australia), we recruited adults (aged ≥18 years) with a confirmed diagnosis of malignant pleural mesothelioma, measurable disease, radiological signs of progression after previous chemotherapy, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of 3 months or more, immunohistochemical evidence of tumour EGFR expression, and adequate bone marrow, liver, and renal function. Patients were given TargomiRs via 20 min intravenous infusion either once or twice a week (3 days apart) in a traditional 3 + 3 dose-escalation design in five dose cohorts. The dose-escalation steps planned were 5 × 10 9 , 7 × 10 9 , and 9 × 10 9 TargomiRs either once or twice weekly, but after analysis of data from the first eight patients, all subsequent patients started protocol treatment at 1 × 10 9 TargomiRs. The primary endpoints were to establish the maximum tolerated dose of TargomiRs as measured by dose-limiting toxicity, define the optimal frequency of administration, and objective response (defined as the percentage of assessable patients with a complete or partial response), duration of response (defined as time from the first evidence of response to disease progression in patients who achieved a response), time to response (ie, time from start of treatment to the first evidence of response) and overall survival (defined as time from treatment allocation to death from any cause). Analyses were based on the full analysis set principle, including every patient who received at least one dose of TargomiRs. The study was closed for patient entry on Jan 3, 2017, and registered with ClinicalTrials.gov, number NCT02369198, and the Australian Registry of Clinical Trials, number ACTRN12614001248651. Findings Between Sept 29, 2014, and Nov 24, 2016, we enrolled 27 patients, 26 of whom received at least one TargomiR dose (one patient died before beginning treatment). Overall, five dose-limiting toxicities were noted: infusion-related inflammatory symptoms and coronary ischaemia, respectively, in two patients given 5 × 10 9 TargomiRs twice weekly; anaphylaxis and cardiomyopathy, respectively, in two patients given 5 × 10 9 TargomiRs once weekly but who received reduced dexamethasone prophylaxis; and non-cardiac pain in one patient who received 5 × 10 9 TargomiRs once weekly. We established that 5 × 10 9 TargomiRs once weekly was the maximum tolerated dose. TargomiR infusions were accompanied by transient lymphopenia (25 [96%] of 26 patients), temporal hypophosphataemia (17 [65%] of 26 patients), increased aspartate aminotransferase or alanine aminotranferase (six [23%] of 26 patients), and increased alkaline phosphatase blood concentrations (two [8%]). Cardiac events occurred in five patients: three patients had electrocardiographic changes, one patient had ischaemia, and one patient had Takotsubo cardiomyopathy. Of the 22 patients who were assessed for response by CT, one (5%) had a partial response, 15 (68%) had stable disease, and six (27%) had progressive disease. The proportion of patients who achieved an objective response was therefore one (5%) of 22, and the duration of the objective response in that patient was 32 weeks. Median overall survival was 200 days (95% CI 94–358). During the trial, 21 deaths occurred, of which 20 were related to tumour progression and one was due to bowel perforation. Interpretation The acceptable safety profile and early signs of activity of TargomiRs in patients with malignant pleural mesothelioma support additional studies of TargomiRs in combination with chemotherapy or immune checkpoint inhibitors. Funding Asbestos Diseases Research Foundation.

Introduction: Although older individuals are more prone to hypoglycaemia, it is not known if they have sufficient understanding of the risks of hypoglycaemia or the factors that predispose to it. We evaluated the effectiveness of hypoglycaemia education and examined the factors that increased susceptibility to hypoglycaemia among older people with diabetes. Methods: Forty-five patients (male/female) aged >65 years and known to have diabetes were identified through outpatient clinics at a secondary care hospital. Information relating to education received, awareness of hypoglycaemia and associated risk factors was collected using a standard questionnaire. Additionally, data regarding demographics, treatment regimes, patient attitudes, hypoglycaemic awareness and risks and barriers to self-management of diabetes was collected. Patients were categorised as low, moderate and high risk based on their responses. Independent sample t-tests and Analysis of Variance were carried out to identify factors contributing to high hypoglycaemic risk. Results: Overall, 70% of the patients reported receiving education about hypoglycaemia from health professionals and 95% of them reported good understanding of hypoglycaemia and were able to self-test. Proportion of women receiving education was, however, lower than men (52% women versus 88% men). Compared with men, women were less likely to recognise (59 versus 73%), or act appropriately to a hypoglycaemic episode (59 versus 78%). The mean number of hypoglycaemic episodes per year (41 versus 12) and the duration of hypoglycaemia (9.9 versus 6.3 min) was also greater among women compared with men. The duration of diabetes (P = 0.018), female gender, type 1 diabetes (0.002) and lack awareness of medications causing hypos (P = 0.006) were strong predictors of hypoglycaemia risk. Conclusions: There are significant gaps in education around hypoglycaemia in older people with diabetes. Women, people with longer duration and type 1 diabetes in particular, need additional attention and future educational initiatives need to address these issues.

Agricultural industries located in coastal catchments adjacent to the Great Barrier Reef Marine Park in Queensland, Australia, are facing increasing pressure to demonstrate that their production systems are environmentally sustainable. Our experiences show that research and technology to improve productivity and profitability can also address environmental issues associated with off-site movement of nutrients. Due to limited water availability, vegetable farmers in the region utilise trickle irrigation and fertigation, often combined with polyethylene mulch film and seedling transplant technology. This system conserves water and allows for accurate and timely placement of fertiliser. The challenges for vegetable production systems in a dry tropical environment are: periods of high summer rainfall on fallow land; inherently low soil carbon with associated impacts on soil health properties (nutrient cycling, resistance to soil erosion); potential for denitrification under mulches; and salinisation of the soil profile. Fertiliser recommendations are based on empirical data rather than calibrated soil and plant tissue diagnostic indices. There is a need to develop science-based tools for objectively assessing and facilitating improved best practice nutrient management on a soil-, site- and crop- specific basis. In collaboration with local vegetable growers, we are modifying a decision support tool from the sugarcane industry for assessing the risk of off-site movement of nitrogen and phosphorus for the horticulture industry. This process is identifying large gaps in available input data (critical soil P test levels, crop growth cycles, nutrient uptake and removal data) for a number of vegetable crops but confirming the potential of the package to deal with the complexity and variability needed to support best management practices for nutrients in vegetable cropping systems.

Background Cytotoxic chemotherapy can be very effective for the treatment of cancer but toxicity on normal tissues often limits patient tolerance and often causes long-term adverse effects. The objective of this study was to assist in the preclinical development of using modified, non-living bacterially-derived minicells to deliver the potent chemotherapeutic doxorubicin via epidermal growth factor receptor (EGFR) targeting. Specifically, this study sought to evaluate the safety and efficacy of EGFR targeted, doxorubicin loaded minicells (designated EGFRminicellsDox) to deliver doxorubicin to spontaneous brain tumors in 17 companion dogs; a comparative oncology model of human brain cancers. Methodology/Principle Findings EGFRminicellsDox were administered weekly via intravenous injection to 17 dogs with late-stage brain cancers. Biodistribution was assessed using single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). Anti-tumor response was determined using MRI, and blood samples were subject to toxicology (hematology, biochemistry) and inflammatory marker analysis. Targeted, doxorubicin-loaded minicells rapidly localized to the core of brain tumors. Complete resolution or marked tumor regression (>90% reduction in tumor volume) were observed in 23.53% of the cohort, with lasting anti-tumor responses characterized by remission in three dogs for more than two years. The median overall survival was 264 days (range 49 to 973). No adverse clinical, hematological or biochemical effects were observed with repeated administration of EGFRminicellsDox (30 to 98 doses administered in 10 of the 17 dogs). Conclusions/Significance Targeted minicells loaded with doxorubicin were safely administered to dogs with late stage brain cancer and clinical activity was observed. These findings demonstrate the strong potential for clinical applications of targeted, doxorubicin-loaded minicells for the effective treatment of patients with brain cancer. On this basis, we have designed a Phase 1 clinical study of EGFR-targeted, doxorubicin-loaded minicells for effective treatment of human patients with recurrent glioblastoma.

Background We have harnessed a novel biological system, the bacterial minicell, to deliver cancer therapeutics to cancer cells. Preclinical studies showed that epidermal growth factor receptor (EGFR)-targeted, paclitaxel-loaded minicells (EGFRminicellsPac) have antitumor effects in xenograft models. To examine the safety of the minicell delivery system, we initiated a first-time-in-human, open-label, phase I clinical study of EGFRminicellsPac in patients with advanced solid tumors. Methodology Patients received 5 weekly infusions followed by a treatment free week. Seven dose levels (1x108, 1x109, 3x109, 1x1010, 1.5x1010, 2x1010, 5x1010) were evaluated using a 3+3 dose-escalation design. Primary objectives were safety, tolerability and determination of the maximum tolerated dose. Secondary objectives were assessment of immune/inflammatory responses and antitumor activity. Principal Findings Twenty eight patients were enrolled, 22 patients completed at least one cycle of EGFRminicellsPac; 6 patients did not complete a cycle due to rapidly progressive disease. A total of 236 doses was delivered over 42 cycles, with a maximum of 45 doses administered to a single patient. Most common treatment-related adverse events were rigors and pyrexia. No deaths resulted from treatment-related adverse events and the maximum tolerated dose was defined as 1x1010 EGFRminicellsPac. Surprisingly, only a mild self-limiting elevation in the inflammatory cytokines IL-6, IL-8 and TNFα and anti-inflammatory IL-10 was observed. Anti-LPS antibody titers peaked by dose 3 and were maintained at that level despite repeat dosing with the bacterially derived minicells. Ten patients (45%; n = 22) achieved stable disease as their best response. Conclusions/Significance This is the first study in humans of a novel biological system that can provide targeted delivery of a range of chemotherapeutic drugs to solid tumor cells. Bispecific antibody-targeted minicells, packaged with the chemotherapeutic paclitaxel, were shown to be safe in patients with advanced solid tumors with modest clinical efficacy observed. Further study in Phase II trials is planned. Trial Registration Australian New Zealand Clinical Trials Registry ACTRN12609000672257

The aim of this study was to gain information relevant to disc repair processes. Limited degradation of the collagen matrix by matrix metalloproteases (MMPs) may facilitate the loosening of cell-cell and cell-matrix interactions within the injured intervertebral disc (IVD) to favour the penetration of blood vessels and migration of fibroblasts into the defect to promote repair processes. Gelatinase A (MMP-2) has a particularly important role to play in angiogenesis, in the present study we investigated the in vitro regulation of MMP-2 by Transforming Growth Factor-beta 1 (TGF-beta 1) and Insulin-like Growth Factor-1 (beta IGF-I) in cells from the nucleus pulposus (NP) of the ovine IVD. Ovine NP cells were grown in alginate bead cultures in complete medium (10% foetal calf serum) for 7 days, established in serum-free conditions for 24 h, then stimulated with TGF-beta 1 (0.1 or 10 ng/ml) or IGF-I (2 or 50 ng/ml) +/-Concanavalin A (20 microg/ml) for an additional 48 h. Conditioned medium was examined for matrix metalloproteases using gelatin zymography, Tissue Inhibitor of Metalloproteinase 2 (TIMP-2) and Membrane Type 1 Matrix Metalloproteinase (MT1-MMP) were immunolocalised in beads. Pro (72 kDa) and active (59 kDa) MMP-2 were the major gelatinolytic MMPs detected in control cultures, the TGF-beta 1 and IGF-I treatments significantly decreased levels of the active MMP-2, inclusion of Concanavalin A resulted in a complete reversal of this trend with IGF-I, and to a lesser extent with TGF-beta 1. Cell surface levels of TIMP-2 and MT1-MMP were decreased by the TGF-beta 1 treatment while IGF-I only appeared to decrease TIMP-2 expression. The findings of this study provide some insight as to why dense avascular connective tissues such as the intervertebral disc have such a poor healing potential.

An analytic solution is presented for the linearized estimation problem arising from the dual-satellite geolocation of the source of a narrowband signal using time- and frequency-difference-of-arrival (TDOA and FDOA, respectively) observations and an altitude constraint. This solution is used to analyze the covariance matrix of the resultant source location estimate, along with the sensitivity of its mean to errors in the presumed source altitude and velocity, and the measured or predicted positions and velocities of the satellites. Following the practice of differential Global Positioning System, the technique of differential calibration is used to reduce or eliminate various sources of solution bias which would otherwise require tight, and consequently expensive, individual calibration.

The growth regulatory activity of the insulin-like growth factor binding proteins (IGFBPs) may be modulated by post-translational modifications such as glycosylation, limited proteolysis and phosphorylation. In this study, we have examined phosphorylation of IGFBP-3 in two breast cancer cell lines: the estrogen receptor negative (ER-ve) Hs578T cell line in which IGFBP-3 is normally expressed, and ER+ve T47D breast cancer cells transfected with IGFBP-3 cDNA (T47DBP-3) and therefore expressing IGFBP-3 constitutively. Metabolic labelling with [32P] orthophosphate revealed that both cell lines secreted phosphorylated IGFBP-3 similar in size to plasma IGFBP-3 phosphorylated in vitro with casein kinase II, and that IGFBP-3 phosphorylation was differentially modulated in the two cell lines. In Hs578T cells, retinoic acid (10–100 nM) increased IGFBP-3 phosphorylation to a maximum of 150% of control. IGF-I, but not [LR3]IGF-I, reduced the proportion of phosphorylated IGFBP-3 in Hs578T conditioned medium, consistent with increased release of non-phosphorylated, cell-associated IGFBP-3. By contrast, IGFBP-3 phosphorylation in T47DBP-3 cells was not affected by retinoic acid or IGF-I, but appeared slightly increased by estradiol. Together these data indicate that phosphorylation of IGFBP-3 in breast cancer cells may be regulated by agents known to affect breast cancer cell proliferation.

Summary Background: Pre-employment competency screening (PECS) has been introduced in some regions in the UK for foundation applicants. There is no consensus on how the process should be run, and this has led to a variety of methods used between and within deaneries. This study aims to look at the acceptability and, in part, the educational impact of PECS in the North Western Foundation School. Methods: An electronic survey was created and sent to all of the foundation applicants assigned to posts in the North Western Deanery. The survey covered attitudes to the PECS process and collected demographic details about their medical school of origin. Free-text comments were analysed for recurring themes by two of the investigators, and variances were discussed until common themes were agreed upon. Results: The questionnaire was sent to 555 candidates with 265 replies. Foundation doctors saw the identification of educational needs, assessment of competency, making provision for support and patient safety as the main purposes of PECS. A majority of respondents felt that PECS was a fair assessment of competencies (90%), and that the process was valuable (80.4%). Discussion: The results suggest that foundation doctors find the PECS process acceptable, and see it as an opportunity to identify educational needs and to be supported in weak areas. There are concerns about the validity of these assessments, and we have suggested recommendations for standardising PECS whilst acknowledging the need for further research.

Abnormal trophoblast growth can cause life-threatening disorders such as ectopic pregnancy, choriocarcinoma, and placenta accreta. EnGeneIC Delivery Vehicles (EDVs) are nanocells that can promote tissue-specific delivery of drugs and may be useful to medically treat such disorders. The objective of this study was to determine whether EDVs loaded with the chemotherapeutic doxorubicin and targeting the epidermal growth factor receptor (EGFR, very highly expressed on the placental surface) can regress placental cells in vitro, ex vivo, and in vivo. In female SCID mice, EGFR-targeted EDVs induced greater inhibition of JEG-3 (choriocarcinoma cells) tumor xenografts, compared with EDVs targeting an irrelevant antigen (nontargeted EDVs) or naked doxorubicin. EGFR-targeted EDVs were more readily taken up by human placental explants ex vivo and induced increased apoptosis (M30 antibody) compared with nontargeted EDVs. In vitro, EGFR-targeted EDVs administered to JEG-3 cells resulted in a dose-dependent inhibition of cell viability, proliferation, and increased apoptosis, a finding confirmed by continuous monitoring by xCELLigence. In conclusion, EGFR-targeted EDVs loaded with doxorubicin significantly inhibited trophoblastic tumor cell growth in vivo and in vitro and induced significant cell death ex vivo, potentially mediated by increasing apoptosis and decreasing proliferation. EDVs may be a novel nanoparticle treatment for ectopic pregnancy and other disorders of trophoblast growth.

The insulin-like growth factors (IGFs) stimulate the proliferation of human breast cancer cells, including the estrogen-dependent cell line MCF-7. These cells secrete regulatory IGF-binding proteins (IGFBPs) which may enhance or attenuate IGF-stimulated cell proliferation. In this study, we have used RIA to quantify the production and regulation of IGFBP-3 and IGFBP-6 by MCF-7 cells in vitro. Under basal (serum- and phenol red-free) conditions, IGFBP-3 and IGFBP-6 accumulated in 72 h-conditioned MCF-7 medium to concentrations of approximately 0.18 nM and 0.02 nM, respectively. Treatment with retinoic acid (RA, 100 nM) increased medium concentrations of IGFBP-3 to 175 +/- 8% (mean +/- SE, n = 4), and IGFBP-6 to 217 +/- 20% of control values. Forskolin (0.5 microM) or dibutyryl cAMP (db-cAMP, 1 mM) increased both proteins 2- to 3-fold. In the presence of 100 nM RA, the stimulation elicited by these agents was enhanced, with IGFBP-3 levels increasing to 6-fold above that seen with RA alone. IGFBP-6 increased 12-fold with RA + forskolin and 20-fold with RA + dbcAMP. Estrogen (10 nM estradiol) reduced basal IGFBP-3 levels by 25% but increased IGFBP-6 1.5- to 2-fold. The stimulatory effect of RA + forskolin on IGFBP-3 was partially reversed by estrogen, whereas RA + forskolin-stimulated IGFBP-6 levels were further increased by estrogen. Increased IGFBP-3 and -6 production in response to RA + forskolin was accompanied by a decrease in IGF-stimulated thymidine incorporation into DNA; by contrast, the bioactivity of an IGF analog that does not bind with IGFBPs, [Gln3, Ala4, Tyr15, Leu16]IGF-I, was unchanged under these conditions. These data demonstrate that modulating the production of IGFBPs can lead to changes in the sensitivity of breast cancer cells to IGFs, and as a result change the cell proliferative effects of these growth factors. Further, IGFBP-3 and IGFBP-6 are differentially regulated by estrogen. Dissecting the roles of the individual IGFBPs is essential to understanding how such differential regulation will ultimately affect IGF-stimulated cell proliferation in breast cancer.

Peer observation of teaching is important in the development of educators. The foundation curriculum specifies teaching competencies that must be attained. We created a developmental model of peer observation of teaching to help our foundation doctors achieve these competencies and develop as educators.A process for peer observation was created based on key features of faculty development. The project consisted of a pre-observation meeting, the observation, a post-observation debrief, writing of reflective reports and group feedback sessions. The project was evaluated by completion of questionnaires and focus groups held with both foundation doctors and the students they taught to achieve triangulation.Twenty-one foundation doctors took part. All completed reflective reports on their teaching. Participants described the process as useful in their development as educators, citing specific examples of changes to their teaching practice. Medical students rated the sessions as better or much better quality as their usual teaching.The study highlights the benefits of the project to individual foundation doctors, undergraduate medical students and faculty. It acknowledges potential anxieties involved in having teaching observed.A structured programme of observation of teaching can deliver specific teaching competencies required by foundation doctors and provides additional benefits.

The dose-limiting toxicity of chemotherapeutics, heterogeneity and drug resistance of cancer cells, and difficulties of targeted delivery to tumors all pose daunting challenges to effective cancer therapy. We report that small interfering RNA (siRNA) duplexes readily penetrate intact bacterially derived minicells previously shown to cause tumor stabilization and regression when packaged with chemotherapeutics. When targeted via antibodies to tumor-cell-surface receptors, minicells can specifically and sequentially deliver to tumor xenografts first siRNAs or short hairpin RNA (shRNA)-encoding plasmids to compromise drug resistance by knocking down a multidrug resistance protein. Subsequent administration of targeted minicells containing cytotoxic drugs eliminate formerly drug-resistant tumors. The two waves of treatment, involving minicells loaded with both types of payload, enable complete survival without toxicity in mice with tumor xenografts, while involving several thousandfold less drug, siRNA and antibody than needed for conventional systemic administration of cancer therapies.

The aim of this study was to compare the midterm functional outcomes of total knee arthroplasty (TKA) and total hip arthroplasty (THA). A cross-sectional postal audit survey of all consecutive patients who had a primary joint replacement at one orthopedic center 5 to 8 years ago was conducted. Participants completed an Oxford hip score or Oxford knee score, which are self-report measures of functional ability. Completed questionnaires were returned from 1112 THA patients and 613 TKA patients, giving a response rate of 72%. The median Oxford knee score of 26 was significantly worse than the median Oxford hip score of 19 (P.001). In conclusion, TKA patients experience a significantly poorer functional outcome than THA patients 5 to 8 years postoperatively.

Background: Recently we demonstrated that members of the miR-15/16 family of microRNAs are implicated as tumor suppressors in MPM. The MesomiR 1 study is a first in man ongoing phase I study testing treatment with miR-15 /16 mimics packaged in EDV TM nanocells targeted with EGFR antibodies (TargomiRs). Methods: Dose escalation phase I study where patients are allowed to continue experimental therapy beyond the phase I period, if TargomiRs are well tolerated. Fifty per cent of the MTD established for EDV TM nanocells = 5 billion nanocells loaded with 1.5 µg miR 15/16 mimics (TargomiRs), was chosen as the first dose level. The study uses a standard 3-6 patient dose escalation cohort design examining weekly/twice weekly schedules with 3 planned dose levels in 6 cohorts. Based on prior experience with EDV TM nanocells, starting dose is modified for individual patients with elevated (> 5pg/mL) baseline IL-6 levels. All patients receive premedication with dexamethasone, promethazine and paracetamol and are monitored for a minimum period 3 hours after the TargomiR infusion. If treatment is well tolerated it can be repeated on 8 weeks cycles followed by repeat imaging. Quality of Life questionnaires are completed on a weekly basis. Results: The study commenced in Sep 2014 and is open in 3 centres. Five MPM patients enrolled to date received 5 billion TargomiRs and experienced a short ( Conclusions: The MesomiR 1 study is ongoing. TargomiR infusions in the first 5 patients were well tolerated and associated with transient cytokine-mediated reactions.

Sir, Hyponatraemia is the commonest biochemical abnormality in hospital patients,1,,2 and is often associated with severe illness and poor outcome. We audited the management and outcomes of hyponatraemia in a large district general hospital. For a period of 3 months starting from January 2004, in-patients with hyponatraemia of

Sarcoidal granulomas are found in sarcoidosis and in reactions to foreign materials. We report the case of an 81-year-old woman with glaucoma who presented with multiple brown-black asymptomatic papules over the chin and involving nasal mucosa and columella of 1-year duration. Biopsy of the nasal mucosa and cutaneous papules showed sarcoidal granulomas associated with brown-black intracellular pigment within multinucleated giant cells. Electron-probe x-ray microanalysis demonstrated high sulfur content. Clinical studies showed no evidence of systemic sarcoidosis. Two of three ophthalmologic drops contained sodium bisulfite; bisulfite is known to cause allergic reactions. Although the exact substance causing the granulomatous reaction is unknown, the distribution of the lesions--nasal mucosa and columella (via the nasal lacrimal duct) and the underlying chin--implicate the eyedrops in the production of the pigmented granulomatous nodules.

Pre-employment competency screening is currently being undertaken in eight out of the 25 foundation schools across the United Kingdom. A T Pattison and colleagues highlight the background to this process, review the current guidance, and look at how screening is being used in some regions

A,RECENT study1 of Peire d'Alvernhe's Chantarai d'aquest trobadors identified one "Guossalbo Roitz" ridiculed by Peire with a certain Spanish nobleman named Gon?alvo Roiz, showed that this man had been in or near Puivert (Aude), where Peire's satire was written, in the summer of 1170, and proposed that the brilliant cortege with which he was travelling had attracted to that spot the troubadours of Peire's satire. Since this group of nobles was going into Aragon escorting Eleanor, the daughter of Henry II of England, to her wedding with Alfonso VIII of Castile, it suggested the possibility that at least some of the troubadours of the satire were attached to the bride's suite. Were such the case, it would seem reasonable to look in the works of Bernart de Ventadorn, Peire Rogier, Peire d'Alvernhe, Giraut de Bornelh and Raimbaut d'Aurenga-all of whom, according to the hypothesis of Appel and Rajna, may have been present in person at the gathering of troubadours depicted by Peire d'Alvernhe-for some reference to historical events in Aragon in the fall of 1170 or early in the year 1171. This is the problem I shall examine in this study, especially in the works of Raimbaut d'Aurenga and Giraut de Bornelh. Giraut suggests immediately a series of poems already studied by Kolsen.2 The group contains poems written in Aragon-one is even a tenson with the King of Aragon -all of which Kolsen believes date from the years 1168-69.3 Let us begin, however, by studying a poem of Raimbaut d'Aurenga (Bartsch, Grundriss, Nr. 389, 33), in which the poet shows an intimate knowledge of conditions at the court of Alfonso II of Aragon. Raimbaut is in love with a Catalan woman of lowly birth.4 He speaks also of an intrigue at the court.

The poet and dramatist, Federico García Lorca, has had an extraordinary popularity since his death in 1936. His poems have been translated into numerous languages and his plays acted in many countries. In the United States his popularity has been much greater among amateur theatrical groups than on the professional stage, where, it must be admitted, his success has been very mediocre. But among the amateurs, and especially here in Minnesota, his works have been performed repeatedly. Every one of his principal plays has been acted in this state, and a number of them on more than one occasion.