Consolidated health economic evaluation reporting standards (CHEERS) statement

<p>Economic evaluations of health interventions pose a particular challenge for reporting. There is also a need to consolidate and update existing guidelines and promote their use in a user friendly manner. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement is an attempt to consolidate and update previous health economic evaluation guidelines efforts into one current, useful reporting guidance. The primary audiences for the CHEERS statement are researchers reporting economic evaluations and the editors and peer reviewers assessing them for publication.</p> <p>The need for new reporting guidance was identified by a survey of medical editors. A list of possible items based on a systematic review was created. A two round, modified Delphi panel consisting of representatives from academia, clinical practice, industry, government, and the editorial community was conducted. Out of 44 candidate items, 24 items and accompanying recommendations were developed. The recommendations are contained in a user friendly, 24 item checklist. A copy of the statement, accompanying checklist, and this report can be found on the ISPOR Health Economic Evaluations Publication Guidelines Task Force website (www.ispor.org/TaskForces/EconomicPubGuidelines.asp).</p> <p>We hope CHEERS will lead to better reporting, and ultimately, better health decisions. To facilitate dissemination and uptake, the CHEERS statement is being co-published across 10 health economics and medical journals. We encourage other journals and groups, to endorse CHEERS. The author team plans to review the checklist for an update in five years.</p&gt

The Determination of Immunomodulation and Its Impact on Survival of Rectal Cancer Patients Depends on the Area Comprising a Tissue Microarray.

BACKGROUND: T cell density in colorectal cancer (CRC) has proven to be of high prognostic importance. Here, we evaluated the influence of a hyperfractionated preoperative short-term radiation protocol (25 Gy) on immune cell density in tumor samples of rectal cancer (RC) patients and on patient survival. In addition, we assessed spatial tumor heterogeneity by comparison of analogue T cell quantification on full tissue sections with digital T cell quantification on a virtually established tissue microarray (TMA). METHODS: A total of 75 RC patients (60 irradiated, 15 treatment-naïve) were defined for retrospective analysis. RC samples were processed for immunohistochemistry (CD3, CD8, PD-1, PD-L1). Analogue (score 0-3) as well as digital quantification (TMA: 2 cores vs. 6 cores, mean T cell count) of marker expression in 2 areas (central tumor, CT; invasive margin, IM) was performed. Survival was estimated on the basis of analogue as well as digital marker densities calculated from 2 cores (Immunoscore: CD3/CD8 ratio) and 6 cores per tumor area. RESULTS: Irradiated RC samples showed a significant decrease in CD3 and CD8 positive T cells, independent of quantification mode. T cell densities of 6 virtual cores approximated to T cell densities of full tissue sections, independent of individual core density or location. Survival analysis based on full tissue section quantification demonstrated that CD3 and CD8 positive T cells as well as PD-1 positive tumor infiltrating leucocytes (TILs) in the CT and the IM had a significant impact on disease-free survival (DFS) as well as overall survival (OS). In addition, CD3 and CD8 positive T cells as well as PD-1 positive TILs in the IM proved as independent prognostic factors for DFS and OS; in the CT, PD-1 positive TILs predicted DFS and CD3 and CD8 positive T cells as well as PD-1 positive TILs predicted OS. Survival analysis based on virtual TMA showed no impact on DFS or OS. CONCLUSION: Spatial tumor heterogeneity might result in inadequate quantification of immune marker expression; however, if using a TMA, 6 cores per tumor area and patient sample represent comparable amounts of T cell densities to those quantified on full tissue sections. Consistently, the tissue area used for immune marker quantification represents a crucial factor for the evaluation of prognostic and predictive biomarker potential

Predicting Outcomes in Pediatric Crohn’s Disease for Management Optimization: Systematic Review and Consensus Statements from PIBD-Ahead Program

A better understanding of prognostic factors within the heterogeneous spectrum of pediatric Crohn's disease (CD) should improve patient management and reduce complications. We aimed to identify evidence-based predictors of outcomes with the goal of optimizing individual patient management. A survey of 202 experts in pediatric CD identified and prioritized adverse outcomes to be avoided. A systematic review of the literature with meta-analysis, when possible, was performed to identify clinical studies that investigated predictors of these outcomes. Multiple national and international face-to-face meetings were held to draft consensus statements based on the published evidence. Consensus was reached on 27 statements regarding prognostic factors for surgery, complications, chronically active pediatric CD, and hospitalization. Prognostic factors for surgery included CD diagnosis during adolescence, growth impairment, NOD2/CARD15 polymorphisms, disease behavior, and positive anti-Saccharomyces cerevisiae antibody status. Isolated colonic disease was associated with fewer surgeries. Older age at presentation, small bowel disease, serology (anti-Saccharomyces cerevisiae antibody, antiflagellin, and OmpC), NOD2/CARD15 polymorphisms, perianal disease, and ethnicity were risk factors for penetrating (B3) and/or stenotic disease (B2). Male sex, young age at onset, small bowel disease, more active disease, and diagnostic delay may be associated with growth impairment. Malnutrition and higher disease activity were associated with reduced bone density. These evidence-based consensus statements offer insight into predictors of poor outcomes in pediatric CD and are valuable when developing treatment algorithms and planning future studies. Targeted longitudinal studies are needed to further characterize prognostic factors in pediatric CD and to evaluate the impact of treatment algorithms tailored to individual patient risk

A voice unknown: Undercurrents in Mussorgsky's 'Sunless'

Mussorgsky's Sunless cycle is aesthetically and stylistically an anomalous member of his oeuvre. Its notably effaced, pared-down, and withdrawn qualities present challenges to critical interpretation. Its uniqueness, however, renders it a crucial work for furnishing the fullest possible picture of Mussorgsky as a creative artist. The author of its texts, Golenishchev-Kutuzov (whose relationship with Mussorgsky at the time of its writing possibly extended beyond the platonic) has been identified by recent scholarship as an essential eye-witness for those to whom Stasov's populist characterization of the composer does not ring entirely true. Golenishchev-Kutuzov believed that in Sunless Mussorgsky first revealed his authentic artistic self. According to Golenishchev-Kutuvoz, Mussorgsky regarded his signal achievement in Sunless to have been the eradication of all elements other than feeling. In other words, he had thrown off the stylistic shackles imposed by the aesthetics of realism and relied entirely on intuitive harmonic invention as the sole conveyor of a purely subjective, affective meaning in the cycle. This hypothesis forms the point of departure for an investigation of select numbers of the cycle. Analysis reveals that the affective aspect is riot the only significant element operative. Alongside remnants of the realist style, there is evidence, of varying degrees of subtlety, for a knowing use of symmetrical pitch organization. Mussorgsky not only adapted the usual referential attachments of symmetrically based chromaticism-typically found in Russian operas of the second half of the nineteenth century-he also, through extremely simple but effective means, synthesized the intuitive harmonic and rational symmetrical elements of the cycle's pitch organization so that the latter emerges seamlessly out of the former. This remarkable synthesis ensures the cycle's uniformity of tone while also allowing for a reading that extends beyond the generally affective to the symbolically more specific. This symbolic level of reading offers several interpretative possibilities, one of which may refer even to the relationship of the poet and the composer. Irrespective of such potentials for interpretation, the most significant achievement in the cycle remains the synthesis of the intuitive/affective and rational/symbolic elements of its organization. Songs 1, 2, 3, and 6 of the cycle are considered in detail

Effect of an Aerosol Box on Intubation in Simulated Emergency Department Airways: A Randomized Crossover Study

Introduction: The use of transparent plastic aerosol boxes as protective barriers during endotracheal intubation has been advocated during the severe acute respiratory syndrome coronavirus 2 pandemic. There is evidence of worldwide distribution of such devices, but some experts have warned of possible negative impacts of their use. The objective of this study was to measure the effect of an aerosol box on intubation performance across a variety of simulated difficult airway scenarios in the emergency department. Methods: This was a randomized, crossover design study. Participants were randomized to intubate one of five airway scenarios with and without an aerosol box in place, with randomization of intubation sequence. The primary outcome was time to intubation. Secondary outcomes included number of intubation attempts, Cormack-Lehane view, percent of glottic opening, and resident physician perception of intubation difficulty. Results: Forty-eight residents performed 96 intubations. Time to intubation was significantly longer with box use than without (mean 17 seconds [range 6-68 seconds] vs mean 10 seconds [range 5-40 seconds], p <0.001). Participants perceived intubation as being significantly more difficult with the aerosol box. There were no significant differences in the number of attempts or quality of view obtained. Conclusion: Use of an aerosol box during difficult endotracheal intubation increases the time to intubation and perceived difficulty across a range of simulated ED patients

Reply to: New Meta- and Mega-analyses of Magnetic Resonance Imaging Findings in Schizophrenia: Do They Really Increase Our Knowledge About the Nature of the Disease Process?

This work was supported by National Institute of Biomedical Imaging and Bioengineering Grant No. U54EB020403 (to the ENIGMA consortium)

Parental diabetes status reveals association of mitochondrial DNA haplogroup J1 with type 2 diabetes

<p>Abstract</p> <p>Background</p> <p>Although mitochondrial dysfunction is consistently manifested in patients with Type 2 Diabetes mellitus (T2DM), the association of mitochondrial DNA (mtDNA) sequence variants with T2DM varies among populations. These differences might stem from differing environmental influences among populations. However, other potentially important considerations emanate from the very nature of mitochondrial genetics, namely the notable high degree of partitioning in the distribution of human mtDNA variants among populations, as well as the interaction of mtDNA and nuclear DNA-encoded factors working in concert to govern mitochondrial function. We hypothesized that association of mtDNA genetic variants with T2DM could be revealed while controlling for the effect of additional inherited factors, reflected in family history information.</p> <p>Methods</p> <p>To test this hypothesis we set out to investigate whether mtDNA genetic variants will be differentially associated with T2DM depending on the diabetes status of the parents. To this end, association of mtDNA genetic backgrounds (haplogroups) with T2DM was assessed in 1055 Jewish patients with and without T2DM parents ('DP' and 'HP', respectively).</p> <p>Results</p> <p>Haplogroup J1 was found to be 2.4 fold under-represented in the 'HP' patients (p = 0.0035). These results are consistent with a previous observation made in Finnish T2DM patients. Moreover, assessing the haplogroup distribution in 'DP' versus 'HP' patients having diabetic siblings revealed that haplogroup J1 was virtually absent in the 'HP' group.</p> <p>Conclusion</p> <p>These results imply the involvement of inherited factors, which modulate the susceptibility of haplogroup J1 to T2DM.</p

Multiscale neural gradients reflect transdiagnostic effects of major psychiatric conditions on cortical morphology

It is increasingly recognized that multiple psychiatric conditions are underpinned by shared neural pathways, affecting similar brain systems. Here, we carried out a multiscale neural contextualization of shared alterations of cortical morphology across six major psychiatric conditions (autism spectrum disorder, attention deficit/hyperactivity disorder, major depression disorder, obsessive-compulsive disorder, bipolar disorder, and schizophrenia). Our framework cross-referenced shared morphological anomalies with respect to cortical myeloarchitecture and cytoarchitecture, as well as connectome and neurotransmitter organization. Pooling disease-related effects on MRI-based cortical thickness measures across six ENIGMA working groups, including a total of 28,546 participants (12,876 patients and 15,670 controls), we identified a cortex-wide dimension of morphological changes that described a sensory-fugal pattern, with paralimbic regions showing the most consistent alterations across conditions. The shared disease dimension was closely related to cortical gradients of microstructure as well as neurotransmitter axes, specifically cortex-wide variations in serotonin and dopamine. Multiple sensitivity analyses confirmed robustness with respect to slight variations in analytical choices. Our findings embed shared effects of common psychiatric conditions on brain structure in multiple scales of brain organization, and may provide insights into neural mechanisms of transdiagnostic vulnerability

Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND). a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension

Background: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses. Methods: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18–58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0–6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0–5·5 vs 6·0–6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181. Findings: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66–1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74–1·53; nominal p=0·753) or the T25FW (0·98, 0·74–1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40–0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108–221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred. Interpretation: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components. Funding: Biogen