tbuckley/cabot-search huggingface dataset:
Functional Changes of Retinal Ganglion Cells and Visual Pathways in Patients with Chronic Leber’s Hereditary Optic Neuropathy during One Year of Follow-up
Authors: Vincenzo Parisi, Lucia Ziccardi, Federico Sadun, Anna Maria De Negri, Chiara La Morgia, Lucilla Barbano, Valerio Carelli, Piero Barboni
Journal: Ophthalmology (2019)

PurposeTo assess changes of retinal ganglion cells (RGCs) and visual pathways' function in patients with Leber's hereditary optic neuropathy (LHON) during 12 months of follow-up of the chronic phase.DesignRetrospective case series.ParticipantsTwenty-two patients with LHON (mean age, 36.3±9.3 years) in the "chronic phase" of the disease, providing 42 eyes (LHON group) with different pathogenic mitochondrial DNA mutations (group 11778: 21 eyes; group 3460: 4 eyes; group 14484: 13 eyes; and group 14568: 4 eyes) were enrolled. Twenty-five age-similar healthy participants, providing 25 eyes, served as controls.MethodsPattern electroretinogram (PERG) and visual evoked potentials (VEP), in response to 60ʹ and 15ʹ checks visual stimuli, were recorded at baseline in all subjects and after 6 and 12 months of follow-up in patients with LHON. At baseline, in all LHON eyes for each PERG and VEP parameter (amplitude and implicit time), the 95% confidence limit (CL) of test–retest variability was calculated. The PERG and VEP mean values observed in LHON eyes were compared (1-way analysis of variance [ANOVA]) with those of controls. During the follow-up, the PERG and VEP differences observed with respect to baseline were evaluated by ANOVA.Main Outcome MeasuresChanges of individual and mean absolute values of 60ʹ and 15ʹ PERG amplitude and VEP amplitude and implicit time at each time point compared with baseline values in the LHON group.ResultsAt baseline, mean values of PERG and VEP parameters detected in the LHON group were significantly (P < 0.01) different with respect to control values. In the LHON group, at 6 and 12 months of follow-up, the majority of eyes showed unmodified (within 95% CL) PERG and VEP values, and mean absolute values of these measures were not significantly (P > 0.01) different from baseline values.ConclusionsIn our untreated patients with chronic LHON, with different specific pathogenic mutations, RGCs and visual pathways function were not significantly modified during 12 months of follow-up. This should be considered in the disease natural history when attempts for treatments are proposed in chronic LHON.
Promises and Perils of Group Clinics for Young People Living With Diabetes: A Realist Review
Authors: Chrysanthi Papoutsi, Grainne Colligan, Ann Hagell, Dougal Hargreaves, Martin Marshall, Shanti Vijayaraghavan, Trisha Greenhalgh, Sarah Finer
Journal: Diabetes Care (2019)

Group clinics are becoming popular as a new care model in diabetes care. This evidence synthesis, using realist review methodology, examined the role of group clinics in meeting the complex needs of young people living with diabetes. Following Realist And Meta-narrative Evidence Synthesis–Evolving Standards (RAMESES) quality standards, we conducted a systematic search across 10 databases. A total of 131 articles met inclusion criteria and were analyzed to develop theoretically informed explanations of how and why group clinics could work (or not) for young people with diabetes. Models of group-based care in the literature varied significantly and incorporated different degrees of clinical and educational content. Our analysis identified four overarching principles that can be applied in different contexts to drive sustained engagement of young people in group clinics: 1) emphasizing self-management as practical knowledge; 2) developing a sense of affinity between patients; 3) providing safe, developmentally appropriate care; and 4) balancing group and individual needs. Implementation of group clinics was not always straightforward; numerous adjustments to operational and clinical processes were required to establish and deliver high-quality care. Group clinics for young people with diabetes offer the potential to complement individualized care but are not a panacea and may generate as well as solve problems.
SP0021 How to Optimize Doppler Settings for Fast Flow: Table 1.
Authors: W.A. Schmidt
Journal: Annals of the Rheumatic Diseases (2014)

<h3></h3> Several rheumatic diseases are affecting blood vessels. Vascular ultrasound is relevant in rheumatology particularly for large-vessel vasculitis, Raynaud9s phenomenon and venous thrombosis. Flow velocities are higher in large vessels when compared to intra-synovial vessels. Colour Doppler, not power Doppler ultrasound should be performed for evaluating large vessel. Power Doppler is used for low blood flow velocities in order to increase the sensitivity for detecting signals. Colour signal sensitivity is usually not a problem in large vessels. Furthermore, colour Doppler ultrasound allows detecting stenoses by demonstrating a phenomenon called “aliasing”: Due to increased flow velocity in stenoses a mixture of colours appears. B-mode and colour Doppler frequency needs to be adjusted according how deeply the vessel is localized below the skin surface. Pulse repetition frequency (PRF) needs to be adjusted according to the blood flow velocities in the vessel (Table). It needs to be increased in case of fast flow for preventing aliasing and impaired image quality. It needs to be decreased in case of low flow velocities in order to provide enough sensitivity for detecting colour signals. In relatively small vessels like the temporal arteries the sonographer needs to make sure that the colour signal does not cover the wall when the colour gain is too high or that it only covers the centre of the lumen when the colour gain is too low. Gain settings need to be tested in normals before ultrasound is done for diagnosis of temporal arteritis. The optimal angle between sound waves and the vessel is 45°. If these are perpendicular the colour quality becomes inadaequate. Ultrasound machines provide a steer function for the colour box that needs to be used in this case. <h3>Conclusion</h3> Settings for large-vessel colour Doppler ultrasound include PRF, B mode frequency, colour frequency and colour gain. The colour gain needs to be adjusted so that the colour does not cover the vessel wall or, if too low, only covers the centre of the vessel lumen. The colour box needs to be steered in order to arrive at a good colour quality. <h3>Disclosure of Interest</h3> W. Schmidt Grant/Research support from: GE, Esaote, Siemens <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.6225
Improved Lentiviral Vectors for the Cure of Hemoglobinopathies
Authors: Laura Breda, Valentina Ghiaccio, Hanyia Zaidi, Silvia Pires Lourenco, Carla Casu, Kim Smith-Whitley, Janet L. Kwiatkowski, Vanessa Carrion, Virginia Guzikowski, Ryo Kurita, Yukio Nakamura, Stefano Rivella
Journal: Blood (2018)
Information for Readers
Authors: Elaine S. Williams
Journal: JAMA (1996)

We hereby thank the 3043 peer reviewers who completed<i>JAMA</i>manuscript reviews in 1995 and whose names appear on pages 813-820. In 1995, it took a median of 24 calendar days from manuscript receipt to rejection, 78 days from receipt to acceptance, and 162 days from receipt to publication. A mean of 26 days was required for peer review; each reviewer handled a mean of 1.6 manuscripts. Fifty percent of the 3970 manuscripts we received in 1995 were sent for external peer review, most often to three reviewers. Forty-five percent of manuscripts were rejected without external review. Six percent of accepted manuscripts (mostly invited editorials and cover stories) did not have external review. The total acceptance rate for manuscripts in 1995 was 15.8%, and the acceptance rate for unsolicited manuscripts was 8.6%. Please see p 813 for the list of the 1995<i>JAMA</i>peer reviewers.
A rare population of tumor antigen-specific CD4+CD8+ double-positive αβ T lymphocytes uniquely provide CD8-independent TCR genes for engineering therapeutic T cells
Authors: Junko Matsuzaki, Takemasa Tsuji, Thinle Chodon, Courtney Ryan, Richard C. Koya, Kunle Odunsi
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> High-affinity tumor antigen-specific T-cell receptor (TCR) gene is required to engineer potent T cells for therapeutic treatment of cancer patients. However, discovery of suitable therapeutic TCR genes is hampered by the fact that naturally occurring tumor antigen-specific TCRs are generally of low-affinity, and artificial modification of TCRs can mediate cross-reactivity to other antigens expressed in normal tissues. Here, we discovered a naturally occurring T-cell clone which expressed high-affinity HLA-A*02:01 (A*02)-restricted TCR against NY-ESO-1 from a patient who had NY-ESO-1-expressing ovarian tumor. <h3>Methods</h3> A*02-restricted NY-ESO-1-specific T-cell clones were established from peripheral blood of patients who had NY-ESO-1-expressing ovarian tumors. TCR α and β chain genes were retrovirally transduced into polyclonally activated T cells. Phenotype and function of the parental and TCR-transduced T cells were analyzed by flow cytometry, ELISA and cytotoxicity assay. In vivo therapeutic efficacy was investigated in a xenograft model using NOD/SCID/IL-2Rγ-deficient (NSG) mice. <h3>Results</h3> A rare population of NY-ESO-1-specific T cells, which we named 19305DP, expressed cell surface CD4, CD8α, and CD8β but not CD56 and recognized A*02<sup>+</sup>NY-ESO-1<sup>+</sup> cancer cell lines in a CD4- and CD8-independent manner. 19305DP showed a gene expression profile that is consistent with a mixed profile of CD4<sup>+</sup> and CD8<sup>+</sup> single-positive T cells. Both CD4<sup>+</sup> and CD8<sup>+</sup> T cells that were retrovirally transduced with 19305DP-derived TCR gene (19305DP-TCR) showed strong reactivity against A*02<sup>+</sup>NY-ESO-1<sup>+</sup> cancer cells, whereas TCR genes from the conventional A*02-restricted NY-ESO-1-specific CD8<sup>+</sup> single-positive T-cell clones functioned only in CD8<sup>+</sup> T cells. Both 19305DP-TCR gene-engineered CD4<sup>+</sup> and CD8<sup>+</sup> T cells eliminated A*02<sup>+</sup>NY-ESO-1<sup>+</sup> tumor xenografts in NSG mice. Finally, based on reactivity against a series of alanine-substituted peptides and a panel of normal human tissue-derived primary cells, 19305DP-TCR was predicted to have no cross-reactivity against any human non-NY-ESO-1 proteins. <h3>Conclusion</h3> Together, our results indicate that the naturally occurring 19305DP-TCR derived from CD4<sup>+</sup>CD8<sup>+</sup> double-positive αβ T cells<b>,</b> is a promising therapeutic TCR gene for effective and safe adoptive T-cell therapy in A*02<sup>+</sup> patients with NY-ESO-1-expressing tumor.
UK remains in middle of Europe health table, with Switzerland top
Authors: Rory Watson
Journal: BMJ (2019)

The UK has been ranked 16th in a wide ranging assessment of 35 national health systems in Europe, just below Portugal (13th), the Czech Republic (14th) and Estonia (15th).

Switzerland topped the latest rankings, followed by the Netherlands and then Norway, while in last place was Albania, preceded by Romania and Hungary.

The rankings were published in the 2018 survey by the Euro Health Consumer Index (EHCI),1 which has been producing annual assessments of the performance of national healthcare systems in Europe since 2005.

The results were based on 46 indicators grouped under six headings: patient …
Therapeutic Inertia and the Legacy of Dysglycemia on the Microvascular and Macrovascular Complications of Diabetes
Authors: Kamlesh Khunti, Samuel Seidu
Journal: Diabetes Care (2019)

Type 2 diabetes is characterized by a continuous decline in β‐cell function with the resultant progressive loss of glycemic control over time (1). The hyperglycemic burden is associated with longer-term microvascular and macrovascular complications. Early diagnosis and intensive glycemic control has conclusively demonstrated a reduction in microvascular complications (2,3) and possibly macrovascular complications over a long period of observation (4), the so-called legacy effect (5). Even though there have been improvements in survival from cardiovascular disease in the general population, people with type 2 diabetes remain at increased risk of cardiovascular mortality compared with matched population control subjects (6). A very high proportion of patients fail to reach the recommended glycemic targets for a considerable period of time after the diagnosis of diabetes (7–9), thus leading to the complications. Guidelines for the treatment of patients with type 2 diabetes suggest that tight glycemic control (defined as glycated hemoglobin [HbA1c] <7.0% [53 mmol/mol]) should be maintained from diagnosis through active titration of combinations of antihyperglycemic medications and lifestyle modification, as appropriate (10). Modeling studies suggest that when this is done through an individualized approach, it leads to reduced costs and increased quality of life (11).

Besides patient-level characteristics such as multimorbidity and poor adherence to treatment recommendations, clinical inertia has been suggested as one key reason for not achieving glucose targets. The term “clinical inertia” in most instances has been used in relation to failure to advance therapy when appropriate to do so (12). However, the definition of therapeutic inertia is now also accepted to reflect the failure to de-intensify treatment when appropriate to do so (12). A number of studies have shown that therapeutic inertia is associated with worse microvascular and macrovascular outcomes. In a cohort study of 105,477 patients, mean HbA1c …
Establishment and application of a panel of PBMC-humanized mouse tumor models in cancer immunotherapy
Authors: L. Bourre, L. Zhang, S. Qi, H. Wu, L. Zhao, X. An, W. Tan, X. Fu, M. Qiao, Q. Shi, W. Yang
Journal: Annals of Oncology (2019)

Background: To meet the rapidly growing I/O market, the demands for fast, relevant and cost effective mouse tumor model systems are also increasing. We developed a panel of straightforward humanized tumor models, designated as MiXeno platform. Methods: CrownBio has established a sizable collection of MiXeno models where human PBMCs were reconstituted in the mouse system for the evaluation in vivo activity of immune checkpoint inhibitors or immune-modulators. These MiXeno models were characterized with tumor response to anti-PD-1 and anti-CTLA4 antibodies, and onset of possible graft versus host disease (GVHD) or graft versus tumor response (GVT) under different settings. To engage both host immune system and tumor antigens, we have developed some specific Mixeno tumor models by inoculating tumor cells over-expressing specific anti-tumor antigens (e.g. EGFR, CD47, Braf or PD-L1) into PBMC-humanized immunocompromised mice. Moreover, to improve capacity and consistency of MiXeno platform, we are conducting studies to characterize and validate commercialized frozen PBMCs for MiXeno model establishment. Results: Models with over-expression of a variety of tumor antigens (e.g. EGFR, CD47, Braf, PD-L1...) were used to develop specific Mixeno tumor models. Meanwhile, in order to overcome the limitation of PBMC shortage, commercialized PBMC has been purchase and implanted into several xenograft models, and exhibit consistent tumor growth with fresh PBMC, as well as human immune component reconstitution. Up to date, a variety of test articles of different categories, including checkpoint inhibitors, T cell modulators and bispecific T cell engagers (e.g. EpCam-CD3, CD47/CD3, BCMA/CD3) have been evaluated using this platform. Merchandized I/O drugs, such as Pembrolizumab, are being tested in commercialized PBMC implanted immunocompromised mice. Conclusions: MiXeno platform are valid model system for the human immuno-modulatory drugs including bispecific antibodies evaluation and will be optimized by introduction of specific Mixeno tumor models, commercial PBMC and B2M mice. Legal entity responsible for the study: CrownBio. Funding: CrownBio. Disclosure: L. Bourre, L. Zhang, S. Qi, H. Wu, L. Zhao, X. An, M. Qiao, Q. Shi, W. Yang: Employee: CrownBio. All other authors have declared no conflicts of interest.
SP0146 Improving Your Graphs and Tables for Publication and Presentation
Authors: M. Boers
Journal: Annals of the Rheumatic Diseases (2014)

<h3></h3> This workshop is an introduction to the principles of good graph and table design as pioneered by Cleveland [1] and Tufte [2] and updated by Few [3] so that the participant can better answer the following questions: <h3>Which of the messages in my research results requires a graph or table?</h3> Recognizing how graphs improve on simple statistics and convey much more information. Knowing when a table is better, or keeping the data in the body text. <h3>How can I best convey the message?</h3> Striving for clear vision by choice of graph, scaling, discrimination of data series, minimizing non-data ink, avoiding chart junk.Striving for clear understanding through a balance between data and explanation. Using order, subheadings, formatting and rules to guide your reader through your table data. <h3>Is my graph/table truthful?</h3> Creating a direct proportion between graph and data quantities, avoiding forms prone to misinterpretation, labels to prevent ambiguity; keeping data in context, avoiding more dimensions in the graph than in the data. <h3>References</h3> Cleveland WS. The elements of graphing data: Hobart Press, Summit, NJ, U.S.A.; 1994. Tufte E. The visual display of quantitative information. 2nd ed: Graphics Press, Cheshire, CT, U.S.A.; 2001. Few S. Show me the numbers. Designing tables and graphs to enlighten. Analytics Press, Oakland, CA, U.S.A.; 2004. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.6161
Lipoprotein(a) levels and risk of future coronary heart disease
Authors: A Bennet, E Di Angelantonio, S Erqou, G Eiriksdottir, G Sigurdsson, M Woodward, A Rumley, GD Lowe, J Danesh, Gudnason
Journal: JAMA Internal Medicine (2008)

Background: Large-scale prospective data are needed to determine whether associations between lipoprotein(a) (Lp[a]) and coronary heart disease (CHD) risk are independent of established risk factors, to characterize the shape of this relationship, and to quantify associations in relevant subgroups.

Methods: Levels of Lp(a) were measured in samples obtained at baseline from 2047 patients who had first-ever nonfatal myocardial infarction or who died of CHD during the study and from 3921 control participants in the Reykjavik Study (n = 18 569), as well as in paired samples obtained 12 years apart from 372 participants to quantify within-person fluctuations.

Results: Baseline Lp(a) levels had little or no correlation with known cardiovascular risk factors, such as age, sex, total cholesterol level, and blood pressure. The Lp(a) values were highly consistent from decade to decade, with a regression dilution ratio (calculated on the log scale) of 0.92 (95% confidence interval, 0.85-0.99). The odds ratio for CHD, unaltered after adjustment for several established risk factors (age, sex, smoking status, blood pressure, total cholesterol, triglycerides level, diabetes mellitus, and body mass index), was 1.60 (95% confidence interval, 1.38-1.85) in a comparison of extreme thirds of baseline Lp(a) levels. Odds ratios were progressively higher with increasing Lp(a) levels and did not vary materially by several individual- or study-level characteristics.

Conclusions: There are independent, continuous associations between Lp(a) levels and risk of future CHD in a broad range of individuals. Levels of Lp(a) are highly stable within individuals across many years and are only weakly correlated with known risk factors. Further assessment of their possible role in CHD prevention is warranted.
Abstract PR14: Nucleation of transcriptional super-enhancers at tumor oncogenes
Authors: Brian J. Abraham, Nicholas Kwiatkowski, Abraham S. Weintraub, Denes Hnisz, Nancy Hannett, Richard A. Young
Journal: Cancer Research (2015)

Abstract Transcriptional super-enhancers drive expression of oncogenes in many cancers and are being targeted with novel transcriptional and epigenetic therapeutics (1,2,3,4). Super-enhancers are acquired in cancers through multiple mechanisms, including DNA translocation of an extant super-enhancer and focal amplification. We recently discovered a novel mechanism by which super-enhancers are nucleated in T cell acute lymphoblastic leukemias (T-ALLs) (5). In this case, a small, monoallelic insertion creates a DNA binding site for a master transcription factor protein, which binds and recruits additional factors to nucleate the super-enhancer, which in turn drives high levels of the TAL1 transcription factor. We describe here a method for unbiased identification of similar genomic insertions that nucleate potentially oncogenic regulatory elements in cancers. This approach uses data from genome-wide ChIP-Seq studies that map locations of enhancer-binding proteins to identify sequences missing from reference genomes. We have found many additional genomic insertions in many additional cancers. I will describe new insights into the regulation of cancer that occur due to nucleation of novel regulatory elements. 1 Hnisz, Abraham, Lee, et al., Cell 2013 2 Loven, Hoke, Lin, et al., Cell 2013 3 Kwiatkowski, et al., Nature, 2014 4 Chipumoro, et al., Cell, 2014 5 Mansour et al., Science 2014 Citation Format: Brian J. Abraham, Nicholas Kwiatkowski, Abraham S. Weintraub, Denes Hnisz, Nancy Hannett, Richard A. Young. Nucleation of transcriptional super-enhancers at tumor oncogenes. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr PR14.
Unifying Design and Analysis for Superiority and Noninferiority Trials With Appropriate End Point
Authors: Brian Claggett, Hajime Uno, Lee-Jen Wei
Journal: JAMA Surgery (2019)

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