tbuckley/cabot-search huggingface dataset:
Gut Microbiota-Associated Activation of TLR5 Induces Apolipoprotein A1 Production in the Liver
Authors: Jensen H.C. Yiu, Kam-Suen Chan, Jamie Cheung, Jin Li, Yan Liu, Yao Wang, William W.L. Fung, Jieling Cai, Samson W.M. Cheung, Bernhard Dorweiler, Eric Y.F. Wan, Patrick Tso, Aimin Xu, Connie W. Woo
Journal: Circulation Research (2020)

Rationale: Dysbiosis of gut microbiota plays an important role in cardiovascular diseases but the molecular mechanisms are complex. An association between gut microbiome and the variance in HDL-C (high-density lipoprotein-cholesterol) level was suggested in a human study. Besides, dietary fat was shown to increase both HDL-C and LDL-C (low-density lipoprotein-cholesterol) levels. We speculate that certain types of gut bacteria responding to dietary fat may help to regulate HDL-C level and potentially affect atherosclerotic development. Objective: We aimed to investigate whether and how high-fat diet (HFD)-associated gut microbiota regulated HDL-C level. Methods and Results: We found that HFD increased gut flagellated bacteria population in mice. The increase in HDL-C level was adopted by mice receiving fecal microbiome transplantation from HFD-fed mouse donors. HFD led to increased hepatic but not circulating flagellin, and deletion of TLR5 (Toll-like receptor 5), a receptor sensing flagellin, suppressed HFD-stimulated HDL-C and ApoA1 (apolipoprotein A1) levels. Overexpression of TLR5 in the liver of TLR5-knockout mice was able to partially restore the production of ApoA1 and HDL-C levels. Mechanistically, TLR5 activation by flagellin in primary hepatocytes stimulated ApoA1 production through the transcriptional activation responding to the binding of NF-κB (nuclear factor-κB) on Apoa1 promoter region. Furthermore, oral supplementation of flagellin was able to stimulate hepatic ApoA1 production and HDL-C level and decrease atherosclerotic lesion size in apolipoprotein E-deficient ( Apoe −/− ) mice without triggering hepatic and systemic inflammation. The stimulation of ApoA1 production was also seen in human ApoA1-transgenic mice treated with oral flagellin. Conclusions: Our finding suggests that commensal flagellated bacteria in gut can facilitate ApoA1 and HDL-C productions in liver through activation of TLR5 in hepatocytes. Hepatic TLR5 may be a potential drug target to increase ApoA1.
OP0150 WHAT IS THE ROLE OF TEMPORAL ARTERY BIOPSY IN GIANT CELL ARTERITIS FAST-TRACK PATHWAYS WHEN TEMPORAL ARTERY ULTRASOUND IS NEGATIVE?
Authors: A. Sachdev, S. Dubey, C. Tiivas, M. George, P. Mehta
Journal: Annals of the Rheumatic Diseases (2020)

Background: A number of centres are now running fast track pathways for diagnosis and management of Giant cell arteritis with ultrasound as the first port of call for diagnosis 1 . Temporal artery biopsies (TABs) have become the second line of investigation, and it is unclear how useful TAB is in this setting. Objectives: This study looked at accuracy of Temporal artery biopsy (TAB) in patients with suspected Giant Cell arteritis (GCA) with negative/inconclusive ultrasound (U/S) and how duration of treatment on steroids prior to these investigations and arterial specimen size affected it. Methods: Prospective study of all patients with suspected GCA referred for TAB when U/S was negative or inconclusive, as part of the local fast-track pathway (Coventry). Database included clinical findings, serological work up, U/S and TAB results and treatment. Sensitivity and specificity of U/S and TAB was calculated and compared based on duration of treatment with steroids. Results: One hundred and nine patients were referred for TAB via Coventry fast-track-pathway. The sensitivity of U/S in this cohort of patients was 9.08% and specificity was 93.33%. After 3 days of steroid this was 0% and 100% respectively. For TAB when done within 10 days of starting steroids, this was 65% and 87.5% respectively. After 20 days of steroids this was 0 % and 100%. The sensitivity and specificity was 20% and 85% when arterial specimen size was 11-15mm and 47% and 100% when specimen size was 16 mm or more. Sensitivity and specificity of U/S of 644 suspected GCA patients was 48% and 98%. Conclusion: Our study demonstrates that TAB plays a relevant role in GCA fast-track-pathways, when U/S is negative/inconclusive. TAB was more sensitive than U/S in this cohort of patients, but overall sensitivity of U/S was higher when calculated for all patients suspected with GCA. Both remain useful tests if performed early. TAB specimen size should ideally be 16mm or more and done within 10 days of starting steroids. References: [1]Jonathan Pinnell, Carl Tiivas, Kaushik Chaudhuri, Purnima Mehta, Shirish Dubey, O38 The diagnostic performance of ultrasound Doppler in a fast-track pathway for giant cell arteritis, Rheumatology , Volume 58, Issue Supplement_3, April 2019, kez105.036, https://doi.org/10.1093/rheumatology/kez105.036 Disclosure of Interests: None declared
Emerging treatment options for extraintestinal manifestations in IBD
Authors: Thomas Greuter, Florian Rieder, Torsten Kucharzik, Laurent Peyrin-Biroulet, Alain M Schoepfer, David T Rubin, Stephan R Vavricka
Journal: Gut (2020)

Extraintestinal manifestations (EIMs) are frequently observed in IBDs and contribute considerably to morbidity and mortality. They have long been considered a difficult to treat entity due to limited therapy options, but the increasing use of anti-tumour necrosis factors has dramatically changed the therapeutic approach to EIM in recent years. Newly emerging therapies such as JAK inhibitors and anti-interleukin 12/23 will further shape the available armamentarium. Clinicians dealing with EIMs in everyday IBD practice may be puzzled by the numerous available biological agents and small molecules, their efficacy for EIMs and their potential off-label indications. Current guidelines on EIMs in IBD do not include treatment algorithms to help practitioners in the treatment decision-making process. Herein, we summarise knowledge on emerging biological treatment options and small molecules for EIMs, highlight current research gaps, provide therapeutic algorithms for EIM management and shed light on future strategies in the context of IBD-related EIMs.
Lung transplantation for COVID-19-associated acute respiratory distress syndrome in a PCR-positive patient
Authors: Christian Lang, Peter Jaksch, Mir Alireza Hoda, György Lang, Thomas Staudinger, Edda Tschernko, Bernhard Zapletal, Silvana Geleff, Helmut Prosch, Riem Gawish, Sylvia Knapp, Oliver Robak, Florian Thalhammer, Alexander Indra, Markus Koestenberger, Robert Strassl, Thomas Klikovits, Kamran Ali, Gottfried Fischer, Walter Klepetko, Konrad Hoetzenecker, Peter Schellongowski
Journal: The Lancet Respiratory Medicine (2020)
Epicardial Adipose Tissue in Patients With Stable Chest Pain
Authors: Borek Foldyna, Roman Zeleznik, Parastou Eslami, Thomas Mayrhofer, Maros Ferencik, Daniel O. Bittner, Nandini M. Meyersohn, Stefan B. Puchner, Hamed Emami, Hugo J.W.L. Aerts, Pamela S. Douglas, Michael T. Lu, Udo Hoffmann
Journal: JACC. Cardiovascular imaging (2020)
HER2 status as predictive marker for Al vs Tam benefit: A TRANS-AIOG meta-analysis of 12129 patients from ATAC, BIG 1-98 and TEAM with centrally determined HER2
Authors: J.M.S. Bartlett, I. Ahmed, M.M. Regan, I. Sestak, E.A. Mallon, P. Dell'Orto, B.J.K. Thurlimann, C. Seynaeve, H. Putter, C.L. Brookes, J.F. Forbes, Colleoni, J. Bayani, C.J.H. van de Velde, G. Viale, J. Cuzick, M. Dowsett, D.W. Rea, Translational Aromatase Inhibitor
Journal: Cancer Research (2016)
Quality Testing of Difficult-to-Make Prescription Pharmaceutical Products Marketed in the US
Authors: Adam C. Fisher, Alex Viehmann, Melika Ashtiani, Richard L. Friedman, Lucinda Buhse, Michael Kopcha, Janet Woodcock
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Health care practitioners and patients must have information to support their confidence in the quality of prescription pharmaceuticals. <h3>Objective</h3> To determine whether there were clear and substantive differences in major quality attributes between difficult-to-make solid oral dosage form pharmaceutical products marketed in the US. <h3>Design, Setting, and Participants</h3> This quality improvement study analyzed US Food and Drug Administration–collected samples of 252 drug products marketed in the US and manufactured in the US, Canada, Europe, India, and the rest of Asia. These drug products were immediate-release solid oral dosage forms considered difficult to make on the basis of product quality history. This sampling included 35 innovator and 217 generic drug samples manufactured by 46 different firms containing 17 different active ingredients. Statistical analysis was performed from February to November 2019. <h3>Main Outcomes and Measures</h3> All products were tested within their shelf life on the basis of the legally recognized tests of the US Pharmacopeia for the major quality attributes of dosage unit uniformity and dissolution. These tests measure dosage consistency and drug release, respectively. The consistency of either attribute was used to calculate a process performance index to describe the variability in manufacturing. <h3>Results</h3> All 252 drug product samples met the US market standards for dosage unit uniformity and dissolution, although the process performance index (Ppk) for dissolution fell below the level of 4-sigma capability (ie, &lt;1 error per 1600) for 11 different manufacturers and for generics in 4 of 5 regions, including the US. As part of a retrospective analysis, manufacturers performing above the median Ppk for either dissolution or dosage unit uniformity submitted fewer product quality defect reports (mean field alert reports of 0.22 and 0.63, respectively) than those falling at or below the median Ppk for these attributes (mean field alert reports of 2.1 and 1.7, respectively). <h3>Conclusions and Relevance</h3> All samples met the US market standards for dosage unit uniformity and dissolution, indicating acceptability for use by patients regardless of manufacturer or region. To our knowledge, this is the largest sampling study of pharmaceutical manufacturers for the US market and these data provide objective insight into the quality of prescription drugs with high manufacturing risks.
Covid-19: US approves emergency use of convalescent plasma despite warnings over lack of evidence
Authors: Elisabeth Mahase
Journal: BMJ (2020)

The US Food and Drug Administration has approved convalescent plasma for emergency use in hospital patients with covid-19.1

The announcement on 23 August said that the FDA had concluded that plasma from recovered patients “may be effective” in treating the virus and that the “potential benefits of the product outweigh the known and potential risks.” The move came despite the absence of results from randomised controlled trials, with only a preprint paper on the effects on hospitalised covid-19 patients being published to date.

The preprint, published on medRxiv on 12 August, examined whether plasma reduced mortality, and included 35 000 patients who received transfusions between 4 April and 4 July at one of the 2800 participating US centres.2 The study, not yet peer reviewed, said, “Earlier use of convalescent plasma was associated …
Withdrawal: “Primary prevention of sickle cell disease using preimplantation genetic testing and in vitro fertilization is cost‐effective.” Christina N. Cordeiro Mitchell, Apoorva Pradhan, Bhuchitra Singh, Rakhi P. Naik, Valerie L. Baker, Sophie M. Lanzkron, Mindy S. Christianson, Lydia H. Pecker
Journal: American Journal of Hematology (2020)

Christina N. Cordeiro Mitchell (2021) Primary prevention of sickle cell disease using preimplantation genetic testing and in vitro fertilization is cost-effective (https://doi.org/10.1002/ajh.25974). The above article, published online on 20 August 2020 in Wiley Online Library (wileyonlinelibrary.com) as an Accepted Article, has been withdrawn by agreement between the authors, the journal Editor in Chief, and John Wiley & Sons Ltd. The article has been withdrawn after the accepted article was posted online, the authors received independent feedback that has prompted them to review their analysis in the article to ensure that the original conclusions are accurate.
THU0152 The disease activity score predicts radiological progression during the following 6 months of observation in a 5 years observational study; an example of advanced longitudinal data analysis
Authors: RB Landewé, A Boonen, DM Van der Heijde, M Boers, S Van der Linden
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> A number of studies have shown that a high level of disease activity is associated with more rapid radiological progression. In those studies <i>time-averaged</i><i>or time-integrated</i> estimates for disease activity have been used. The concept of time-averaged disease activity does not entirely reflect reality, because disease activity is rarely constant over time. An inherent shortcoming of time-averaged estimates is that they do not really <i>predict</i> radiological outcome. <h3>Objectives</h3> To investigate, using multivariate longitudinal regression analysis, whether disease activity can <i>predict</i> radiological progression with a fixed time lag of 6 months. <h3>Methods</h3> 5 years follow-up data of RA-patients having participated in the COBRA trial (a 56-weeks double blind controlled trial in 146 patients with early, DMARD-naive, RA which compared COBRA-combination therapy with sulfasalazine monotherapy) were used. After the completion of the trial, patients had been followed for another 4 years, and X-rays of hands and feet, as well as assessments for disease activity, were obtained with 6 months intervals. X-rays were scored according to the van der Heijde-modified Sharp-method in a chronological order. The 28 joints disease activity score (DAS28) was calculated. Generalised estimating equations (GEE) was used to study the relationship between DAS28 and time (explanatory variables) and radiological damage (dependent variable). Every individual damage score was adjusted for its previous score (6 months earlier) (autoregression) in order to study radiological <h3>Results</h3> The interpretation of the beta's in the Table 1 is that each additional DAS28 point, measured at any time point, predicts a mean radiological progression of 0.52 Sharp-points during the following 6 months interval. The negative sign for time indicates that radiological progression in this study decreased over time. <h3>Conclusion</h3> By using GEE we have shown that DAS measured at any time point during a 5 years follow-up predicts radiological progression during the following 6 months. GEE is an appropriate method to study longitudinal relationships between outcome- and explanatory variables in RA.
Development of a Machine Learning Model for Survival Risk Stratification of Patients With Advanced Oral Cancer
Authors: Yi-Ju Tseng, Hsin-Yao Wang, Ting-Wei Lin, Jang-Jih Lu, Chia-Hsun Hsieh, Chun-Ta Liao
Journal: JAMA Network Open (2020)

<h3>Importance</h3> A tool for precisely stratifying postoperative patients with advanced oral cancer is crucial for the treatment plan, such as intensifying or deintensifying the regimen to improve their quality of life and prognosis. <h3>Objective</h3> To develop and validate a machine learning–based algorithm that can provide survival risk stratification for patients with advanced oral cancer who have comprehensive clinicopathologic and genetic data. <h3>Design, Setting, and Participants</h3> In this prognostic cohort study, the elastic net penalized Cox proportional hazards regression–based risk stratification model was developed and validated using single-center data collected between January 1, 1996, and December 31, 2011. In total, comprehensive clinicopathologic and genetic data (including clinical, pathologic, and 44 cancer-related gene variant profiles) of 334 patients with stage III or IV oral squamous cell carcinoma were used to develop and validate the algorithm in this 15-year cohort study. Data analysis was conducted between February 1, 2018, and May 6, 2020. <h3>Main Outcomes and Measures</h3> The main outcomes were cancer-specific survival, distant metastasis–free survival, and locoregional recurrence–free survival. Model performance was compared in terms of the Akaike information criterion and the Harrell concordance index (C index). <h3>Results</h3> Complete data were available for 334 patients (315 men; median age at onset, 48 years [interquartile range, 42-56 years]). The predictive models using comprehensive clinicopathologic and genetic data outperformed those using clinicopathologic data alone. In the groups of postoperative patients receiving adjuvant concurrent chemoradiotherapy, the models demonstrated higher classification performance than those using clinicopathologic data alone in cancer-specific survival (mean [SD] C index, 0.689 [0.050] vs 0.673 [0.051];<i>P</i> = .02) and locoregional recurrence–free survival (mean [SD] C index, 0.693 [0.039] vs 0.678 [0.035];<i>P</i> = .004). The classification performance in distant metastasis–free survival was not different (mean [SD] C index, 0.702 [0.056] vs 0.688 [0.048];<i>P</i> = .09). <h3>Conclusions and Relevance</h3> A risk stratification model using comprehensive clinicopathologic and genetic data accurately differentiated the high-risk group from the low-risk group in cancer-specific survival and locoregional recurrence–free survival for postoperative patients with advanced oral cancer. This algorithm could be used through an online calculator to provide additional personalized information for postoperative management of patients with advanced oral squamous cell carcinoma.
Subanalyses of the outcome of two carboplatin-based regimens in the treatment of advanced NSCLC
Authors: O. Hansen, T. K. Schytte, K. H. Hansen, P. Sørensen
Journal: Journal of Clinical Oncology (2009)

e19067 Background: Recent data suggest that various chemotherapy regimen may have different efficacy in subsets of patients (pts.) with advanced NSCLC. For that reason we studied if it was also the case for two Carboplatin regimens, Carboplatin-Vinorelbine (CV) and Carboplatin-Gemcitabine (CG), which were used as standard treatments in our centre for two periods Methods: From 1998–2007, 800 consecutive pts. were treated with a 3-weekly schedule of C, AUC=5, plus either V (30 mg/m 2 d.1+8), or G (1000 mg/m 2 d.1+8) for 4–6 cycles. CV was used as the standard regimen 1998 - 2003, and CG, 2004 - 2007. All pts. were followed to death, and most data have been prospectively recorded, but supplemented with retrospectively collected data from pts. files. The endpoint of this study was crude survival. The data was analysed according to performance status (PS), gender, age, and histology (adenoca., squamous, other NSCLC) Results: 313 pts. were treated with CV, 487 with CG. Median, 1 yr and 2 yr survival was for CV: 8.6 m, 34% and 15%, and for CG: 8.6 m, 37% and 12%, p=0.32. Analysed by histology, adenoca.'s had better median survival, 9.7 m., than non-adenoca., 8.1 m, p= .002, females better than males 10.0 m. vs. 7.9 m., p=.008, and PS 0–1 better than PS=2, 10.0 m. vs. 4.7 m. (p=.000). Age was of no importance. Cox-analyses was performed separately in the two genders. In females, PS 0–1, adenoca. and CG regimen were statistically significant favourable prognostic factors while in males only PS 0–1 were of significance. In the 379 pts. with adenoca., PS and gender were of significance while the chemotherapy was of borderline significance (p=.06). In non- adenoca.'s, only PS was of significance Conclusions: While CV and CG were overall equal effective in the treatment of NSCLC, CG may be the superior regimen in females, and in adenoca.'s. No trends for differential efficacy was found in any other subset of patients [Table: see text]
Phase II trial of pharmacodynamically (PDally)-guided optimal biologic dose titration (OBDT) of sorafenib (S) in combination with metronomic cyclophosphamide (mC) in advanced neuroendocrine tumors (aNET)
Authors: M. A. Quintela-Fandino, A. Young, S. Webster, M. Grewal, L. Wang, M. J. Moore, M. Krzyzanowska, T. W. Mak, L. L. Siu
Journal: Journal of Clinical Oncology (2009)

3526 Background: There is a paucity of reliable PD assays for guiding individual OBDT. PD effects of kinase inhibitors have been previously measured in static tissues. We developed a dynamic flow-cytometric PD assay that quantitates RAF signal transduction capacity (STC) based on the differential MEK´s phosphor-status in stimulated vs. basal conditions (phosphor-shift [PS]) in PBMCs. In a pilot study of 7 patients (pt) with advanced solid tumors in a phase I trial (unpublished data) the % of PS inhibition (I) 7 days after starting S at 400 mg BID showed a 10-fold interpatient variation and correlation with TTP. PDGFR-B/VEGFR2 blockade plus mC showed synergistic effect in the RIP1-Tag2 mouse NET model (J Clin Oncol. 23:939) In this phase II trial of aNET a double antiagniogenic strategy is undertaken: PD-guided OBDT of S + mC. Methods: Eligibility criteria included: unresectable NET with documented PD within 6 months prior to entry; ECOG 0–2; unlimited prior therapy but S; octreotide allowed. Therapy: pt start run-in phase with S at 200mg bid + 50 mg QD fixed dose of mC. After 7 d they escalate to 400 mg BID of S regardless of RAF STC assay results. RAF STC and toxicity are then assessed Q14d, escalating S at 200 mg BID increments until any of the following is achieved: a) 90% RAF STC I; b) maximum S dose of 800 mg BID; or c) intolerable Gr 2 or G3+ toxicity. Once S dose is determined based on these criteria, cycle 1 begins. Design: Simon 2-stage optimal; P0 = 0.05 P1 = 0.2; α =0.05 β = 0.1. Results: Accrual: 10 pt M:F = 6:4, islet cell:carcinoid = 5:5, age median 56 (40–79), ECOG 0:1 = 5:5. S doses (mg BID) at cycle 1 were 200 (2 pt)/400 (5)/600 (2)/800 (1); corresponding cycle 1 day 1RAF STC I (%) were 5, 53/94, 100, 95, 16, 65/25, 41/71, respectively (R 2 = 0.13 p = 0.72) Most frequent Gr 3 non-hematologic possibly related adverse events in 30 cycles: hand-foot (2 pt), hypertension, abdominal pain, diarrhea, vomiting, lipase, ileal perforation (1 each). Disease control rate (9 evaluable pt): 78% (95% CI: 52–100%) (1PR, 6 SD). Conclusions: This approach appears feasible/safe. Large interpatient S dose differences are needed to achieve RAF SCT I/toxicity balance. No S dose-RAF SCT I relation is shown. Disease control rate is promising. No significant financial relationships to disclose.
Developing a delivery science for artificial intelligence in healthcare
Authors: Ron C. Li, Steven M. Asch, Nigam H. Shah
Journal: npj Digital Medicine (2020)

Artificial Intelligence (AI) has generated a large amount of excitement in healthcare, mostly driven by the emergence of increasingly accurate machine learning models. However, the promise of AI delivering scalable and sustained value for patient care in the real world setting has yet to be realized. In order to safely and effectively bring AI into use in healthcare, there needs to be a concerted effort around not just the creation, but also the delivery of AI. This AI "delivery science" will require a broader set of tools, such as design thinking, process improvement, and implementation science, as well as a broader definition of what AI will look like in practice, which includes not just machine learning models and their predictions, but also the new systems for care delivery that they enable. The careful design, implementation, and evaluation of these AI enabled systems will be important in the effort to understand how AI can improve healthcare.