tbuckley/cabot-search huggingface dataset:
Cell surface GRP78 activation by anti-GRP78 autoantibodies in relation to prostate tumour growth via tissue factor activation.
Authors: Ali Al-Hashimi, Richard Austin, Bobby Shayegan
Journal: Journal of Clinical Oncology (2018)

31 Background: Prostate cancer (PC) is characterized by increased prothrombotic state due to enhanced tissue factor (TF) expression/procoagulant activity (PCA). We and others observed that GRP78, a molecular chaperone, is expressed on the surface of PC cells where it functions as a signaling receptor to promote cell proliferation and survival. Further, exposure of GRP78 on the surface of PC cells stimulates the production of anti-GRP78 autoantibodies in PC patients. We have reported that binding of these autoantibodies to cell surface GRP78 enhances TF PCA. We hypothesize that this autoantibody/cell surface GRP78 complex interaction increases PC progression and that disruption of this complex would represent a viable target for the treatment of advanced PC. Methods: Wild type, TF knockdown DU145 cells, and NOD/SCID mouse model system was used to investigate the effect of anti-GRP78 autoantibodies on tumor growth. Protein expression was determined using western blotting and qRT-PCR. TF activity was determined using the TF PCA continuous assay. Blood samples from patients diagnosed with PC were obtained from the Ontario Tumour Bank and St. Joseph’s Hamilton. Results: Pre-prostatectomy patients demonstrated high levels of anti-GRP78 autoantibodies (60-100µg/ml) vs. healthy individuals (5-10µg/ml). These titers were significantly reduced 24-weeks post prostatectomy. We show here that anti-GRP78 autoantibodies upregulate TF and its PCA through a mechanism involving depletion of ER Ca2+ stores. This very effect on ER Ca2+ stores also caused activation of the unfolded protein response, a pro-survival cellular pathway. Furthermore, these autoantibodies were shown to accelerate tumor growth in a NOD/SCID mouse model. Finally, heparin and low molecular weight heparin were shown to interfere with the binding of these antibodies to cancer cells and prevent PC cell activation. Conclusions: We have identified the function of an agent in patients' blood, anti-GRP78 autoantibodies, that correlate with PC stage in patients and increase TF PCA and promote PC progression in mice. The effect of this autoantibody can be reversed using heparin, thus, this acts as a new potential therapeutic target for PC.
A Novel, Well‐Resolved Direct Laser Bioprinting System for Rapid Cell Encapsulation and Microwell Fabrication
Authors: Zongjie Wang, Xian Jin, Zhenlin Tian, Frederic Menard, Jonathan F. Holzman, Keekyoung Kim
Journal: Advanced Healthcare Materials (2018)

Abstract A direct laser bioprinting (DLBP) system is introduced in this work. The DLBP system applies visible‐laser‐induced photo‐crosslinking at a wavelength of 405 nm using the photoinitiator VA‐086. It is shown that such a system can fabricate vertical structures with fine features (less than 50 µm) and high cell viability (greater than 95%). Experimental characterizations and theoretical simulations are presented, and good agreement is seen between the experiments and theory. The DLBP system is applied to the fabrication of (1) cell‐laden hydrogel microgrids, (2) hydrogel microwells, as well as a test of (3) cell encapsulation, and (4) cell seeding. The DLBP system is found to be a promising tool for bioprinting.
Growth of <i>Mycobacterium tuberculosis</i> in vivo segregates with host macrophage metabolism and ontogeny
Authors: Lu Huang, Evgeniya V. Nazarova, Shumin Tan, Yancheng Liu, David G. Russell
Journal: The Journal of Experimental Medicine (2018)

To understand how infection by Mycobacterium tuberculosis (Mtb) is modulated by host cell phenotype, we characterized those host phagocytes that controlled or supported bacterial growth during early infection, focusing on the ontologically distinct alveolar macrophage (AM) and interstitial macrophage (IM) lineages. Using fluorescent Mtb reporter strains, we found that bacilli in AM exhibited lower stress and higher bacterial replication than those in IM. Interestingly, depletion of AM reduced bacterial burden, whereas depletion of IM increased bacterial burden. Transcriptomic analysis revealed that IMs were glycolytically active, whereas AMs were committed to fatty acid oxidation. Intoxication of infected mice with the glycolytic inhibitor, 2-deoxyglucose, decreased the number of IMs yet increased the bacterial burden in the lung. Furthermore, in in vitro macrophage infections, 2-deoxyglucose treatment increased bacterial growth, whereas the fatty acid oxidation inhibitor etomoxir constrained bacterial growth. We hypothesize that different macrophage lineages respond divergently to Mtb infection, with IMs exhibiting nutritional restriction and controlling bacterial growth and AMs representing a more nutritionally permissive environment.
Factors Associated With Variation in Long-term Acute Care Hospital vs Skilled Nursing Facility Use Among Hospitalized Older Adults
Authors: Anil N. Makam, Oanh Kieu Nguyen, Lei Xuan, Michael E. Miller, James S. Goodwin, Ethan A. Halm
Journal: JAMA Internal Medicine (2018)

Despite providing an overlapping level of care, it is unknown why hospitalized older adults are transferred to long-term acute care hospitals (LTACs) vs less costly skilled nursing facilities (SNFs) for postacute care.To examine factors associated with variation in LTAC vs SNF transfer among hospitalized older adults.We conducted this retrospective observational cohort study of hospitalized older adults (≥65 years) transferred to an LTAC vs SNF during fiscal year 2012 using national 5% Medicare data.Predictors of LTAC transfer were assessed using a multilevel mixed-effects model adjusting for patient-, hospital-, and region-level factors. We estimated variation partition coefficients and adjusted hospital- and region-specific LTAC transfer rates using sequential models.Among 65 525 hospitalized older adults (42 461 [64.8%] women; 39 908 [60.9%] ≥85 years) transferred to an LTAC or SNF, 3093 (4.7%) were transferred to an LTAC. We identified 29 patient-, 3 hospital-, and 5 region-level independent predictors. The strongest predictors of LTAC transfer were receiving a tracheostomy (adjusted odds ration [aOR], 23.8; 95% CI, 15.8-35.9) and being hospitalized in close proximity to an LTAC (0-2 vs >42 miles; aOR, 8.4, 95% CI, 6.1-11.5). After adjusting for case-mix, differences between patients explained 52.1% (95% CI, 47.7%-56.5%) of the variation in LTAC use. The remainder was attributable to hospital (15.0%; 95% CI, 12.3%-17.6%), and regional differences (32.9%; 95% CI, 27.6%-38.3%). Case-mix adjusted LTAC use was very high in the South (17%-37%) compared with the Pacific Northwest, North, and Northeast (<2.2%). From the full multilevel model, the median adjusted hospital LTAC transfer rate was 2.1% (10th-90th percentile, 0.24%-10.8%). Even within a region, adjusted hospital LTAC transfer rates varied substantially (intraclass correlation coefficient [ICC], 0.26; 95% CI, 0.23-0.30).Although many patient-level factors were associated with LTAC use, half of the variation in LTAC vs SNF transfer is independent of patients' illness severity or clinical complexity, and is explained by where the patient was hospitalized and in what region, with far greater use in the South. Even among hospitals in regions with similar LTAC access, there was considerable variation in LTAC use. Given the higher expense associated with LTACs vs SNFs, greater attention is needed to define the optimal role of LTACs in the postacute care of older adults.
A comparative prospective observational study of children and adults with immune thrombocytopenia: 2‐year follow‐up
Authors: Alexandra Schifferli, Andreas Holbro, Meera Chitlur, Michael Coslovsky, Paul Imbach, Hugo Donato, Mohsen Elalfy, Elena Graciela, John Grainger, Susanne Holzhauer, Cecilia Riccheri, Francesco Rodeghiero, Marco Ruggeri, Hannah Tamary, Tatjana Uglova, Runhui Wu, Thomas Kühne
Journal: American Journal of Hematology (2018)

Abstract Comparative clinical studies of children and adults with immune thrombocytopenia (ITP) are poorly covered in the literature. However, the accepted classification of ITP—childhood ITP and adult ITP—results in considerable differences in treatment protocols and practice guidelines. The analysis of the Pediatric and Adult Registry on Chronic ITP (PARC‐ITP) of patients at first presentation demonstrated fewer differences in clinical and laboratory findings at initial diagnosis between children and adults than expected. The present report of 2‐year follow‐up data supports the hypothesis that there are common aspects of childhood and adult ITP. Data of 3360 children and 420 adults were collected during the time of 2004 until 2015 at initial diagnosis. Follow‐up information was available for 51% and 33% of children and 66% and 49% of adults at 12‐ and 24‐months, respectively. Similarities were found in unexpected areas of ITP, such as the rate of late remission at 12 and 24 months, reported bleeding sites, platelet count in bleeders, and the frequency of treated patients with persistent or chronic ITP. Differences were confirmed for the overall rate of remission and treatment modalities. Unexpected differences were found in the percentage of nonbleeders, with more adults in the nonbleeder group. More studies are needed to investigate different age groups with the aim to optimize their management.
Deep Learning and Its Applications in Biomedicine
Authors: Chensi Cao, Feng Liu, Hai Tan, Deshou Song, Wenjie Shu, Weizhong Li, Yiming Zhou, Xiaochen Bo, Zhi Xie
Journal: Genomics Proteomics & Bioinformatics (2018)

Advances in biological and medical technologies have been providing us explosive volumes of biological and physiological data, such as medical images, electroencephalography, genomic and protein sequences. Learning from these data facilitates the understanding of human health and disease. Developed from artificial neural networks, deep learning-based algorithms show great promise in extracting features and learning patterns from complex data. The aim of this paper is to provide an overview of deep learning techniques and some of the state-of-the-art applications in the biomedical field. We first introduce the development of artificial neural network and deep learning. We then describe two main components of deep learning, i.e., deep learning architectures and model optimization. Subsequently, some examples are demonstrated for deep learning applications, including medical image classification, genomic sequence analysis, as well as protein structure classification and prediction. Finally, we offer our perspectives for the future directions in the field of deep learning.
Medical textbook authors received £11m in undisclosed payments from drug and device makers
Authors: Nigel Hawkes
Journal: BMJ (2018)

Medical textbooks widely used by students and young doctors are riddled with undeclared conflicts of interest, a study has found.

While virtually every leading medical journal now requires authors to declare any potential conflicts of interest, the same rules do not apply to textbooks widely used in the US, says a team from Bowdoin College in Brunswick, Maine, in findings published in AJOB Empirical Bioethics .1

The most striking example is Harrison’s Principles of Internal Medicine , now in its 20th edition. By searching a database of payments made to US doctors by …
William Gordon Reeves
Authors: Olly Reeves
Journal: BMJ (2018)

Gordon Reeves was educated at the Perse School, Cambridge, and Guy’s Hospital Medical School, London. After completing house and registrar appointments at Guy’s, University College Hospital, and other London hospitals, he undertook lecturer posts at Guy’s and the Royal Postgraduate Medical School. He was appointed consultant immunologist and senior lecturer at Nottingham University in 1973, becoming professor of immunology in 1985. He published many articles and research papers; contributed to, …
Sexual assault allegations against doctors are rising, but most are cleared
Authors: Abi Rimmer
Journal: BMJ (2015)

The number of allegations of sexual assault made against doctors is increasing, but most doctors are cleared after investigation, the Medical Defence Union has said.

The MDU said that allegations of sexual assault against its members had risen by 66% over a decade, from 12 allegations in 2003 to 20 in 2013. However, of …
PROGNOSTIC IMPORTANCE OF POOR CARDIORESPIRATORY FITNESS IN PATIENTS WITH CANCER REFERRED FOR EXERCISE TREADMILL TESTING
Authors: John D. Groarke, David L. Payne, Brian Claggett, Mandeep Mehra, Jingyi Gong, Jesse Caron, Syed Mahmood, Jon Hainer, Tom Neilan, Ann H. Partridge, Marcelo Di Carli, Lee W. Jones, Anju Nohria
Journal: Journal of the American College of Cardiology (2018)
Elbasvir/grazoprevir and sofosbuvir for hepatitis C virus genotype 3 infection with compensated cirrhosis: A randomized trial
Authors: Graham R. Foster, Kosh Agarwal, Matthew E. Cramp, Sulleman Moreea, Stephen Barclay, Jane Collier, Ashley S. Brown, Stephen D. Ryder, Andrew Ustianowski, Daniel M. Forton, Ray Fox, Fiona Gordon, William M. Rosenberg, David J. Mutimer, Jiejun Du, Christopher L. Gilbert, Ernest Asante‐Appiah, Janice Wahl, Michael N. Robertson, Eliav Barr, Barbara Haber
Journal: Hepatology (2018)

Many direct-acting antiviral regimens have reduced activity in people with hepatitis C virus (HCV) genotype (GT) 3 infection and cirrhosis. The C-ISLE study assessed the efficacy and safety of elbasvir/grazoprevir (EBR/GZR) plus sofosbuvir (SOF) with and without ribavirin (RBV) in compensated cirrhotic participants with GT3 infection. This was a phase 2, randomized, open-label study. Treatment-naive participants received EBR/GZR + SOF + RBV for 8 weeks or EBR/GZR + SOF for 12 weeks, and peginterferon/RBV treatment-experienced participants received EBR/GZR + SOF ± RBV for 12 weeks or EBR/GZR + SOF for 16 weeks. The primary endpoint was HCV RNA <15 IU/mL 12 weeks after the end of treatment (sustained virologic response at 12 weeks [SVR12]). Among treatment-naive participants, SVR12 was 91% (21/23) in those treated with RBV for 8 weeks and 96% (23/24) in those treated for 12 weeks. Among treatment-experienced participants, SVR12 was 94% (17/18) and 100% (17/17) in the 12-week arm, with and without RBV, respectively, and 94% (17/18) in the 16-week arm. Five participants failed to achieve SVR: 2 relapsed (both in the 8-week arm), 1 discontinued due to vomiting/cellulitis (16-week arm), and 2 discontinued (consent withdrawn/lost to follow-up). SVR12 was not affected by the presence of resistance-associated substitutions (RASs). There was no consistent change in insulin resistance, and 5 participants reported serious adverse events (pneumonia, chest pain, opiate overdose, cellulitis, decreased creatinine). High efficacy was demonstrated in participants with HCV GT3 infection and cirrhosis. Treatment beyond 12 weeks was not required, and efficacy was maintained regardless of baseline RASs.Data from this study support the use of EBR/GZR plus SOF for 12 weeks without RBV for treatment-naive and peginterferon/RBV-experienced people with GT3 infection and cirrhosis (ClinicalTrials.gov NCT02601573). (Hepatology 2018;67:2113-2126).
Language tests for EU doctors set to start in June
Authors: Abi Rimmer
Journal: BMJ (2014)

The General Medical Council has announced that it will be able to test the English language competence of doctors from other European Union countries from June this year.

The Department of Health in England confirmed in January that it would implement a UK-wide plan to allow the GMC to begin the tests.1

After a public consultation the regulator announced that it would require doctors from other European Union countries to provide evidence of their English skills or to undergo a language assessment if it had concerns about their ability to communicate effectively.2 The GMC said that it expected to introduce the checks in June, subject to the legislative process.

At the same …
PERFORMANCE OF PRESTABILIZATION SHOCK INDEX AS A PREDICTOR OF MORTALITY IN PATIENTS ADMITTED WITH ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION: THE ATHEROSCLEROSIS RISK IN COMMUNITIES SURVEILLANCE STUDY
Authors: Michael W. Chambers, Eric A. Whitsel, George Stouffer, Amil Shah, Melissa Caughey
Journal: Journal of the American College of Cardiology (2018)
Safety and Effectiveness of Second-Generation Drug-Eluting Stents in Patients With Left Main Coronary Artery Disease
Authors: Pil Hyung Lee, Osung Kwon, Jung-Min Ahn, Cheol Hyun Lee, Do-Yoon Kang, Jung-Bok Lee, Soo-Jin Kang, Seung-Whan Lee, Young-Hak Kim, Cheol Whan Lee, Seong-Wook Park, Duk-Woo Park, Seung-Jung Park
Journal: Journal of the American College of Cardiology (2018)
Noninvasive detection of clinically relevant copy number alterations in diffuse large B-cell lymphoma.
Authors: Michael C. Jin, David Matthew Kurtz, Mohammad Shahrokh Esfahani, Florian Scherer, Alexander F.M. Craig, Joanne Soo, Michael Siavash Khodadoust, Ruth Sharon Saganty, Jacob J. Chabon, Joseph Schroers-Martin, Henning Stehr, Ranjana H. Advani, Davide Rossi, Gianluca Gaidano, Jason R. Westin, Maximilian Diehn, Ash A. Alizadeh
Journal: Journal of Clinical Oncology (2017)

7507 Background: Somatic copy number alterations (SCNAs) are common and clinically important genomic events in lymphomas. For example, MYC and BCL2 amplifications are associated with adverse outcomes (Quesada, ASH 2016), while PD-L1 ( CD274) amplifications are associated with improved response to checkpoint inhibitors (Ansell, NEJM 2015). However, noninvasive detection of these events from circulating tumor DNA (ctDNA) remains difficult. Using CAPP-Seq, a targeted high-throughput sequencing platform, we developed a method to profile both focal and broad SCNAs from plasma. Methods: We profiled plasmas from a cohort of 75 pretreatment diffuse large B-cell lymphoma patients and 48 healthy controls. Focal SCNAs were evaluated at ultra-high depths (~10,000x), allowing for detection of lesions at ~1% ctDNA fraction. Thresholds were tuned to allow a false positive rate of 1%, which was empirically validated in an independent healthy cohort (n = 15), yielding a panel-wide false discovery rate of ~2.3% (0% in our genes of interest). Sequencing reads outside the targeted regions were separately pooled and analyzed to evaluate arm and chromosome level SCNAs. Results: We detected SCNAs in clinically relevant genes at the frequencies reported in literature, including amplifications in MYC (8.0%), BCL2 (24.0%), and BCL6 (14.7%) and deletions in TP53 (13.3%) and CDKN2A (9.3%). Remarkably, 26.7% of the cohort demonstrated amplification of both PD-L1 and PD-L2 ( PDCD1LG2). Furthermore, we discovered amplifications in PD-L2, but not PD-L1, in 13.3% of our patients. Interestingly, PD-L1 amplifications were more common in patients with relapsed lymphoma than in those with treatment-naïve disease (43.5% vs 19.2%, p = 0.02). Most PD-L1 amplifications were focal (65%) while the remainder typically involved &gt; 80% of Chr9p. Corresponding tissue profiling data is in progress and will also be presented. Conclusions: Noninvasive sampling of lymphoma ctDNA enables detection of both focal and broad SCNAs, including amplifications of MYC, BCL2, and PD-L1. The ability to noninvasively profile copy number altered regions allows for biopsy-free discovery of clinically significant structural alterations in lymphoma patients.
Biomarkers for prediction of renal replacement therapy in acute kidney injury: a systematic review and meta-analysis
Authors: Sebastian J. Klein, Anna K. Brandtner, Georg F. Lehner, Hanno Ulmer, Sean M. Bagshaw, Christian J. Wiedermann, Michael Joannidis
Journal: Intensive Care Medicine (2018)

Acute kidney injury (AKI) frequently occurs in critically ill patients and often precipitates use of renal replacement therapy (RRT). However, the ideal circumstances for whether and when to start RRT remain unclear. We performed evidence synthesis of the available literature to evaluate the value of biomarkers to predict receipt of RRT for AKI. We conducted a PRISMA-guided systematic review and meta-analysis including all trials evaluating biomarker performance for prediction of RRT in AKI. A systematic search was applied in MEDLINE, Embase, and CENTRAL databases from inception to September 2017. All studies reporting an area under the curve (AUC) for a biomarker to predict initiation of RRT were included. Sixty-three studies comprising 15,928 critically ill patients (median per study 122.5 [31–1439]) met eligibility. Forty-one studies evaluating 13 different biomarkers were included. Of these biomarkers, neutrophil gelatinase-associated lipocalin (NGAL) had the largest body of evidence. The pooled AUCs for urine and blood NGAL were 0.720 (95% CI 0.638–0.803) and 0.755 (0.706–0.803), respectively. Blood creatinine and cystatin C had pooled AUCs of 0.764 (0.732–0.796) and 0.768 (0.729–0.807), respectively. For urine biomarkers, interleukin-18, cystatin C, and the product of tissue inhibitor of metalloproteinase-2 and insulin growth factor binding protein-7 showed pooled AUCs of 0.668 (0.606–0.729), 0.722 (0.575–0.868), and 0.857 (0.789–0.925), respectively. Though several biomarkers showed promise and reasonable prediction of RRT use for critically ill patients with AKI, the strength of evidence currently precludes their routine use to guide decision-making on when to initiate RRT.
Asthma health services utilisation before, during and after pregnancy: a population-based cohort study
Authors: Teresa To, Laura Y. Feldman, Jingqin Zhu, Andrea S. Gershon
Journal: European Respiratory Journal (2018)

During pregnancy, females with asthma may be at higher risk of exacerbation. The objective of this study was to determine whether females with asthma in Ontario, Canada have increased health services utilisation (HSU) during pregnancy. Rates of asthma-specific, asthma-related and non-pregnancy-related HSU were calculated in a population-based cohort of pregnant females with asthma. Poisson regression with repeated measures was used to determine adjusted rate ratios and 95% confidence intervals of HSU during and 1 year after pregnancy, compared to the year before pregnancy. The cohort consisted of 103 976 pregnant females with asthma. Compared to the year prior to pregnancy, hospitalisation rates per 100 person-months during pregnancy increased 30% for asthma (from 0.016 to 0.020), 24% for asthma-related conditions (from 0.012 to 0.015) and decreased 37% for non-pregnancy-related conditions (from 0.24 to 0.15). Emergency department visits for asthma and asthma-related conditions did not increase significantly during pregnancy. During pregnancy, physician office visits decreased 19% for asthma (from 2.20 to 1.79), 10% for asthma-related conditions (from 9.44 to 8.47) and increased 74% for non-pregnancy-related conditions (from 56.4 to 98.2). Hospitalisations for asthma and asthma-related conditions increased during pregnancy, demonstrating that the overall increase in non-pregnancy-related physician office visits may not meet the primary care needs of pregnant females with asthma.
College calls for more private sector involvement in training surgeons
Authors: Helen Jaques
Journal: BMJ (2013)

The Royal College of Surgeons has raised concerns that the independent sector is not “contributing as fully as it should” to the training of the medical workforce. The college has called for private healthcare organisations to play a more prominent role in the delivery of surgical education and training.

In a position statement the college said that the private sector has taken on many procedures within the postgraduate syllabus for surgeons and is likely to take on more surgical services in the future, through local commissioning and the “any qualified provider” …