Nuclear expression of Lyn, a Src family kinase member, is associated with poor prognosis in renal cancer patients

Background: 8000 cases of renal cancer are diagnosed each year in the UK, with a five-year survival rate of 50 %. Treatment options are limited; a potential therapeutic target is the Src family kinases (SFKs). SFKs have roles in multiple oncogenic processes and promote metastases in solid tumours. The aim of this study was to investigate SFKs as potential therapeutic targets for clear cell renal cell carcinoma (ccRCC). Methods: SFKs expression was assessed in a tissue microarray consisting of 192 ccRCC patients with full clinical follow-up. SFK inhibitors, dasatinib and saracatinib, were assessed in early ccRCC cell lines, 786-O and 769-P and a metastatic ccRCC cell line, ACHN (± Src) for effects on protein expression, apoptosis, proliferation and wound healing. Results: High nuclear expression of Lyn and the downstream marker of activation, paxillin, were associated with decreased patient survival. Conversely, high cytoplasmic expression of other SFK members and downstream marker of activation, focal adhesion kinase (FAK) were associated with increased patient survival. Treatment of non-metastatic 786-O and 769-P cells with dasatinib, dose dependently reduced SFK activation, shown via SFK (Y419) and FAK (Y861) phosphorylation, with no effect in metastatic ACHN cells. Dasatinib also increased apoptosis, while decreasing proliferation and migration in 786-O and 769-P cell lines, both in the presence and absence of Src protein. Conclusions: Our data suggests that nuclear Lyn is a potential therapeutic target for ccRCC and dasatinib affects cellular functions associated with cancer progression via a Src kinase independent mechanism

Junior doctors’ communication with hospital pharmacists about prescribing: findings from a qualitative interview study

Objectives To explore factors affecting communication between Foundation Year (FY) 1 doctors and hospital pharmacists about prescribing from the junior doctors’ perspective. Methods Trained interviewers (n=4) conducted semistructured interviews with FY1 doctors who were purposively sampled from three hospitals in England. FY1 doctors were asked about their experiences of communication with hospital pharmacists about their prescribing; instances where they disagreed with or did not implement a hospital pharmacist’s recommendation; and their preferences for communicating with hospital pharmacists about prescribing. Interviews were audiorecorded, transcribed verbatim and analysed thematically. Results A total of 27 FY1 doctors were interviewed. Findings were categorised into four main themes: (1) nature and context of communication; (2) FY1 doctors’ perceptions of communication with hospital pharmacists; (3) factors influencing FY1 doctors’ decision whether to act on pharmacists’ prescribing recommendations; and (4) suggestions to improve communication with pharmacists. FY1 doctors and hospital pharmacists generally communicated well. FY1 doctors appreciated and frequently acted on pharmacists’ advice yet there was deference to senior medical staff when advice differed. Joint ward rounds, pharmacist-led teaching sessions and a standardised approach to communication were all suggested as ways to improve communication and may increase the likelihood of pharmacists’ recommendations being acted on. Conclusions FY1 doctors and hospital pharmacists communicated frequently about medication prescribing. Issues occurred when there were differences in professional judgement between senior medical staff and pharmacists but these were usually resolved satisfactorily for the FY1 doctor. Further interventions to improve communication and safe prescribing could involve a multidisciplinary and systems approach

Magnetic phase transitions in Gd64Sc36 studied using non-contact ultrasonics

The speed and attenuation of ultrasound propagation can be used to determine material properties and identify phase transitions. Standard ultrasonic contact techniques are not always convenient due to the necessity of using couplant; however, recently reliable non-contact ultrasonic techniques involving electromagnetic generation and detection of ultrasound with electromagnetic acoustic transducers (EMATs) have been developed for use on electrically conducting and/or magnetic materials. We present a detailed study of magnetic phase transitions in a single crystal sample of Gd64Sc36 magnetic alloy using contact and non-contact ultrasonic techniques for two orientations of external magnetic field. Phase diagrams are constructed based on measurements of elastic constant C33, the attenuation and the efficiency of generation when using an EMAT. The EMATs are shown to provide additional information related to the magnetic phase transitions in the studied sample, and results identify a conical helix phase in Gd64Sc36 in the magnetic field orientation

Promotion of access to essential medicines for Non-Communicable Diseases: Practical implications of the UN Political Declaration

Access to medicines and vaccines to prevent and treat non-communicable diseases (NCDs) is unacceptably low worldwide. In the 2011 UN political declaration on the prevention and control of NCDs, heads of government made several commitments related to access to essential medicines, technologies, and vaccines for such diseases. 30 years of experience with policies for essential medicines and 10 years of scaling up of HIV treatment have provided the knowledge needed to address barriers to long-term effective treatment and prevention of NCDs. More medicines can be acquired within existing budgets with efficient selection, procurement, and use of generic medicines. Furthermore, low-income and middle-income countries need to increase mobilisation of domestic resources to cater for the many patients with NCDs who do not have access to treatment. Existing initiatives for HIV treatment offer useful lessons that can enhance access to pharmaceutical management of NCDs and improve adherence to long-term treatment of chronic illness; policy makers should also address unacceptable inequities in access to controlled opioid analgesics. In addition to off-patent medicines, governments can promote access to new and future on-patent medicinal products through coherent and equitable health and trade policies, particularly those for intellectual property. Frequent conflicts of interest need to be identified and managed, and indicators and targets for access to NCD medicines should be used to monitor progress. Only with these approaches can a difference be made to the lives of hundreds of millions of current and future patients with NCDs

Quality of private and public ambulatory health care in low and middle income countries: systematic review of comparative studies

Paul Garner and colleagues conducted a systematic review of 80 studies to compare the quality of private versus public ambulatory health care in low- and middle-income countries

Duality Cascade in Brane Inflation

We show that brane inflation is very sensitive to tiny sharp features in extra dimensions, including those in the potential and in the warp factor. This can show up as observational signatures in the power spectrum and/or non-Gaussianities of the cosmic microwave background radiation (CMBR). One general example of such sharp features is a succession of small steps in a warped throat, caused by Seiberg duality cascade using gauge/gravity duality. We study the cosmological observational consequences of these steps in brane inflation. Since the steps come in a series, the prediction of other steps and their properties can be tested by future data and analysis. It is also possible that the steps are too close to be resolved in the power spectrum, in which case they may show up only in the non-Gaussianity of the CMB temperature fluctuations and/or EE polarization. We study two cases. In the slow-roll scenario where steps appear in the inflaton potential, the sensitivity of brane inflation to the height and width of the steps is increased by several orders of magnitude comparing to that in previously studied large field models. In the IR DBI scenario where steps appear in the warp factor, we find that the glitches in the power spectrum caused by these sharp features are generally small or even unobservable, but associated distinctive non-Gaussianity can be large. Together with its large negative running of the power spectrum index, this scenario clearly illustrates how rich and different a brane inflationary scenario can be when compared to generic slow-roll inflation. Such distinctive stringy features may provide a powerful probe of superstring theory.Comment: Corrections in Eq.(5.47), Eq (5.48), Eq(5.49) and Fig

Incarceration history and risk of HIV and hepatitis C virus acquisition among people who inject drugs: a systematic review and meta-analysis

Background People who inject drugs (PWID) experience a high prevalence of incarceration and might be at high risk of HIV and hepatitis C virus (HCV) infection during or after incarceration. We aimed to assess whether incarceration history elevates HIV or HCV acquisition risk among PWID. Methods In this systematic review and meta-analysis, we searched MEDLINE, Embase, and PsycINFO databases for studies in any language published from Jan 1, 2000 until June 13, 2017 assessing HIV or HCV incidence among PWID. We included studies that measured HIV or HCV incidence among community-recruited PWID. We included only studies reporting original results and excluded studies that evaluated incident infections by self-report. We contacted authors of cohort studies that met the inclusion or exclusion criteria, but that did not report on the outcomes of interest, to request data. We extracted and pooled data from the included studies using random-effects meta-analyses to quantify the associations between recent (past 3, 6, or 12 months or since last follow-up) or past incarceration and HIV or HCV acquisition (primary infection or reinfection) risk among PWID. We assessed the risk of bias of included studies using the Newcastle-Ottawa Scale. Between-study heterogeneity was evaluated using the I2 statistic and the P-value for heterogeneity. Findings We included published results from 20 studies and unpublished results from 21 studies. These studies originated from Australasia, western and eastern Europe, North and Latin America, and east and southeast Asia. Recent incarceration was associated with an 81% (relative risk [RR] 1·81, 95% CI 1·40–2·34) increase in HIV acquisition risk, with moderate heterogeneity between studies (I2=63·5%; p=0·001), and a 62% (RR 1·62, 95% CI 1·28–2·05) increase in HCV acquisition risk, also with moderate heterogeneity between studies (I2=57·3%; p=0·002). Past incarceration was associated with a 25% increase in HIV (RR 1·25, 95% CI 0·94–1·65) and a 21% increase in HCV (1·21, 1·02–1·43) acquisition risk. Interpretation Incarceration is associated with substantial short-term increases in HIV and HCV acquisition risk among PWID and could be a significant driver of HCV and HIV transmission among PWID. These findings support the need for developing novel interventions to minimise the risk of HCV and HIV acquisition, including addressing structural risks associated with drug laws and excessive incarceration of PWID

Intravenous immunoglobulin treatment in childhood encephalitis (IgNiTE): a randomised controlled trial

Objective: To investigate whether intravenous immunoglobulin (IVIG) improves neurological outcomes in children with encephalitis when administered early in the illness. // Design: Phase 3b multicentre, double-blind, randomised placebo-controlled trial. // Setting: Twenty-one hospitals in the UK. // Participants: Children aged 6 months to 16 years with a diagnosis of acute or subacute encephalitis, with a planned sample size of 308. // Intervention: Two doses (1 g/kg/dose) of either IVIG or matching placebo given 24–36 hours apart, in addition to standard treatment. // Main outcome measure: The primary outcome was a ‘good recovery’ at 12 months after randomisation, defined as a score of≤2 on the Paediatric Glasgow Outcome Score Extended. // Secondary outcome measures: The secondary outcomes were clinical, neurological, neuroimaging and neuropsychological results, identification of the proportion of children with immune-mediated encephalitis, and IVIG safety data. // Results: 18 participants were recruited from 12 hospitals and randomised to receive either IVIG (n=10) or placebo (n=8) between 23 December 2015 and 26 September 2017. The study was terminated early following withdrawal of funding due to slower than anticipated recruitment, and therefore did not reach the predetermined sample size required to achieve the primary study objective; thus, the results are descriptive. At 12 months after randomisation, 9 of the 18 participants (IVIG n=5/10 (50%), placebo n=4/8 (50%)) made a good recovery and 5 participants (IVIG n=3/10 (30%), placebo n=2/8 (25%)) made a poor recovery. Three participants (IVIG n=1/10 (10%), placebo n=2/8 (25%)) had a new diagnosis of epilepsy during the study period. Two participants were found to have specific autoantibodies associated with autoimmune encephalitis. No serious adverse events were reported in participants receiving IVIG. // Conclusions: The IgNiTE (ImmunoglobuliN in the Treatment of Encephalitis) study findings support existing evidence of poor neurological outcomes in children with encephalitis. However, the study was halted prematurely and was therefore underpowered to evaluate the effect of early IVIG treatment compared with placebo in childhood encephalitis. // Trial registration number: Clinical Trials.gov NCT02308982; ICRCTN registry ISRCTN15791925

Comparing Brane Inflation to WMAP

We compare the simplest realistic brane inflationary model to recent cosmological data, including WMAP 3-year cosmic microwave background (CMB) results, Sloan Digital Sky Survey luminous red galaxies (SDSS LRG) power spectrum data and Supernovae Legacy Survey (SNLS) Type 1a supernovae distance measures. Here, the inflaton is simply the position of a $D3$-brane which is moving towards a $\bar{D}3$-brane sitting at the bottom of a throat (a warped, deformed conifold) in the flux compactified bulk in Type IIB string theory. The analysis includes both the usual slow-roll scenario and the Dirac-Born-Infeld scenario of slow but relativistic rolling. Requiring that the throat is inside the bulk greatly restricts the allowed parameter space. We discuss possible scenarios in which large tensor mode and/or non-Gaussianity may emerge. Here, the properties of a large tensor mode deviate from that in the usual slow-roll scenario, providing a possible stringy signature. Overall, within the brane inflationary scenario, the cosmological data is providing information about the properties of the compactification of the extra dimensions.Comment: 45 pages 11 figure

Therapeutic DNA vaccine induces broad T cell responses in the gut and sustained protection from viral rebound and AIDS in SIV-infected rhesus macaques.

Immunotherapies that induce durable immune control of chronic HIV infection may eliminate the need for life-long dependence on drugs. We investigated a DNA vaccine formulated with a novel genetic adjuvant that stimulates immune responses in the blood and gut for the ability to improve therapy in rhesus macaques chronically infected with SIV. Using the SIV-macaque model for AIDS, we show that epidermal co-delivery of plasmids expressing SIV Gag, RT, Nef and Env, and the mucosal adjuvant, heat-labile E. coli enterotoxin (LT), during antiretroviral therapy (ART) induced a substantial 2-4-log fold reduction in mean virus burden in both the gut and blood when compared to unvaccinated controls and provided durable protection from viral rebound and disease progression after the drug was discontinued. This effect was associated with significant increases in IFN-γ T cell responses in both the blood and gut and SIV-specific CD8+ T cells with dual TNF-α and cytolytic effector functions in the blood. Importantly, a broader specificity in the T cell response seen in the gut, but not the blood, significantly correlated with a reduction in virus production in mucosal tissues and a lower virus burden in plasma. We conclude that immunizing with vaccines that induce immune responses in mucosal gut tissue could reduce residual viral reservoirs during drug therapy and improve long-term treatment of HIV infection in humans