tbuckley/cabot-search huggingface dataset:
Inhalers: to switch or not to switch? That is the question
Authors: Anna Claire Murphy
Journal: Thorax (2019)

We know that there is an increasing prevalence of asthma and COPD worldwide, leading to increased inhaler use. Chapter 3 of the British National Formulary1 has grown significantly over the years in terms of the number of inhaler options. There are currently, in the UK, more than 20 different inhaler devices available, with over 118 possible combinations of drug and device to prescribe. The inhaler market has become very crowded, with patents expiring for some of the most widely used inhaled drugs. Several analogues of branded inhaled corticosteroids/long-acting β2-adrenoceptor agonists (ICS/LABA) fixed-dose combinations have entered the market with different inhaler devices, and longer-acting ‘me-too’ formulations have appeared. Incorrect or suboptimal patient technique in using inhalers has led to yet further inhaler devices being developed, and combination/triple inhalers have been launched to support patients.

Current clinical evidence suggests that, although existing inhaled therapy has the potential to control disease in most patients with asthma, control is often not achieved in practice.2 Suboptimal inhaler technique is the prominent reason for the lack of efficacy; no matter how good a drug or device is, it cannot be effective if the drug does not reach the targeted airways. Inhaler errors are associated with worsening in disease control, increased rate of exacerbations, increased healthcare resource consumption, and consequently increased healthcare expenditure.3–5 A recent systematic literature review and meta-analysis found that incorrect inhaler technique is common across devices, with up to 100% of patients demonstrating at least one error. Moreover, up to 92% of patients experience critical errors, that is, one that may impact the effectiveness of the delivered drug.6 While Chrystyn et al ’s3 team found high critical error rates reported across all devices, their meta-analysis and systematic review highlighted significant gaps in knowledge regarding different inhalers and associated error …
Evaluation of the Extended-Release/Long-Acting Opioid Prescribing Risk Evaluation and Mitigation Strategy Program by the US Food and Drug Administration
Authors: James Heyward, Lily Olson, Joshua M. Sharfstein, Elizabeth A. Stuart, Peter Lurie, G. Caleb Alexander
Journal: JAMA Internal Medicine (2019)

<h3>Importance</h3> Extended-release/long-acting (ER/LA) opioids have caused substantial morbidity and mortality in the United States, yet little is known about the efforts of the US Food and Drug Administration (FDA) and drug manufacturers to reduce adverse outcomes associated with inappropriate prescribing or use. This review of 9739 pages of FDA documents obtained through a Freedom of Information Act request aimed to investigate whether the FDA and ER/LA manufacturers were able to assess the effectiveness of the ER/LA Risk Evaluation and Mitigation Strategy (REMS) program by evaluating manufacturer REMS assessments and FDA oversight of these assessments. <h3>Observations</h3> The REMS program was implemented largely as planned. The FDA's goal was for 60% of ER/LA prescribers to take REMS-adherent continuing education (CE) between 2012 and 2016; 27.6% (88 316 of 320 000) of prescribers had done so by 2016. Audits of REMS programs indicated close adherence to FDA content guidelines except for financial disclosures. Nonrepresentative cross-sectional surveys of self-selected prescribers suggested modestly greater ER/LA knowledge among CE completers than noncompleters, and claims-based surveillance indicated slowly declining ER/LA prescribing, although the contribution of the REMS to these trends could not be assessed. The effectiveness of the REMS program for reducing adverse outcomes also could not be assessed because the analyses used nonrepresentative samples, lacked adequate controls for confounding, and did not link prescribing or clinical outcomes to prescribers' receipt of CE training. Although the FDA had requested studies tracking adverse outcomes as a function of CE training, the FDA concluded that these studies had not been performed as of the 60-month report in 2017. <h3>Conclusions and Relevance</h3> Five years after initiation, the FDA and ER/LA manufacturers could not conclude whether the ER/LA REMS had reduced inappropriate prescribing or improved patient outcomes. Alternative observational study designs would have allowed for more rigorous estimates of the program's effectiveness.
Exome sequencing reveals a high prevalence of BRCA1 and BRCA2 founder variants in a diverse population-based biobank
Authors: Noura S. Abul-Husn, Emily R. Soper, Jacqueline A. Odgis, Sinead Cullina, Dean Bobo, Arden Moscati, Jessica E. Rodriguez, Ruth J. F. Loos, Judy H. Cho, Gillian M. Belbin, Sabrina A. Suckiel, Eimear E. Kenny
Journal: Genome Medicine (2019)

Pathogenic variants in BRCA1 and BRCA2 (BRCA1/2) lead to increased risk of breast, ovarian, and other cancers, but most variant-positive individuals in the general population are unaware of their risk, and little is known about prevalence in non-European populations. We investigated BRCA1/2 prevalence and impact in the electronic health record (EHR)-linked BioMe Biobank in New York City.Exome sequence data from 30,223 adult BioMe participants were evaluated for pathogenic variants in BRCA1/2. Prevalence estimates were made in population groups defined by genetic ancestry and self-report. EHR data were used to evaluate clinical characteristics of variant-positive individuals.There were 218 (0.7%) individuals harboring expected pathogenic variants, resulting in an overall prevalence of 1 in 139. The highest prevalence was in individuals with Ashkenazi Jewish (AJ; 1 in 49), Filipino and other Southeast Asian (1 in 81), and non-AJ European (1 in 103) ancestry. Among 218 variant-positive individuals, 112 (51.4%) harbored known founder variants: 80 had AJ founder variants (BRCA1 c.5266dupC and c.68_69delAG, and BRCA2 c.5946delT), 8 had a Puerto Rican founder variant (BRCA2 c.3922G>T), and 24 had one of 19 other founder variants. Non-European populations were more likely to harbor BRCA1/2 variants that were not classified in ClinVar or that had uncertain or conflicting evidence for pathogenicity (uncertain/conflicting). Within mixed ancestry populations, such as Hispanic/Latinos with genetic ancestry from Africa, Europe, and the Americas, there was a strong correlation between the proportion of African genetic ancestry and the likelihood of harboring an uncertain/conflicting variant. Approximately 28% of variant-positive individuals had a personal history, and 45% had a personal or family history of BRCA1/2-associated cancers. Approximately 27% of variant-positive individuals had prior clinical genetic testing for BRCA1/2. However, individuals with AJ founder variants were twice as likely to have had a clinical test (39%) than those with other pathogenic variants (20%).These findings deepen our knowledge about BRCA1/2 variants and associated cancer risk in diverse populations, indicate a gap in knowledge about potential cancer-related variants in non-European populations, and suggest that genomic screening in diverse patient populations may be an effective tool to identify at-risk individuals.
Proteomic analysis of intracellular protein corona of nanoparticles elucidates nano-trafficking network and nano-bio interactions
Authors: Mengmeng Qin, Jian Zhang, Minghui Li, Dan Yang, Dechun Liu, Siyang Song, Jijun Fu, Hua Zhang, Wenbing Dai, Xueqing Wang, Yiguang Wang, Bing He, Qiang Zhang
Journal: Theranostics (2020)

The merits of nanomedicines are significantly impacted by the surrounding biological environment. Similar to the protein corona generated on the surface of nanoparticles in the circulation system, the intracellular protein corona (IPC) might be formed on nanoparticles when transported inside the cells. However, little is known currently about the formation of IPC and its possible biological influence. Methods: Caco-2 cells, a classical epithelial cell line, were cultured in Transwell plates to form a monolayer. Gold nanoparticles (AuNPs) were prepared as the model nanomedicine due to their excellent stability. Here we focused on identifying IPC formed on the surface of AuNPs during cell transport. The nanoparticles in the basolateral side of the Caco-2 monolayer were collected and analyzed by multiple techniques to verify IPC formation. High-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics was utilized to analyze the composition of IPC proteins. In particular, we established a dual-filtration strategy to exclude various interference in IPC identification. Based on the subcellular localization of specific IPC proteins, we elicited the nano-trafficking network of AuNPs. The transport pathways of AuNPs identified by proteomic analysis were also verified by various conventional technologies. Finally, we explored the influence of IPC on the uptake and stress response of endothelium. Results: The existence of IPC was demonstrated on the surface of AuNPs, in which 227 proteins were identified. Among them, 40 proteins were finally ascertained as the specific IPC proteins. The subcellular location analysis indicated that these "specific" IPC proteins could back-track the transport pathways of nanoparticles in the epithelial cell monolayer. According to the subcellular distribution of IPC proteins and co-localization, we discovered a new pathway of nanoparticles from endosomes to secretory vesicles which was dominant during the transcytosis. After employing conventional imageology and pharmacology strategies to verify the result of proteomic analysis, we mapped a comprehensive intracellular transport network. Our study also revealed the merits of IPC analysis, which could readily elucidate the molecular mechanisms of transcytosis. Besides, the IPC proteins increased the uptake and stress response of endothelium, which was likely mediated by extracellular matrix and mitochondrion-related IPC proteins. Conclusion: The comprehensive proteomic analysis of IPC enabled tracing of transport pathways in epithelial cells as well as revealing the biological impact of nanoparticles on endothelium.
Recurrence After Resection of Pancreatic Ductal Adenocarcinoma
Authors: Terence M. Williams, Chris Crane, Karyn Goodman
Journal: JAMA Surgery (2020)

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Colorectal cancer molecular markers and subtypes in relation to disease survival
Authors: Amanda I Phipps, Peter T Campbell, Barbara Banbury, Daniel Buchanan, Andrew T Chan, Dallas English, Alton B Farris, Graham G Giles, Tabitha Harrison, Roger Milne, Polly A Newcomb, Martha L Slattery, Melissa Southey, Shuji Ogino, Ulrike Peters
Journal: Cancer Research (2018)
IgE-reactive proteins defined by 88 fish-allergic children, predicting the allergenicity of 66 Asia-Pacific fish species
Authors: T Ruethers, AC Taki, R Nugraha, S Karnaneedi, TT Cao, D Dai, T Shanmuganathan, M Leeming, S Nie, NA Williamson, SS Mehr, DE Campbell, AL Lopata
Journal: Allergy (2019)
18F-FDG PET/CT Findings in a Patient With Primary Mucinous Cystadenocarcinoma of the Breast
Authors: Yujing Hu, Congna Tian, Xinchao Zhang, Qiang Wei, Yanzhu Bian
Journal: Clinical Nuclear Medicine (2019)

Abstract A 50-year-old woman presented with a mass in the upper outer quadrant of her left breast, which proved to be a mucinous cystadenocarcinoma by biopsy. An 18 F-FDG PET/CT was performed for staging, which showed that the breast tumor was the only lesion with abnormal 18 F-FDG avidity. Breast-conserving surgery was performed following a negative sentinel lymph node biopsy of the left axilla, and primary mucinous cystadenocarcinoma of the breast was finally diagnosed.
Modulation of Biliary Cancer Chemo‐Resistance Through MicroRNA‐Mediated Rewiring of the Expansion of CD133+ Cells
Authors: Pietro Carotenuto, Somaieh Hedayat, Matteo Fassan, Vincenzo Cardinale, Andrea Lampis, Vincenza Guzzardo, Caterina Vicentini, Aldo Scarpa, Luciano Cascione, Daniele Costantini, Guido Carpino, Domenico Alvaro, Michele Ghidini, Francesco Trevisani, Robert Te Poele, Massimiliano Salati, Sofia Ventura, Georgios Vlachogiannis, Jens C. Hahne, Luke Boulter, Stuart J. Forbes, Rachel V. Guest, Umberto Cillo, Ian Said‐Huntingford, Ruwaida Begum, Elizabeth Smyth, Vasiliki Michalarea, David Cunningham, Lorenza Rimassa, Armando Santoro, Massimo Roncalli, Vladimir Kirkin, Paul Clarke, Paul Workman, Nicola Valeri, Chiara Braconi
Journal: Hepatology (2019)

Changes in single microRNA (miRNA) expression have been associated with chemo-resistance in biliary tract cancers (BTCs). However, a global assessment of the dynamic role of the microRNome has never been performed to identify potential therapeutic targets that are functionally relevant in the BTC cell response to chemotherapy.
A phase I/II study with a highly selective ALK inhibitor CH5424802 in ALK-positive non-small cell lung cancer (NSCLC) patients: Updated safety and efficacy results from AF-001JP.
Authors: Kazuhiko Nakagawa, Katsuyuki Kiura, Makoto Nishio, Takashi Seto, Makoto Maemondo, Akira Inoue, Toyoaki Hida, Nobuyuki Yamamoto, Hiroshige Yoshioka, Masao Harada, Yuichiro Ohe, Naoyuki Nogami, Kengo Takeuchi, Tadashi Shimada, Tomohiro Tanaka, Tomohide Tamura
Journal: Journal of Clinical Oncology (2013)

8033 Background: Anaplastic lymphoma kinase (ALK) is a constitutively activated tyrosine kinase in a subset of NSCLC with ALK fusion gene derived from chromosomal rearrangement. Previously, CH5424802, a highly selective, second-generation ALK inhibitor, has demonstrated clinically meaningful antitumor activity and a favorable toxicity profile (ESMO 2012). Here we report the updated results of this study. Methods: Patients (Pts) with ALK-positive NSCLC and no prior ALK inhibitor therapy were treated with CH5424802 at 300 mg bid until progressive disease or intolerable toxicity to investigate the efficacy and safety. Results: As of the cut-off date of Dec. 14, 2012, 58 pts have been treated with CH5424802: median age 49.5 years, M/F 25/33, ECOG PS 0/1 26/32, never-smoker 60.3%, ≥2 prior chemotherapy regimens 62%. Among the 46 pts in phase II part of this study, the overall response rate was 93.5% (95% CI: 82.1%, 98.6%) with 2 CRs and 41 PRs. Tumor shrinkage by 30% (PR) was achieved quickly with 65% occurring within 3 weeks of treatment and 87% within 6 weeks. With a median follow-up period of 12.6 months, 47/58 pts (40/46 pts in phase II part) were still on study treatment, and the median treatment duration has passed 10.3 months. The major treatment-related AEs were dysgeusia (21/58, 36%), rash, AST increased, blood bilirubin increased (19/58, 33% each), constipation and blood creatinine increased (17/58, 29% each), mostly grade 1-2. The major treatment-related grade 3 AEs were neutrophil count decreased (4/58, 7%). No grade 4 or fatal AEs were observed. Treatment-related visual disorders, vomiting and nausea were rare and mild. Conclusions: In patients with ALK-positive NSCLC but naïve to any ALK inhibitor therapy, treatment with CH5424802 demonstrated generally mild toxicity and lead to high response rate of 93.5% and durable treatment beyond 10 months, expecting that treatment duration can be longer than that of crizotinib. CH5424802 is therefore a promising new ALK inhibitor for NSCLC. Clinical trial information: JapicCTI-101264.
Cartilage-binding antibodies induce pain through immune complex–mediated activation of neurons
Authors: Alex Bersellini Farinotti, Gustaf Wigerblad, Diana Nascimento, Duygu B. Bas, Carlos Morado Urbina, Kutty Selva Nandakumar, Katalin Sandor, Bingze Xu, Sally Abdelmoaty, Matthew A. Hunt, Kristina Ängeby Möller, Azar Baharpoor, Jon Sinclair, Kent Jardemark, Johanna T. Lanner, Ia Khmaladze, Lars E. Borm, Lu Zhang, Fredrik Wermeling, Mark S. Cragg, Johan Lengqvist, Anne-Julie Chabot-Doré, Luda Diatchenko, Inna Belfer, Mattias Collin, Kim Kultima, Birgitta Heyman, Juan Miguel Jimenez-Andrade, Simone Codeluppi, Rikard Holmdahl, Camilla I. Svensson
Journal: The Journal of Experimental Medicine (2019)

Rheumatoid arthritis-associated joint pain is frequently observed independent of disease activity, suggesting unidentified pain mechanisms. We demonstrate that antibodies binding to cartilage, specific for collagen type II (CII) or cartilage oligomeric matrix protein (COMP), elicit mechanical hypersensitivity in mice, uncoupled from visual, histological and molecular indications of inflammation. Cartilage antibody-induced pain-like behavior does not depend on complement activation or joint inflammation, but instead on tissue antigen recognition and local immune complex (IC) formation. smFISH and IHC suggest that neuronal Fcgr1 and Fcgr2b mRNA are transported to peripheral ends of primary afferents. CII-ICs directly activate cultured WT but not FcR{\gamma} chain-deficient DRG neurons. In line with this observation, CII-IC does not induce mechanical hypersensitivity in FcR{\gamma} chain-deficient mice. Furthermore, injection of CII antibodies does not generate pain-like behavior in FcR{\gamma} chain-deficient mice or mice lacking activating Fc{\gamma}Rs in neurons. In summary, this study defines functional coupling between autoantibodies and pain transmission that may facilitate the development of new disease-relevant pain therapeutics.
Clinical trial design in small cell lung cancer: Surrogate endpoints and statistical evolution.
Authors: Myles Nickolich, Pingfu Fu, Shahab Babakoohi, Afshin Dowlati
Journal: Journal of Clinical Oncology (2012)

7087 Background: Small cell lung cancer (SCLC) is a devastating disease for which little recent therapeutic advance has been achieved. SCLC trial design and reporting may have an impact on the interpretation of studies conducted. Furthermore the use of surrogate endpoints in SCLC has not been explored. Methods: Through examining all phase II and III SCLC trials published in the Journal of Clinical Oncology (8,471 patients from 66 trials between 1983-2010), we examined how SCLC trial reporting and design has evolved, determining if the type I error, power, and sample size calculations were provided. We assessed primary endpoints for all trials and sought to discover if response rate (RR) or progression-free survival (PFS) correlated with overall survival (OS). We analyzed response and survival outcomes for associations using Pearson correlation coefficient and differences between data groups by ANOVA followed by Tukey’s multiple comparison procedure. Results: There were increased reporting trends of statistical design in power (16.7% in 1986-1996 to 77.8% of trials in 2006-2010 [p=0.001]) and type I error (22.2% in 1986-1996 to 72.2% in 2006-2010 [p=0.005]). 72.2% of trials published in 1986-1996 failed to report a primary endpoint whereas only 5.56% of trials in 2006-2010 failed to do so (p=0.004). Of phase II trials, primary endpoint was identified as RR in 65%, OS in 25%, and PFS in 10% (p&lt;0.0001). There is a strong correlation between RR and both PFS (p=0.013) and OS (p=0.012) in extensive-stage disease (ED) but not limited-stage disease (LD) (p=0.978 for PFS, p=0.193 for OS). This correlation is for partial response rate (pRR) but not complete response rate. RR (p=0.029) exhibits a negative trend over time with a dramatic and significant decrease in RR across all studies starting in 2005. A strong positive correlation exists between PFS and OS for LD (p=0.036) and ED (p=0.058). We found no change in median overall survival (p=0.383). Conclusions: Over time there has been improvement in reporting the essential statistical data for proper interpretation of SCLC trials. No change in survival was seen over the past 28 years. RR should be evaluated as a surrogate endpoint for OS in ED but not LD. pRR correlates with OS and PFS in both LD and ED.
Annals Graphic Medicine - More Than Suturing Wounds
Authors: Annie Zhu, Arnav Agarwal
Journal: Annals of Internal Medicine (2020)

Web Exclusives7 January 2020Annals Graphic Medicine - More Than Suturing WoundsFREEAnnie Zhu, BHSc and Arnav Agarwal, MDAnnie Zhu, BHScSearch for more papers by this author and Arnav Agarwal, MDSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G19-0063 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G19-0063.Author/Illustrator Information: Annie Zhu is a medical student at the University of Toronto. She is interested in sequential art and exploring narratives in medicine. Her other illustrations and comics can be found at cazezhu.carbonmade.com. Dr. Arnav Agarwal is an internal medicine resident at the University of Toronto. He is passionate about clinical epidemiology research, health advocacy and allyship, and medical curriculum development and has a deep appreciation for art and narrative writing as media for reflection and advocacy. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 7 January 2020Volume 172, Issue 1Page: W28KeywordsClinical epidemiologyConflicts of interestDisclosureHealth care ePublished: 7 January 2020 Issue Published: 7 January 2020 Copyright & PermissionsCopyright © 2020 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...