tbuckley/cabot-search huggingface dataset:
Advancing the beneficial use of machine learning in health care and medicine: Toward a community understanding
Authors: Linda Nevin
Journal: PLoS Medicine (2018)

Due to the abundance of health data and growing computational power, machine learning (ML) is engaging health researchers in a process of discovery around developing data-driven algorithms to make clinically reliable predictions.ML has the potential to provide effective tools to improve outcomes and reduce costs in health care, and the clinical community should partake in developing and evaluating these discoveries.However, if misguided applications are to be avoided, methodological savvy will be needed to develop, interpret and implement ML in medicine [1,2].In preparing PLOS Medicine's Special Issue (SI) on Machine Learning in Health and Biomedicine, Guest Editors Atul Butte, Suchi Saria, and Aziz Sheikh, and the PLOS Medicine Editors, have identified two principles in the design and reporting of ML studies that we believe should guide researchers in advancing the beneficial use of ML in healthcare and medicine.These principles, which also inform PLOS Medicine's editorial priorities for manuscript submissions in this field, require first, that models derived through ML are demonstrably fit for their stated clinical purpose, and second, that researchers undertake and report appropriate efforts to validate these models in external datasets. Fit-for-purpose performanceAn ML model need not be ready for off-the-shelf, practice-changing implementation to make a valuable contribution, but must achieve a clear purpose.The current SI includes reports on ML approaches that have undergone retrospective validation and are now ready for prospective testing, ML at early stages of validation, and head-to-head comparisons between standard epidemiological and ML approaches that suggest future directions without themselves establishing clinical utility.The articles vary widely in the intended application or "use cases" for their models.In a study from Soo-Jin Kang and colleagues, ML deploying imaging data from intravascular coronary angiography was used to diagnose coronary ischemia without a more invasive measurement-fractional flow reserve-that is currently the diagnostic standard [3].The authors were not trying to challenge the standard of care, but to improve diagnosis when resource constraints or clinical indications make fractional flow reserve impractical or unsuitable.For applications intended to provide pragmatic options for nonideal circumstances, model performance can be benchmarked against current practice rather than recommended practice, as long as the limitations of the advance are clear to readers.Early research planning should consider clinically acceptable performance characteristics for the targeted application, and a clear description of its intended use-and inappropriate
Inhibition of VEGF-C-induced VEGFR-3 activity and lymphatic endothelial cell function by the tyrosine kinase inhibitor AZD2171
Authors: Caroline Heckman, Tanja Holopainen, Maria Wirzenius, Salla Keskitalo, Michael Jeltsch, Stephen Wedge, Juliane Jurgensmeier
Journal: Cancer Research (2007)

2999  Solid tumors express a range of growth factors required to sustain their growth and promote their dissemination. Among these factors is vascular endothelial growth factor-A (VEGF-A), the key angiogenic stimulant, and VEGF-C, a primary mediator of lymphangiogenesis. Small molecule tyrosine kinase inhibitors can prevent VEGF signaling activity by targeting the VEGF receptors and are an effective approach to impede tumor progression. The indole-ether quinazoline AZD2171 is a highly potent ATP-competitive inhibitor of VEGFR-2 (KDR) kinase, with additional activity against VEGFR-1 (Flt-1) and -3 (Flt-4), that has been shown in experimental models to prevent VEGF-A-induced angiogenesis and primary tumor growth (Wedge et al.Cancer Res 2005;65:4389-4400). For these studies we wished to further assess the ability of AZD2171 to inhibit VEGFR-3 and its associated functions. Upon binding its ligands VEGF-C or -D, VEGFR-3 becomes activated with the resulting signaling cascade eventually translated into increased proliferation, survival and migration of lymphatic and blood vascular endothelial cells. At concentrations of ≤1 nM AZD2171 inhibited VEGFR-3 phosphorylation in porcine aortic endothelial cells selectively expressing the human receptor, and in human dermal microvascular endothelial cells (HDMVECs). In HDMVECs, AZD2171 prevented phosphorylation of signaling molecules downstream of VEGFR-2 and -3, ERK1/2, Akt and CREB, induced by the VEGFR-2 and -3-specific ligands VEGF-E and -C156S, respectively. Additionally, AZD2171 blocked VEGF-E- and -C156S-induced proliferation of both lymphatic and blood vascular endothelial cells at similar concentrations, and prevented ligand-induced endothelial cell cord formation in a Matrigel assay. The effects of AZD2171 on VEGF-C-induced lymphangiogenesis are currently being assessed in vivo. These studies, together with previous results, not only demonstrate that AZD2171 may be an effective means of preventing tumor progression by inhibition of VEGFR-2 activity and angiogenesis, but may also prevent further tumor spread by inhibiting VEGFR-3 activity and, consequently, lymphangiogenesis.
Juvenile Nasal Angiofibroma on 68Ga-PSMA PET/CT
Authors: Pirabu Sakthivel, Arun Prashanth, Alok Thakar, Rajeev Kumar, Rakesh Kumar
Journal: Clinical Nuclear Medicine (2018)

The prostate-specific membrane antigen (PSMA) is highly expressed in prostatic cancer. However, PSMA expression is also noted in various benign and malignant nonprostatic neoplasms in the endothelial cells of tumor-associated neovasculature. We performed Ga-PSMA PET/CT in a 14-year-old boy with juvenile nasal angiofibroma (JNA) to explore its theranostic potential. The scan revealed high uptake in the lesion. Performance of PSMA PET/CT in JNA opens up new frontiers with respect to radiological staging, early recurrence identification, and perhaps even radioligand therapy of residual/recurrent JNAs in the future.
Frontline oncology care team primary palliative symptom guideline education, the oncology care model, and emergency department visits.
Authors: Susan McInnes, Cheryl M Carrino, Laura Shoemaker
Journal: Journal of Clinical Oncology (2018)

143 Background: The Oncology Care Model (OCM) is a novel 5-year quality-based Oncology payment and care delivery program established by the Centers for Medicare &amp; Medicaid Service in 2016. OCM prioritizes high-quality, coordinated care for patients undergoing chemotherapy (chemo pts.) Participating centers provide augmented services to enhance care and meet quality goals. Challenging symptoms (sxs) are common among chemo pts and may lead to hospitalization and decreased quality of life. Specialist palliative care teams are not able to see all chemo pts with active sxs. Front line oncology care teams (FLC) need education on primary palliative sx management. Methods: Cleveland Clinic Taussig Cancer Institute is one of 181 practices voluntarily participating in OCM. Locations include main campus and 5 regional cancer offices with 100 oncologists caring for about 4,000 chemotherapy patients annually. Our OCM team engaged Oncology (Onc) and Palliative Medicine (PM) providers to standardize sx management. Education was provided to FLC of all disciplines. Electronic record analytics were used to determine emergency department (ED) utilization. Results: A multidisciplinary team of Onc and PM experts developed guidelines for 4 common sxs (chemotherapy-induced neuropathy, persistent cancer pain, nausea/vomiting and constipation. Guidelines were approved by key Onc and PM staff and made available to all providers online. There were 4 educational sessions for FLCs to all sites in 2017. Urgent sx outpatient appointment slots were created in oncology offices to address uncontrolled sx. From Dec 2017 to May 2018, ED visits for all cancer patients at main campus decreased from 500/month to 453/month (9.4%.) Reductions in ED visits were also seen at 2 hospitals adjacent to regional cancer centers (16% and 6%.) Conclusions: OCM participation provided an opportunity to improve care quality at our institution. Primary palliative sx guidelines were successfully developed by an interdisciplinary team and disseminated to FLC. Urgent sx management appointments were made available in oncology offices. These interventions coincided with a reduction in ED visits for all cancer patients.
Transmembrane domain-mediated Lck association underlies bystander and costimulatory ICOS signaling
Authors: Zurong Wan, Xingxing Shao, Xingyu Ji, Lihui Dong, Jiacheng Wei, Zhuqing Xiong, Wanli Liu, Hai Qi
Journal: Cellular and Molecular Immunology (2018)

The B7-family inducible costimulator (ICOS) activates phosphoinositide-3 kinase (PI3K) and augments calcium mobilization triggered by the T-cell receptor (TCR). We surprisingly found that the entire cytoplasmic domain of ICOS is dispensable for its costimulation of calcium mobilization. This costimulatory function relies on the unique transmembrane domain (TMD) of ICOS, which promotes association with the tyrosine kinase Lck. TMD-enabled Lck association is also required for p85 recruitment to ICOS and subsequent PI3K activation, and Lck underlies both the bystander and costimulatory signaling activity of ICOS. TMD-replaced ICOS, even with an intact cytoplasmic domain, fails to support TFH development or GC formation in vivo. When transplanted onto a chimeric antigen receptor (CAR), the ICOS TMD enhances interactions between T cells and antigen-presenting target cells. Therefore, by revealing an unexpected function of the ICOS TMD, our study offers a new perspective for the understanding and potential application of costimulation biology.
The feasibility of an inpatient intervention to improve end-of-life care in gynecologic oncology patients.
Authors: Allison Puechl, Stephanie Lim, Tracy Truong, Laura Havrilesky, Brittany Anne Davidson
Journal: Journal of Clinical Oncology (2018)

69 Background: Unscheduled hospitalizations in patients with advanced cancer predicts &lt; 6 month median survival. Patients with cancer hospitalized near the end of life (EOL) often receive aggressive treatments without survival advantages and have poor quality-of-life. EOL discussions and palliative care (PC) services reduce aggressive care. Methods: An intervention was designed to decrease aggressive EOL care in Gynecologic Oncology (GO) inpatients at a high risk for death within 6 months. Inclusion criteria were advanced gynecologic cancer and 1 of the following: bowel obstruction, failure to thrive, dehydration, cancer-related pain, malignant pleural effusion or ascites, or PCN management. Patients were identified by the care team on admission. An independent auditor assessed if patients were appropriately identified. Eligible patients received a 3-part high risk Gynecologic Oncology (HR-GO) bundle: 1) PC consult, 2) goals of care (GOC) conversation ≤ 48 hours of admission, and 3) PC follow-up within 2 weeks of discharge. Data was collected through chart review. Barriers to bundle implementation were identified. Results: 83 eligible patients were admitted between 8/2017-4/2018. 38 patients (46%) had multiple hospital admissions. 41 patients (49%) received the entire bundle during at least one hospital admission. During their 1st hospital admission, 30% of patients received all 3 parts of the HR-GO bundle. Among those who did not receive the entire bundle, 43% had two components missing. PC follow-up was the most commonly missed component, followed by a GOC conversation within 48 hours of admission. As identified by the auditor, twenty percent of eligible patients were not placed into the study cohort during their first hospital admission. Two barriers to bundle implementation were identified:1) the dependence on care team members to identify high-risk patients and 2) the avoidance of needed GOC discussions when patient’s 1° attending was unavailable. Conclusions: The implementation of an inpatient intervention to decrease aggressive EOL care in GO patients is feasible however barriers must be addressed. Currently work on an automated system to identify patients for intervention is ongoing.
Discharge Home From Critical Care: Comparing Different Healthcare Systems—Reply
Authors: Henry T. Stelfox, Daniel J. Niven, Kirsten M. Fiest
Journal: JAMA Internal Medicine (2018)

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Association of Psychotic Experiences With Subsequent Risk of Suicidal Ideation, Suicide Attempts, and Suicide Deaths
Authors: Kathryn Yates, Ulla Lång, Martin Cederlöf, Fiona Boland, Peter Taylor, Mary Cannon, Fiona McNicholas, Jordan DeVylder, Ian Kelleher
Journal: JAMA Psychiatry (2018)

<h3>Importance</h3> Recent research has highlighted that psychotic experiences are far more prevalent than psychotic disorders and associated with the full range of mental disorders. A particularly strong association between psychotic experiences and suicidal behavior has recently been noted. <h3>Objective</h3> To provide a quantitative synthesis of the literature examining the longitudinal association between psychotic experiences and subsequent suicidal ideation, suicide attempts, and suicide deaths in the general population. <h3>Data Sources</h3> We searched PubMed, Excerpta Medica Database, Cumulative Index to Nursing and Allied Health Literature, and PsycINFO from their inception until September 2017 for longitudinal population studies on psychotic experiences and subsequent suicidal ideation, suicide attempts, and suicide death. <h3>Study Selection</h3> Two authors searched for original articles that reported a prospective assessment of psychotic experiences and suicidal ideation, suicide attempts, or suicide death in general population samples, with at least 1 follow-up point. <h3>Data Extraction and Synthesis</h3> Two authors conducted independent data extraction. Authors of included studies were contacted for information where necessary. We assessed study quality using the Newcastle-Ottawa Quality Assessment Scale. We calculated pooled odds ratios using a random-effects model. A secondary analysis assessed the mediating role of co-occurring psychopathology. <h3>Main Outcomes and Measures</h3> Psychotic experiences and subsequent suicidal ideation, suicide attempts, and suicide death. <h3>Results</h3> Of a total of 2540 studies retrieved, 10 met inclusion criteria. These 10 studies reported on 84 285 participants from 12 different samples and 23 countries. Follow-up periods ranged from 1 month to 27 years. Individuals who reported psychotic experiences had an increase in the odds of future suicidal ideation (5 articles; n = 56 191; odds ratio [OR], 2.39 [95% CI,1.62-3.51]), future suicide attempt (8 articles; n = 66 967; OR, 3.15 [95% CI, 2.23-4.45]), and future suicide death (1 article; n = 15 049; OR, 4.39 [95% CI, 1.63-11.78]). Risk was increased in excess of that explained by co-occurring psychopathology: suicidal ideation (adjusted OR, 1.59 [95% CI, 1.09-2.32]) and suicide attempt (adjusted OR, 2.68 [95% CI, 1.71-4.21]). <h3>Conclusions and Relevance</h3> Individuals with psychotic experiences are at increased risk of suicidal ideation, suicide attempts, and suicide death. Psychotic experiences are important clinical markers of risk for future suicidal behavior.
Abiraterone Acetate for Nonmetastatic Castration-Resistant Prostate Cancer—The Forgotten Dance Partner?
Authors: Zachary Klaassen, Christopher J. D. Wallis, Neil E. Fleshner
Journal: JAMA Oncology (2018)

This Viewpoint uses results of randomized clinical trials to explore whether the use of abiraterone acetate plus prednisone is a cost-effective and appropriate treatment option for patients with nonmetastatic castration-resistant prostate cancer.
Prediction of Hepatocellular Carcinoma After Sustained Virological Responses Using Magnetic Resonance Elastography
Authors: Mayu Higuchi, Nobuharu Tamaki, Masayuki Kurosaki, Keiya Watakabe, Leona Osawa, Wan Wang, Mao Okada, Takao Shimizu, Kenta Takaura, Hitomi Takada, Shun Kaneko, Yutaka Yasui, Kaoru Tsuchiya, Hiroyuki Nakanishi, Jun Itakura, Yuka Takahashi, Namiki Izumi
Journal: Clinical Gastroenterology and Hepatology (2018)
Safety, tolerability, pharmacokinetic and escalating single doses of PCK3145 in patients with metastatic hormone resistant prostatic cancer (HRPC)
Authors: Helene Dulude, Chandra Panchal, Luc Daigneault, Seema Garde, Shafaat A. Rabbani, Richard Cowan, Anne Armstrong, Marcia Ruiz, Robert Hawkins
Journal: Cancer Research (2004)

4473  Introduction and Objective: Prostate secretory protein (PSP94) within PSA and PAP is one of the three most abundant protein in the seminal fluid. PSP94 has demonstrated antiproliferative and anti-tumour activity both in vitro and in vivo animal models. PCK3145 is a synthetic 15-mer peptide that matches the natural sequence of amino acids 31 to 45 of the prostate secretory protein (PSP94) and has demonstrated similar antiproliferative and antitumoral activity in the animal models PC3 and the Dunning rat R-3327 MLL. The mechanism of action of PCK3145 is not fully elucidated but may be related in part to induction of apoptosis. The primary objective of this clinical study was to evaluate the safety and the tolerability of PCK3145 administered i.v. over a range of potentially therapeutic doses. The secondary objectives were to determine the pharmacokinetic profile and to evaluate efficacy data using tumour assessments and tumour markers. Methods: Since October 2002, 12 metastatic Hormone Resistant Prostatic Cancer (HRPC) patients have been receiving treatment in this open-label, non-randomized, dose-escalation study in which successive cohorts of at least 4 patients are receiving 4 ascending doses (5, 20, 40 and 80 mg/m2) of PCK3145 (33-day cycle of treatment consisting of PCK3145 administration three times per week for 26 days, followed by a 7-day Post-Treatment Observation Period). The dose escalation is based on dose-limiting toxicity (DLT). Results: Preliminary characteristics (n = 8) are that the median age is 67 y (53-75) and the median time from HRPC to enrolment is 12.5 months (0.7-34). The Karnofsky Performance Status, remained high. The majority of the patients received hormonal therapy, had radiotherapy and TURP (Transurethral Prostatectomy). Sites of disease were mainly bone and lymph node. Serious Adverse Events (SAEs) reported so far are all unlikely or unrelated to study drug. Preliminary results indicate that the half-life of PCK3145 is 20 minutes and tumor assessments suggest that the patients are having stable disease at least after one cycle. Some patients showed a decline in PSA levels (one of them by almost 50%). All patients who had plasma MMP-9 levels over 100 ug/L before treatment had reductions ranging from 34% to 90% after two cycles of treatment. In the other patients that had low levels of MMP-9 prior to treatment, they remained low and only increased in two cases when cancer relapse was deemed to have occurred. Conclusions: These clinical results are very interesting and suggest the potential role of PCK3145 in the intervention of the metastatic process. The marked reduction in plasma MMP-9 levels of patients receiving PCK3145 treatment clearly indicates a biochemical effect, and provides a potentially novel mechanism of action of this small molecule in these patients.
Health Research Priority Setting: The Duties of Individual Funders
Authors: Leah Pierson, Joseph Millum
Journal: The American Journal of Bioethics (2018)

The vast majority of health research resources are used to study conditions that affect a small, advantaged portion of the global population. This distribution has been widely criticized as inequitable and threatens to exacerbate health disparities. However, there has been little systematic work on what individual health research funders ought to do in response. In this article, we analyze the general and special duties of research funders to the different populations that might benefit from health research. We assess how these duties apply to governmental, multilateral, nonprofit, and for-profit organizations. We thereby derive a framework for how different types of funders should take the beneficiaries of research into account when they allocate scarce research resources.
Preventing overdiagnosis and the harms of too much sport and exercise medicine
Authors: Daniel J Friedman, Karim M Khan
Journal: British Journal of Sports Medicine (2018)

Do I really need this test, treatment or procedure? What are the downsides? What happens if I do nothing? And are there simpler, safer options? 

These four questions, promoted by Choosing Wisely Canada, featured prominently at the two 2018 conferences, Too Much Medicine in Helsinki, Finland (figure 1), and the sixth annual Preventing Overdiagnosis conference in Copenhagen, Denmark. Over 600 of the world’s leading researchers and thinkers in preventing overdiagnosis came together for two weeks in August 2018 to highlight the problems caused by medical excess and to identify evidence-informed practices to wind back the harms of too much medicine.



Figure 1 
You can review highlights from the Too Much Medicine symposium on Twitter  @TooMuchMed.



This education review aims to bring the sport and exercise medicine reader up to date on this topic. An expanded version with additional references and resources is provided in the online supplementary file.

### Supplementary data

[bjsports-2018-100039supp001.docx] 

Too many people are being overdiagnosed, leading to overtreatment and wasted resources that could be better spent preventing or treating genuine illness. While debates about its definition continue, narrowly defined, overdiagnosis refers to deviations, abnormalities, risk factors and pathologies that would never cause symptoms or early death. It relates to problems of overmedicalisation and disease mongering, resulting in what one keynote speaker described as a ‘tsunami of overtreatment’.

As a review in BMJ discovered1 (figure 2), many factors drive overdiagnosis and cause harm, including cultural beliefs that ‘more is better’, financial incentives, expanding disease definitions and lowering treatment thresholds. While clinicians have been, and will forever be, challenged to balance Hippocratic notions of beneficence and non-maleficence, the scales are heavily tipped by the underlying influence of industry—such as Big Pharma, divisions of the media more interested in promotion than journalism, and medical journals serving professional rather than public interest. Attempting to summarise discussions …