tbuckley/cabot-search huggingface dataset:
Managing intensive care admissions when there are not enough beds during the COVID-19 pandemic: a systematic review
Authors: Carina S B Tyrrell, Oliver T Mytton, Sarah V Gentry, Molly Thomas-Meyer, John Lee Y Allen, Antony A Narula, Brendan McGrath, Martin Lupton, Jo Broadbent, Aliko Ahmed, Angelique Mavrodaris, Anees Ahmed Abdul Pari
Journal: Thorax (2020)

The surge in cases of severe COVID-19 has resulted in clinicians triaging intensive care unit (ICU) admissions in places where demand has exceeded capacity. In order to assist difficult triage decisions, clinicians require clear guidelines on how to prioritise patients. Existing guidelines show significant variability in their development, interpretation, implementation and an urgent need for a robust synthesis of published guidance. To understand how to manage which patients are admitted to ICU, and receive mechanical ventilatory support, during periods of high demand during the COVID-19 pandemic, a systematic review was performed. Databases of indexed literature (Medline, Embase, Web of Science, and Global Health) and grey literature (Google.com and MedRxiv), published from 1 January until 2 April 2020, were searched. Search terms included synonyms of COVID-19, ICU, ventilation, and triage. Only formal written guidelines were included. There were no exclusion criteria based on geographical location or publication language. Quality appraisal of the guidelines was performed using the Appraisal of Guidelines for Research and Evaluation Instrument II (AGREE II) and the Appraisal of Guidelines for Research and Evaluation Instrument Recommendation EXcellence (AGREE REX) appraisal tools, and key themes related to triage were extracted using narrative synthesis. Of 1902 unique records identified, nine relevant guidelines were included. Six guidelines were national or transnational level guidance (UK, Switzerland, Belgium, Australia and New Zealand, Italy, and Sri Lanka), with one state level (Kansas, USA), one international (Extracorporeal Life Support Organization) and one specific to military hospitals (Department of Defense, USA). The guidelines covered several broad themes: use of ethical frameworks, criteria for ICU admission and discharge, adaptation of criteria as demand changes, equality across health conditions and healthcare systems, decision-making processes, communication of decisions, and guideline development processes. We have synthesised the current guidelines and identified the different approaches taken globally to manage the triage of intensive care resources during the COVID-19 pandemic. There is limited consensus on how to allocate the finite resource of ICU beds and ventilators, and a lack of high-quality evidence and guidelines on resource allocation during the pandemic. We have developed a set of factors to consider when developing guidelines for managing intensive care admissions, and outlined implications for clinical leads and local implementation.
CTNI-67. EFFICACY AND SAFETY OF LAROTRECTINIB IN PATIENTS WITH TROPOMYOSIN RECEPTOR KINASE (TRK) FUSION PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS: AN EXPANDED DATASET
Authors: Sébastien Perreault, François Doz, Alexander Drilon, Birgit Geoerger, Valentina Boni, Julia Chisholm, Steven G Dubois, Juneko E Grilley-Olson, David S Hong, Antoine Italiano, HyoungJin Kang, Karsten Nysom, Ingrid Øra, Cormac Owens, Johannes H Schulte, Makoto Tahara, David Ziegler, Benjamin Ellezam, John A Reeves, Marc Fellous, Esther De La Cuesta, Theodore W Laetsch, Cornelis M van Tilburg
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND TRK fusion proteins are oncogenic drivers of various CNS and non-CNS tumors. Larotrectinib, a highly selective FDA- and EMA-approved TRK inhibitor, demonstrated an objective response rate (ORR) of 79% across various non-CNS cancers (Hong et al. Lancet Oncol. 2020). We report data in an expanded set of TRK fusion primary CNS tumors treated with larotrectinib. METHODS Patients with primary CNS tumors harboring an NTRK gene fusion treated with larotrectinib in two clinical trials (NCT02637687, NCT02576431) were identified. Disease status was investigator-assessed (RANO). Data cutoff: July 15, 2019. RESULTS Twenty-four patients with TRK fusion primary CNS tumors were identified. Eighteen patients had gliomas (13 high-grade and five low-grade). Median age was 8.0 years (range 1.3–79.0), with 20 patients &amp;lt; 18 years old. ORR was 29% (95% CI 13–51%); best responses were two complete responses, five partial responses (two pending confirmation), 15 stable disease, and two progressive disease. The 24-week disease control rate was 63% (95% CI 41–81%). For the five confirmed responders, median time to best response was 1.8 months and median duration of response was 4.9 months (range 1.7+ to 10.1+). Median progression-free survival was 11.0 months (range 1.1 to 19.8+) and median overall survival was not reached (range 1.9+ to 21.4+) at a median follow-up of 6.0 months. Treatment duration ranged from 1.2 to 21.4+ months; three patients continued treatment beyond progression. Treatment-emergent adverse events (TEAEs) were mainly Grade 1 and 2. Grade 3–4 TEAEs occurred in 10 patients, with two deemed related to larotrectinib. The most common neurological TEAE was headache in three patients (Grade 1–2). No patients discontinued larotrectinib due to AEs. CONCLUSIONS Larotrectinib was active and well tolerated in patients with TRK fusion primary CNS tumors. These results support testing for NTRK gene fusions in patients with primary CNS tumors.
Gut Microbiome Directs Hepatocytes to Recruit MDSCs and Promote Cholangiocarcinoma
Authors: Qianfei Zhang, Chi Ma, Yi Duan, Bernd Heinrich, Umberto Rosato, Laurence P. Diggs, Lichun Ma, Soumen Roy, Qiong Fu, Zachary J. Brown, Simon Wabitsch, Vishal Thovarai, Jianyang Fu, Dechun Feng, Benjamin Ruf, Linda L. Cui, Varun Subramanyam, Karen M. Frank, Sophie Wang, David E. Kleiner, Thomas Ritz, Christian Rupp, Bin Gao, Thomas Longerich, Alexander Kroemer, Xin Wei Wang, Mathuros Ruchirawat, Firouzeh Korangy, Bernd Schnabl, Giorgio Trinchieri, Tim F. Greten
Journal: Cancer Discovery (2020)

Gut dysbiosis is commonly observed in patients with cirrhosis and chronic gastrointestinal disorders; however, its effect on antitumor immunity in the liver is largely unknown. Here we studied how the gut microbiome affects antitumor immunity in cholangiocarcinoma. Primary sclerosing cholangitis (PSC) or colitis, two known risk factors for cholangiocarcinoma which promote tumor development in mice, caused an accumulation of CXCR2+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC). A decrease in gut barrier function observed in mice with PSC and colitis allowed gut-derived bacteria and lipopolysaccharide to appear in the liver and induced CXCL1 expression in hepatocytes through a TLR4-dependent mechanism and an accumulation of CXCR2+ PMN-MDSCs. In contrast, neomycin treatment blocked CXCL1 expression and PMN-MDSC accumulation and inhibited tumor growth even in the absence of liver disease or colitis. Our study demonstrates that the gut microbiome controls hepatocytes to form an immunosuppressive environment by increasing PMN-MDSCs to promote liver cancer. SIGNIFICANCE: MDSCs have been shown to be induced by tumors and suppress antitumor immunity. Here we show that the gut microbiome can control accumulation of MDSCs in the liver in the context of a benign liver disease or colitis.See related commentary by Chagani and Kwong, p. 1014.This article is highlighted in the In This Issue feature, p. 995.
Health-Related Quality of Life in Transplant-Ineligible Patients With Newly Diagnosed Multiple Myeloma: Findings From the Phase III MAIA Trial
Authors: Aurore Perrot, Thierry Facon, Torben Plesner, Saad Z. Usmani, Shaji Kumar, Nizar J. Bahlis, Cyrille Hulin, Robert Z. Orlowski, Hareth Nahi, Peter Mollee, Karthik Ramasamy, Murielle Roussel, Arnaud Jaccard, Michel Delforge, Lionel Karlin, Bertrand Arnulf, Ajai Chari, Jianming He, Kai Fai Ho, Rian Van Rampelbergh, Clarissa M. Uhlar, Jianping Wang, Rachel Kobos, Katharine S. Gries, John Fastenau, Katja Weisel
Journal: Journal of Clinical Oncology (2020)

To evaluate the effects of daratumumab, lenalidomide, and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) on patient-reported outcomes (PROs) in the phase III MAIA study.PROs were assessed on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item and the EuroQol 5-dimensional descriptive system at baseline and every 3 months during treatment. By mixed-effects model, changes from baseline are presented as least squares means with 95% CIs.A total of 737 transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma were randomly assigned to D-Rd (n = 368) or Rd (n = 369). Compliance with PRO assessments was high at baseline (> 90%) through month 12 (> 78%) for both groups. European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item global health status scores improved from baseline in both groups and were consistently greater with D-Rd at all time points. A global health status benefit was achieved with D-Rd, regardless of age (< 75 and ≥ 75 years), baseline Eastern Cooperative Oncology Group (ECOG) performance status score, or depth of response. D-Rd treatment resulted in significantly greater reduction in pain scores as early as cycle 3 (P = .0007 v Rd); the magnitude of change was sustained through cycle 12. Reductions in pain with D-Rd were clinically meaningful in patients regardless of age, ECOG status, or depth of response. Similarly, PRO improvements were observed with D-Rd and Rd on the EuroQol 5-dimensional descriptive system visual analog scale score.D-Rd compared with Rd was associated with faster and sustained clinically meaningful improvements in PROs, including pain, in transplant-ineligible patients with newly diagnosed multiple myeloma regardless of age, baseline ECOG status, or depth of treatment response.
Art in Endoscopy: “Palm tree”
Authors: Alessandro Mussetto
Journal: Endoscopy (2020)

A palm tree-like jejunal angioectasia was found at capsule endoscopy in a patient referred to us because of suspected small-bowel bleeding. The image shows one of the most common small-bowel lesions in this clinical context. However, detecting the source of suspected small-bowel bleeding can be challenging because of several factors, namely, suboptimal timing of capsule endoscopy, poor preparation, and the intermittent bleeding pattern of some vascular lesions. Thus, at capsule endoscopy the gastroenterologist may encounter a small-bowel lesion with the same gratitude as a desert explorer sighting a palm tree oasis.
Abstract P473: Social Determinants of Cardiovascular Health Among Afro-Caribbean Immigrants in New York City
Authors: Sabena Thomas, Amna Umer, Yvonne Commodore-mensah, Danielle Davidov, Christiaan Abildso
Journal: Circulation (2020)

Introduction: Research on cardiovascular health (CVH) and risk factors among immigrants has been well-documented. Less is known about social influences on CVH, among black immigrants. Despite having the largest population of black immigrants in the U.S., Afro-Caribbean (AC) immigrants have been underrepresented in health research. We examined the social determinants of CVH among AC immigrants (Guyanese, Haitian and Jamaican) in New York City (NYC). Hypothesis: We hypothesized that social determinants of CVH will vary among the three ethnic sub-groups of AC immigrants. Methods: We included 1691 AC immigrants who reported their race as non-Hispanic Black and country of birth (COB) as Guyana (n= 369), Haiti (n= 291) or Jamaica (n= 1031) in the 2010-2014 administrations of the New York City Community Health Survey. Logistic regression analysis was performed to assess the association between social determinants and CVH (ideal vs intermediate/poor) using AHA’s CVH metrics. Results: The majority of the sample was female (59.2%) and reported high school education or less (53.9%). Most AC immigrants reported to have ideal CVH (71.3%). Education was significantly associated with CVH only among Jamaican immigrants. Jamaican immigrants with ≤ high school education were more likely to have intermediate/poor CVH compared to those with ≥ some college education. Conclusions: These findings suggest that social determinants influencing CVH differ among AC immigrant sub-groups in NYC. These findings suggest that social determinants influencing CVH differ among AC immigrant sub-groups in NYC. National surveillance efforts should obtain more complete data on country of origin and oversample racial/ethnic minority groups in order to better understand their CVH outcomes. Future research should examine other social factors that may influence CVH among black immigrants.
Iqgap3-Ras axis drives stem cell proliferation in the stomach corpus during homoeostasis and repair
Authors: Junichi Matsuo, Daisuke Douchi, Khine Myint, Naing Naing Mon, Akihiro Yamamura, Kazuyoshi Kohu, Dede Liana Heng, Sabirah Chen, Nur Astiana Mawan, Napat Nuttonmanit, Ying Li, Supriya Srivastava, Shamaine Wei Ting Ho, Nicole Yee Shin Lee, Hong Kai Lee, Makoto Adachi, Atsushi Tamura, Jinmiao Chen, Henry Yang, Ming Teh, Jimmy Bok-Yan So, Wei Peng Yong, Patrick Tan, Khay Guan Yeoh, Linda Shyue Huey Chuang, Sachiko Tsukita, Yoshiaki Ito
Journal: Gut (2020)

Tissue stem cells are central regulators of organ homoeostasis. We looked for a protein that is exclusively expressed and functionally involved in stem cell activity in rapidly proliferating isthmus stem cells in the stomach corpus.We uncovered the specific expression of Iqgap3 in proliferating isthmus stem cells through immunofluorescence and in situ hybridisation. We performed lineage tracing and transcriptomic analysis of Iqgap3 +isthmus stem cells with the Iqgap3-2A-tdTomato mouse model. Depletion of Iqgap3 revealed its functional importance in maintenance and proliferation of stem cells. We further studied Iqgap3 expression and the associated gene expression changes during tissue repair after tamoxifen-induced damage. Immunohistochemistry revealed elevated expression of Iqgap3 in proliferating regions of gastric tumours from patient samples.Iqgap3 is a highly specific marker of proliferating isthmus stem cells during homoeostasis. Iqgap3+isthmus stem cells give rise to major cell types of the corpus unit. Iqgap3 expression is essential for the maintenance of stem potential. The Ras pathway is a critical partner of Iqgap3 in promoting strong proliferation in isthmus stem cells. The robust induction of Iqgap3 expression following tissue damage indicates an active role for Iqgap3 in tissue regeneration.IQGAP3 is a major regulator of stomach epithelial tissue homoeostasis and repair. The upregulation of IQGAP3 in gastric cancer suggests that IQGAP3 plays an important role in cancer cell proliferation.
CTNI-30. THERAPEUTIC EFFECTS OF RADIOTHERAPY WITH CONCOMITANT AND ADJUVANT TEMOZOLOMIDE VERSUS RADIOTHERAPY WITH CONCOMITANT TEMOZOLOMIDE ALONE IN CHILDREN WITH DIPG: A SINGLE-CENTER EXPERIENCE WITH 82 CASES
Authors: Mingyao Lai, Juan Li, Qingjun Hu, Jiangfen Zhou, Shaoqun Li, Lei Wen, Linbo Cai
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE To retrospectively analyze the therapeutic effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy with concomitant temozolomide alone for pediatric diffuse intrinsic pontine glioma (DIPG), and to evaluate the value of temozolomide in the treatment of pediatric DIPG. METHODS The clinical data of children with confirmed DIPG in Guangdong Sanjiu Brain Hospital between January 1, 2010 and December 30, 2019 were collected. The inclusive criteria included (1) receiving a total radiotherapy dose of 54 Gy in 27 fractions, (2) treated with concomitant temozolomide chemotherapy, and (3) with or without adjuvant temozolomide chemotherapy. RESULTS A total of 82 pediatric patients were eligible for the study, with a median age of 7 years (range 2–16 years). The median follow-up was 8.6 months (range 2–28 months) and the median survival time was 9.4 months. The median survival time of 66 patients treated with radiotherapy with concomitant and adjuvant temozolomide was 9.8 months, longer than 7.5 months of the other 16 patients treated with radiotherapy with concomitant temozolomide alone, with statistical differences (P=0.010). Moreover, bevacizumab and nimotuzumab didn’t bring survival benefits to patients with disease recurrence or progression. Hematological toxicity (Grade IV) was not found. CONCLUSION Radiotherapy with concomitant and adjuvant temozolomide prolongs the survival time of children with DIPG.
Associations among circulating sphingolipids, β-cell function, and risk of developing type 2 diabetes: A population-based cohort study in China
Authors: Huan Yun, Liang Sun, Qingqing Wu, Geng Zong, Qibin Qi, Huaixing Li, He Zheng, Rong Zeng, Liming Liang, Xu Lin
Journal: PLoS Medicine (2020)

Background Animal studies suggest vital roles of sphingolipids, especially ceramides, in the pathogenesis of type 2 diabetes (T2D) via pathways involved in insulin resistance, β-cell dysfunction, and inflammation, but human studies are limited. We aimed to evaluate the associations of circulating sphingolipids with incident T2D and to explore underlying mechanisms. Methods and findings The current study included 826 men and 1,148 women who were aged 50–70 years, from Beijing and Shanghai, and without T2D in 2005 and who were resurveyed in 2011. Cardiometabolic traits were measured at baseline and follow-up surveys. A total of 76 sphingolipids were quantified using high-coverage targeted lipidomics. Summary data for 2-sample Mendelian randomization were obtained from genome-wide association studies of circulating sphingolipids and the China Health and Nutrition Survey ( n = 5,731). During the 6-year period, 529 participants developed T2D. Eleven novel and 3 reported sphingolipids, namely ceramides (d18:1/18:1, d18:1/20:0, d18:1/20:1, d18:1/22:1), saturated sphingomyelins (C34:0, C36:0, C38:0, C40:0), unsaturated sphingomyelins (C34:1, C36:1, C42:3), hydroxyl-sphingomyelins (C34:1, C38:3), and a hexosylceramide (d18:1/20:1), were positively associated with incident T2D (relative risks [RRs]: 1.14–1.21; all P &lt; 0.001), after multivariate adjustment including lifestyle characteristics and BMI. Network analysis further identified 5 modules, and 2 modules containing saturated sphingomyelins showed the strongest associations with increased T2D risk (RR Q4 versus Q1 = 1.59 and 1.43; both P trend &lt; 0.001). Mediation analysis suggested that the detrimental associations of 13 sphingolipids with T2D were largely mediated through β-cell dysfunction, as indicated by HOMA-B (mediation proportion: 11.19%–42.42%; all P &lt; 0.001). Moreover, Mendelian randomization evidenced a positive association between a genetically instrumented ceramide (d18:1/20:1) and T2D (odds ratio: 1.15 [95% CI 1.05–1.26]; P = 0.002). Main limitations in the current study included potential undiagnosed cases and lack of an independent population for replication. Conclusions In this study, we observed that a panel of novel sphingolipids with unique structures were positively associated with incident T2D, largely mediated through β-cell dysfunction, in Chinese individuals.
Identification of Incidental Skin Cancers Among Adults Referred to Dermatologists for Suspicious Skin Lesions
Authors: Sharif Omara, David Wen, Benjamin Ng, Rakesh Anand, Rubeta N. Matin, Kathy Taghipour, Ben Esdaile
Journal: JAMA Network Open (2020)

The incidence of skin cancer is increasing and evaluation of the utility of total body skin examination (TBSE) in detecting incidental skin cancers is warranted.To evaluate the proportion and rate of incidental skin cancer detection in urgent skin cancer clinics and investigate the rate of incidental skin cancer detection in 2 groups based on the degree of clinical suspicion of the index lesion for malignancy.A multicenter retrospective cohort study with a case note review of consecutive secondary care consultations was conducted using data from 2 urgent suspected skin cancer screening clinics in UK National Health Service trusts. The study was performed from January 1, 2015, to March 31, 2016, and data analysis was performed from October 14, 2018, to February 1, 2019. Patients included those presenting with a skin lesion suspicious of malignancy who were referred to the urgent suspected skin cancer clinic (N = 5944) over 15 months. Patients who accepted and received a TBSE were subsequently included in the analysis.The proportion and rate of incidental skin cancer detection through TBSE and whether a clinically suspicious (malignant) index lesion was associated with a higher chance of having a malignant incidental lesion.Of the 5944 patients referred to the clinic, 4726 individuals (79.5%) were evaluated. In the cohort included in the analyses, the median age was 57 years (interquartile range, 39-73 years); 2567 patients (54.3%) were women. A total of 1117 skin cancers were identified; of these, 242 lesions (21.7%) were detected incidentally through TBSE, including 197 of 570 (34.6%) basal cell carcinomas, 16 of 250 (6.4%) squamous cell carcinomas, and 25 of 215 (11.6%) melanomas. The detection rate of incidental malignant lesions was 5.1 lesions per 100 patients examined (5.1%; 95% CI, 4.5%-5.8%). There was a higher detection rate of histologically confirmed incidental malignant lesions in individuals with clinically suspicious index lesions requiring biopsy (10.9%; 95% CI, 9.5%-12.5%) compared with those presenting with clinically benign index lesions (2.0%; 95% CI, 1.6%-2.5%) (P < .001).The findings of this study support the use of TBSE for urgent skin cancer referrals, highlighting the potential harms of solitary lesion assessment in a subgroup. Individuals presenting with a clinically suspicious index lesion requiring biopsy are most likely to benefit from TBSE and should be counseled regarding the benefit.