A bayesian meta-analysis of multiple treatment comparisons of systemic regimens for advanced pancreatic cancer

© 2014 Chan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background: For advanced pancreatic cancer, many regimens have been compared with gemcitabine (G) as the standard arm in randomized controlled trials. Few regimens have been directly compared with each other in randomized controlled trials and the relative efficacy and safety among them remains unclear

The Endogenous Th17 Response in NO<inf>2</inf>-Promoted Allergic Airway Disease Is Dispensable for Airway Hyperresponsiveness and Distinct from Th17 Adoptive Transfer

Severe, glucocorticoid-resistant asthma comprises 5-7% of patients with asthma. IL-17 is a biomarker of severe asthma, and the adoptive transfer of Th17 cells in mice is sufficient to induce glucocorticoid-resistant allergic airway disease. Nitrogen dioxide (NO2) is an environmental toxin that correlates with asthma severity, exacerbation, and risk of adverse outcomes. Mice that are allergically sensitized to the antigen ovalbumin by exposure to NO2 exhibit a mixed Th2/Th17 adaptive immune response and eosinophil and neutrophil recruitment to the airway following antigen challenge, a phenotype reminiscent of severe clinical asthma. Because IL-1 receptor (IL-1R) signaling is critical in the generation of the Th17 response in vivo, we hypothesized that the IL-1R/Th17 axis contributes to pulmonary inflammation and airway hyperresponsiveness (AHR) in NO2-promoted allergic airway disease and manifests in glucocorticoid-resistant cytokine production. IL-17A neutralization at the time of antigen challenge or genetic deficiency in IL-1R resulted in decreased neutrophil recruitment to the airway following antigen challenge but did not protect against the development of AHR. Instead, IL-1R-/- mice developed exacerbated AHR compared to WT mice. Lung cells from NO2-allergically inflamed mice that were treated in vitro with dexamethasone (Dex) during antigen restimulation exhibited reduced Th17 cytokine production, whereas Th17 cytokine production by lung cells from recipient mice of in vitro Th17-polarized OTII T-cells was resistant to Dex. These results demonstrate that the IL-1R/Th17 axis does not contribute to AHR development in NO2-promoted allergic airway disease, that Th17 adoptive transfer does not necessarily reflect an endogenously-generated Th17 response, and that functions of Th17 responses are contingent on the experimental conditions in which they are generated. © 2013 Martin et al

The influence of body weight on the pulmonary oxygen uptake kinetics in pre-pubertal children during moderate- and heavy intensity treadmill exercise

To assess the influence of obesity on the oxygen uptake (V˙O2) kinetics of pre-pubertal children during moderate- and heavy intensity treadmill exercise. We hypothesised that obese (OB) children would demonstrate significantly slower V˙O2 kinetics than their normal weight (NW) counterparts during moderate- and heavy intensity exercise. 18 OB (9.8 ± 0.5 years; 24.1 ± 2.0 kg m2) and 19 NW (9.7 ± 0.5 years; 17.6 ± 1.0 kg m2) children completed a graded-exercise test to volitional exhaustion and two submaximal constant work rate treadmill tests at moderate (90 % gas exchange threshold) and heavy (∆40 %) exercise intensities. Bodyweight significantly influenced the V˙O2 kinetics during both moderate- and heavy exercise intensities (P < 0.05). During moderate intensity exercise, the phase II τ (OB: 30 ± 13 cf. NW: 22 ± 7 s), mean response time (MRT; OB: 35 ± 16 cf. NW: 25 ± 10 s), phase II gain (OB: 156 ± 21 cf. NW: 111 ± 18 mLO2 kg−1 km−1) and oxygen deficit (OB: 0.36 ± 0.11 cf. NW: 0.20 ± 0.06 L) were significantly higher in the OB children (all P < 0.05). During heavy intensity exercise, the τ (OB: 33 ± 9 cf. NW: 27 ± 6 s; P < 0.05) and phase II gain (OB: 212 ± 61 cf. NW: 163 ± 23 mLO2 kg−1 km−1; P < 0.05) were similarly higher in the OB children. A slow component was observed in all participants during heavy intensity exercise, but was not influenced by weight status. In conclusion, this study demonstrates that weight status significantly influences the dynamic V˙O2 response at the onset of treadmill exercise in children and highlights that the deleterious effects of being obese are already manifest pre-puberty

Annual and seasonal movements of migrating short-tailed shearwaters reflect environmental variation in sub-Arctic and Arctic waters

The marine ecosystems of the Bering Sea and adjacent southern Chukchi Sea are experiencing rapid changes due to recent reductions in sea ice. Short-tailed shearwaters Puffinus tenuirostris visit this region in huge numbers between the boreal summer and autumn during non-breeding season, and represent one of the dominant top predators. To understand the implications for this species of ongoing environmental change in the Pacific sub-Arctic and Arctic seas, we tracked the migratory movements of 19 and 24 birds in 2010 and 2011, respectively, using light-level geolocators. In both years, tracked birds occupied the western (Okhotsk Sea and Kuril Islands) and eastern (southeast Bering Sea) North Pacific from May to July. In August–September of 2010, but not 2011, a substantial proportion (68 % of the tracked individuals in 2010 compared to 38 % in 2011) moved through the Bering Strait to feed in the Chukchi Sea. Based on the correlation with oceanographic variables, the probability of shearwater occurrence was highest in waters with sea surface temperatures (SSTs) of 8–10 °C over shallow depths. Furthermore, shearwaters spent more time flying when SST was warmer than 9 °C, suggesting increased search effort for prey. We hypothesized that the northward shift in the distribution of shearwaters may have been related to temperature-driven changes in the abundance of their dominant prey, krill (Euphausiacea), as the timing of krill spawning coincides with the seasonal increase in water temperature. Our results indicate a flexible response of foraging birds to ongoing changes in the sub-Arctic and Arctic ecosystems

Qualitative meta-synthesis of user experience of computerised therapy for depression and anxiety

Objective: Computerised therapies play an integral role in efforts to improve access to psychological treatment for patients with depression and anxiety. However, despite recognised problems with uptake, there has been a lack of investigation into the barriers and facilitators of engagement. We aimed to systematically review and synthesise findings from qualitative studies of computerised therapies, in order to identify factors impacting on engagement. Method: Systematic review and meta-synthesis of qualitative studies of user experiences of computer delivered therapy for depression and/or anxiety. Results: 8 studies were included in the review. All except one were of desktop based cognitive behavioural treatments. Black and minority ethnic and older participants were underrepresented, and only one study addressed users with a comorbid physical health problem. Through synthesis, we identified two key overarching concepts, regarding the need for treatments to be sensitive to the individual, and the dialectal nature of user experience, with different degrees of support and anonymity experienced as both positive and negative. We propose that these factors can be conceptually understood as the ‘non-specific’ or ‘common’ factors of computerised therapy, analogous to but distinct from the common factors of traditional face-to-face therapies. Conclusion: Experience of computerised therapy could be improved through personalisation and sensitisation of content to individual users, recognising the need for users to experience a sense of ‘self’ in the treatment which is currently absent. Exploiting the common factors of computerised therapy, through enhancing perceived connection and collaboration, could offer a way of reconciling tensions due to the dialectal nature of user experience. Future research should explore whether the findings are generalisable to other patient groups, to other delivery formats (such as mobile technology) and other treatment modalities beyond cognitive behaviour therapy. The proposed model could aid the development of enhancements to current packages to improve uptake and support engagement

Huntington's disease and its therapeutic target genes: a global functional profile based on the HD Research Crossroads database.

BACKGROUND: Huntington's disease (HD) is a fatal progressive neurodegenerative disorder caused by the expansion of the polyglutamine repeat region in the huntingtin gene. Although the disease is triggered by the mutation of a single gene, intensive research has linked numerous other genes to its pathogenesis. To obtain a systematic overview of these genes, which may serve as therapeutic targets, CHDI Foundation has recently established the HD Research Crossroads database. With currently over 800 cataloged genes, this web-based resource constitutes the most extensive curation of genes relevant to HD. It provides us with an unprecedented opportunity to survey molecular mechanisms involved in HD in a holistic manner. METHODS: To gain a synoptic view of therapeutic targets for HD, we have carried out a variety of bioinformatical and statistical analyses to scrutinize the functional association of genes curated in the HD Research Crossroads database. In particular, enrichment analyses were performed with respect to Gene Ontology categories, KEGG signaling pathways, and Pfam protein families. For selected processes, we also analyzed differential expression, using published microarray data. Additionally, we generated a candidate set of novel genetic modifiers of HD by combining information from the HD Research Crossroads database with previous genome-wide linkage studies. RESULTS: Our analyses led to a comprehensive identification of molecular mechanisms associated with HD. Remarkably, we not only recovered processes and pathways, which have frequently been linked to HD (such as cytotoxicity, apoptosis, and calcium signaling), but also found strong indications for other potentially disease-relevant mechanisms that have been less intensively studied in the context of HD (such as the cell cycle and RNA splicing, as well as Wnt and ErbB signaling). For follow-up studies, we provide a regularly updated compendium of molecular mechanism, that are associated with HD, at http://hdtt.sysbiolab.eu Additionally, we derived a candidate set of 24 novel genetic modifiers, including histone deacetylase 3 (HDAC3), metabotropic glutamate receptor 1 (GRM1), CDK5 regulatory subunit 2 (CDK5R2), and coactivator 1ß of the peroxisome proliferator-activated receptor gamma (PPARGC1B). CONCLUSIONS: The results of our study give us an intriguing picture of the molecular complexity of HD. Our analyses can be seen as a first step towards a comprehensive list of biological processes, molecular functions, and pathways involved in HD, and may provide a basis for the development of more holistic disease models and new therapeutics

Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis.

Molecular, genetic and pathological evidence suggests that deficits in GABAergic parvalbumin-positive interneurons contribute to schizophrenia pathophysiology through alterations in the brain's excitation-inhibition balance that result in impaired behaviour and cognition. Although the factors that trigger these deficits are diverse, there is increasing evidence that they converge on a common pathological hub that involves NMDA receptor hypofunction and oxidative stress. These factors have been separately linked to schizophrenia pathogenesis, but evidence now suggests that they are mechanistically interdependent and contribute to a common schizophrenia-associated pathology

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Elevated glutamine/glutamate ratio in cerebrospinal fluid of first episode and drug naive schizophrenic patients

BACKGROUND: Recent magnetic resonance spectroscopy (MRS) studies report that glutamine is altered in the brains of schizophrenic patients. There were also conflicting findings on glutamate in cerebrospinal fluid (CSF) of schizophrenic patients, and absent for glutamine. This study aims to clarify the question of glutamine and glutamate in CSF of first episode and drug naive schizophrenic patients. METHOD: Levels of glutamine and glutamate in CSF of 25 first episode and drug-naive male schizophrenic patients and 17 age-matched male healthy controls were measured by a high performance liquid chromatography. RESULTS: The ratio (126.1 (median), 117.7 ± 27.4 (mean ± S.D.)) of glutamine to glutamate in the CSF of patients was significantly (z = -3.29, p = 0.001) higher than that (81.01 (median), 89.1 ± 22.5 (mean ± S.D.)) of normal controls although each level of glutamine and glutamate in patients was not different from that of normal controls. CONCLUSION: Our data suggests that a disfunction in glutamate-glutamine cycle in the brain may play a role in the pathophysiology of schizophrenia

Teaching appropriate interactions with pharmaceutical company representatives: The impact of an innovative workshop on student attitudes

BACKGROUND: Pharmaceutical company representatives (PCRs) influence the prescribing habits and professional behaviour of physicians. However, the skills for interacting with PCRs are not taught in the traditional medical school curriculum. We examined whether an innovative, mandatory workshop for third year medical students had immediate effects on knowledge and attitudes regarding interactions with PCRs. METHODS: Surveys issued before and after the workshop intervention solicited opinions (five point Likert scales) from third year students (n = 75) about the degree of bias in PCR information, the influence of PCRs on prescribing habits, the acceptability of specific gifts, and the educational value of PCR information for both practicing physicians and students. Two faculty members and one PCR led the workshop, which highlighted typical physician-PCR interactions, the use of samples and gifts, the validity and legal boundaries of PCR information, and associated ethical issues. Role plays with the PCR demonstrated appropriate and inappropriate strategies for interacting with PCRs. RESULTS: The majority of third year students (56%, 42/75) had experienced more than three personal conversations with a PCR about a drug product since starting medical school. Five percent (4/75) claimed no previous personal experience with PCRs. Most students (57.3%, 43/75) were not aware of available guidelines regarding PCR interactions. Twenty-eight percent of students (21/75) thought that none of the named activities/gifts (lunch access, free stethoscope, textbooks, educational CD-ROMS, sporting events) should be restricted, while 24.0% (8/75) thought that students should be restricted only from sporting events. The perceived educational value of PCR information to both practicing physicians and students increased after the workshop intervention from 17.7% to 43.2% (chi square, p = .0001), and 22.1% to 40.5% (p = .0007), respectively. Student perceptions of the degree of bias of PCR information decreased from 84.1% to 72.9% (p = .065), but the perceived degree of influence on prescribing increased (44.2% to 62.1% (p = .02)). CONCLUSIONS: Students have exposure to PCRs early in their medical training. A single workshop intervention may influence student attitudes toward interactions with PCRs. Students were more likely to acknowledge the educational value of PCR interactions and their impact on prescribing after the workshop intervention