Although mutations in DNA are the best-studied source of neoantigens that determine response to immune checkpoint blockade, alterations in RNA splicing within cancer cells could similarly result in ...neoepitope production. However, the endogenous antigenicity and clinical potential of such splicing-derived epitopes have not been tested. Here, we demonstrate that pharmacologic modulation of splicing via specific drug classes generates bona fide neoantigens and elicits anti-tumor immunity, augmenting checkpoint immunotherapy. Splicing modulation inhibited tumor growth and enhanced checkpoint blockade in a manner dependent on host T cells and peptides presented on tumor MHC class I. Splicing modulation induced stereotyped splicing changes across tumor types, altering the MHC I-bound immunopeptidome to yield splicing-derived neoepitopes that trigger an anti-tumor T cell response in vivo. These data definitively identify splicing modulation as an untapped source of immunogenic peptides and provide a means to enhance response to checkpoint blockade that is readily translatable to the clinic.
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•Pharmacologic modulation of splicing enhances immune checkpoint blockade efficacy•RBM39 degradation and type I PRMT inhibition are well tolerated by immune cells•Splicing perturbation induces splicing-derived neoepitopes that are immunogenic•Rigorous framework for the identification of splicing-derived antigenic peptides
By provoking production of “neoantigens” that are recognized by immune cells, drugs that modulate RNA splicing can enhance cancer immunotherapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose
Our objective was to revise the definition of acute respiratory distress syndrome (ARDS) using a conceptual model incorporating reliability and validity, and a novel iterative approach with ...formal evaluation of the definition.
Methods
The European Society of Intensive Care Medicine identified three chairs with broad expertise in ARDS who selected the participants and created the agenda. After 2 days of consensus discussions a draft definition was developed, which then underwent empiric evaluation followed by consensus revision.
Results
The Berlin Definition of ARDS maintains a link to prior definitions with diagnostic criteria of timing, chest imaging, origin of edema, and hypoxemia. Patients may have ARDS if the onset is within 1 week of a known clinical insult or new/worsening respiratory symptoms. For the bilateral opacities on chest radiograph criterion, a reference set of chest radiographs has been developed to enhance inter-observer reliability. The pulmonary artery wedge pressure criterion for hydrostatic edema was removed, and illustrative vignettes were created to guide judgments about the primary cause of respiratory failure. If no risk factor for ARDS is apparent, however, objective evaluation (e.g., echocardiography) is required to help rule out hydrostatic edema. A minimum level of positive end-expiratory pressure and mutually exclusive PaO
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thresholds were chosen for the different levels of ARDS severity (mild, moderate, severe) to better categorize patients with different outcomes and potential responses to therapy.
Conclusions
This panel addressed some of the limitations of the prior ARDS definition by incorporating current data, physiologic concepts, and clinical trials results to develop the Berlin definition, which should facilitate case recognition and better match treatment options to severity in both research trials and clinical practice.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The efficacy of drotrecogin alpha (activated) (DrotAA) for sepsis has been controversial. In this trial, there was no significant difference in all-cause mortality at 28 or 90 days between adults ...with sepsis who were treated with DrotAA and those treated with placebo.
Recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), was approved for the treatment of severe sepsis in 2001 on the basis of the Prospective Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study,
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a phase 3 international, randomized, controlled trial that was stopped early for efficacy after the enrollment of 1690 patients with severe sepsis. Absolute mortality in the intention-to-treat population was reduced by 6.1 percentage points, a relative risk reduction of 19.4%. Subsequent subgroup analysis suggested that the mortality benefit was limited to patients with increased illness severity (i.e., those with more than one . . .
The fruit of the authors' more than 15 years of using and writing about ePortfolios in general education and disciplinary programs and courses, this book is a comprehensive and practical guide to the ...use of the ePortfolio as a pedagogy that facilitates the integrative learning that is a central goal of higher education. Faculty and administrators of programs using ePortfolios can use this guide to help their students work individually on an ePortfolio or as part of a class or program requirement. Readers will discover through examples of student portfolios and targeted exercises how to assist students in making their learning visible to themselves, their peers, their instructors and their future employers While interest in ePortfolios has exploded-because they provide an easier and more comprehensive ways to assess student learning than traditional portfolios, and because they have the potential to transformatively develop students' ability to connect and apply their knowledge-faculty and administrators all too often are disappointed by the lackluster ePortfolios that students submit. Reynolds and Patton demonstrate how systematically embedding practices in the classroom that engage students in integrative learning practices dramatically improves outcomes. The authors describe easy to use and practical strategies for faculty to incorporate integrative ePortfolios in their courses and curricula, and create the scaffolding to develop students' skills and metacognition. The book opens by outlining the underlying learning theory and the key concepts of integrative learning and by describing the purpose, structure and implementation of ePortfolios. Subsequent sections cover classroom practices and assignments to help students understand themselves as learners; make connections between course content, their personal lives, and to the curriculum; bridge theory to practice; and consider issues of audience and communication and presentation in developing their portfolios. Th
The West Antarctic Ice Sheet Divide (WAIS Divide, WD) ice core is a newly drilled, high-accumulation deep ice core that provides Antarctic climate records of the past ∼68 ka at unprecedented temporal ...resolution. The upper 2850 m (back to 31.2 ka BP) have been dated using annual-layer counting. Here we present a chronology for the deep part of the core (67.8–31.2 ka BP), which is based on stratigraphic matching to annual-layer-counted Greenland ice cores using globally well-mixed atmospheric methane. We calculate the WD gas age–ice age difference (Δage) using a combination of firn densification modeling, ice-flow modeling, and a data set of δ15N-N2, a proxy for past firn column thickness. The largest Δage at WD occurs during the Last Glacial Maximum, and is 525 ± 120 years. Internally consistent solutions can be found only when assuming little to no influence of impurity content on densification rates, contrary to a recently proposed hypothesis. We synchronize the WD chronology to a linearly scaled version of the layer-counted Greenland Ice Core Chronology (GICC05), which brings the age of Dansgaard–Oeschger (DO) events into agreement with the U/Th absolutely dated Hulu Cave speleothem record. The small Δage at WD provides valuable opportunities to investigate the timing of atmospheric greenhouse gas variations relative to Antarctic climate, as well as the interhemispheric phasing of the "bipolar seesaw".
Summary These guidelines for use of narrowband (TL‐01) ultraviolet B have been prepared for dermatologists by the British Photodermatology Group on behalf of the British Association of ...Dermatologists. They present evidence‐based guidance for treatment of patients with a variety of dermatoses and photodermatoses, with identification of the strength of evidence available at the time of preparation of the guidelines, and a brief overview of background photobiology.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Summary Background Depression is a common, debilitating, and costly disorder. Many patients request psychological therapy, but the best-evidenced therapy—cognitive behavioural therapy (CBT)—is ...complex and costly. A simpler therapy—behavioural activation (BA)—might be as effective and cheaper than is CBT. We aimed to establish the clinical efficacy and cost-effectiveness of BA compared with CBT for adults with depression. Methods In this randomised, controlled, non-inferiority trial, we recruited adults aged 18 years or older meeting Diagnostic and Statistical Manual of Mental Disorders IV criteria for major depressive disorder from primary care and psychological therapy services in Devon, Durham, and Leeds (UK). We excluded people who were receiving psychological therapy, were alcohol or drug dependent, were acutely suicidal or had attempted suicide in the previous 2 months, or were cognitively impaired, or who had bipolar disorder or psychosis or psychotic symptoms. We randomly assigned participants (1:1) remotely using computer-generated allocation (minimisation used; stratified by depression severity Patient Health Questionnaire 9 (PHQ-9) score of <19 vs ≥19, antidepressant use, and recruitment site) to BA from junior mental health workers or CBT from psychological therapists. Randomisation done at the Peninsula Clinical Trials Unit was concealed from investigators. Treatment was given open label, but outcome assessors were masked. The primary outcome was depression symptoms according to the PHQ-9 at 12 months. We analysed all those who were randomly allocated and had complete data (modified intention to treat mITT) and also all those who were randomly allocated, had complete data, and received at least eight treatment sessions (per protocol PP). We analysed safety in the mITT population. The non-inferiority margin was 1·9 PHQ-9 points. This trial is registered with the ISCRTN registry, number ISRCTN27473954. Findings Between Sept 26, 2012, and April 3, 2014, we randomly allocated 221 (50%) participants to BA and 219 (50%) to CBT. 175 (79%) participants were assessable for the primary outcome in the mITT population in the BA group compared with 189 (86%) in the CBT group, whereas 135 (61%) were assessable in the PP population in the BA group compared with 151 (69%) in the CBT group. BA was non-inferior to CBT (mITT: CBT 8·4 PHQ-9 points SD 7·5, BA 8·4 PHQ-9 points 7·0, mean difference 0·1 PHQ-9 points 95% CI −1·3 to 1·5, p=0·89; PP: CBT 7·9 PHQ-9 points 7·3; BA 7·8 6·5, mean difference 0·0 PHQ-9 points –1·5 to 1·6, p=0·99). Two (1%) non-trial-related deaths (one 1% multidrug toxicity in the BA group and one 1% cancer in the CBT group) and 15 depression-related, but not treatment-related, serious adverse events (three in the BA group and 12 in the CBT group) occurred in three 2% participants in the BA group (two 1% patients who overdosed and one 1% who self-harmed) and eight (4%) participants in the CBT group (seven 4% who overdosed and one 1% who self-harmed). Interpretation We found that BA, a simpler psychological treatment than CBT, can be delivered by junior mental health workers with less intensive and costly training, with no lesser effect than CBT. Effective psychological therapy for depression can be delivered without the need for costly and highly trained professionals. Funding National Institute for Health Research.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract Pathologic features of Parkinson's disease (PD) include death of dopaminergic neurons in the substantia nigra, presence of α-synuclein containing Lewy bodies, and iron accumulation in ...PD-related brain regions. The observed iron accumulation may be contributing to PD etiology but it also may be a byproduct of cell death or cellular dysfunction. To elucidate the possible role of iron accumulation in PD, we investigated genetic variation in 16 genes related to iron homeostasis in three case–control studies from the United States, Australia, and France. After screening 90 haplotype tagging single nucleotide polymorphisms (SNPs) within the genes of interest in the US study population, we investigated the five most promising gene regions in two additional independent case–control studies. For the pooled data set (1289 cases, 1391 controls) we observed a protective association (OR = 0.83, 95% CI: 0.71–0.96) between PD and a haplotype composed of the A allele at rs1880669 and the T allele at rs1049296 in transferrin ( TF ; GeneID: 7018). Additionally, we observed a suggestive protective association (OR = 0.87, 95% CI: 0.74-1.02) between PD and a haplotype composed of the G allele at rs10247962 and the A allele at rs4434553 in transferrin receptor 2 ( TFR2 ; GeneID: 7036). We observed no associations in our pooled sample for haplotypes in SLC40A1 , CYB561 , or HFE . Taken together with previous findings in model systems, our results suggest that TF or a TF - TFR2 complex may have a role in the etiology of PD, possibly through iron misregulation or mitochondrial dysfunction within dopaminergic neurons.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Clinical trial managers play a vital role in the design and conduct of clinical trials in the UK. There is a current recruitment and retention crisis for this specialist role due to a complex set of ...factors, most likely to have come to a head due to the COVID-19 pandemic. Academic clinical trial units and departments are struggling to recruit trial managers to vacant positions, and multiple influences are affecting the retention of this highly skilled workforce. Without tackling this issue, we face major challenges in the delivery on the Department of Health and Social Care's Future of UK Clinical Research Delivery implementation plan. This article, led by a leading network of and for UK Trial Managers, presents some of the issues and ways in which national stakeholders may be able to address this.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The current literature demonstrates an association between both size and presence of TBI and its effects on mortality; however, it does not readily address the morbidity and associated functional ...outcomes of those who survive. We hypothesize that the likelihood of discharge to home decreases with advancement of age in the presence of TBI. This is a single-center study of trauma registry data, inclusive years July 1, 2016, to October 31, 2021. The inclusion criteria was based upon age (≥40 years), and ICD10 diagnosis of a TBI. Disposition to home without services was the dependent variable. 2031 patients were included in the analysis. We hypothesized correctly that the likelihood of discharge to home decreases (by 6%) with advancement of age (per year) in the presence of intracranial hemorrhage.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
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