tbuckley/cabot-search huggingface dataset:
RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies
Authors: Benjamin J. Solomon, Lavinia Tan, Jessica J. Lin, Stephen Q. Wong, Sebastian Hollizeck, Kevin Ebata, Brian B. Tuch, Satoshi Yoda, Justin F. Gainor, Lecia V. Sequist, Geoffrey R. Oxnard, Oliver Gautschi, Alexander Drilon, Vivek Subbiah, Christine Khoo, Edward Y. Zhu, Michele Nguyen, Dahlia Henry, Kevin R. Condroski, Gabrielle R. Kolakowski, Eliana Gomez, Joshua Ballard, Andrew T. Metcalf, James F. Blake, Sarah-Jane Dawson, Wayne Blosser, Louis F. Stancato, Barbara J. Brandhuber, Steve Andrews, Bruce G. Robinson, S. Michael Rothenberg
Journal: Journal of Thoracic Oncology (2020)

IntroductionNovel rearranged in transfection (RET)-specific tyrosine kinase inhibitors (TKIs) such as selpercatinib (LOXO-292) have shown unprecedented efficacy in tumors positive for RET fusions or mutations, notably RET fusion-positive NSCLC and RET-mutated medullary thyroid cancer (MTC). However, the mechanisms of resistance to these agents have not yet been described.MethodsAnalysis was performed of circulating tumor DNA and tissue in patients with RET fusion-positive NSCLC and RET-mutation positive MTC who developed disease progression after an initial response to selpercatinib. Acquired resistance was modeled preclinically using a CCDC6-RET fusion-positive NSCLC patient-derived xenograft. The inhibitory activity of anti-RET multikinase inhibitors and selective RET TKIs was evaluated in enzyme and cell-based assays.ResultsAfter a dramatic initial response to selpercatinib in a patient with KIF5B-RET NSCLC, analysis of circulating tumor DNA revealed emergence of RET G810R, G810S, and G810C mutations in the RET solvent front before the emergence of clinical resistance. Postmortem biopsy studies reported intratumor and intertumor heterogeneity with distinct disease subclones containing G810S, G810R, and G810C mutations in multiple disease sites indicative of convergent evolution on the G810 residue resulting in a common mechanism of resistance. Acquired mutations in RET G810 were identified in tumor tissue from a second patient with CCDC6-RET fusion-positive NSCLC and in plasma from patients with additional RET fusion-positive NSCLC and RET-mutant MTC progressing on an ongoing phase 1 and 2 trial of selpercatinib. Preclinical studies reported the presence of RET G810R mutations in a CCDC6-RET patient-derived xenograft (from a patient with NSCLC) model of acquired resistance to selpercatinib. Structural modeling predicted that these mutations sterically hinder the binding of selpercatinib, and in vitro assays confirmed loss of activity for both anti-RET multikinase inhibitors and selective RET TKIs.ConclusionsRET G810 solvent front mutations represent the first described recurrent mechanism of resistance to selective RET inhibition with selpercatinib. Development of potent inhibitor of these mutations and maintaining activity against RET gatekeeper mutations could be an effective strategy to target resistance to selective RET inhibitors.
Soft and Ion‐Conducting Materials in Bioelectronics: From Conducting Polymers to Hydrogels
Authors: Manping Jia, Marco Rolandi
Journal: Advanced Healthcare Materials (2020)

Abstract Bioelectronics devices that directly interface with cells and tissue have applications in neural and cardiac stimulation and recording, electroceuticals, and brain machine interfaces for prostheses. The interface between bioelectronic devices and biological tissue is inherently challenging due to the mismatch in both mechanical properties (hard vs soft) and charge carriers (electrons vs ions). In addition to conventional metals and silicon, new materials have bridged this interface, including conducting polymers, carbon‐based nanomaterials, as well as ion‐conducting polymers and hydrogels. This review provides an update on advances in soft bioelectronic materials for current and future therapeutic applications. Specifically, this review focuses on soft materials that can conduct both electrons and ions, and also deliver drugs and small molecules. The future opportunities and emerging challenges in the field are also highlighted.
A National Survey of the Frequency of Drug Company Detailing Visits and Free Sample Closets in Practices Delivering Primary Care
Authors: Ashleigh C. King, Lisa M. Schwartz, Steven Woloshin
Journal: JAMA Internal Medicine (2020)

ducted with similar methods.The mean duration of leave for staff (6.0 weeks) was less than that for faculty (8.6 weeks) and similar to that for residents (5.7 weeks). 1,2At 3 institutions, leave policies differed by staff titles, highlighting further institutional disparities among employees.Because administrative staff are among the lowest-paid individuals at medical schools, they are at increased risk of attrition when family leave is unpaid. 3 The study's generalizability may be limited because we surveyed only 12 schools.We focused on institutional policies for paid leave, but actual salary coverage may differ from written policies.State-sponsored leave and individual departmental leave policies were not assessed.Policy changes made after confirmation in summer 2019 may not be reflected.We used medical school faculty and residents as the relevant comparators for administrative staff; however, these are not equivalent positions at other employers in the community.That said, from the perspective of promoting equity in the workforce, it can be argued that family leave policies should be adequate and uniform across organizations, regardless of the type or tenure of employment.Despite the benefits of paid childbearing leave for both mother 4 and child, 5 as well as support by the American Academy of Pediatrics of proposed legislation requiring 12 weeks of paid leave, 6 there is no federal mandate for employers to provide paid childbearing leave.Given that administrative staff are critical to the functioning of medical schools, instituting more generous childbearing and family leave policies would be an opportunity for the medical profession to lead by example in promoting equity and wellbeing in the workforce.
A phase IB study of ipilimumab with peginterferon alfa-2b in patients with unresectable melanoma.
Authors: Ragini Reiney Kudchadkar, Geoffrey Thomas Gibney, Jeffrey Weber, Ann Chen, Kim Smith, Stephanie Merek
Journal: Journal of Clinical Oncology (2013)

9079 Background: Peginterferon alfa-2b (Sylatron) as adjuvant therapy has been shown to benefit patients with high-risk resected melanoma and some interferon studies have shown that the induction of autoantibodies may correlate with benefit. Ipilimumab (IPI, Yervoy) is a fully human anti-CTLA-4 antibody that induces autoimmune toxicity that in some cases appears to correlate with clinical benefit. This study was performed to assess whether ipilimumab can be safely administered with peginterferon alfa-2b. Methods: This study combined IPI at 3mg/kg every 3 weeks for 4 doses along with concurrent peginterferon alfa-2b at 3 mcg/kg weekly for up to 156 weeks or until disease progression, unacceptable toxicity or patient decision to discontinue. The study was designed to obtain toxicity, tolerability and autoimmune antibody data and to define a well-tolerated dose of the combination. Results: Median age was 61 with 9 female and 8 male subjects. There were 3 patients (pts) with partial responses, 1 stable disease, and 6 with progressive disease in 10 pts evaluable for response thus far. Six pts have not yet completed cycle 1 and therefore are not evaluable for response at the time of this publication but will be presented. One pt withdrew consent prior to finishing cycle 1. Toxicities from peginterferon alfa-2b 3mcg/kg were dose-limiting with 7 pts requiring dose reduction in peginterferon alfa-2b secondary to toxicity. The Grade 3 events leading to dose reductions were nausea and vomiting, leucopenia, dehydration, and hyponatremia. peginterferon alfa-2b was dose reduced to 2 mcg/kg weekly in future pts after these toxicities were noted. No Grade 3 or 4 toxicities attributable to ipilimumab have occurred thus far. No Grade 3 or 4 events have been noted to date in the10 pts initiated at 2 mcg/kg of peginterferon alfa-2b. There was no significant change in the presence autoantibodies (ANA, anti-double stranded DNA, antithyroglobulin, antimicrosomal antibodies, and anticardiolipin antibodies) between responders and non-responders in the evaluable pts. Conclusions: Peginterferon alfa-2b added to IPI results in an excellent response rate in this small population. Peginterferon alpha-2b at 2 mcg/kg weekly with IPI at 3 mg/kg every 3 weeks appears well-tolerated and the combination warrants further exploration. Clinical trial information: NCT01496807.
A Disclosure Form for Work Submitted to Medical Journals
Authors: Darren B. Taichman, Joyce Backus, Christopher Baethge, Howard Bauchner, Annette Flanagin, Fernando Florenzano, Frank A. Frizelle, Fiona Godlee, Laragh Gollogly, Abraham Haileamlak, Sung-Tae Hong, Richard Horton, Astrid James, Christine Laine, Pamela W. Miller, Anja Pinborg, Eric J. Rubin, Peush Sahni
Journal: JAMA (2020)

Many factors, including professional and personal relationships and activities, can influence the design, conduct, and reporting of the clinical science that informs health care decisions.The potential for conflict of interest exists when these relationships and activities may bias judgment. 1Many stakeholders-editors, peer reviewers, clinicians, educators, policy makers, patients, and the public-rely on the disclosure of authors' relationships and activities to inform their assessments.Trust in the transparency, consistency, and completeness of these disclosures is essential.Ten years ago, the International Committee of Medical Journal Editors (ICMJE) adopted the "ICMJE Form for the Disclosure of Potential Conflicts of Interest" as a uniform mechanism for collecting and reporting authors' relationships and activities that readers might consider relevant to a published work. 2 The goal was to avoid the confusion (and often ensuing controversy) created when journals vary in how they collect and report this information.We believe a uniform disclosure form has been helpful, but problems remain.First, the software supporting the current form is increasingly problematic, making its use difficult or impossible for an increasing number of authors.More important, however, is that many authors and readers misunderstand, misapply, or misinterpret the disclosures.Although some individuals violate the public trust by purposefully hiding relevant relationships and activities, we believe most authors are committed to transparent reporting and consider it as vital to the advancement of clinical science.Nonetheless, disagreement, confusion, and controversy regarding authors' disclosures arise when opinions differ over which relationships and activities to report.An author might not report an item that others deem important because of a difference in opinion regarding what is "relevant," confusion over definitions, or a simple oversight.Some authors may be concerned that readers will interpret the listing of any item as a "potential conflict of interest" as indicative of problematic influence and wrongdoing, a concern often raised regarding the requirement to report publicly funded grants.For their part, some readers fail to recognize that their own relationships and activities influence how they assess the work of others and what they deem to be a "conflict" for others or themselves.We propose several changes to the ICMJE disclosure form to help address these issues.
‘My hip is damaged’: a qualitative investigation of people seeking care for persistent hip pain
Authors: Beatriz I R de Oliveira, Anne Julia Smith, Peter P B O'Sullivan, Samantha Haebich, Daniel Fick, Riaz Khan, Samantha Bunzli
Journal: British Journal of Sports Medicine (2020)

Clinicians who use the biopsychosocial approach to manage musculoskeletal pain disorders aim to understand how patients make sense of their symptoms. Treatment includes targeting the negative beliefs and coping responses that can lead to progressive pain and disability. We aimed to explore how people seeking care for persistent hip pain and disability make sense of their symptoms.Cross-sectional qualitative study. People were eligible if they were aged ≥18 years, were consulting an orthopaedic surgeon for persistent hip pain and offered a non-surgical intervention. Data were collected through interviews that explored patients' beliefs about the identity (diagnosis), causes, consequences, timeline and controllability of their symptoms, their strategies to cope with pain and their experiences in seeking healthcare. Transcribed interview data were analysed thematically using a framework approach.Sixteen people (median age=51, range=33-73 years; median duration hip pain=3 years, range=3 months-20 years) participated. Most participants (10/16) believed their pain was caused by an exercise-related injury. Because of the results of imaging and interactions with healthcare professionals, all participants believed they had damaged hip structures. All described ineffective strategies to manage their pain and multiple failed treatments. For many (7/16), a lack of control over symptoms threatened their physical and mental health.The way participants with persistent hip pain and disability made sense of their symptoms contributed to them avoiding physical activity, and it impaired their sleep, emotional well-being and physical health.
Writing outpatient letters to patients
Authors: Hugh Rayner, Martha Hickey, Ian Logan, Nigel Mathers, Peter Rees, Robina Shah
Journal: BMJ (2020)

### What you need to know

In many countries (including the UK and Australia) it is still common practice for hospital doctors to write letters to patients’ general practitioners (GPs) following outpatient consultations, and for patients to receive copies of these letters. However, our experience suggests that hospital doctors who have changed their practice to include writing letters directly to patients have more patient centred consultations and experience smoother handovers with other members of their multidisciplinary teams.1 Writing letters to patients is also being used as an educational tool for improving medical students’ empathy and rapport with patients.23

A large proportion of patient complaints and litigation originate from poor communication.4 Correspondence that is delayed, not patient centred, and lacking information has been highlighted as a risk to patient safety.5 Writing prompt letters directly to patients can help reduce these risks.6

In this article, we offer practical advice on how to construct letters to be sent directly to patients, and suggest how these letters might encourage collaborative working centred on patients’ needs and wishes.

Evidence on this topic is limited but includes a small number of quality improvement studies looking at the impact of clinic doctors writing letters directly to patients or to the parents of paediatric patients, and these have consistently shown positive outcomes.

Four of us—Hugh Rayner, Nigel Mathers, Peter Rees, and Robina Shah—contributed to the 2018 guidelines on writing outpatient letters to patients for the Academy of Medical Royal Colleges (AoMRC) in the UK.7 These guidelines were based on our personal …
Pediatric Implications of Opioid-Specific Parental Drug Use
Authors: Vineet Pasam Reddy, Abhimanyu S. Ahuja
Journal: JAMA Pediatrics (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Application of an ex-vivo drug sensitivity platform towards achieving complete remission in a refractory T-cell lymphoma
Authors: Sanjay de Mel, Masturah B. M. Rashid, Xi Yun Zhang, Jasmine Goh, Chun Tsu Lee, Li Mei Poon, Esther H. L. Chan, Xin Liu, Wee Joo Chng, Yen Lin Chee, Joanne Lee, Yi Ching Yuen, Jing Quan Lim, Burton K. H. Chia, Yurike Laurensia, DaChuan Huang, Wan Lu Pang, Daryl Ming Zhe Cheah, Esther Kam Yin Wong, Choon Kiat Ong, Tiffany Tang, Soon Thye Lim, Siok Bian Ng, Soo Yong Tan, Hoi-Yin Loi, Lip Kun Tan, Edward K. Chow, Anand D. Jeyasekharan
Journal: Blood Cancer Journal (2020)
MAIT Cells in Health and Disease
Authors: Nicholas M. Provine, Paul Klenerman
Journal: Annual Review of Immunology (2020)

Mucosal-associated invariant T (MAIT) cells have been attracting increasing attention over the last few years as a potent unconventional T cell subset. Three factors largely account for this emerging interest. Firstly, these cells are abundant in humans, both in circulation and especially in some tissues such as the liver. Secondly is the discovery of a ligand that has uncovered their microbial targets, and also allowed for the development of tools to accurately track the cells in both humans and mice. Finally, it appears that the cells not only have a diverse range of functions but also are sensitive to a range of inflammatory triggers that can enhance or even bypass T cell receptor-mediated signals-substantially broadening their likely impact in health and disease. In this review we discuss how MAIT cells display antimicrobial, homeostatic, and amplifier roles in vivo, and how this may lead to protection and potentially pathology.
Variation in Tdap and Influenza Vaccination Coverage Among Pregnant Women by Insurance Type — Florida, 2016–2018
Authors: Taylor A. Merritt, Sonja A. Rasmussen, Melissa A. Bright, Dikea Roussos-Ross, Shireen Madani Sims, Matthew J. Gurka, Lindsay A. Thompson
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

Infants are at increased risk for pertussis-associated morbidity and mortality, and pregnant women and their infants are more likely than other patient populations to experience severe influenza-related illness (1,2). The Advisory Committee on Immunization Practices (ACIP) recommends that all women receive the tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine during each pregnancy, preferably during the early part of gestational weeks 27-36 (3). ACIP also recommends that women who are or might be pregnant during the influenza season receive the inactivated influenza vaccine at any time during pregnancy (4). Despite these recommendations, coverage with Tdap and influenza vaccines during pregnancy has been low, with approximately one half of women receiving each vaccine and only one third receiving both, based on a survey during March-April 2019 (5). Data obtained through a retrospective chart review of randomly selected pregnant women who delivered at the University of Florida Health Shands Hospital in Gainesville, Florida, from January 1, 2016, to December 31, 2018, were analyzed to assess vaccination coverage by insurance type. Because the Florida Medicaid policy at that time did not cover these vaccines during pregnancy, the hospital system offered Tdap and influenza vaccines at no additional cost to mothers during the immediate postpartum hospital stay. Among 341 women, 68.6% of privately insured and 13.4% with Medicaid received Tdap during pregnancy, and among 316 women, 70.4% of privately insured and 35.6% with Medicaid received influenza vaccine during pregnancy. Many women, especially those with Medicaid, were vaccinated in the immediate postpartum period, when vaccination was available at no cost, increasing Tdap vaccination rates to 79.3% for privately insured and 51.7% for women with Medicaid; influenza vaccination rates rose to 72.0% for privately insured and 43.5% for women with Medicaid. These data suggest that the state Medicaid policy to not cover these vaccines during pregnancy might have significantly reduced coverage among its enrollees.
In plantar fasciitis, corticosteroid injections and placebo do not differ for reducing pain at ≤ 12 weeks
Authors: Nancy J. Heisel
Journal: Annals of Internal Medicine (2020)

ACP Journal Club21 January 2020In plantar fasciitis, corticosteroid injections and placebo do not differ for reducing pain at ≤ 12 weeksNancy J. Heisel, MDNancy J. Heisel, MDAdventist Medical Group, Portland, Oregon, USA (N.J.H.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJ202001210-008 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationWhittaker GA, Munteanu SE, Menz HB, et al. Corticosteroid injection for plantar heel pain: a systematic review and meta-analysis. BMC Musculoskelet Disord. 2019;20:378. https://pubmed.ncbi.nlm.nih.gov/31421688Clinical Impact RatingsGIM/FP/GP: References1 Nahin RL. Prevalence and pharmaceutical treatment of plantar fasciitis in United States adults. J Pain. 2018;19:885-96. [PMID: 29597082] Google Scholar2 Schneider HP, Baca JM, Carpenter BB, et al. American College of Foot and Ankle Surgeons clinical consensus statement: diagnosis and treatment of adult acquired infracalcaneal heel pain. J Foot Ankle Surg. 2018;57:370-81. [PMID: 29284574] Google Scholar Author, Article, and Disclosure InformationAffiliations: Adventist Medical Group, Portland, Oregon, USA (N.J.H.)Disclosures: The commentator has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M19-2922.This article was published at Annals.org on 7 January 2020. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 21 January 2020Volume 172, Issue 2Page: JC8KeywordsAnestheticsBloodBody mass indexDatabasesDrugsGrading of Recommendations Assessment Development and EvaluationMedical risk factorsResearch designSystematic reviews ePublished: 21 January 2020 Issue Published: 21 January 2020 Copyright & PermissionsCopyright © 2020 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...