Characterization of Dendritic Cells Transduced with Venezuelan Equine Encephalitis Virus Replicon Particles as Therapeutic Cancer Vaccines

Cancer vaccines seek to harness the specificity of T and B lymphocytes for reduction of tumor burden, as well as prevention of recurrent disease by establishing immunological memory. Because of their ability to initiate adaptive immune responses, dendritic cells (DCs) presenting tumor antigens have frequently been used as cancer vaccines. Unfortunately, induction of therapeutic responses in cancer patients has been sporadic, suggesting that current DC vaccines are unable to surmount tolerance against tumor antigens. The transduction of DCs with recombinant viral vectors may be a viable strategy for augmenting the ability of DC vaccines to break tolerance, as this approach can be used to efficiently deliver tumor antigens to DCs in the context of an immunostimulatory viral infection. Therefore, we have investigated the potential of DCs transduced with Venezuelan equine encephalitis virus replicon particles (VRPs) as cancer vaccines. VRPs could efficiently transduce human and murine immature DCs ex vivo, leading to high-level transgene expression, DC maturation, secretion of proinflammatory cytokines and efficient presentation of VRP-encoded antigens to T cells. VRP-transduced DCs (VRP-DCs) expressing a truncated neu oncoprotein stimulated neu-specific T cell and antibody responses and induced regression of established tumors in nontolerant mice. In contrast, VRP-DCs failed to induce robust antitumor responses in mice tolerant to neu, and were likewise unable to inhibit tumor growth. Depletion of CD4+CD25+ regulatory T cells (Treg) improved the effectiveness of VRP-DC vaccines in tolerant mice, demonstrating that VRP-DCs alone were unable to overcome Treg activity. Furthermore, provision of tolerant mice with neu-specific T cells from nontolerant mice did not augment vaccine efficacy, indicating that tolerogenic mechanisms are dominant over effector T cell activity. These results demonstrate that while highly immunogenic, virally-activated DCs cannot break tolerance against self/tumor antigens. Moreover, these findings imply that potent DC vaccines alone are unlikely to induce therapeutic antitumor immunity unless additional measures are undertaken to inhibit immunoregulatory mechanisms

The pattern of underlying cause of death in patients with inflammatory bowel disease in England: a record linkage study

Background and Aims: Numerous studies have established that mortality risk in IBD patients is higher than the general population, but the causes of death have seldom been examined. We aimed to describe causes of death in IBD. Methods: A matched cohort study using UK general practice data from Clinical Practice Research Datalink linked to death registration records. We described the distribution of causes of death among IBD patients by age at death and time since IBD diagnosis. We estimated age-specific mortality rates and hazard ratios of death in multivariable Cox proportional hazards models. Results: 20,293 IBD patients were matched to 83,261 non-IBD patients. The mortality rate was 40% higher in IBD patients (2005 deaths) than in non-IBD patients (6024 deaths) (adjusted overall hazard ratio = 1.4, 95% CI = 1.4—1.5), with greater risk of death in Crohn’s disease (hazard ratio = 1.6, 1.5—1.7) than in ulcerative colitis (1.3, 1.3—1.4). Causes attributable to IBD constituted 3.7% of all deaths in ulcerative colitis and 8.3% in Crohn’s disease. Among IBD patients, death was less likely to be due to circulatory, respiratory or neoplastic diseases than non-IBD patients. In both IBD and non-IBD patients all these causes became more clinically important with advancing age, with the commonest neoplastic cause of death being lung cancer, rather than gastrointestinal cancers. Conclusion: IBD patients have an additional risk of death. Most IBD patients die of circulatory or respiratory causes, and the contribution to mortality from long-term complications of IBD are clinically less important

Is Clinical Tolerance Possible after Allergen Immunotherapy?

There is a growing evidence that allergen immunotherapy (AIT) can provide significant and long-lasting clinical benefit for a number of allergic individuals. However, it is less clear if AIT results in clinical tolerance, which is characterized by a persistent state of clinical non-reactivity to allergens after therapy is finished. Addressing this knowledge gap is particularly relevant for patients undergoing AIT for food allergies, as anything less than complete tolerance could have potentially devastating consequences. An increasing number of studies, in particular those involving oral immunotherapy, are attempting to assess tolerance induction following AIT. Clinical tolerance does appear to be achievable in a subset of patients undergoing AIT, but whether this is equivalent to the type of tolerance observed in nonallergic individuals remains unknown. Developing established criteria for assessing tolerance induction, as well as the use of consistent terminology when describing clinical tolerance, will be important for determining the disease-modifying potential of AIT

The silence of self-knowledge

Gareth Evans famously affirmed an explanatory connection between answering the question whether p and knowing whether one believes that p. This is commonly interpreted in terms of the idea that judging that p constitutes an adequate basis for the belief that one believes that p. This paper formulates and defends an alternative, more modest interpretation, which develops from the suggestion that one can know that one believes that p in judging that p

The GALEX Arecibo SDSS Survey. VIII. Final Data Release -- The Effect of Group Environment on the Gas Content of Massive Galaxies

We present the final data release from the GALEX Arecibo SDSS Survey (GASS), a large Arecibo program that measured the HI properties for an unbiased sample of ~800 galaxies with stellar masses greater than 10^10 Msun and redshifts 0.025<z<0.05. This release includes new Arecibo observations for 250 galaxies. We use the full GASS sample to investigate environmental effects on the cold gas content of massive galaxies at fixed stellar mass. The environment is characterized in terms of dark matter halo mass, obtained by cross-matching our sample with the SDSS group catalog of Yang et al. Our analysis provides, for the first time, clear statistical evidence that massive galaxies located in halos with masses of 10^13-10^14 Msun have at least 0.4 dex less HI than objects in lower density environments. The process responsible for the suppression of gas in group galaxies most likely drives the observed quenching of the star formation in these systems. Our findings strongly support the importance of the group environment for galaxy evolution, and have profound implications for semi-analytic models of galaxy formation, which currently do not allow for stripping of the cold interstellar medium in galaxy groups.Comment: 36 pages, 16 figures. Accepted for publication in MNRAS. Version with supplementary material available at http://www.mpa-garching.mpg.de/GASS/pubs.php . GASS released data can be found at http://www.mpa-garching.mpg.de/GASS/data.ph

Oral and sublingual immunotherapy for food allergy: current progress and future directions

Food allergies are increasing in prevalence and present an emerging epidemic for westernized countries. Strict dietary avoidance is the only approved management for food allergy, but accidental exposures regularly occur, leading to significant patient anxiety and decreased quality of life. Over the past decade, oral and sublingual immunotherapies have emerged as potential treatments for food allergy. While several small clinical trials have demonstrated that immunotherapy can desensitize food-allergic individuals, strategies for further enhancing safety and definitively establishing long-term efficacy are needed. This review presents an overview of recent oral and sublingual immunotherapy trials, and provides a glimpse into what the next generation of food immunotherapy may entail

A Resident Retreat with Emergency Medicine Specific Mindfulness Training Significantly Reduces Burnout and Perceived Stress

Introduction: We hypothesize that a resident retreat with mindfulness training tailored for Emergency Medicine (EM) physicians can significantly reduce levels of burnout and perceived stress in EM residents. Methods: We conducted an intervention study of 60 EM residents undergoing an annual resident retreat with a 2.5-hour mindfulness training. The retreat was a department-funded 2-day off-site experience with a wellness theme. The training was developed and delivered by an EM physician (JO\u27S) who is a Mindfulness-Based Stress Reduction (MBSR) teacher trainee, and a certified MBSR teacher (MD). The training focused on techniques that can be used on shift, such as mindful breathing, handwashing, eating/drinking, walking, and anchoring before resuscitations. The cohort contained an equal distribution of 1st, 2nd and 3rd year residents who received a financial incentive. The subjects completed the Maslach Burnout Inventory, Perceived Stress Scale and Mindful Attention and Awareness Scale at three time points: Time 1 - one month prior, Time 2 – one week post, Time 3 – one month post. Results: The subjects were 60 EM residents (54% Male, 46% Female) with an average age of 29. Completion rates at the three time points were 70% (n = 42), 60% (n = 36) and 50% (n = 30) respectively. We found that Perceived Stress (ω2 = 0.15, p \u3c 0.01) and Emotional Exhaustion (ω2 = 0.21, p \u3c 0.01) decreased significantly over time in a linear progression across the three sampling periods. Though mindfulness as a trait did not change significantly during the study period, in the month after the retreat, 64% of resident respondents at Time 3 (n = 32) reported using the mindfulness techniques learned from the training at least 2 or 3 times a week on shift and 52% (n = 31) reported using them at least 2 or 3 times a week at home. Conclusions: An EM resident retreat that included an EM specific mindfulness training significantly reduced perceived stress and emotional exhaustion. The learned mindfulness skills were readily adopted for use on shift. Further studies should investigate effectiveness of mindfulness training outside of the retreat format. Other wellness / academic activities that occur within the socially supportive milieu of a retreat could lead to the same significant reduction in burnout and perceived stress seen in the current study

Utilization of Wellness Practices For Burnout and Stress During COVID-19 Among an Interdisciplinary Cohort of Emergency Healthcare Workers

Introduction: The Coronavirus Disease (COVID-19) introduced additional stress to the baseline occupational stressors of emergency care workers. The objectives of this study were to evaluate perceived stress and burnout and the utilization and perceived benefit of wellness practices among emergency healthcare workers (EHCWs), including: emergency physicians, advanced practice providers (APPs), nurses, and departmental administrative staff during the COVID-19 pandemic. Methods: A cross-sectional 28-item electronic survey of EHCWs at three hospitals in a major United States city was used to measure participants’ utilization and perceived benefit of wellness practices, burnout (2-item measure), overall stress (perceived stress scale), and stress related to COVID-19. Results: The sample consisted of 260 respondents (response rate 44.6%, 583 eligible). Over one-half (56.5%) reported burnout from their job and a majority (58.5%) reported moderate to high stress. Wellness activities including regular exercise and engaging in hobbies were associated with lower reports of burnout. Higher stress levels were reported by participants who had tested positive for COVID-19. Nurses reported the highest rates of burnout overall (80.6%). Females reported higher rates of burnout than males across the cohort (64.5 vs 41.9%, p = 0.001), and female APPs reported significantly higher burnout than did male APPs (69.2 vs 38.5%, p = 0.048). Participants reported donated personal protective equipment (PPE) and meals on shift were extremely helpful. Conclusion: The COVID-19 pandemic was a significant contributor to the stress of EHCWs. Regular engagement in wellness activities was associated with lower rates of burnout. The benefit of engagement in wellness practices, both individual practices and organizational interventions are paramount to mitigate stress and burnout in EHCWs

A Comprehensive Residency Wellness Curriculum

Introduction: Resident physician burnout is an epidemic in medical education. There are several wellness curricula published, but few describe a comprehensive program to address wellness. Our objectives were to develop and pilot a longitudinal resident wellness curriculum and assess for feasibility and sustainability. Methods: We surveyed emergency medicine (EM) residents from two residency programs in the United States to assess a baseline level of burnout using the Maslach Burnout Inventory. We developed a comprehensive and longitudinal wellness curriculum for EM residents that incorporated all domains identified by the American College of Emergency Physicians Wellness Wheel. Mindfulness practice was incorporated throughout the curriculum. Results: A convenience sample of 106 EM residents were sent the baseline survey. A response rate of 69% was achieved, the median age of the respondents was 29 years, and 44.5% were female. Overall, 67.5% (95% CI: 50.5; 80.8%) reported burnout in at least one of the three domains of the Maslach Burnout inventory. 34.8% reported burnout in the personal accomplishment domain, 40.8% reported depersonalization, and 44.3% reported emotional exhaustion. The wellness curriculum was successfully implemented at the Georgia-based residency program. The curriculum has proven to be sustainable since it began in 2016. Quantitative statistical testing for the post-intervention survey was not possible due to a low response rate. However, subjective receivability was high, with participants describing these sessions as high-yield, informative and practical. Conclusions: Burnout is highly prevalent among EM residents. We provide a curriculum developed for an EM residency program that is multifaceted and comprehensive, including basic wellness topics, mindfulness, financial and medicolegal issues, as well as topics that address the stresses specific to clinical emergency medicine. The curriculum has been in place in its current form since 2016 and has proven to be sustainable

The GALEX Arecibo SDSS survey: III. Evidence for the Inside-Out Formation of Galactic Disks

We analyze a sample of galaxies with stellar masses greater than $10^{10} M_{\odot}$ and with redshifts in the range $0.025<z<0.05$ for which HI mass measurements are available from the GALEX Arecibo SDSS Survey (GASS) or from the Arecibo Legacy Fast ALFA survey (ALFALFA). At a given value of $M_*$, our sample consists primarily of galaxies that are more HI-rich than average. We constructed a series of three control samples for comparison with these HI-rich galaxies. As expected, HI-rich galaxies differ strongly from galaxies of same stellar mass that are selected without regard to HI content. The majority of these differences are attributable to the fact that galaxies with more gas are bluer and more actively star-forming. In order to identify those galaxy properties that are causally connected with HI content, we compare results derived for the HI sample with those derived for galaxies matched in stellar mass, size and NUV-$r$ colour. The only photometric property that is clearly attributable to increasing HI content, is the colour gradient of the galaxy. Galaxies with larger HI fractions have bluer, more actively star-forming outer disks compared to the inner part of the galaxy. HI-rich galaxies also have larger $g$-band radii compared to $i$-band radii. Our results are consistent with the "inside-out" picture of disk galaxy formation, which has commonly served as a basis for semi-analytic models of the formation of disks in the context of Cold Dark Matter cosmologies. The lack of any intrinsic connection between HI fraction and galaxy asymmetry suggests that gas is accreted smoothly onto the outer disk.Comment: 18 pages, 20 figures. Accepted for publication in MNRAS. GASS publications and released data can be found at http://www.mpa-garching.mpg.de/GASS/index.ph